BRIGHTON, UK—In underserved communities throughout the world low rates of early breast cancer detection are key drivers of mortality, according to the findings of research from Uganda, the United Kingdom and Nigeria. A range of low cost community-based interventions could be used to modify these drivers, the research concludes. Huge reductions of breast cancer mortality in underserved communities could be achieved by prioritizing early detection, according to lead author Deborah Ikhile PhD, from the Brighton and Sussex Medical School at the University of Brighton in Sussex UK, who discussed the implications of her findings with the Audio Journal of Oncology's Peter Goodwin at the Royal Society of Medicine’s 2023 Tackling Inequalities conference.  This could be achieved—even where costly mass screening was not possible—by health education delivered through existing social and cultural structures that were presently being overlooked or ignored, her study concluded. “Breast cancer is beyond an individual disease,” said Dr. Ikhile. “Doctors, researchers, clinicians, decision-makers need to have in-depth understanding of the social determinants that influence a woman’s ability to present early or not.” Her group’s five-year survey with structured interviews among women in rural and semi-rural communities of Uganda had concluded that ‘structural violence’ was a root cause of late breast cancer detection. This consisted of multiple disservices to women, unintentionally perpetrated through inappropriate medical care structures. Poor health education plus myopic national, global and donor priorities, all combined with negative attitudes to women, and a failure to engage with the well-established grass-roots local organizations in the community. According to Dr. Ikhile, existing local services and social infrastructures could be harnessed to turn around breast cancer detection. The present-day two-fold excess of mortality from breast cancer among most black African women everywhere (as compared their white counterparts in privileged communities) could largely be eliminated by effective early detection.  It was necessary to overcome factors such as stigma, misogyny, fear and gender prejudice from the global level downwards.  She believed Uganda was not exceptional and that the findings were relevant to cancer detection in underserved communities everywhere. Dr. Ikhile’s interest in getting to the bottom of breast cancer inequalities began when she was still living in Nigeria and had (what turned out to be) a benign breast lump. Because she had access to private medicine her parents were able to get prompt diagnosis, followed by surgical excision. But this sensitized her to the plight of millions of women in low-resourced communities who did not have access to private health care. The research in Uganda sought to identify the challenges and barriers to breast cancer detection and to investigate how these issues could be addressed within a primary care context. The findings showed that cancer in Uganda was beyond individual control. “What came out is that, beyond your lack of knowledge, your lack of awareness, beyond fear, beyond attitude: Other factors, like community support, primary care services, even the clinician’s pressures, all these factors come into play, and support us to look at a holistic view to breast cancer detection,” Dr. Ikhile said. The survey also found that even after eventual detection of breast cancer there was often no easy access to follow-up care and services. The whole agenda surrounding campaigns such as the Early Detection Saves Lives initiative had been flawed, as these had often centered around victim-blaming—making it seem as though the women were responsible for not detecting breast cancer early. But this was not a reality for most women, according to Dr. Ikhile. “The reality for women is that they want to know.  They felt disempowered because of the lack of knowledge.” “What came out of the interviews was a lack of awareness: Of what breast cancer is, of the signs and symptoms, even the risk factors, and even how to go for screening, how to detect breast cancer. And fear actually came up as a huge issue. They saw cancer as a death sentence, like: If I get breast cancer I’m going to die.” Dr. Ikhile also highlighted the issue of stigma. Women were afraid to go to national cancer screening services for fear of being stigmatized as cancer victims, she said. “So, even if screening were organized they would not go, just because of that perception of being assumed to have cancer.” Dr. Ikhile’s research uncovered a very low level of knowledge about breast cancer and what to do if you suspected you had it, she said. This was very different from the UK where she had studied black African women living in a typical city in the English Midlands, Nottingham. “They were generally aware of breast cancer,” she said. This was a stark contrast to some of the local communities she had studied in Uganda, where she learned there was not even a local word for breast cancer. “So even [with the signs] they really don’t know what disease it is, because they don’t understand what it means in the local language.” And fatalism contributed to lack of action against breast cancer, often linked to spiritual or religious beliefs. When she was asked to explain what structural violence consisted of in the study community, Ikhile said the concept of structural violence looked at the way government and local service structures were partnered to help perpetuate the health or sickness of individuals. “There were a lot of underlying factors. It is not enough to say that a woman does not know enough about breast cancer. It is not enough to say a woman has fear,” she said. “So, the study sought to find what perpetuated that fear, and what were the underlying factors promoting or influencing that lack of knowledge.” “One of the factors that came out was that there was no cancer policy in the country. Uganda did not have any national cancer policy at the time of the study.” This resulted in no national strategy or direction to guide how cancer should be controlled in the country. Medical priorities were also found to be inappropriate for breast cancer. For one thing communicable diseases were in competition with cancer for resources.  To make matters worse, most of the priorities in Uganda were driven by international donors, said Dr. Ikhile, which—despite being well-intentioned—were not sufficiently well-informed about the true needs of the people.  For example: Funding for HIV would inevitably prioritize HIV and donors targeting cardiovascular disease would similarly not have cancer in their sights.  Breast cancer was clearly being overlooked. Even donor funding for breast cancer could overlook early detection among widely spread—often rural—communities, in favor of breast cancer treatments which were not even appropriate for many patients with the late stages of breast cancer frequently forming the majority of those eventually diagnosed in these underserved communities. And the benefit of costly screening programs had to be questioned, according to Ikhile, who favored education programs. “What is important is knowing your breast,” she said. This was in a context of the study findings that most women interviewed did not even know that breast lumps could be a sign of breast cancer.  And they were even being wrongly advised by primary care teams, who were also insufficiently knowledgeable about breast cancer.  Women needed to know that any changes in their breasts indicated that they should find help. Gender norms and gender roles could also inhibit actions needed for detecting breast cancer, the study found.  Traditional values about the place of women in society and deference to men could negatively influence breast cancer outcomes, particularly in rural communities. But there was a positive finding from the research. ”Sensitizing men as champions for women’s health could be a great motivator for women, wives, daughters, mothers, who could then seek care.” Awareness was the key to resolving these issues, said Dr. Ikhile. This needed to be among all members of the community: women, husbands, and health-care practitioners. “What is important is understanding the social and cultural environment and the factors that influence ability to seek or not to seek help.” She also stressed ‘cultural competence’ among doctors: “Knowing how to deliver care in a culturally competent manner, interacting with a woman in a way that won’t lead to fear. It is very important to know where your patient is coming from,” she said. Happily, in the case of African communities there were often strong social bonds and structures that were available to be harnessed, said Ikhile. “So, they can use those pathways to create awareness and use organizations like churches and community health workers who are trusted people. She also saw the need for doctors to be very much part of the community health awareness strategy, rather than being left in ivory towers to treat patients only after diagnosis. Dr. Ikhile regarded grass-roots understanding of the local communities, and engagement with local organizations, as bedrocks of a plan to achieve timely detection of breast cancer.  “It is very important for donors to engage and work hand-in-hand with those actually on the ground to implement any of the projects,” she said.

Audio Journal of Oncology, February 14 2023, Reporting from the American Society of Hematology Annual Meeting (ASH), December 2022 An interview with Amy A. Kirkwood MSc, Senior Statistician at the Cancer Research UK & UCL Cancer Trials Centre, University College, London, UK Interviewer: Peter M Goodwin TITLE: Options Identified for in Acute Lymphoblastic Leukemia NEW ORLEANS, USA—A big study conducted over an extended period of time has shown that there is scope for reducing the intensity of chemotherapy for patients with acute lymphoblastic leukema (ALL) and (the rarer) lymphoblastic lymphoma (LBL). Modifications to standard protocols offer scope for sparing many children the potential toxicity of full-does standard regimens without compromising cure rates. Amy Kirkwood, Chief Statistician from University College, London tells the Audio Journal of Oncology (AJO) about her group’s findings from the randomized phase three UKALL 2011 study, reported (at the American Society of Hematology (ASH) 2022 Annual Meeting), showing that adjustments to current multi-agent chemotherapy regimens brought changes in outcome. She concludes that more gentle treatments may be possible for many patients while maintaining or improving efficacy for those at high risk. https://ashpublications.org/blood/article/140/Supplement%201/516/488151/High-Dose-Methotrexate-Does-Not-Reduce-the-Risk-of The treatment of ALL had improved hugely in the last 50 years, first author Amy A. Kirkwood MSc, Senior Statistician at the Cancer Research UK & UCL Cancer Trials Centre, University College, London, UK, told the AJO after giving her report at ASH. “We now have about 95 percent survival. About 15 percent of children will relapse. But we know that 50 years ago we were curing about 50 per cent of people with half the treatment. So, we know that we are overtreating large numbers of children,” she said. So, trials were now looking at treatment reductions, and at trying to identify high-risk patients to design new ways of improving efficacy for that group only, she said. “We want to try and decrease treatment for the majority who will do well,” Kirkwood noted. Specifically, the trial found that using high-dose methotrexate (HDM) did not improve central nervous system (CNS) relapse—contrary to some expectations. According to the UKALL 2011 study findings, it may have improved bone marrow relapse for some sub-groups of patients with B-lineage disease, however. The trial also found that with some chemotherapy regimens the addition of monthly “pulses” of vincristine and dexamethasone (in the maintenance phase of treatment) had been un-necessary. They proved to be “non-inferior” for bone marrow relapse—compared with the standard practice of including such pulses. This suggested that pulse-free treatment could potentially be an option for some patients. Study details The UKALL 2011 study allocated patients to study arms in accordance with their risks, as stratified by National Cancer Institute (NCI) risk, cytogenetics and “end of induction minimum residual disease” (MRD). The aim was to assess whether elements of treatment could potentially be de-escalated without loss of efficacy. Randomizations were allocated within the several different standard “blocks” of chemotherapy. Firstly, in the “induction” block of chemotherapy (aiming to get rid of most of the disease) there was a randomization between two different dose schedules of dexamethasone. A short (higher) dose schedule was compared with standard dexamethasone dosing. The aim had been to look at whether steroid dose could influence the incidence of side effects. This was followed by the “consolidation” block all in which all patients were treated the same. Kirkwood said they saw no difference from steroid dosing schedule changes. “We were hoping to see a difference in steroid-related morbidity and mortality, so that randomization [was] closed,” she said. And, there had also been some “worrying trends” that maybe the patients treated with a shorter dexamethasone schedule (higher dose) were relapsing more often, she commented. The second randomization (in the “interim maintenance” phase of treatment) was between standard and high-dose methotrexate. Although this was looking primarily for any impact of methotrexate dose on CNS relapse (and had found: “No difference at all”) Kirkwood noted there had been an effect of methotrexate dose on bone-marrow relapse. “Overall, we didn’t see a difference. But we found an interaction between the first randomization (the short versus standard dexamethasone) and the high methotrexate dose randomization.” The results were different depending on which steroid dose a patient had received initially. “If you had short dexamethasone up-front, then the high-dose methotrexate didn’t improve your bone marrow relapse risk. But if you had the standard dexamethasone up front, it looked like it might improve your bone marrow relapse risk. And we don’t know what caused this,” she said. After the next block of treatment (called “delayed intensification” in which all patients had the same therapy) the third randomization was during the “maintenance” treatment. Patients either did, or did not, receive the monthly “pulses” of vincristine and dexamethasone. Primarily, the aim had been to see if the pulses had any effect on the bone marrow relapse rate. “[It] was non-inferior. We saw a small decrease. But it was within our pre-specified margin of five percent,” said Kirkwood. The team concluded it had been safe to remove the pulses. “However, we did see a ‘bit of a decrease’ in terms of event-free survival—over the five percent limit,” she said. In terms of practical recommendations coming out of the UKALL 2011 study Kirkwood noted that knowledge about safe and effective options for changing methotrexate dose had been clarified. “We found that the patients who had standard dexamethasone, standard interim maintenance, didn’t have high [methotrexate] dose, and then went on to have pulses, had very similar outcomes to those that had the high-dose methotrexate. So that may be a trade-off: that you give the high-dose, you don’t give the pulses. Or, you give our standard [dose and] you still give the pulses.” “The removal of pulses is probably safe in some groups of patients, but we still need to do further analysis,” she said. “The vast majority of children will be cured with front-line therapy. And our protocols are now working hard to try and pull out those small groups patients that are going to do badly and make sure they get the treatment that is best for them.” ASH ABSTRACT DETAILS: ABSTRACT 214 High Dose Methotrexate Does Not Reduce the Risk of CNS Relapse in Children and Young Adults with Acute Lymphoblastic Leukaemia and Lymphoblastic Lymphoma. Results of the Randomised Phase III Study UKALL 2011 Program: Oral and Poster Abstracts Type: Oral Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Clinical Trials Hematology Disease Topics & Pathways: Non-Biological therapies, Chemotherapy, Combination therapy, Therapies Saturday, December 10, 2022: 2:45 PM Amy A. Kirkwood, MSc1*, Nicholas Goulden, MD, PhD, MRCPath2*, John Moppett, PhD FRCPath3*, Sujith Samarasinghe, PhD, FRCPath4*, Jon Mee5*, Rachael Hough, MD FRCPath6*, Pamela R. Kearns, PhD, FRCPC7*, Sarah Lawson, MBBS FRCPath8*, Clare J. Rowntree, MBBS PhD9* and Ajay Vora, MD10 1Cancer Research UK & UCL Cancer Trials Centre, University College London, London, United Kingdom 2Great Ormond Street Hospital, London, United Kingdom 3Department of Haematology, Bristol Children's Hospital, Bristol, United Kingdom 4Department of Paediatric Haematology, Great Ormond Street Hospital for Children, London, United Kingdom 5Cancer Clinical Trials Unit, Birmingham University, Birmingham, United Kingdom 6University College Hospital, University College of London, London, United Kingdom 7Cancer Research UK Clinical Trials Unit (CRCTU), University of Birmingham, Birmingham, United Kingdom 8Birmingham Children's Hospital, Birmingham, United Kingdom 9Department of Haematology, University Hospital of Wales, Cardiff, United Kingdom 10Department of Haematology, Great Ormond Street Hospital for Children, London, United Kingdom Introduction UKALL 2011 randomised children and young adults (up to 25) with Acute Lymphoblastic Leukaemia (ALL) or Lymphoblastic Lymphoma (LBL). The aims were to reduce induction toxicity (R1: Short [14 days] vs Standard [28 days] dexamethasone), CNS relapse risk (R2IM: HD MTX (HDM) vs standard interim maintenance (SIM)) and maintenance morbidity (R2pulses: Vincristine (VCR)/dexamethasone pulses or not). R1 results were presented at ASH 2017 and did not show a reduction in toxicity with short dexamethasone. Results of R2IM and R2pulses are reported here. Patients and Methods Patients were stratified by NCI risk, cytogenetics and end of induction MRD to receive Regimens A (NCI standard risk, MRD low risk), B (NCI high risk, MRD low risk) or C (Cytogenetic poor risk or MRD intermediate risk regardless of NCI risk). MRD high risk (end of consolidation MRD >0.5%, n=14) were not eligible for randomisation and received off protocol therapy. R2 was a factorial randomisation stratified by factors including NCI and MRD risk groups and resulted in 4 arms: HDM with pulses, HDM without pulses, standard interim maintenance (SIM) with pulses (standard of care) and SIM without pulses. SIM was for 2 months with oral mercaptopurine/MTX, monthly pulses and single IT MTX in Regimens A and B, and 5 doses of escalating IV MTX (Capizzi) + VCR + 2 doses of Pegylated asparaginase in Regimen C. HDM was given at a dose of 5g/m2 x 4 doses 2 weeks apart, low dose 6-MP and 2 doses of Pegylated asparaginase (Regimen C only). The primary endpoint for R2IM was the CNS relapse rate (CNSR) and for R2pulses was the bone marrow relapse rate (BMR) in ALL only; non-inferiority, 5% margin at 5 years. Event Free Survival (EFS) was considered a primary endpoint for both. Results Of the 2750 patients registered on trial between April 2012 and December 2018, 1902 were randomised to R1 (closed April 2017) and 1570 to R2. Median age 5 years (IQR: 3-11), 83% B-ALL, 12% T-ALL, 1% B-LBL and 4% T-ABL, 43% NCI high risk. Median follow-up for R1 is 76 months and R1 or R2 is 72 months. Overall, we found no difference in CNSR (HR: 0.99 (0.65-1.51), p=0.97, 5-year rates: 5.6% and 5.6%), or any other endpoints for R2IM. However, there was an interaction between the R1 and R2IM randomisations (p=0.006 for EFS) with inferior outcomes for patients treated with short dexamethasone followed by HDM, particularly in those who did not receive pulses (Figure 1). Limiting analyses to patients treated with standard dexamethasone (N=995, including those that received it after closure of R1) there was a significant reduction in BMR rate with HDM (HR 0.62 (95% CI: 0.40 - 0.95) p = 0.029) and a trend for improvements in EFS and OS (HRs: 0.75 (95%CI: 0.53 – 1.04), p=0.087 and 0.61 (0.37 – 1.03), p=0.067) but no difference in CNSR. In subgroup analyses there were no significant interactions, but the effect appeared stronger for B-lineage, NCI high risk and MRD low risk patients (Figure 2). Overall, the BMR for R2pulses was non-inferior (+2.1% increase BMR at 5 years for ALL patients (95% CI: -1.4% to 4.7%), HR 1.22 (95%CI: 0.89 – 1.67). Considering all four R2 treatment arms in standard dexamethasone only, standard IM without pulses has a lower EFS, whilst there is no appreciable benefit of pulses in HDM treated patients; 5-year EFS difference: -2.8% (95% CI: -7.4% to 4.4%) and BMR (ALL): +0.4% (-6.7% to 4.3%). Conclusions HDM does not improve CNSR within a UKALL treatment backbone, but pre-specified analyses suggest it may improve BMR for some sub-groups of B-lineage patients when given following standard dexamethasone induction. Although the ‘no pulses’ arm was non-inferior overall for BMR, further sub-group and toxicity analyses are to be performed and will presented at the meeting. Acknowledgements Children with Cancer, Blood Cancer (grant ref 09042) and Cancer Research UK funded the trial. Disclosures: Kirkwood: Kite: Consultancy, Honoraria. Rowntree: Pfizer: Membership on an entity's Board of Directors or advisory committees; Lilly: Membership on an entity's Board of Directors or advisory committees; KITE pharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. PRESS RELEASE 2022: High-dose methotrexate may make post-treatment steroids unnecessary for some children with ALL or LBL 214: High Dose Methotrexate Does Not Reduce the Risk of CNS Relapse in Children and Young Adults with Acute Lymphoblastic Leukaemia and Lymphoblastic Lymphoma. Results of the Randomised Phase III Study UKALL 2011 The results of a new study answer some questions and raise new ones about the optimal treatment strategy for children and young adults living with acute lymphoblastic leukemia (ALL) or lymphoblastic leukemia (LBL). The randomized study is the first to test whether the use of a shorter, higher-dose course of dexamethasone (a steroid) during the first phase of cancer treatment is associated with reduced toxicity. It also analyzed the effects of using a higher dose of the chemotherapy drug methotrexate and of omitting pulses of dexamethasone along with the chemotherapy drug vincristine monthly following initial treatment. Monthly pulses of vincristine and dexamethasone are commonly used as a “maintenance” strategy to help prevent cancer from coming back in the first few years following treatment. The findings indicate that an initial course of daily higher dose dexamethasone (10mg/m2) spanning two weeks did not reduce toxicity compared to the standard regimen (6 mg/m2), which lasts four weeks. The results also indicate that, when given with the standard dexamethasone regimen, high-dose methotrexate reduces the risk of bone marrow but not central nervous system relapse for some sub-groups of ALL and that pulses of dexamethasone and vincristine may not have added benefit in patients who have received high dose methotrexate. “Based on our results, if you give high-dose methotrexate after standard dexamethasone in the induction phase, omission of pulses may not reduce the chance of cure, although that conclusion should be considered tentative given the confounding interactions,” said Ajay Vora, MD, of the Great Ormond Street Hospital for Children in London. According to initial study findings, pulses were associated with an increased risk of behavior change, muscle weakness, and high blood sugar; the researchers are currently analyzing the data further to assess the effect of the pulses on quality of life. The trial had two main phases and examined three main questions. For the first phase, researchers randomized 1,902 patients to receive either a two-week higher-dose course or a four-week course of dexamethasone during initial treatment. The results for that phase, reported in 2017, indicated the short course of steroids brought no reduction in toxicity and may be slightly less effective. For the second phase, researchers randomized 1,570 patients to four groups: high-dose methotrexate plus dexamethasone and vincristine pulses, high-dose methotrexate without pulses, standard-dose methotrexate with pulses, and standard-dose methotrexate without pulses. Some patients were enrolled in both phases of the trial while others only participated in one phase or the other. Key endpoints for the second phase focused on whether the steroid pulses could be safely omitted without affecting bone marrow relapse or five-year event-free survival and whether the high-dose methotrexate could improve rates of relapse in the central nervous system. For high dose methotrexate, the results showed no significant differences overall for most endpoints. Researchers did find a significant interaction with the dexamethasone regimen given in the first phase, with patients treated with the four- week schedule showing improvements in bone marrow relapse rates when treated with high dose methotrexate. Overall, the results suggested that steroid pulses could be safely omitted without adversely affecting bone marrow relapse. However, omitting the pulses was associated with a decrease in event- free-survival overall. This effect was smaller in those treated with four-week dexamethasone and high dose methotrexate, suggesting it may be possible to omit pulses with this treatment schedule. 2 “We found that the interactions are highly significant, which is something nobody expected,” said Dr. Vora. “In addition, we were surprised that high-dose methotrexate seems to bring a benefit with respect to relapses primarily in the bone marrow and not the central nervous system, and we don’t have a biologically plausible explanation for that finding.” Going forward, researchers will be analyzing quality of life outcomes related to the dexamethasone- vincristine pulses for further insights into the possible benefits of skipping this added therapy. They will also study outcomes at longer follow-ups to ensure these results hold. In addition, they noted that other studies are underway to further illuminate optimal treatment strategies for different patient subgroups. Amy Kirkwood, University College London, will present this study during an oral presentation on Saturday, December 10, 2022, at 2:45 p.m. Central time in room 265-268.  

Interview with Matthias Stelljes MD, Head of the Allogeneic Stem Cell Program at the University of Münster, Germany NEW ORLEANS, USA—For your patients with acute myeloid leukemia (AML) the benefit of prompt allogeneic hematopoietic cell transplantation (alloHCT) extends to those whose disease has relapsed or is refractory to induction therapy, and should not be delayed in favor of further intensive chemotherapy in an attempt to achieve a complete remission. That’s according to conclusions from the randomized phase three ASAP (As Soon As Possible) Trial, reported by German researchers at the American Society of Hematology (ASH) 2022 Annual Meeting. https://ashpublications.org/blood/article/140/Supplement%201/9/488703/In-Patients-with-Relapsed-Refractory-AML “Allogeneic stem cell transplantation is a very potent strategy which is curative for many patients,” said senior author of the study, Johannes Schetelig, Prof. Dr. med., at the University of Dresden in Germany. “Our study suggests that the international standard of bringing patients into remission first should be questioned, as it proves that allotransplant should be considered a standard treatment option even for patients with active disease.” The new study was the first prospective randomized trial to assess whether or not high-dose “salvage chemotherapy” (to attempt to bring about a complete remission) made a difference in long-term outcomes after a stem cell transplant. Patients whose AML had relapsed or who did not respond to initial chemotherapy had similar outcomes when they proceeded directly to alloHCT compared with those who underwent intensive chemotherapy in the attempt to achieve complete remission first. Retrospective data had established that having a complete remission prior to allogeneic hematopoietic cell transplantation was indeed a favorable risk factor for patients with AML. But the ASAP Trial had been the first to examine this relationship prospectively, the researchers noted. “We were astonished. We never expected these results,” Schetelig said. “Patients did not gain additional benefit from salvage chemotherapy at all. It suggests we should think about starting the process of allotransplantation as soon as possible.” In previous phase two trials the researchers had found transplanting patients who had active disease brought a benefit. “We had some good experience in the past where we were able to successfully treat patients with an allogeneic stem cell transplantation even in the setting of active disease,” said first author of the ASAP study, Matthias Stelljes MD, Head of the Allogeneic Stem Cell Program at the University of Münster, Germany. Stelljes acknowledged that the majority of centers did not usually perform alloHCT in patients with relapsed or refractory AML with active disease. The new findings from ASAP, however, ran counter to the common practice of offering prompt transplantation only to patients who were in complete remission and clearly imply that many patients could skip the additional step of having salvage chemotherapy before receiving a transplant. The study enrolled 281 patients treated for relapsed or refractory AML in Germany. Half of them were randomized to proceed directly to alloHCT and remaining half had salvage chemotherapy first. The median time from randomization to transplant was four weeks among those proceeding directly to a transplant and eight weeks among those receiving salvage chemotherapy first. Researchers tracked outcomes for a median of just over three years. In the standard arm patients had salvage therapy with high dose cytarabine (ara-C) and mitoxantrone and then received an allogeneic transplant. This was either in subsequent remission or with active disease in those in whom no remission could be achieved, Stelljes told the Audio Journal of Oncology. “In the experimental arm we did not perform any salvage treatment. We just tried to get the patient as soon as possible to transplant. We were able to get most of the patients, without additional therapy, to allo transplant within three to four weeks,” he said. The two study groups showed similar outcomes in all key endpoints. The primary endpoint of complete remission 56 days after transplant was achieved in 84.1 percent of patients in the direct-to-transplant arm and 81.3 percent of patients in the salvage chemotherapy arm. The groups also had similar rates of overall survival at one year (around 70 per cent). Just over half of them were alive three years after randomization. In the experimental arm, patients were followed under a policy of “watchful waiting” which permitted some treatment while the search for a transplant donor was in progress, but not at doses aimed at achieving complete remission. Three quarters of them had transplants before any such treatment was needed, Stelljes noted. Since transplantation could only take place if a donor was available, the search for a donor began at primary diagnosis, Stelljes said, and not at the time of relapse of refractory disease. He highlighted the role of clonal selection of resistant cancer cells that can arise from the exposure patients have to cancer drugs. Prompt transplantation reduces the time during which patients are exposed to chemotherapy and should increase the success rate of transplantation in achieving long remissions, he noted. “The main message is: Contact your transplant center as soon as possible, and stay in contact with the transplant center.” NOTES: Study favors immediate progression to stem cell transplant for hard-to-treat AML even without achieving complete remission first ABSTRACT 4, American Society of Hematology 2022 Annual Meeting, New Orleans, USA. TITLE:In Patients with Relapsed/Refractory AML Sequential Conditioning and Immediate Allogeneic Stem Cell Transplantation (allo-HCT) Results in Similar Overall and Leukemia-Free Survival Compared to Intensive Remission Induction Chemotherapy Followed By Allo-HCT: Results from the Randomized Phase III ASAP Trial ABSTRACT 4 ASH 2022: In Patients with Relapsed/Refractory AML Sequential Conditioning and Immediate Allogeneic Stem Cell Transplantation (allo-HCT) Results in Similar Overall and Leukemia-Free Survival Compared to Intensive Remission Induction Chemotherapy Followed By Allo-HCT: Results from the Randomized Phase III ASAP Trial Program: General Sessions Session: Plenary Scientific Session Hematology Disease Topics & Pathways: MDS, clinical trials, AML, adult, Acute Myeloid Malignancies, Research, Clinical Research, Chronic Myeloid Malignancies, Diseases, therapy sequence, Therapies, Myeloid Malignancies, Human, Study Population Sunday, December 11, 2022, 2:00 PM-4:00 PM Matthias Stelljes, Prof. Dr. med.1, Jan Moritz Middeke, MD2*, Gesine Bug, MD3*, Eva-Maria Wagner, MD4*, Lutz Peter Mueller, MD5*, Schmid Christoph6*, Stefan W. Krause, MD7*, Wolfgang Bethge, MD8*, Edgar Jost9*, Uwe Platzbecker, MD10*, Stefan Klein, MD11, Jörg Schubert12*, Judith Niederland13*, Martin Kaufmann, MD14, Kerstin Schäfer-Eckart15*, Markus Schaich, MD16*, Henning Baldauf17*, Friedrich Stölzel18*, Cathleen Petzold, PhD17*, Christoph Röllig, MD, MSC19*, Nael Alakel, MD20*, Björn Steffen, MD21*, Beate Hauptrock22*, Christian Reicherts, MD23*, Christoph Schliemann, MD24*, Hubert Serve, MD21, Alexander H. Schmidt, MD, PhD25, Martin Bornhäuser, MD26*, Jan-Henrik Mikesch, PD, MD24* and Johannes Schetelig, MD, MSc17,20 1Department of Medicine / Hematology and Oncology, University of Muenster, Muenster, Germany 2Department of Internal Medicine I, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany 3Department of Medicine II, Hematology and Oncology, University Hospital Frankfurt, Frankfurt, Germany 4Haematology and Oncology, University Medical Center, University Medicine Mainz, Mainz, Germany 5University Hospital, Martin-Luther-University Halle-Wittenberg, Halle, Germany, Halle (Saale), Germany 6Augsburg University Hospital and Medical Faculty, Augsburg, Germany, Augsburg, Germany 7University Hospital Erlangen, Germany, Erlangen, Germany 8Department of Hematology, Oncology, Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany 9University Hospital Aachen, Germany, Aachen, Germany 10Department for Hematology, Cell Therapy and Hemostaseology, University of Leipzig Medical Center, Leipzig, Germany 11Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany 12Elblandklinikum, Riesa, Germany, Riesa, Germany 13Helios Klinikum Berlin-Buch, Berlin, Germany, Berlin-Buch, Germany 14Medical Centre, Robert-Bosch-Hospital,, Stuttgart, Germany 15Department of Internal Medicine V, Nuremberg Hospital North, Paracelsus Medical University, Nuremberg, Germany 16Department of Hematology, Oncology and Palliative Care, Rems-Murr-Klinikum Winnenden, Germany, Winnenden, Germany 17Clinical Trials Unit, DKMS gGmbH, Dresden, Germany 18University Hospital, TU Dresden,Germany, Dresden, Germany 19University Hospital, TU Dresden, Germany, Dresden, Germany 20University Hospital TU Dresden, Germany, Dresden, Germany 21Department of Hematology and Oncology, University Hospital Frankfurt am Main, Frankfurt am Main, Germany 22University Hospital Mainz, Germany, Mainz, Germany 23Department of Hematology, Oncolog and Pneumology, University of Münster, Muenster, Germany 24Department of Hematology, Oncolog and Pneumology, University of Münster, Münster, Germany 25DKMS gGmbH, Tubingen, Germany 26Department of Medicine I, University Hospital Carl Gustav Carus Dresden, Dresden, Germany Introduction: For patients (pts) with AML, a complete remission (CR) prior to allogeneic hematopoietic cell transplantation (alloHCT) is a favourable risk factor. However, whether pts with relapsed or refractory (r/r) AML benefit from an attempt to induce CR with intensive chemotherapy (CT) prior to alloHCT is unknown. Sequential conditioning within 12 days prior to alloHCT with high-dose cytarabine or melphalan followed by reduced intensity conditioning leads to good results as well. Therefore, we asked whether intensive remission induction CT prior to alloHCT really improves outcome compared to immediate alloHCT after sequential conditioning without attempt to induce a CR before transplantation. Methods: Adult pts with poor responsive non-favourable AML after first induction therapy (IT-1) or AML relapse, eligible for intensive CT and alloHCT, with either a matched sibling donor (MSD), an HLA-compatible (≥9/10) unrelated donor (UD) or ongoing donor search with two potential UD with ≥90% HLA-matching probability were enrolled. Patients were randomized 1:1 to a remission induction strategy (RIST-arm) with 3 g/m2 cytarabine (1 g/m2 for pts >60 years) twice daily on days 1-3 plus 10 mg/m2 mitoxantrone on days 3-5 (HAM) and subsequent alloHCT (remission induction strategy, RIST-arm) or to disease control (DISC-arm) prior to sequential conditioning and alloHCT. In the DISC-arm watchful waiting (w&w) was recommended, but low-dose cytarabine (LDAC) and single doses of mitoxantrone were permitted for disease-control. The primary endpoint was treatment success, defined as CR@day56 after alloHCT. Statistically, the goal was to show non-inferiority (NIF) for the DISC-arm with a NIF-margin of 5% and a one-sided alpha of 2.5%. Major secondary endpoints were overall survival from randomization and leukemia-free survival from CR@day56. Results: A total number of 281 pts (183 pts with poor response after IT-1 and 98 pts after relapse) were enrolled. The full analysis set comprised 276 pts after exclusion of five pts due to violation of inclusion criteria. Median age was 61 years (interquartile range [IQR] 52-66 years) and the HCT-CI was ≥3 in 37.3% of pts. At randomization, 39 pts had MSD, 133 pts had an HLA-compatible UD with confirmed HLA-typing, and 104 pts had ongoing UD searches. 272 pts were treated per protocol, 138 pts in the DISC- and 134 in the RIST-arm. In the DISC-arm 105 of 138 pts (76%) were kept on w&w until start of sequential conditioning, while 33 pts (24%) needed disease-control measures. In the RIST-arm all pts received HAM. Sixty-two out of 134 pts (46%) achieved a CR. Five pts received a second course of intensive CT. The remaining pts proceeded to alloHCT without further attempts to induce a CR. The median time to alloHCT was 4 weeks in the DISC-arm and 8 weeks in the RIST arm. At 24 weeks from randomization 98% and 96% of pts had been transplanted in the DISC and RIST arm, respectively. Figure 1 A shows incidences of alloHCT and CR achievement in both arms. The primary endpoint CR@day56 after alloHCT was reached by 84.1% of pts in the DISC-arm and 81.3% of pts in the RIST-arm (test for non-inferiority, p=0.047). One-year leukemia-free survival from CR@day56 was 71.5% in the DISC-arm and 69.9% in the RIST-arm (z test, p=0.8). The median follow-up from randomization is 37 months. According to the intention-to-treat, 1-year and 3-years overall survival from randomization was 69.1% (95%-CI, 60.6-76.1%) versus 71.9% (95%-CI, 63.3-78.9%) and 51.0% (95%-CI, 41.8-59.6%) versus 54.2% (95%-CI, 44.4-62.9%) in the DISC- versus RIST-arm, respectively (log-rank p=0.47) (Figure 1B). Conclusions: This is the first randomized controlled trial, which questioned the benefit of intensive remission induction CT prior to alloHCT for pts with r/r AML. Chemotherapy with high-dose cytarabine and mitoxantrone before alloHCT did not result in a higher overall success rate and did not confer a survival advantage. Watchful waiting followed by sequential conditioning and alloHCT resulted in comparable overall CR rates and survival. These data support sequential conditioning and alloHCT without prior remission induction CT whenever a stem cell donor is readily available. Finally, these results underline the importance of facilitating alloHCT as most effective anti-leukemic therapy in patients with r/r AML and stress the need for starting donor search at diagnosis.

Ibrutinib Enables Transplant-Free Therapy for Mantle Cell Lymphoma NEW ORLEANS, USA—Many patients eligible for autologous stem cell transplantation for their mantle cell lymphoma (under current best practice recommendations) could be treated as effectively—and potentially with less toxicity—with the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, according to findings from Munich, Germany. The Randomized Triangle Trial, conducted by the European Mantle Cell Lymphoma Network, reported positive findings about a transplant-free approach to the American Society of Hematology 2022 Annual Meeting. https://ashpublications.org/blood/article/140/Supplement%201/1/490022/Efficacy-and-Safety-of-Ibrutinib-Combined-with Audio Journal of Oncology correspondent Peter Goodwin talked with study leader Martin Dreyling MD PhD, Professor of Medicine at LMU (Ludwig Maximilian University) Hospital in Munich, Germany about their findings that strongly suggest standard chemotherapy plus ibrutinib (with or without autologous stem cell transplantation) should be the new first-line standard of care for patients with mantle cell lymphoma. Toxicity But the German team also noted that the high efficacy of chemotherapy brought high toxicity rates. So, they compared the standard induction (with a cytarabine-containing regimen plus autologous transplant and rituximab maintenance) with two experimental arms, said Dreyling. “One was a simple add-on design—which means ibrutinib [was] added to [standard] induction and maintenance. And the third arm was even more interesting: substituting for autologous transplant.” “The add-on design resulted in a significant improvement of progression free survival—around 15 per cent after three years: in my opinion highly clinically relevant,” he said. Also, the study found that a group of difficult-to-treat patients—those whose tumors had p53 gene alterations—had specifically benefited from the addition of ibrutinib. Patients who took the targeted drug ibrutinib had rates of failure-free survival (FFS) and overall survival (OS) that were similar to the current standard of care—whether or not they received a stem cell transplant in addition to ibrutinib. Those treated with ibrutinib who did not have ASCT had significantly lower rates of toxicity. And in the arm in which ibrutinib was added to transplantation, the toxicity was no higher than among patients treated with standard of care, the study found. “We are moving away from intensive chemotherapy to [a] targeted approach. The new standard of care in younger patients is still a combination of chemo plus ibrutinib. The future, I hope, will be skipping chemotherapy [altogether] and moving to a purely targeted approach—hopefully leading to better outcomes, but definitely better tolerability of our treatment regimens,” Dreyling told OT. Study details The trial enrolled 870 adult patients up to 65 (median age 57 years) treated for MCL in 13 European countries and Israel. All patients were eligible for ASCT. 288 of them (group A) were assigned to receive standard care (high-dose cytarabine-containing immunochemotherapy followed by ASCT and rituximab maintenance). 292 patients (group A + I) were treated with the same standard care plus ibrutinib, and 290 patients received ibrutinib without having a transplant (group I). Transplant not superior After a median follow-up of 31 months, group A failed to show superiority over group I in terms of FFS (three-year FFS was 72 per cent compared with 86 per cent in group I (p=0.9979, hazard ratio: 1.77). In group A+I, the FFS was superior to group A: 88 per cent compared with 72 per cent in group A (p=0.0008, hazard ratio: 0.52). OS was 86 per cent in group A, 91 per cent in group A+I, and 92 per cent in group I. Toxicities The study found no substantial differences in the incidence of grade three to five adverse events (AEs) during induction with R-CHOP/R-DHAP versus ibrutinib-R-CHOP/R-DHAP. But during maintenance therapy there were substantially more grade three to five AEs in group A+I as compared either to group A or to group I. Neutropenia, leukopenia, febrile neutropenia, infections and cardiac disorders were all increased—many doubled in incidence—suggesting that ibrutinib may be best used as a replacement for stem cell transplantation rather than an addition. “We have to wait for the full results,” said Dreyling. “So far, we don’t see any difference between [the] two ibrutinib curves for progression-free survival and overall survival. But already both curves are numerically superior to the old standard, autologous transplant only. I think clinicians will interpret these results as suggesting you may essentially substitute autologous transplant with ibrutinib to avoid its well-known long-term toxicities,” he said. “From the perspective of toxicity, the ideal regimen is a combination of conventional chemotherapy plus ibrutinib,” said Dreyling. His reasoning for reaching this conclusion was that not only had failure free survival improved when ibrutinib had been added to standard transplant therapy but the removal of transplantation altogether had proved highly beneficial. Avoiding transplantation The head-to-head comparison of ibrutinib versus ASCT had been even more interesting, he said, because skipping autologous transplant significantly reduced toxicity—which is what the study found. “When we started, we said autologous transplant had to be superior to remain the standard of care. However, to our surprise, what we observed was a flip-around of the curve. In fact, the ibrutinib arm was superior to autologous transplant.” Overall survival Although the statistical analysis had not yet be completed, both of the ibrutinib-containing arms of the study resulted in numerically superior overall survival. “That somewhat confirms that the life cycle of autologous transplant—in my opinion—is over and we now move on to the targeted approaches,” said Dreyling. There was a big gain to be made for patients by skipping the acute toxicity of transplantation, Dreyling said. This was in the range of 60 per cent incidence of grade three to five myelosuppression and a 20 per cent infection rate caused by it. “This is totally skipped in the ibrutinib-only arm,” he said. Quality of life Dreyling said that from the doctor’s perspective ASCT was easy, but was not at all easy from the patient’s perspective. “We have a lot of patients with delayed reduction of general quality of life. And therefore, I think this is really an important step forward—besides all the late toxicities of autologous transplant we couldn’t yet analyze so far,” he said. Dreyling pointed out emphatically that the study had been led and funded by academic institutions which he said was hugely important. “This study proves the role of academic trials—independently performed,” he said. Recruiting almost 900 patients with mantle cell lymphoma—also proved the value of international collaboration, he said. ASH 2022 Annual Meeting ABSTRACT 1: Efficacy and Safety of Ibrutinib Combined with Standard First-Line Treatment or As Substitute for Autologous Stem Cell Transplantation in Younger Patients with Mantle Cell Lymphoma: Results from the Randomized Triangle Trial By the European MCL Network Program: General Sessions Session: Plenary Scientific Session Hematology Disease Topics & Pathways: Research, clinical trials, adult, Lymphomas, non-Hodgkin lymphoma, Non-Biological therapies, Clinical Research, B Cell lymphoma, Chemotherapy, Diseases, aggressive lymphoma, Therapies, Lymphoid Malignancies, young adult , Study Population, Human Sunday, December 11, 2022, 2:00 PM-4:00 PM Martin Dreyling, MD1, Jeanette K. Doorduijn, MD, PhD2, Eva Gine, MD, PhD3, Mats Jerkeman, MD, PhD4, Jan Walewski, MD5, Martin Hutchings, MD, PhD6*, Ulrich Mey, MD7,8, Jon Riise, MD, PhD9*, Marek Trneny, MD10, Vibeke K.J. Vergote11*, Melania Celli12*, Ofer Shpilberg, MD, MPH13*, Maria Gomes da Silva14*, Sirpa Leppa, MD, PhD15, Linmiao Jiang16*, Christiane Pott17*, Wolfram Klapper, MD18*, Döndü Gözel1*, Christian Schmidt, MD1*, Michael Unterhalt, MD, PhD1*, Marco Ladetto, MD19 and Eva Hoster1,20* 1Department of Internal Medicine III, LMU University Hospital Munich, Munich, Germany 2Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands 3Department of Hematology, Hospital Clinic of Barcelona, IDIBAPS, CIBERONC, GELTAMO, Barcelona, Spain 4Division of Oncology, Skane University Hospital and Lund University, Lund, Sweden 5Department of Lymphoid Malignancies, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland 6Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark 7Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland 8Oncology and Hematology, Kantonsspital Graubünden, Chur, Switzerland 9Department of Oncology, Oslo University Hospital, Oslo, Norway 10First Department of Internal Medicine - Hematology, General University Hospital and First Faculty of Medicine, Charles University, Prague, Czech Republic 11Department of Hematology, University Hospitals Leuven, Leuven, Belgium 12U.O. di Ematologia, Ospedale degli Infermi di Rimini, Rimini, Italy 13Institute of Hematology, Assuta Medical Centers, Tel-Aviv, Israel 14Department of Hematology, Instituto Português de Oncologia de Lisboa, Lisbon, Portugal 15Department of Oncology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland 16Institute for Medical Information Processing, Biometry and Epidemiology (IBE), LMU University Munich, Munich, Germany 17Clinic for Internal Medicine II - Haematology, Oncology, University Clinic Schleswig-Holstein, Kiel, Germany 18Department of Pathology, Hematopathology Section and Lymph Node Registry, Universitätsklinikum Schleswig-Holstein, Kiel, Germany 19Department of Translational Medicine, University of Eastern Piedmont and Az Ospedaliera Santi Antonio e Biagio e Cesare Arrigo, Alessandria, Italy 20Institute for Medical Information Processing, Biometry and Epidemiology, LMU Munich, Munich, Germany On behalf of the European MCL Network ML and EH contributed equally Introduction: High-dose cytarabine-containing immunochemotherapy followed by autologous stem cell transplantation (ASCT) and rituximab maintenance represents the current standard of care for younger mantle cell lymphoma (MCL) patients. The BTK-inhibitor ibrutinib has shown promising efficacy in relapsed (Dreyling et al, Hemasphere 2022) and previously untreated older MCL patients (Wang et al., NEJM 2022). In 2016, the European MCL Network initiated the randomized, open-label, 3-arm TRIANGLE trial to evaluate the addition of ibrutinib to standard treatment (arm A+I) in comparison to the previous standard treatment (arm A) and an ibrutinib containing treatment without ASCT (arm I). Patients and methods: Patients with previously untreated, advanced stage II-IV MCL, up to 65 years and suitable for high-dose cytarabine and ASCT were randomized 1:1:1 to the 3 trial arms A, A+I, and I in 13 European countries and Israel. Study treatment consisted of 3 cycles R-CHOP/R-DHAP without (arm A) or with ibrutinib added to R-CHOP cycles and 2 years maintenance (arms A+I, I). ASCT was planned for responding patients of arms A and A+I. Rituximab maintenance could be applied according to national guidelines in all responding patients irrespective of the trial arm. For the primary outcome, failure-free survival (FFS), stable disease at the end of induction, any progression, or death were counted as events. Three pairwise log-rank tests for FFS were monitored with regular pre-planned interim analyses maintaining each a one-sided 0.0167 significance level. A pre-defined decision criterion based on the statistical significance of the treatment comparisons was established to determine the future treatment recommendation. Secondary outcomes were overall response (OR), complete remission (CR), overall survival (OS), and grade 3-5 AEs. Results: Between July 2016 and December 2020, 870 patients were randomized to A (n=288), A+I (n=292), and I (n=290). Median age was 57 years (range 27-68), 76% of the patients were male, 87% had stage IV, and 58%/27%/15% had low/intermediate/high risk MIPI. OR and CR rates were 94% and 36% of 272 evaluable patients in arm A (R-CHOP/R-DHAP) as compared to 98% and 45% of 559 evaluable patients in the combined A+I/I arms (ibrutinib-R-CHOP/R-DHAP). After a median follow-up of 31 months, A failed to show superiority over I in terms of FFS with 3-year FFS 72% (A) vs. 86% (I; p=0.9979, hazard ratio: 1.77, Figure 1A). A+I was superior to A in terms of FFS with 3-year FFS 88% (A+I) vs. 72% (A; p=0.0008, hazard ratio: 0.52). Subgroup analyses by the intention to apply rituximab maintenance did not change the main results on the lack of superiority of A vs. I and the superiority of A+I vs. A . Statistical monitoring for the FFS comparison of A+I vs. I is still ongoing. Three-year OS was 86% in A, 91% in A+I, and 92% in I (Figure 1B). There were no substantial differences in the occurrence of grade 3-5 AEs during induction with R-CHOP/R-DHAP vs ibrutinib-R-CHOP/R-DHAP (neutropenia: 47%/49% of patients, leukopenia: 15%/15%, febrile neutropenia: 9%/12%, infections and infestations: 9%/12%, cardiac disorders: 2%/3%). The two ASCT-containing arms did not substantially differ in grade 3-5 AEs (A/A+I: neutropenia: 36%/33%, febrile neutropenia: 20%/22%, leukopenia: 17%/17%, infections and infestations: 17%/20%). In contrast, during maintenance, there were substantially more grade 3-5 AEs in A+I as compared to A and I (A+I/A/I: neutropenia: 44%/17%/23%, leukopenia: 4%/2%/2%, febrile neutropenia: 6%/3%/3%, infections and infestations: 25%/13%/19%, cardiac disorders: 3%/1%/4%). Conclusions: The addition of ibrutinib during induction and as maintenance with or without ASCT showed strong efficacy with acceptable toxicity. It has been clearly demonstrated that the current standard high-dose regimen is not superior to the new ibrutinib-containing regimen without ASCT. More follow-up is needed to clarify the role of ASCT in the context of ibrutinib-containing treatment. However, the current results already support the use of ibrutinib in the first-line treatment of younger MCL patients.

January 10, 2023 Fast Durable Responses to Bi-Specific Antibody Therapy In Heavily Pre-Treated Multiple Myeloma INTERVIEW WITH: Ajai Chari MD, Associate Professor of Medicine and Director of Clinical Research in the Multiple Myeloma Program at Mount Sinai School of Medicine in New York, USA. NEW ORLEANS, USA—The bispecific antibody talquetamab, classed as a “T-cell redirecting therapy” achieved high response rates in the phase one/two multi-national MonumenTAL-1 study investigating 288 patients who had heavily pre-treated refractory multiple myeloma. Findings reported at the American Society of Hematology 2022 Annual Meeting showed that nearly three-quarters of patients treated had “complete” or “very good partial” responses within one or two months, and median response durations of around nine months.https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.8015 “Remarkably in this unmet need we saw response rates of 73 to 74 per cent. The responses were maintained in triple-class refractory patients, penta-drug refractory patients, ISS (International Staging System) three high-risk disease,” said Ajai Chari MD, Associate Professor of Medicine and Director of Clinical Research in the Multiple Myeloma Program at Mount Sinai School of Medicine in New York, USA. “The median time to response was one month—which is outstanding. And the median time to “best response” was slightly over two months—which is great, because it means that these patients who had explosive disease (these are not CAR-T cherry-picked patients with really indolent progression) were benefiting in high percentages—and quickly, and deeply,” Chari told the Audio Journal of Oncology. Although patients with extra-medullary disease had fared slightly less well, their responses had still been good, he said. “Even there, there was an impressive 50 per cent response rate.” Talquetamab was an off-the-shelf bispecific antibody, that binds to both T cells and multiple myeloma cells, said Chari. This facilitates an immune response to destroy myeloma cells by bringing T cells to the cancer. Its twin targets were the CD3 T-cell receptors and the cancer cell surface receptor known as G protein-coupled receptor family C group 5 member D (GPRC5D). “[Previously] we only had naked antibodies. And a bispecific antibody is different. Like with all antibodies it has the Y-shaped structure, but unlike typical antibodies it binds two different targets. One target is the T cell—with CD3; and the other target is GPRC5D, which is a novel target in myeloma. It’s over-expressed particularly on malignant plasma cells, less so on normal plasma cells, and—importantly—not on the hematopoietic stem cell compartment—Which we think is a favorable finding,” said Chari. “You basically can engage the patient’s own T-cells to try to attack the myeloma. And it’s a little surprising how remarkable this whole approach has been: Because patients with myeloma who are entering these studies have typically five to six lines of therapy over six years, are usually in their late sixties [or] early seventies, and you wouldn’t think that their T-cells would even be robust, and fit, and present, enough to generate results—let alone the outstanding results we’re seeing,” he said. In the MonumenTAL-1 study, patients with relapsed/refractory multiple myeloma, were treated with either of two recommended dosing regimens: 0.40 mg/kg of talquetamab subcutaneously at weekly intervals, or 0.80 mg/kg every other week. Results Patients in the weekly and bi-weekly dose regimens (equivalent in overall dose intensity) had similar outcomes in terms of response rates and toxicities. Nearly a third of patients had complete responses. More than half had “very good” partial responses. The responses deepened with time, and continued to a median of nine months duration. Median progression-free survival was 7.5 months. The median time to a measurable response was approximately 1.2 months with either dosing regimen, and the median duration of response was 9.3 months in the patients treated with the weekly dosing. “This means that three-quarters of these patients are looking at a new lease on life,” said Chari. “We’re hoping that this will soon become available so that patients can benefit.” Side effects were relatively frequent, but mild in most patients. About three-quarters experienced cytokine release syndrome (immune activation—typically causing a fever). More than half of the study cohort had skin-related side effects such as rash. About a half reported dysgeusia (taste changes), and a similar proportion of study subjects had nail disorders. Only one in twenty patients discontinued talquetamab treatment early due to side effects. Since response rates observed in the early-phase MonumenTAL-1 study had been, higher than with most currently accessible therapies, Chari suggested talquetamab could potentially be proven to be a viable option for patients with refractory multiple myeloma and offer the possibility of extending life. Chari told the Audio Journal of Oncology he regarded bispecific antibodies as an alternative T-cell redirection strategy comparable to chimeric antigen receptor therapy (CAR-T)—that had achieved notable successes in hematologic malignancy in certain academic centers of excellence recently. But bi-specific antibodies could potentially be more universally available, because off-the-shelf agents could more easily be distributed to a wider range of patients—without the need to individualize the therapeutic agent in each case. “There’s every reason to hope that these could be brought to the community oncologist near you so you don’t have to keep going to these academic centers,” he said. ASH 2022: 157 Talquetamab, a G Protein-Coupled Receptor Family C Group 5 Member D x CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Phase 1/2 Results from MonumenTAL-1Clinically Relevant Abstract Program: Oral and Poster Abstracts Type: Oral Session: 653. Myeloma and Plasma Cell Dyscrasias: Prospective Therapeutic Trials: Bispecific Monoclonal Antibodies in Myeloma Hematology Disease Topics & Pathways: Biological therapies, Research, Clinical Research, Plasma Cell Disorders, Diseases, Therapies, Lymphoid Malignancies Saturday, December 10, 2022: 12:00 PM Ajai Chari1*, Cyrille Touzeau2*, Carolina Schinke3, Monique C. Minnema, MD, PhD4, Jesus Berdeja, MD5, Albert Oriol6*, Niels WCJ Van De Donk, MD7, Paula Rodriguez Otero8*, Elham Askari9*, Maria-Victoria Mateos, MD10, Luciano J. Megala Costa, MD, PhD11, Jo Caers, PhD12, Leo Rasche, MD13*, Amrita Y. Krishnan, MD, FACP14, Deeksha Vishwamitra15*, Xuewen Ma15*, Xiang Qin15*, Katharine S. Gries, PhD, PharmD16*, Michela Campagna17*, Tara Masterson15*, Brandi Hilder15*, Jaszianne Tolbert15, Thomas Renaud18*, Jenna D. Goldberg18*, Christoph Heuck15*, Jesús San-Miguel, MD, PhD19 and Philippe Moreau, MD20* 1Mount Sinai School of Medicine, New York, NY 2Centre Hospitalier Universitaire de Nantes, Nantes, France 3Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR 4University Medical Center Utrecht, Utrecht, Netherlands 5Sarah Cannon Research Institute, Nashville, TN 6Hospital Germans Trias I Pujol, Barcelona, Spain 7Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, Netherlands 8University of Navarra, Pamplona, Spain 9Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain 10University Hospital of Salamanca/IBSAL/CIC, Salamanca, Spain 11University of Alabama at Birmingham, Birmingham, AL 12University of Liege, Liege, Belgium 13University Hospital of Würzburg, Würzburg, Germany 14City of Hope Comprehensive Cancer Center, Duarte, CA 15Janssen Research & Development, Spring House, PA 16Janssen Global Services, Raritan, NJ 17Janssen-Cilag, Madrid, Spain 18Janssen Research & Development, Raritan, NJ 19Universidad de Navarra, Pamplona, Spain 20University Hospital Hôtel-Dieu, Nantes, France Introduction: G protein-coupled receptor family C group 5 member D (GPRC5D) has limited expression in normal human tissue but is highly expressed on malignant plasma cells, making it a promising immunotherapy target for patients (pts) with multiple myeloma (MM). Talquetamab is a first-in-class, off-the-shelf, T-cell redirecting bispecific antibody targeting both GPRC5D and CD3 receptors. MonumenTAL-1 is a phase 1/2 trial (NCT03399799/NCT04634552) of talquetamab in pts with RRMM. In phase 1 of MonumenTAL-1, collective safety, efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) data supported selection of 2 recommended phase 2 doses (RP2Ds) for talquetamab: 0.405 mg/kg subcutaneous (SC) weekly (QW) and 0.8 mg/kg SC every other week (Q2W). Here, we report results for pts treated at these RP2Ds in phase 1 and 2 of MonumenTAL-1. Methods: Eligible pts in phase 1 had measurable MM and had progressed on or were intolerant to standard therapies. Pts in phase 2 had received ≥3 prior lines of therapy (LOT), including ≥1 proteasome inhibitor, ≥1 immunomodulatory drug, and ≥1 anti-CD38 monoclonal antibody (ie, triple-class exposed). In phase 1, 0.405 mg/kg SC QW was a putative RP2D; this was modified to 0.4 mg/kg SC QW in phase 2 for convenience. Phase 1 and 2 data were combined for analysis. Step-up dosing was used to mitigate risk of severe cytokine release syndrome (CRS). Primary endpoint of phase 2 was overall response rate (ORR) per IMWG criteria based on independent committee review. Key secondary endpoints were duration of response (DOR), rate of very good partial response or better (≥VGPR), rate of complete response or better (≥CR), time to response, progression-free survival (PFS), and incidence of AEs. AEs were graded by CTCAE v4.03; CRS events were graded per ASTCT criteria. PD parameters were measured at baseline and through day 1 of cycle 2. Results: As of May 16, 2022, 288 pts with no prior exposure to T-cell redirecting therapies had received talquetamab at the RP2Ds in phase 1 or 2. In 143 pts treated at 0.4 mg/kg QW (median time since diagnosis: 6.7 years), median age was 67 years (range 46–86), pts received a median of 5 prior LOT (range 2–13), 31.1% had high-risk cytogenetics, 23% had extramedullary disease, 19.6% had ISS stage 3 disease, 100%/74% were triple-class exposed/refractory, and 73%/29% were penta-drug exposed/refractory; median follow-up was 11.0 months (range 0.5+–26.1). Baseline characteristics were similar among 145 pts who received 0.8 mg/kg Q2W (median follow-up: 5.1 months [range 0.2+–17.9]). In 143 pts treated at 0.4 mg/kg QW, ORR was 73% (≥VGPR: 58%; ≥CR: 29%). Responses were durable and deepened over time (Figure). Median time to response was 1.2 months (range 0.2–5.0). Median time to CR was 2.1 months (range 1.1–12.4). Median DOR was 9.3 months (95% CI, 6.6–20.2; range 1–23+). Median PFS was 7.5 months (95% CI, 5.7–9.2 [38% censored]). ORRs in pts who were triple-class refractory (72% [76/106]) and penta-drug refractory (71% [30/42]) were comparable to the overall population. Efficacy at 0.8 mg/kg Q2W will be presented at the meeting. The most common AEs at 0.4 mg/kg QW/0.8 mg/kg Q2W were CRS (79%/72%; grade 3: 2%/1%; grade 4: 0%/0%), dysgeusia (48%/46%; grade 3/4: not applicable [NA]), and anemia (45%/39%; grade 3: 31%/25%; grade 4: 0%/0%]); skin-related AEs occurred in 56%/68% (grade 3: 0%/1%; grade 4: NA) and nail disorders in 52%/43% (grade 3: 0%/0%; grade 4: NA) of patients. Cytopenias, including neutropenia in 34%/28% (grade 3: 20%/17%; grade 4: 10%/6%) and thrombocytopenia in 27%/27% (grade 3: 10%/8%; grade 4: 10%/8%), were generally limited to the first few cycles. At 0.4 mg/kg QW/0.8 mg/kg Q2W, infections occurred in 57%/50% of pts (grade ≥3: 19%/13%); 4.9%/6.2% discontinued, 8.4%/13.8% had dose delays, and 14.7%/6.2% had dose reductions due to AEs. There were 2 deaths due to COVID-19 (1 patient at each RP2D). Talquetamab exposure was comparable at the two RP2Ds. No clinically significant effect of anti-talquetamab antibodies on PK, efficacy, or AEs was observed. PD changes were comparable at both RP2Ds and consistent with talquetamab activity, including T-cell activation, redistribution, and induction of cytokines. Conclusions: Talquetamab demonstrated robust efficacy and manageable safety in pts with heavily pretreated RRMM. Additional phase 1 studies (NCT04586426; NCT04108195; NCT05050097) are evaluating talquetamab in combination with other agents in pts with RRMM. ASH 2022 PRESS BRIEF: Talquetamab Generates High Response Rate in Patients with Hard-to-treat Multiple Myeloma 157: Talquetamab, a G Protein-Coupled Receptor Family C Group 5 Member D x CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Phase 1/2 Results from MonumenTAL-1 In an early-phase trial, nearly three-quarters of patients who received talquetamab, a first-in-class experimental immunotherapy for multiple myeloma, saw a significant reduction in cancer burden within a few months. The study participants had all been previously treated with at least three different therapies without achieving lasting remission, suggesting talquetamab could offer new hope for patients with hard-to-treat multiple myeloma. “This means that three-quarters of these patients are looking at a new lease on life,” said Ajai Chari, MD, of The Tisch Cancer Institute at Mount Sinai in New York. “We’re hoping that this will soon become available so that patients can benefit.” Talquetamab binds to both T cells and multiple myeloma cells. This activates an immune response to destroy myeloma cells by bringing T cells to the cancer, a strategy that researchers described as “bringing your army to the enemy.” It also uses a different target than other approved therapies; in this case, the target is a receptor expressed on the surface of cancer cells known as GPRC5D. Multiple myeloma is a blood cancer that forms in plasma cells. Several treatments are available, but the prognosis can be very poor and many patients survive less than a year if the disease doesn’t respond to therapy or returns after several different treatments. The study enrolled a total of 288 patients who were unable to tolerate existing therapies or showed disease progression after at least three multiple myeloma therapies. After an initial phase generated encouraging results in terms of safety and efficacy, researchers began enrolling additional patients to assess the agent’s efficacy with two different dosing regimens—0.4 mg/kg weekly and 0.8 mg/kg every other week. Data from patients who had received these same dosing regimens in the first phase were included in the analysis for the second phase. Seventy-four percent of those receiving 0.4 mg/kg of talquetamab weekly and 73% of those receiving 0.8 mg/kg every other week saw a measurable improvement of their cancer following treatment, the primary endpoint for the trial’s second phase. More than 30% of patients in both groups had a complete response (no detection of myeloma-specific markers) or better and nearly 60% had a “very good partial response” or better (indicating the cancer was substantially reduced but not necessarily down to zero). The median time to a measurable response was approximately 1.2 months in both dosing groups and the median duration of response is 9.3 months to date with weekly dosing. Researchers are continuing to collect data on the duration of response in the group receiving 0.8 mg/kg every other week and for patients in both dosing groups who had a complete response or better. Side effects were relatively frequent, but typically mild. About three-quarters of patients experienced cytokine release syndrome (a sign of immune activation common with therapies that redirect T cells, typically causing a fever); 60% experienced skin-related side effects such as rash; about half reported taste changes; and about half reported nail disorders. Researchers said 5-6% of patients stopped talquetamab treatment early due to side effects. The response rate observed in this cohort, which Dr. Chari explained is higher than that of most currently accessible therapies, suggests talquetamab could offer a viable option for patients with hard-to-treat myeloma, offering a chance to extend patient lifespans. In a separate cohort, 51 patients who had previously received therapies that redirect T cells showed a response to talquetamab. In addition, several other studies are underway to assess the use of talquetamab in combination with other existing and investigational multiple myeloma therapies, which could allow patients to have similar or improved benefits, potentially in earlier stages of treatment. This study was funded by Janssen Research & Development LLC. Ajai Chari, The Tisch Cancer Institute at Mount Sinai, will present this study during an oral presentation on Saturday, December 10, 2022, at 12:00 noon in R02-R05.

An interview with: Byoung Chul Cho MD PhD, Thoracic Medical Oncologist, from the Yonsei Cancer Center at Yonsei University College of Medicine in Seoul, South Korea. BARCELONA, Spain—A “next generation” ROS1 tyrosine kinase inhibitor (TKI), repotrectinib—studied in the phase one/two Trident-1 study among patients whose advanced non-small cell lung cancers (NSCLC) had tested positive for the ROS1 fusion protein receptor tyrosine kinase (encoded by the ROS1 oncogene)—resulted in high response rates with low toxicities, according to results reported at the 2022 European Organisation for Research and Treatment of Cancer-National Cancer Institute-American Association for Cancer Research (EORTC-NCI-AACR) Symposium on Molecular Targets and Cancer Therapeutics. Byoung Chul Cho discusses the trial and its clinical implications for patients with ROS1 positive NSCLC (one or two per cent of all lung cancer cases). Among the study patients treated at 150 hospitals around the world, some had never been treated with a ROS1 TKI, some had already been treated with one ROS1 TKI, some had been treated with a ROS1 TKI and platinum-based chemotherapy, and some had been treated with two different ROS TKIs. As of June 20, 2022, the primary efficacy population had included 71 TKI-naive patients and 56 TKI-pretreated patients with no prior chemotherapy. “In TKI-naïve patients repotrectinib showed a 78 per cent objective response rate (tumor reduction of at least 30 per cent) and the 12 months duration of response was 86 per cent,” said Cho after his late breaking session at the Symposium. In the patients who had no prior chemotherapy who had been treated with a previous-generation ROS1 TKI he said they also found a good response rate. “Repotrectinib showed a 37 per cent objective response rate with a six months duration of response [of] 79 per cent,” he said. A significant issue with ROS1 TKI treatment had been that patients usually developed the so-called G2032R resistance mutation that rendered further TKI therapy ineffective. “The G2032R resistance mutation is the most common resistance mechanism,” said Cho. “Repotrectinib showed objective response rate of 58 per cent in this population.” Anti mTrk activity Another putative advantage for the investigational agent in Trident-1 had been that it also inhibited mutated tropomyosin receptor kinase receptor (Trk: usually pronounced “track”) a molecular feature often found in association with ROS1. “So, in the Trident-1 trial we also evaluated the activity and safety of repotrectinib in m-Trk fusion-positive solid tumors in both TKI naïve and TKI pretreated populations,” Cho said. A phase one study by Besse and colleagues from Villejuif, France—working on Trident-1 in collaboration with Cho and others—had already found that repotrectinib demonstrated efficacy in TKI-naïve and TKI-pretreated patients and was generally well tolerated. https://aacrjournals.org/mct/article/20/12_Supplement/P02-01/675917/Abstract-P02-01-Repotrectinib-in-patients-with Brain metastases When Cho was asked about the impact of the new TKI on cranial metastases he said the drug had been effective. “CNS metastasis is one of the commonest sites of metastasis after progression on a ROS1 TKI. In this study we [observed] a very high intracranial activity of repotrectinib in both TKI naïve and TKI pre-treated populations.” Nearly 90 per cent of the small number of patients with measurable tumors in the brain not previously treated with a ROS1 TKI had intracranial objective responses (iORR). Just less than half of those already treated with one prior ROS1—and half of those treated with one prior ROS1 TKI and chemotherapy—had iORR. But none of the patients pre-treated with both chemotherapy and a TKI had responded. Cho said that repotrectinib had been generally well tolerated. “The most common side effects were low grade: grade one or two. The most common was low-grade dizziness. It occurred in about 60 per cent of patients,” he said. But despite this relatively high incidence of dizziness the incidence of treatment discontinuation had been low, he said—less than ten per cent. “With around 16 months median follow up, the median duration of response to repotrectinib treatment in TKI naïve patients has not yet been met. This is very meaningful, and a clear measure to utilize repotrectinib in the TKI naïve setting,” said Cho. “The number two message is: We also demonstrated a high response rate in TKI-pre-treated ROS1 positive lung cancer. And we also demonstrated the activity of repotrectinib in G2032R mutant ROS1 positive lung cancer,” he said. Strongest data He regarded the data as the strongest yet seen with a TKI in this setting. “In our study we demonstrated the potential role and value of repotrectinib in both TKI naïve and TKI pretreated ROS1 positive advanced stage NSCLC,” he said. For many patients with the ROS1 marker, Cho predicted an important role for repotrectinib in picking up the baton to take over from previous generation TKI therapy. “Because the current standard of care at the time of diagnosis of advanced stage ROS1 positive lung cancer is a ROS1 TKI such as crizotinib, or entractinib, so: After 15 or 20 month of progression-free survival the majority of patients experience disease progression due to acquired resistance. So, in the second line setting we [currently] only have cytotoxic chemotherapy. So, these data support the use of repotrectinib in the setting of resistance to prior ROS1 TKI in the first-line setting,” Cho said. “Our data suggest that repotrectinib could represent a potential new treatment option for patients with ROS1 positive NSCLC in both TKI naïve and TKI pre-treated populations,” he concluded. 230106 Byoung clip project PRODUCTION MASTER 720P230106 Byoung clip project PRODUCTION MASTER 720P Abstract P02-01: Repotrectinib in patients with NTRKfusion-positive advanced solid tumors: update from the registrational phase 2 TRIDENT-1 trial Benjamin Besse; Christina Baik; Christoph Springfeld; Alice Hervieu; Victor Moreno; Lyudmila Bazhenova; Jessica J. Lin; D. Ross Camidge; Benjamin Solomon; Vamsidhar Velcheti; Anthonie J. van der Wekken; Enriqueta Felip; Dipesh Uprety; Denise Trone; Shanna Stopatschinskaja; Byoung Chul Cho; Alexander Drilon ABSTRACT: Background: NTRK fusions drive a broad range of solid tumors. Two FDA approved TRK tyrosine kinase inhibitors (TKIs) have demonstrated efficacy in patients (pts) with NTRK fusion+ advanced solid tumors; however, emergent TRK solvent front (SF) and gatekeeper resistance mutations occur. Repotrectinib is a next-generation ROS1/TRK TKI with potency against wildtype and mutant forms of ROS1 and TRK. In preclinical studies, repotrectinib was more potent than larotrectinib, entrectinib, and selitrectinib against wildtype TRK, SF and gatekeeper mutations. Early interim data from the Phase 1/2 TRIDENT-1 trial led to Fast Track designation by the FDA for repotrectinib in TRK TKI-pretreated pts. This abstract is an updated analysis of this population and the first presentation of repotrectinib activity in TRK TKI-naïve pts. Methods: Pts with NTRKfusion+ advanced solid tumors were enrolled into the ongoing registrational Phase 2 TRIDENT-1 trial (NCT03093116). Pts with no prior TRK TKIs were enrolled into Expansion Cohort 5 (EXP-5) and pts who received up to 2 lines of prior TRK TKIs were enrolled into EXP-6. Prior chemotherapy and/or immunotherapy were allowed in both cohorts. The primary endpoint is cORR by Blinded Independent Central Review using RECIST v1.1. Results: As of efficacy data cutoff date of 28 July 2021, 8 pts in EXP-5 and 19 pts in EXP-6 had at least 2 post-baseline scans and were evaluable for efficacy analysis. Median age was 63 y (range 33–80) in EXP-5 and 50 y (range 23–81) in EXP-6; median number of prior lines of chemo/immunotherapy was 1 (range 0–2) in EXP-5 and 1 (range 0–4) in EXP-6. In EXP-6, 79% (15/19) of pts received 1 prior TRK TKI. Confirmed responses were reported by physician assessment. In EXP-5, cORR was 63% (5 of 8 pts; 95% CI: 24–91%) with DOR from 1.9+ to 7.4+ months (mo). In EXP-6, cORR was 47% (9 of 19 pts; 95% CI: 24–71%) with DOR from 1.9+ to 15.1 mo. In 10 pts enrolled in EXP-6 with a SF mutation, the cORR was 60% (6 of 10 pts; 95% CI: 26–88%). Median duration of treatment was 6.3 mo (range 0.9–13.4+) in EXP-5 and 8.1 mo (range 1.1–20.8) in EXP-6. An updated safety analysis for Phase 1 and Phase 2 (n=243) based on a data cut-off date of 4 May 2021 was conducted. Repotrectinib was generally well tolerated. Treatment-emergent adverse events (TEAEs) observed in ≥20% of patients were dizziness (62%), dysgeusia (43%), constipation (33%), dyspnea (30%), paresthesia (28%), anemia (26%), and fatigue (26%). The majority (77%) of dizziness TEAEs were Grade 1 and 4% were Grade 3; none of the dizziness events led to treatment discontinuation. Dose modifications remained infrequent (24% of pts had a dose reduction and 10% of pts discontinued study drug due to a TEAE). Conclusions: Repotrectinib is a next-generation ROS1 and TRK inhibitor. In an ongoing registrational Phase 2 trial, repotrectinib demonstrated efficacy in TRK TKI-naïve and TKI-pretreated pts and was generally well tolerated. Enrollment in the multi-cohort Phase 2 trial is ongoing. Citation Format: Benjamin Besse, Christina Baik, Christoph Springfeld, Alice Hervieu, Victor Moreno, Lyudmila Bazhenova, Jessica J. Lin, D. Ross Camidge, Benjamin Solomon, Vamsidhar Velcheti, Anthonie J. van der Wekken, Enriqueta Felip, Dipesh Uprety, Denise Trone, Shanna Stopatschinskaja, Byoung Chul Cho, Alexander Drilon. Repotrectinib in patients with NTRKfusion-positive advanced solid tumors: update from the registrational phase 2 TRIDENT-1 trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P02-01.

ARROS-1 Study Finds ROS1 Tyrosine Kinase Inhibitor Has Promise as a Tumor Agnostic Therapy BARCELONA, Spain—Findings from a study of a new investigational therapy targeting the ROS-1 receptor tyrosine kinase—mutated in some cancers—were reported at the 2022 EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics conference held in Barcelona. First author Medical Oncologist Alex Drilon MD, Chief of the Early Drug Development Service at Memorial Sloan-Kettering Cancer Center in New York, gave the Audio Journal of Oncology his take on the safety and preliminary clinical activity of NVL-520: described as a “highly selective ROS1 inhibitor” in patients with solid tumors—mainly non-small cell lung cancer (NSCLC). Patients selected for the study had gene rearrangements in the ROS-1 receptor tyrosine kinase. The aim was to test whether targeting gene fusions which are molecular driver of cancer could be more valid than individualising therapy to tumors of a specific organ. Text from symposium ABSTRACT 8: TITLE: Safety and preliminary clinical activity of NVL-520, a highly selective ROS1 inhibitor, in patients with advanced ROS1 fusion-positive solid tumors AUTHORS: A. Drilon1, B. Besse2, D.R. Camidge3, S.H.I. Ou4, S.M. Gadgeel5, M.L. Johnson6, A. Calles7, M.J. de Miguel8, A.I. Spira9, E. Felip10, G. Lopes11, A.J. van der Wekken12, Y.Y. Elamin13, J. Green14, Y. Sun15, J. Soglia16, V.W. Zhu14, J.J. Lin17 INSTITUTIONS: Memorial Sloan Kettering Cancer Center, Early Drug Development Service, New York, US, Institut Gustave Roussy, Cancer Medicine, Villejuif, France, University of Colorado Cancer Center- Anschutz Medical Campus, Thoracic Oncology, Aurora, USA, University of California Irvine Medical Center, Medicine, Orange, USA, Henry Ford Cancer Institute, Internal Medicine, Detroit, USA, Sarah Cannon Research Institute, Oncology, Nashville, USA, Hospital Universitario Gregorio Marañón, Medical Oncology, Madrid, Spain, START Madrid- HM CIOCC, Medical Oncology, Madrid, Spain, NEXT Oncology - Virginia Cancer Specialists, Thoracic and Phase I Program, Fairfax, USA, Hospital Vall d'Hebron, Oncology, Barcelona, USA, Sylvester Comprehensive Cancer Center- University of Miami Miller School of Medicine, Medical Oncology- Thoracic Medical Oncology, Miami, USA, University of Groningen and University Medical Centre Groningen, Pulmonary Oncology, Groningen, Netherlands, MD Anderson Cancer Center, Thoracic Head & Neck Medical Oncology, Houston, USA, Nuvalent Inc., Clinical Development, Cambridge, USA, Nuvalent Inc., Biology, Cambridge, USA, Nuvalent Inc., Translational Development, Cambridge, USA, Massachusetts General Hospital, Medicine, Boston, USA BACKGROUND: Oncogenic ROS1 fusions drive various malignancies, including 1-3% of non-small cell lung cancers (NSCLC). Rationally designed ROS1 tyrosine kinase inhibitors (TKIs) that surpass the limitations of FDA/EMA-approved (crizotinib/entrectinib) or other investigational agents are a medical need. The novel ROS1 TKI NVL-520 is highly selective and designed to avoid the neurologic toxicities associated with ROS1 TKIs that concurrently inhibit TRK (entrectinib/repotrectinib/taletrectinib). Furthermore, NVL-520 is brain-penetrant and targets a diverse array of ROS1 fusions and recalcitrant resistance mutations, including the ROS1 G2032R solvent-front mutation. MATERIALS AND METHODS: ARROS-1 (NCT05118789) is a global, tumor-agnostic, phase 1/2 trial of NVL-520. In the ongoing phase 1 dose escalation, patients are required to have a previously treated ROS1 fusion-positive solid tumor, including NSCLC treated with ≥1 prior ROS1 TKI. Primary objectives are to determine the recommended phase 2 dose (RP2D) and, if applicable, the maximum tolerated dose. Additional objectives include safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity. Response (RECIST v1.1) was investigator assessed. Data cut: June 13, 2022. RESULTS: Twenty patients (19 NSCLC, 1 pancreatic cancer) have received NVL-520 orally at dose levels of 25-100 mg once daily. Patients received a median of 3 (range: 1-9) prior anticancer therapies, including any ROS1 TKI (100%); investigational ROS1 TKI (85%, including lorlatinib in 55%, repotrectinib in 40%); ≥2 ROS1 TKIs (75%); any chemotherapy (80%); ≥2 lines of chemotherapy (50%). At baseline, 55% had CNS metastases and 45% had ROS1 G2032R. No dose-limiting toxicities (DLTs), dose reductions, or drug-related treatment discontinuations have been reported. All treatment-related adverse events (TRAEs) were grade 1. The only TRAE in >1 patient was nausea (n=2). NVL-520 PK analyses demonstrated dose-dependent exposure. Among 12 efficacy-evaluable patients with ROS1+ NSCLC treated at 25-75 mg QD, 6 confirmed partial responses (PRs) were achieved. Shrinkage or resolution of intracranial metastases were observed; no patients had intracranial progression. A PR was achieved in most (n=5/7) ROS1 G2032R-mutant cancers, including lorlatinib or repotrectinib pretreated tumors. Circulating tumor DNA analyses showed reductions of ROS1 variant allele frequency. The RP2D has not been identified and dose escalation continues. CONCLUSIONS: NVL-520 has been well-tolerated up to 100 mg daily with favorable pharmacokinetics. Activity has been demonstrated in heavily pretreated patients (of whom 70% received ≥2 prior ROS1 TKIs plus chemotherapy), including those with brain metastases and the G2032R mutation.

Pan-AKT Inhibitor Tumor Agnostic Targeting was Safe and Effective in Phase One Study BARCELONA, Spain—Patients with solid tumors expressing mutated AKT oncogenes responded to therapy with a pan-AKT inhibitor ipatasertib in a phase one study reported at the 2022 EORTC—NCI—AACR symposium on Molecular Targets and Cancer Therapeutics. Nearly a quarter of the patients treated with the AKT blocker had their tumors shrink. These included patients with breast, endometrial cancer and salivary gland cancers. And tumors remained stable in just over half of the remaining patients. The first author at the Barcelona symposium, Kevin Kalinsky MD MS, Director of Breast Medical Oncology, Emory University at Winship Cancer Institute, Hematology and Medical Oncology, Atlanta, USA talks with Peter Goodwin.

BARCELONA, Spain—Although having a mutated MYC molecule is a distinguishing molecular factor in many solid tumors it has been considered “undruggable” — having a shortage of potential and actual mechanisms for cancer inhibition. But it now looks as though MYC could be a viable target for cancer drugs. A phase one study of a “pan-MYC inhibitor” OMO 103 has made promising findings in both safety and efficacy according to a findings given to the 2022 EORTC-NCI-AACR symposium. First author of the study, Elena Garralda MD, Head of Early Drug Development Unit at Vall d'Hebron Hospital in Barcelona gave the Audio Journal of Oncology’s Peter Goodwin the details:

New Molecular Drug has Clinical Activity in Hepatocellular Carcinoma Interview with: Maria Reig MD PhD, Professor and Head of the Barcelona Clinic Liver Cancer (BCLC) Unit, Hospital Clinic Barcelona at Barcelona University, Spain. BARCELONA, Spain—A phase one study of new drug targeting the monopolar spindle 1 enzyme was found to be safe—with reversible neutropenia as the commonest side effect—and to have clinical activity in patients with relapsed or refractory unresectable hepatocellular carcinoma (HCC). Maria Reig MD PhD announced the study findings at the 2022 European Organisation for Research and Treatment of Cancer-National Cancer Institute-American Association for Cancer Research (EORTC-NCI-AACR) Symposium on Molecular Targets and Cancer Therapeutics. She gave the Audio Journal of Oncology’s Peter Goodwin more details of this new type of treatment, that she says works in a very different way from the current options for treating liver cancer.

PARIS, France—Patients who had cell therapy as second-line treatment for their advanced melanoma lived twice as long without disease progression compared with those who merely continued with pure immunotherapy. This finding came from a phase three randomized study reported at the 2022 Congress of the European Society for Medical Oncology (ESMO) by Amsterdam-based researchers, who said some of the patients may have been cured. The second-line cell therapy consisted of re-infusion of autologous tumor infiltrating cells that had been harvested from patients own tumors and expanded ex-vivo. This followed initial immunotherapy with the checkpoint inhibitor ipilimumab. The Audio Journal of Oncology hears from first author John B. Haanen MD PhD, Leader of Immunotherapy Research and Consultant in Medical Oncology at the Netherlands Cancer Institute in Amsterdam, in discussion with Peter Goodwin.

BARCELONA, Spain—Next generation sequencing is now an essential part of care for glioma in adults, according to research on BRAF targeting as treatment for this disease reported at the 2022 EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium. Karisa Schreck MD PhD, from Johns Hopkins Hospital, Baltimore, Maryland in the USA talked with Peter Goodwin to discuss her team’s findings from a study looking at the relationship between BRAF oncogene mutations and anti-BRAF therapy outcomes in comparison with pediatric glioma treatment, for which BRAF targeting is already data driven. She tells the Audio Journal of Oncology how the findings have brought clarity to therapy decision-making with adult patients who have glioma and test positive for BRAF oncogene mutations—and that some of them could potentially be treated with existing BRAF-targeted drugs that have already been licensed for use in other BRAF-driven cancers.

PARIS, France—the open-label international phase three randomized IPSOS study reported at the 2022 European Society for Medical Oncology congress that patients with non-small cell lung cancer who were not fit enough to be recommended standard platinum doublet chemotherapy lived longer when treated with the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab than patients in a comparison group who received a single-agent chemotherapy regimen. https://cslide.ctimeetingtech.com/esmo2022/attendee/confcal/session/calendar/2022-09-12 Faced with the reality that a large unfit population of patients with non-small cell lung cancer cannot be recommended standard treatment (and who typically received single agent chemotherapy, or best supportive car) Siow Ming Lee, PhD FRCP, IPSOS Trial Chair, Professor of Medical Oncology and Consultant Medical Oncologist at University College London Hospital, told the Audio Journal of Oncology’s Peter Goodwin how they investigated the use of single-agent atezolizumab checkpoint inhibition immunotherapy in patients deliberately chosen for their low performance status who had no proven options for initial treatment.

HEIDELBERG, Germany—André Pfob, Clinical Research Assistant from the University Breast Unit at Heidelberg University Hospital, Germany tells the Audio Journal of Oncology’s correspondent Peter Goodwin about the machine learning techniques his group has been using to help identify patients who can be spared further treatment after neo-adjuvant therapy. REFERENCE: Annals of Surgery https://journals.lww.com/annalsofsurgery/Abstract/9000/Towards_Patient_Centered_Decision_Making_in_Breast.93648.aspx ABSTRACT: Objective: We developed, tested, and validated machine learning algorithms to predict individual patient-reported outcomes at 1-year follow-up to facilitate individualized, patient-centered decision-making for women with breast cancer. Summary Background Data: Satisfaction with breasts is a key outcome for women undergoing cancer-related mastectomy and reconstruction. Current decision-making relies on group-level evidence which may lead to sub-optimal treatment recommendations for individuals. Methods: We trained, tested, and validated three machine learning algorithms using data from 1921 women undergoing cancer-related mastectomy and reconstruction conducted at eleven study sites in North America from 2011 to 2016. Data from 1921 women undergoing cancer-related mastectomy and reconstruction were collected prior to surgery and at 1-year follow-up. Data from 10 of the 11 sites was randomly split into training and test samples (2:1 ratio) to develop and test three algorithms (logistic regression with elastic net penalty, Extreme Gradient Boosting tree, and neural network) which were further validated using the additional site's data. Accuracy and area-under-the-receiver-operating-characteristics-curve (AUC) to predict clinically-significant changes in satisfaction with breasts at 1-year follow-up using the validated BREAST-Q were the outcome measures. Results: The three algorithms performed equally well when predicting both improved or decreased satisfaction with breasts in both testing and validation datasets: For the testing dataset median accuracy= 0.81 (range 0.73–0.83), median AUC= 0.84 (range 0.78–0.85). For the validation dataset median accuracy= 0.83 (range 0.81–0.84), median AUC= 0.86 (range 0.83–0.89). Conclusion: Individual patient-reported outcomes can be accurately predicted using machine learning algorithms, which may facilitate individualized, patient-centered decision-making for women undergoing breast cancer treatment.

PARIS, France—Long remissions and “potential cures” were reported at the 2022 Annual Meeting of the European Society for Medical Oncology (ESMO) in patients with newly diagnosed advanced ovarian cancers expressing the BRCA mutation who were treated with the poly ADP ribose polymerase (PARP) inhibitor olaparib after initial therapy. Two thirds of women were alive seven years later in the phase three SOLO1 trial of olaparib maintenance therapy compared with placebo. The lead author of the study, Paul DiSilvestro MD, Professor in the Department of Obstetrics & Gynecology and Director of the Program of Women's Oncology at Women & Infants Hospital, Brown University in Providence Rhode Island, gives the details to the Audio Journal of Oncology’s Peter Goodwin.

ATLANTA, USA—A new research method has elucidated cellular processes (involving mutated TP53 oncogene) that can convert a relatively benign myeloproliferative neoplasm into acute myeloid leukemia. Findings from Oxford University in the UK (using the novel genetic sequencing tool called: single cell multi omics) were reported at the American Society of Hematology (ASH) 2021 Annual Meeting Plenary Session, by Oxford scientist Alba Rodriguez-Meira DPhil, PhD, from the Weatherall Institute of Molecular Medicine in Oxford—winner of an ASH Abstract Achievement Award. She discusses her award-winning research with Audio Journal of Oncology reporter Peter Goodwin. In an inspiring oral presentation at ASH, Alba Rodriguez-Meira explained how her group’s research on the TP53 gene had made it possible to analyze the genome of a large number of individual cells from a relatively small sample of patients and healthy controls. https://ash.confex.com/ash/2021/webprogram/Paper150191.html The study findings should provide predictive, prognostic and therapeutic tools that could improve otherwise dismal outcomes in subgroups of patients with hematologic malignancies. “Our single cell multi omics analysis, coupled with in-vitro and in-vivo analysis, has allowed us to depict a model of TP53 -mediated transformation in myeloproliferative neoplasms in which inflammatory signaling leads to suppression of wild-type and MPN cells while giving a fitness advantage to TP53 [mutated] cells with leukemic stem-cell properties. From our study we hope to find this is applicable to many other cancer types,” said Rodriguez-Meira at the ASH session. Single-cell multi omics analysis in a small patient cohort can theoretically be used to derive the gene signature that is highly relevant in much larger patient cohorts.

PARIS, France—Particulate air pollution was identified as a key step in malignant transformation from benign DNA to non-small cell lung cancer according to a report delivered to the 2022 Congress of the European Society for Medical Oncology (ESMO). Charles Swanton FRCP BSc PhD, Professor and Senior Group Leader of the Francis Crick Institute, Consultant Oncologist at University College London Hospital specializing in Thoracic Oncology and ESMO Scientific Co-Chair, told the Audio Journal of Oncology that prevention was better than cure wherever possible, and that the oncogenic mechanisms his group’s research had uncovered held important keys to reducing the cancer burden globally. https://cslide.ctimeetingtech.com/esmo2022/attendee/confcal/session/calendar/2022-09-09 Swanton’s group had investigated the relationship between air pollution and lung cancer in never smokers. “We’ve tried to establish how air pollution causes lung cancer,” he told OT. “Through a series of steps involving animal models and human analyses we’ve found that air pollution results in the release of a cytokine called: interleukin 1-beta from epithelial cells in the lung, that generates and transforms cells with pre-existing mutations—that occur normally due to aging—into tumor cells.” He discussed his findings during the ESMO congress in Paris with the Audio Journal of Oncology’s Peter Goodwin.

UK & NETHERLANDS—Following the the AJO Podcast interview with Professor Harry de Koning MD PhD, from the Erasmus University in Rotterdam, who discussed his research published in the New England Journal of Medicine that supports the widespread introduction of computed tomographic (CT) screening to detect lung cancer, this edition of the podcast hears from Professor David Baldwin MD, from Nottingham England, who comments on the clinical implications of these findings. ROTTERDAM—Erasmus University Medical Center—The New England Journal of Medicine paper has confirmed the viability of computed tomographic (CT) screening for detecting cases of lung cancer early in high-risk individuals—namely those who smoke heavily and or have done so for decades. A big new randomized study has confirmed that many deaths from lung cancer could be prevented by continuing and augmenting the global roll-out of computed tomographic (CT) screening for long-term heavy smokers. This follows important findings from the USA in which CT scanning was compared with chest X-ray for lung cancer detection that also came to the conclusion that many deaths from lung cancer can be prevented. Now that the professional community has confirmation from a separate study in a different continent with an alternative method of assessing CT (volumetric) the case for using CT screening for lung cancer may be considered to be convincing. The Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON) population-based randomized controlled trial published in the New England Journal of Medicine emphasises the pivotal importance of addressing the epidemic of lung cancer which even today accounts for nearly a fifth of all cancer deaths worldwide. https://www.nejm.org/doi/full/10.1056/NEJMoa1911793 In the Audio Journal of Oncology podcast first author Harry de Koning, MD PhD, Professor of Public Health at Erasmus MC University Medical Centre in Rotterdam, the Netherlands, told reporter Peter Goodwin how a 24 per cent reduction in lung cancer mortality was found among men (after 10 years follow up) in the screening arm as compared to the control arm. Women did even better.  Koning makes the case for global adoption of CT scanning as a key method of reducing cancer deaths, which he says can be done at an affordable cost. In this interview David Baldwin MD puts the research into global focus holding out the prospect for preventing deaths from lung cancer.        

Second Study Confirms Lung Cancer CT Screening Cuts Deaths NETHERLANDS—Erasmus University Medical Center, Rotterdam—Research published in the New England Journal of Medicine has confirmed the viability of computed tomographic (CT) screening for detecting cases of lung cancer early in high-risk individuals—namely those who smoke heavily and or have done so for decades. A big new randomized study has confirmed that many deaths from lung cancer could be prevented by continuing and augmenting the global roll-out of computed tomographic (CT) screening for long-term heavy smokers. This follows important findings from the USA in which CT scanning was compared with chest X-ray for lung cancer detection that also came to the conclusion that many deaths from lung cancer can be prevented. Now that the professional community has confirmation from a separate study in a different continent with an alternative method of assessing CT (volumetric) the case for using CT screening for lung cancer may be considered to be convincing. The Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON) population-based randomized controlled trial published in the New England Journal of Medicine emphasises the pivotal importance of addressing the epidemic of lung cancer which even today accounts for nearly a fifth of all cancer deaths worldwide. https://www.nejm.org/doi/full/10.1056/NEJMoa1911793 In the Audio Journal of Oncology podcast first author Harry de Koning, MD PhD, Professor of Public Health at Erasmus MC University Medical Centre in Rotterdam, the Netherlands, tells reporter Peter Goodwin how a 24 per cent reduction in lung cancer mortality was found among men (after 10 years follow up) in the screening arm as compared to the control arm. Women did even better.  Koning makes the case for global adoption of CT scanning as a key method of reducing cancer deaths, which he says can be done at an affordable cost.    

&nbsp; <strong>Audio Journal of Oncology</strong> &nbsp; SAN DIEGO—The first-line treatment of choice for older patients with chronic lymphocytic leukemia (CLL) should now be single agent ibrutinib according to conclusions drawn from the Alliance North American Intergroup Study A041202 reported at the 2018 Annual Meeting of the American Society of Hematology (ASH). https://ashpublications.org/blood/article/132/Supplement%201/6/265980/Ibrutinib-Alone-or-in-Combination-with-Rituximab “Unless there is a good reason why patients should be on bendamustine plus rituximab (meaning that they are inappropriate for ibrutinib) ibrutinib is the most reasonable choice for front line therapy,” said lead study author Jennifer A. Woyach MD, an associate professor at the Ohio State University Comprehensive Cancer Center of Ohio State University in Columbus, OH. &nbsp; Woyach told a press briefing that when they randomized patients “one to one to one” between three options for treatment: bendamustine  plus rituximab, ibrutinib given as a single agent daily until disease progression, or ibrutinib given in combination with rituximab, there was a clear superiority for the ibrutinib-containing regimens. &nbsp; “Progression-free survival was longer in the two ibrutinib-containing arms than in the bendamustine plus rituximab arm. And there was no difference in the progression-free survival between the two ibrutinib-containing arms.” &nbsp; Woyach said they had conducted the trial to try to define the most optimal therapy for older patients with CLL.  “We know that those patients are under-represented in many of our clinical trials,” she said. “So it’s hard to know whether much of our therapy can be extrapolated to this older patient group.” &nbsp; Since ibrutinib had already been compared in earlier studies to chlorambucil in the phase three setting (leading to its FDA approval) it had never been compared to a chemo-immuntherapy regimen used in the CLL, she said.  “So we tried to pick the most effective immunochemotherapy regimen for older patients—which is bendamustine plus rituximab—so that there would really be an effective comparator.” &nbsp; In Woyach’s data there was no difference in progression free survival between patients treated with ibrutinib alone and those who received ibrutinib plus rituximab. “So ibrutinib alone would be the standard,” she said. &nbsp; When she was asked about her choice of bendamustine plus rituximab as the comparator treatment she said there had been two reasons.  Of the two chemo-immunotherapy regimens used in older patients (bendamustine plus rituximab and chlorambucil plus obinutuzumab) at the time the study was designed only the bendamustine regimen had been FDA approved, she said. “[But] regardless of that bendamistine plus rituximab does have superior progression free survival when you look at comparing across studies,” said Woyach. &nbsp; Her interpretation of the study results? “For most patients this tells us that ibrutinib is the most effective drug for front-line CLL,” she said. &nbsp; &nbsp;