A multitude of presentations were available to attendees at the 2022 ASCO Annual Meeting, including hundreds in the hematologic malignancies tracks. In addition to coverage in The ASCO Post of the major news stories at the meeting, here we offer summaries of additional studies of special interest in hematology—one study in chronic myeloid leukemia and two in follicular lymphoma.
Asciminib in Chronic-Phase Chronic Myeloid Leukemia
Asciminib achieved more major molecular responses compared with bosutinib in patients with chronic myeloid leukemia in chronic phase (CML-CP), according to an updated analysis of results of the phase III ASCEMBL trial.1
With 96 weeks of follow-up, these results demonstrate that asciminib provides long-term benefit in adults with previously treated CML-CP. The rate of major molecular response at week 96, a key secondary endpoint, was more than doubled in patients who received asciminib compared with bosutinib: 37.6% vs 15.8%, respectively.
Over time, asciminib also attained deeper molecular response rates—defined as greater reductions in BCR::ABL1 transcript levels—vs bosutinib. At week 96, the 4-log reduction (MR4) rate (international standard ratio [BCR::ABL1IS] ≤ 0.01%) was 17.2% in the asciminib group compared with 10.5% in the bosutinib group. The 4.5-log reduction (MR4.5) rate (BCR::ABL1IS ≤ 0.0032%) was 10.8% with asciminib vs 5.3% with bosutinib.
Jorge E. Cortes, MD
“The primary analysis found a similar benefit of asciminib compared with bosutinib at 24 weeks and at 48 weeks, and the difference has actually increased in favor of asciminib at the 96-week time point,” said lead author Jorge E. Cortes, MD, Director of the Georgia Cancer Center, Augusta, Georgia. “We, of course, care about seeing deeper molecular responses. These patients are very heavily pretreated, and the immediate outcome is cytogenetic response and major molecular response. But it is gratifying to see that we are starting to see deep molecular responses, and again, in that category there is a benefit for asciminib.”
Dr. Cortes added: “These results continue to support the use of asciminib as a new CML therapy, with the potential to transform the standard of care.”
ASCEMBL Details
ASCEMBL enrolled patients who had CML-CP and treatment failure on or intolerance to their most recent tyrosine kinase inhibitor. Those with tyrosine kinase inhibitor intolerance were required to have BCR::ABL1IS > 0.1% at baseline. Patients with T3151 or V299L point mutations were not eligible for enrollment. Patients were stratified by major cytogenetic response status at baseline (yes vs no).
A total of 233 patients were randomly assigned 2:1 to receive asciminib at 40 mg twice daily (n = 157) or bosutinib at 500 mg once daily (n = 76). The median duration of follow-up was 2.3 years from randomization to last contact date. The median duration of treatment exposure was 23.7 months for asciminib vs 7 months for bosutinib.
Subgroup analyses showed that the benefit of asciminib was consistent across all prespecified subgroups. The probability of maintaining a major molecular response for at least 72 weeks was 96.7% for asciminib compared with 92.9% with bosutinib. At the time of the analysis, the median duration of major molecular response was not reached for either arm. The probability of maintaining MR4 was about 95% in both arms.
The median time to treatment failure was 24 months for asciminib vs 6 months for bosutinib. The rate of freedom from treatment failure at 2 years was 50.6% vs 18.9%, respectively.
Treatment discontinuations due to adverse effects remained low with asciminib across the duration of the trial. At 96 weeks, treatment discontinuation rates due to adverse events were 7% with asciminib compared with 25% with bosutinib. The most frequently cited reason for treatment discontinuation was lack of efficacy (24.2% vs 35.5%, respectively).
The most common grade 3 or higher adverse events for asciminib vs bosutinib were thrombocytopenia (22.4% vs 9.2%), neutropenia (19.9% vs 15.8%), diarrhea (0% vs 10.5%), and increased alanine aminotransferase (0.6% vs 14.5%). Arterial occlusive events, an adverse event of concern, were not increased over time in patients treated with asciminib. The exposure-adjusted rate of such events (per 100 patient-years) was 3.0 and 1.4, respectively, for asciminib and boustinib.
Asciminib is unique in that it inhibits the ABL1 kinase activity of BCR-ABL1 by targeting the ABL myristoyl pocket. It is approved by the U.S. Food and Drug Administration for the treatment of patients with Philadelphia chromosome (Ph)-positive CML-CP previously treated with at least two tyrosine kinase inhibitors and for adults with Ph-positive CML-CP with a T315I mutation.
Zanubrutinib Plus Obinutuzumab in Relapsed or Refractory Follicular Lymphoma
The addition of zanubrutinib to obinutuzumab improved the overall response rate, overall survival, and progression-free survival compared with obinutuzumab alone in patients with relapsed or refractory follicular lymphoma (FL), according to findings from the phase II ROSEWOOD trial.2 No unexpected safety findings emerged during the trial.
At a median follow-up of 12.5 months, the median progression-free survival rate was 27.4 months in the zanubrutinib-plus-obinutuzumab arm vs 11.2 months in the obinutuzumab monotherapy arm (P = .004). The 18-month overall survival rate was 85.4% vs 72.6%, respectively, although the study was not powered to detect a difference in overall survival.
Pier Luigi Zinzani, MD, PhD
Overall response rate (the primary endpoint) was 68.3% with zanubrutinib plus obinutuzumab vs 45.8% with obinutuzumab alone (P = .0017), with a complete response rate of 37.2% vs 19.4%, respectively (P = .0083).
“The combination of zanubrutinib plus obinutuzumab has a favorable benefit-risk profile and represents a potential combination therapy for patients with relapsed/refractory follicular lymphoma,” said lead author Pier Luigi Zinzani, MD, PhD, of the Institute of Hematology, “L. e A. Seràgnoli,” University of Bologna, Italy. Dr. Zinzani pointed out that approved treatment options for relapsed/refractory FL are limited and associated with significant toxicities.
ROSEWOOD Details
The ROSEWOOd trial enrolled patients with relapsed or refractory FL who had received two or more prior systemic treatments, including an anti-CD20 antibody and an alkylator-based combination therapy. A total of 217 patients were randomly assigned 2:1 to receive either zanubrutinib plus obinutuzumab or obinutuzumab monotherapy. Obinutuzumab was given in both arms on days 1, 8, and 15 of cycle 1; day 1 of cycles 2 through 6; and then every 8 weeks (up to 20 doses maximum). Zanubrutinib was administered at 160 mg twice daily until progressive disease or unacceptable toxicity.
Patients with confirmed progressive disease or no response at 12 months in the obinutuzumab arm were allowed to cross over to the combination regimen. The primary analysis cutoff was October 8, 2021. In the combination arm, 50% of patients were still on treatment at data cutoff. In the obinutuzumab arm, 26% of patients were still on treatment, with the major reason for discontinuation being disease progression followed by crossover to combination therapy.
The median number of prior lines of therapy was three in each treatment arm, and about one-quarter of patients in each arm had received three or more prior lines. Approximately one-third of patients (34.5%) in the combination arm and 40.3% in the obinutuzumab monotherapy arm had an elevated level of lactate dehydrogenase at screening. Approximately one-half of patients in each arm were refractory to rituximab.
In a subgroup analysis of overall response rate, zanubrutinib plus obinutuzumab was superior to obinutuzumab alone across subgroups. The 18-month response rate was 70.9% in the combination therapy arm and 54.6% in the obinutuzumab-alone arm.
Investigator-assessed overall response rate after crossover was an exploratory endpoint. For 29 patients who crossed over to zanubrutinib plus obinutuzumab from obinutuzumab alone, the overall response rate was 24.1%.
The median time to next antilymphoma treatment was not reached in the zanubrutinib-plus-obinutuzumab arm vs 12.1 months in the obinutuzumab-alone arm ( P < .0001).
Epcoritamab Plus Rituximab/Lenalidomide in Relapsed/Refractory FL
The addition of the bispecific antibody epcoritamab to treatment with rituximab and lenalidomide (R2) achieved a 100% response rate, with a low incidence of low-grade cytokine-release syndrome in patients with relapsed/refractory follicular lymphoma, according to an analysis of arm 2a of the EPCORE NHL-2 trial.3
All of the 28 evaluable patients in arm 2a achieved a response to treatment with the triplet regimen at any time point, and a complete metabolic response was achieved in 96% of them; the one remaining patient achieved a partial metabolic response. About 93% of patients maintained a response at 6 weeks, and the other 7% had stable disease.
Lorenzo Falchi, MD
“Epcoritamab with [rituximab/lenalidomide] showed encouraging results, with all patients in arm 2a achieving a response, and in most, a complete response,” said lead author Lorenzo Falchi, MD, a medical oncologist in the Lymphoma Service at Memorial Sloan Kettering Cancer Center. According to Dr. Falchi and coauthors, these updated data support further exploration of epcoritamab plus rituximab/lenalidomide in patients with relapsed/refractory FL.
Epcoritamab is a subcutaneously administered bispecific antibody that binds to CD3 on T cells and CD20 on B cells. In a previous phase I/II clinical trial, epcoritamab monotherapy at 48 mg produced an 88% overall response rate among 68 evaluable patients with heavily pretreated B-cell non-Hodgkin lymphoma and a complete response rate of 45%.4
EPCORE NHL-2 Details
The ongoing open-label EPCORE NHL-2 study is evaluating the combination of epcoritamab and several other agents for the treatment of B-cell non-Hodgkin lymphoma. Arm 2 of the trial focused on the triplet regimen of rituximab and lenalidomide with epcoritamab, administered at two different schedules in the two expansion cohorts. In the dose-escalation cohort, patients received step-up dosing of epcoritamab at 24 mg (n = 3) or 48 mg (n = 3) weekly for the first three cycles, then every 2 weeks for the next six cycles, and every 4 weeks thereafter. Intravenous rituximab was administered weekly at 375 mg/m2 for cycle 1 and every 4 weeks for cycles 2 through 5, and oral lenalidomide was administered at 20 mg daily for 21 days of each of the 12 cycles. Corticosteroid prophylaxis was also given during cycle 1.
In the first expansion cohort, patients received subcutaneous epcoritamab at 48 mg by the prior schedule (arm 2a), and the second expansion cohort (arm 2b) received epcoritamab at 48 mg weekly for the first two cycles and then every 4 weeks thereafter, both with standard doses of rituximab and lenalidomide. Dr. Falchi and coauthors reported the results of arm 2a at a poster session.
Eligible patients had CD20-positive relapsed or refractory FL, stage II to IV, grade 1 to 3A. All patients were required to have symptomatic disease, an Eastern Cooperative Oncology Group performance status of 0 to 2, measurable disease, and adequate organ function. The primary endpoints of the dose-escalation cohort were dose-limiting toxicity, safety, and tolerability, and in the dose-expansion arms, antitumor activity.
Patients in arm 2a were followed for a median of 8.6 months (range = 3.3–14.6 months), with 77% still receiving treatment at the time of data cutoff on March 25, 2022. The median duration of treatment was 8.5 months (range = 0.3–13.3 months). In arm 2b, the median follow-up was 2.2 months (range = 0–4.7 months).
“Based on response rates at 6 weeks, patients in arm 2b also achieved encouraging [benefit],” Dr. Falchi noted. This cohort will continue treatment for up to 2 years; Dr. Falchi focused his remarks on arm 2a.
In arm 2a, treatment-emergent adverse events led to epcoritamab dose delays in 43% of patients and treatment discontinuation in 7%. No fatal treatment-related adverse events have been reported in this cohort to date.
In arm 2a, the most common treatment-emergent adverse events of any grade were injection-site reactions in 53% of patients, cytokine-release syndrome in 50%, constipation in 47%, neutropenia in 47%, fatigue in 40%, cough in 37%, and rash in 33%. Neutropenia was the most frequent grade 3 or 4 treatment-emergent adverse event.
The occurrence of cytokine-release syndrome was mainly predictable, with most cases occurring after the first full dose by cycle 1, day 15. One case of grade 2 immune effector cell–associated neurotoxicity was reported, but the event resolved in 4 days and did not lead to treatment discontinuation.
DISCLOSURE: Dr. Cortes has served as a consultant or advisor to Astellas Pharma; Bio-Path Holdings, Bristol Myers Squibb, Centessa Pharmaceuticals, Gilead Sciences, Jazz Pharmaceuticals, Menarini, Novartis, Pfizer, and Takeda; and has received institutional research funding from AbbVie/Genentech, Actuate Therapeutics, Astellas Pharma, Bio-Path Holdings, Bristol Myers Squibb, Jazz Pharmaceuticals, Novartis, Pfizer, Sellas Life Sciences, Sun Pharma, and Takeda. Dr. Zinzani has served as a consultant or advisor to ADC Therapeutics, BeiGene, Bristol Myers Squibb, Celltrion, EUSA Pharma, Gilead Sciences, Incyte, Janssen-Cilag, Kyowa Hakko Kirin, MSD, Novartis, Roche, Sandoz, Secura Bio, Servier, Takeda, and TG Therapeutics; and has served on speakers bureaus for EUSA Pharma, MSD, and Novartis. Dr. Falchi has served as a consultant or advisor to AbbVie, ADC Therapeutics, Genmab, and Roche/Genentech; and has received research funding from Genmab and Roche/Genentech.
REFERENCES
1. Rea D, Mauro MJ, Hochhaus A, et al: Efficacy and safety results from -ASCEMBL, a phase 3 study of asciminib versus bosutinib in patients with chronic myeloid leukemia in chronic phase after ≥ 2 prior tyrosine kinase inhibitors: Week 96 update. 2022 ASCO Annual Meeting. Abstract 7004. Presented June 3, 2022.
2. Zinzani PL, Mayer J, Auer R, et al: Zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy in patients with relapsed or refractory follicular lymphoma: Primary analysis of the phase 2 randomized ROSEWOOD trial. 2022 ASCO Annual Meeting. Abstract 7510. Presented June 3, 2022.
3. Falchi L, Leppä S, Wahlin BE, et al: Subcutaneous epcoritamab with rituximab + lenalidomide in patients with relapsed or refractory follicular lymphoma: Update from phase 1/2 trial. 2022 ASCO Annual Meeting. Abstract 7524. Presented June 3, 2022.
4. Hutchings M, Mous R, Clausen MR, et al: Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: An open-label, phase 1/2 study. Lancet 398:1157-1169, 2021.
