In June, HRW’s OR:BIT (Oncology Research Business Insights Team) attended the 25th European Hematology Association (EHA) Congress, which brings together healthcare professionals with a passion for haematology. The congress covered a wide range of haematology areas, including stem cell physiology, leukaemia, lymphoma, myeloma and many more! The event, originally planned to take place in Frankfurt, Germany, was instead held virtually for the first time in EHA’s history, from June 11-14 – an experience that we are now becoming accustomed to, following our virtual ASCO congress attendance. A few weeks on, OR:BIT member Gemma McConnell (Research Director) reflects on the key data that emerged from the event… A new standard of care in R/R cHL: Positive data from KEYNOTE-204 Although data from KEYNOTE-204 had previously been presented earlier this year, at the annual ASCO conference, given that the results look set to be practice-changing, late-breaking abstract LB2600 was deemed worthy of a prime position in the Presidential Symposium session at EHA25.1 Professor Zinzani presented KEYNOTE-204, in which patients with relapsed/refractory classical Hodgkin lymphoma (R/R cHL), who had relapsed after autologous stem cell transplant (auto-SCT) or were ineligible for auto-SCT and had failed one prior line of treatment, were treated with anti-PD-1 immune checkpoint inhibitor pembrolizumab monotherapy (Merck & Co.’s Keytruda) or the antibody-drug conjugate targeting CD30, brentuximab vedotin (Seattle Genetics and Takeda’s Adcetris), the current standard of care (SOC) for cHL relapsing after SCT. Patients treated with pembrolizumab showed a statistically significant and clinically meaningful improvement in PFS, one of the trial’s dual primary endpoints, compared with brentuximab vedotin (13.2 vs 8.3 months; HR: 0.65; P = 0.00271), with no new safety signals reported. The PFS benefit was across key subgroups of patients with R/R cHL, including those with primary refractory disease or those who did not receive prior autologous SCT. Furthermore, higher response rates and more durable responses were associated with pembrolizumab vs brentuximab vedotin (ORR of 65.6% vs 54.2%; DoR of 20.7 vs 13.8 months). Pembrolizumab has been approved for use in R/R cHL, in the US and Europe, since 2017, based on the Phase II KEYNOTE-087 trial, as a later line treatment— relapsing after three or more lines of treatment in the US and following failure of brentuximab vedotin in Europe. KEYNOTE-204 will continue to evaluate the trial’s other dual primary endpoint, overall survival: however, the data strongly support the earlier use of pembrolizumab in R/R setting. Professor Zinzani concluded that “Pembrolizumab should be considered the preferred treatment option and standard of care for the treatment of R/R cHL in patients who have relapsed after auto-SCT or are ineligible for auto-SCT” New treatment paradigm in AML: Confirmative data from VIALE-A In the late-breaking oral session on Sunday 14th June, Dr DiNardo presented, for the first time, data from the Phase III VIALE-A trial, a randomized double-blinded trial evaluating the combination of azacytidine and venetoclax (AbbVie/Roche’s Venclexta/Venclyxto), compared to azacytidine plus a placebo, in treatment-naïve AML patients ineligible for intensive induction chemotherapy.2 The addition of venetoclax significantly improved overall survival, by ~5 months compared to azacitidine alone (14.7 vs 9.6 months; HR: 0.66; p<0.001). The venetoclax combination also significantly improved rates of composite complete remission (CR + CRi) (66% vs 28%; p<0.001) and was associated with responses that occurred more quickly, were more durable, and with increased incidence of transfusion independence. Older patients with newly diagnosed AML (aged 75 years or over), or those that have significant comorbidities, are often unable to tolerate intensive induction chemotherapy, with alternatives such as low-dose hypomethylating agents or cytarabine associated with inferior outcomes. In November 2018, the FDA granted accelerated approval to venetoclax in combination with azacitidine, or decitabine, or low-dose cytarabine (LDAC) for the treatment of newly diagnosed AML in adults aged 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. Earlier in the year, it was reported that the Phase III VIALE-C trial, of venetoclax in combination with LDAC vs LDAC plus placebo did not meet its primary endpoint. However, the positive data from VIALE-A will be used to support the full approval of venetoclax in combination with azacytidine, with the aim of establishing this combination as a new standard of care for older patients with AML. Promising treatment in multiple myeloma: Promising data from IKEMA Also in the late-breaking abstract oral session on Sunday 14th June, data from the Phase III IKEMA trial were presented, for the first time, by Professor Morea. IKEMA is evaluating isatuximab (Sanofi’s Sarclisa), a CD38-targeting monoclonal antibody, in combination with carfilzomib (Amgen’s Kyprolis) and dexamethasone (Isa-Kd) vs carfilzomib and dexamethasone alone (Kd) in relapsed multiple myeloma (MM) following 1-3 prior lines of treatments.3 It was stressed that the comparator Kd arm of the study performed well, with a mPFS of 19.15 months (in-line with that reported in the Phase III ENDEAVOR study), however a clear benefit was seen with the addition of isatuximab, reducing risk of disease progression or death by 47% (HR 0.531; p=0.0007), with the mPFS (the trial’s primary endpoint) not yet reached at the time of the interim analysis. Positively, a PFS benefit was observed across all subgroups. Furthermore, the isatuximab combination delivered considerable depth of response, a secondary endpoint in the trial, with undetectable levels of MM; the rate of minimal residual disease (MRD)-negativity was almost 30% of patients in the Isa-Kd arm vs 13% of patients treated with Kd. Time to next treatment was also significantly delayed with the addition of isatuximab (HR 0.566). At this interim analysis, there was no separation of the OS curves, however data are still immature. In terms of safety, there were higher rates of grade 3/4 adverse events with the triplet combination (76.8% vs. 67.2%), however the number of fatal events was low and comparable between arms and there was no increase in the rate of treatment discontinuation with the addition of isatuximab. Infusion-related treatment reactions with isatuximab were only reported in the first cycle of treatment and was grade 1 or 2 in severity, indicating the triplet combination is feasible with manageable toxicity. Isatuximab is currently approved in combination with pomalidomide and dexamethasone, for the treatment of R/R MM following at least two prior therapies. Data from IKEMA will form the basis for global regulatory submissions for later this year, allowing for earlier use of isatuximab, in combination with Kd, for R/R MM. Strong presence for CAR T-cell therapy CAR T-cell therapy continues to make waves, and had a strong presence at EHA25, with a Special Session dedicated to CAR T, looking at the future of CAR T and real-life experiences, along with presentation of data from ongoing CAR T trials, such as ZUMA-5, evaluating axicabtagene ciloleucel (Kite/Gilead’s Yescarta) in R/R non-Hodgkin lymphoma.4, 5, 6 More is being done to try and leverage CAR T’s strengths by addressing the therapy’s weaknesses. Well known limitations associated with CAR T continue to frustrate, such as varying responses in liquid tumours (duration of response), T-cell exhaustion, culturing difficulties, and difficulty in ‘killing’ tumour cells that escape T-cell detection through loss or downregulation of the target antigen. However, with around 500 trials in CAR T currently ongoing, working to find solutions to these challenges, the hope is that CAR T will maximise its potential in haematological malignancies, with strategies also in place to develop CAR T-cell therapy for solid tumours. There are high aspirations for fourth generation CAR T-cell therapy, which look to improve CAR (chimeric antigen receptor) efficacy, through a ‘mix and match’ approach of CAR expressors to direct recognition of multiple antigens, and through enhancing bystander immunity. Increasing CAR T-cell sensitivity is also a focus, with methods to off-set T-cell exhaustion and low levels of CAR antigen expression on tumour cells of interest (HIT CAR was fleetingly and intriguingly mentioned as a promising future direction by Dr. M Sadelain)5. There are many other avenues being explored for CAR T, such as the use of combination therapies (such as using gamma radiation as a conditioning regiment for CAR T), target selection (cancers with low mutation burden are of particular interest for CAR T), and cellular substrates (exploring CAR T-cell sources beyond autologous T-cells, to allogeneic and even in vitro generation of CAR T-cells)…the future is exciting for CAR T! Final thoughts Attending oncology conferences is a real privilege and, for me, a humbling experience to witness the coming together of academia, Pharma, healthcare professionals, patients and support groups (among others!) to drive advances in cancer care. While I missed not physically being at the EHA25 event…soaking up the atmosphere, being surrounded by a host of inspirational people, marvelling at the grandeur of the Exhibition Hall, and having the chance to bump into friends, ex-colleagues and clients, the virtual EHA25 event was well organised, had easy navigable content, and offered increased flexibility. As expected, EHA25 has fuelled HRW’s oncology/haematology interest and furthered our knowledge, helping us to better understand our clients’ needs and importantly offer solutions. HRW’s OR:BIT will continue to monitor the latest oncology developments and we look forward to attending ESMO in a couple months’ time! Get in touch to find out more about our capabilities within the oncology space. By Gemma McConnell References EHA25 Abstract: #LB2600 Phase 3, Randomized, Open-Label Study of Pembrolizumab Versus Brentuximab Vedotin for Treatment of Relapsed or Refractory Classical Hodgkin Lymphoma: KEYNOTE-204. Presenter: Dr Pier Luigi Zinzani EHA25 Abstract: #LB2601 VIALE-A: A Randomized, Double-blind, Placebo-Controlled Study of Venetoclax with Azacitidine vs Azacitidine in Treatment-naïve Patients with Acute Myeloid Leukemia Ineligible for Intensive Chemotherapy. Presenter: Dr Courtney D. DiNardo EHA25 Abstract: #LB2603. Isatuximab plus Carfilzomib and dexamethasone vs Carfilzomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma (IKEMA): Interim Analysis of a Phase 3, Randomized, Open-Label Study. Presenter: Prof. Philippe Moreau EHA25 Abstract: S287. Interim Analysis of ZUMA-5: A phase II study of axicabtagene ciloleucel (axi-cel) in patients (pts) with relapsed/refractory indolent non-Hodgkin lymphoma (R/R iNHL). Presenter: Prof. Caron A. Jacobson Oral Presentation #p291-1. The future of CAR T. Presenter: Dr. Michel Sadelain Oral Presentation #p291-2. Real life CAR T treatment. Presenter: Prof. Catherine Thieblemont Apply Now!