Primary analysis of the ELM-2 study

In the setting of relapsed/refractory follicular lymphoma (FL), progression-free survival (PFS) deteriorates with successive relapses, which implies a high unmet need for therapies that can improve disease control and extend survival after relapse [1]. The Fc-silenced CD20 x CD3 bispecific antibody odronextamab is being investigated in patients with relapsed/refractory B-cell malignancies in the multicohort, multicenter, phase II ELM-2 study. At EHA 2024, Taszner et al. presented the primary analysis for the FL cohort (n = 128) [2].

These patients had FL grade 1-3a and were refractory to, or had relapsed after, ≥ 2 lines of treatment that included an anti-CD20 antibody and an alkylator. Their median number of prior lines was 3 (range, 2–13). Seventy-two percent were refractory to the last line of therapy. Double refractoriness to anti-CD20 antibody therapy and an alkylator was present in 41 %. In 49 % of patients, progression of disease had occurred within 24 months of the initiation of first-line treatment (POD24).

Odronextamab was stepped up in cycle 1 to mitigate the risk of cytokine release syndrome (CRS). During the induction phase in cycles 2–4, treatment consisted of odronextamab 80 mg on days 1, 8 and 15 intravenously. This was followed by the maintenance period with 160 mg administered Q2W. The two-weekly intervals could be changed to four-weekly intervals in patients who had achieved complete response (CR) for ≥ 9 months. Anti-infection prophylaxis included immunoglobulin supplementation in patients with severe hypogammaglobulinemia (i.e., < 400 mg/dL) or recurrent episodes of infection with immunoglobulin levels of 400–600 mg/dL, as well as antivirals and Pneumocystis jirovecii pneumonia prophylaxis.

Durable responses in a heavily pretreated population

Among 128 individuals included in the FL cohort of the ELM-2 study, 85 % completed ≥4 cycles of treatment. The objective response rate (ORR), which was defined as the primary endpoint, was 80 % after a median follow-up of 20 months. CR was obtained in 73 %. Median duration of objective response and CR was 23 and 25 months, respectively. Subgroup analyses yielded consistent efficacy regarding ORR across most prespecified high-risk subgroups including those with POD24, refractoriness to the last line of treatment, and double refractoriness.

Median PFS was 21 months in all patients and was longer in those with CR compared to those with partial response (PR; 28 vs. 11 months). At 12 months, 79 % vs. 50 % of patients with CR and PR, respectively, were alive and progression-free. Median OS had not been reached in the total population, with 12-month and 24-month OS rates of 86 % and 70 %, respectively. While median OS had not been reached in the group that achieved CR, this was 18 months in the partial responders. At 24 months, the OS rates were 81 % vs. 19 % for patients with CR vs. PR.

PFS was also assessed by MRD status in 64 patients with available samples. According to this, PFS was longer in those who were MRD-negative on day 15 of cycle 4 than in the group retaining MRD-positive status (HR, 0.30; Figure 1). None of the 14 patients in the biomarker population who discontinued odronextamab due to disease progression achieved MRD negativity on or after day 15 of cycle 4. Another exploratory biomarker analysis investigated best overall response by CD20 expression. These data indicated that even patients with low or undetectable CD20 expression by immunohistochemistry or mRNA level measurement could achieve (complete) remission.

The treatment-emergent adverse events (­TEAEs) were generally manage­able and consistent with previous reports. CRS was the most common treatment-related ­TEAE (56 %), followed by neutropenia (30 %), infusion-related reactions (29 %), pyrexia (24 %) and anemia (20 %). CRS events were almost exclusively grade 1 or 2 and showed a median duration of 8 hours. Any-grade infections occurred in 80 %; here, 37 % were due to COVID-19. The rates of infections reflected a population with underlying B-cell functional impairment due to the malignancy and prior exposure to immunosuppressive therapy. Grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in one patient. ­­TEAEs prompted treatment interruption/delay in 63 %. Four patients (3 %) died due to treatment-related ­TEAEs including pneumonia and progressive multifocal leukoencephalopathy.

According to the authors’ conclusion, odronextamab might offer an important off-the-shelf treatment option for heavily pretreated patients with relapsed/refractory FL. At present, the phase III trials OLYMPIA-1 (NCT06091254), OLYMPIA-2 (NCT06097364) and OLYMPIA-5 (NCT06149286) are evaluating odronextamab in earlier lines of therapy.

Figure 1: Odronextamab: progression-free survival by MRD status on day 15 of cycle 4.

<h3>Mosunetuzumab: efficacy across high-risk cohorts</h3>
The CD20 x CD3 bispecific antibody mosunetuzumab is in clinical use for the treatment of patients with relapsed/refractory FL after ≥ 2 prior therapies, representing an off-the-shelf, fixed-duration option without mandatory hospitalization. In the pivotal phase II setting, mosunetuzumab treatment has given rise to high ORR and CR rates as well as durable responses in a heavily pretreated population [3, 4]. A subgroup analysis of high-risk patients after &gt; 3 years of follow-up was reported at EHA 2024 by Assouline et al. [5]. Patients with and without POD24 were compared to each other (n = 47 and 43, respectively), as were those in the third and fourth lines (n = 35 and 55, respectively) and patients aged &lt; 65 and ≥ 65 years (n = 60 and 30, respectively). After step-up dosing in cycle 1, patients who achieved CR at cycle 8 discontinued mosunetuzumab at that time. Those who had either PR or stable disease at cycle 8 continued the treatment for a total of 17 cycles.

CR rates across the high-risk subgroups were consistent with the overall population (n = 90) that showed an ORR of 78 % and a CR rate of 60 % (<strong>Figure 2</strong>). Patients who received mosunetuzumab in the third line experienced the highest CR rate of 68.6 %. Median duration of CR had not been reached in the total group. At 30 months, duration of CR was 71 % overall and was again maintained across the subgroups, with the highest rate observed in the third-line cohort (77 %). Patients with POD24 and non-POD24 showed similar 36-month rates for PFS (44 % vs. 42 %) and OS (84 % vs. 81 %). Also, older patients did not have different outcomes compared to the younger cohort (36-month rates for PFS, 47 % vs. 42%; and for OS, 86 % vs. 81 %). For patients in the third line of treatment, as compared to those in the fourth line, the PFS benefit was numerically higher (36-month rates, 54 % vs. 36 %), while OS was comparable (85 % vs. 82 %). Together with the CR findings, these data suggest more favorable outcomes with mosunetuzumab in earlier <em>versus</em> later lines.

The safety profile across subgroups was consistent with that observed in the overall population. In patients aged ≥ 65 years, the rate of serious infections (17 %) did not exceed the respective overall rate (20 %). Grade ≥ 3 serious infections primarily included urinary tract infections (3 %), pneumonia (2 %), septic shock (2 %), COVID-19 (2 %) and Epstein-Barr viremia (2 %). Serious infections predominantly occurred in the first four cycles, with only three events being reported beyond cycle 8. Neutropenia was reported in 29 % overall. CRS events emerged in 44 %; most of them were graded as 1 or 2. In the group aged ≥ 65 years, the CRS rates were lower than in the younger age group (30 % vs. 52 %), suggesting that this treatment is safe in older patients. No mosunetuzumab-related fatal AEs occurred, and the rate of treatment-related AEs leading to discontinuation was low at 2 %.

A biomarker analysis showed that mosunetuzumab therapy allows for the recovery of B cells and immunoglobulins in patients with CR after completion of fixed-duration treatment. The authors concluded that mosunetuzumab offers a favorable benefit-risk ratio as an outpatient, fixed-duration regimen for patients with relapsed/refractory FL and a broad range of baseline and disease characteristics.

Figure 2: Consistent response rates with mosunetuzumab across high-risk subgroups

Optimizing treatment with epcoritamab

In the phase I/II EPCORE NHL-1 trial, treatment with the subcutaneous CD3 x CD20 bispecific antibody epcoritamab has led to deep and durable responses in patients with relapsed/refractory FL after ≥ 2 prior therapies [6]. The ORR was 82 %, with CRs occurring in 63 %. Seventy-two percent of complete responders were shown to maintain CR at 18 months. With respect to safety, the analysis yielded low-grade CRS and ICANS events that all resolved. However, further reductions in the incidence and severity of CRS and ICANS are an important goal as this may enhance accessibility and decrease healthcare resource utilization.

Therefore, Vitolo et al. compared the outcomes in the pivotal cohort of the EPCORE NHL-1 study (n = 128) with those in the cycle 1 optimization (C1 OPT) cohort (n = 86) [7]. In the pivotal cohort, step-up dosing included two steps in cycle 1 before administration of the first full dose of 48 mg on day 15 (Figure 3). CRS prophylaxis with prednisolone was implemented. In the C1 OPT cohort, on the other hand, dosing was increased in three steps prior to the first full dose of 48 mg on day 22 of cycle 1. Here, CRS prophylaxis included dexamethasone and recommendations for adequate hydration. Hospitalization was not mandatory in this group, while patients in the pivotal cohort were hospitalized for 24 hours following the first full dose.

Both cohorts contained patients with relapsed/refractory FL grade 1-3a after ≥ 2 prior lines of therapy including ≥ 1 regimen with an anti-CD20 antibody. This was a high-risk population with a high unmet need. Approximately half of patients in each cohort had POD24, and most were double refractory to CD20-targeted treatment and an alkylating agent. Ann Arbor stage III-IV disease was present in 85 % and 92 % in the pivotal and C1 OPT cohorts, respectively. Sixty-one percent and 51 %, respectively, had Follicular Lymphoma International Prognostic Index scores of 3-5. The primary objective for the C1 OPT cohort was the incidence and severity of CRS, as well as feasibility of treatment in the outpatient setting. At the time of the analysis, treatment was ongoing in 74 % in the C1 OPT cohort after a median follow-up of 5.7 months. The first full dose had been administered in 95 %.

Figure 3: Step-up dosing (SUD) of epcoritamab in the pivotal and C1 OPT cohorts of the EPCORE NHL-1 trial

Reductions in CRS and ICANS rates

The study met its primary endpoint. CRS was reported in 66 % in the pivotal cohort vs. 49 % in th C1 OPT cohort, with lower rates of grade 2 and no 3 CRS events in the C1 OPT cohort. ICANS occurred in 6 % in the pivotal cohort, while no events were observed in the C1 OPT cohort (Table). In both cohorts, CRS emerged mostly after the first full dose and was essentially confined to cycle 1. All CRS events resolved, and none led to epcoritamab discontinuation. The decreased incidence and severity of CRS was reflected by lower IL-6 levels 24 hours after the first full dose in the C1 OPT cohort compared to the pivotal cohort.

Fifty-four percent of patients in the C1 OPT cohort received the first full dose in an outpatient setting while they were being closely monitored for CRS. Regardless of hospitalization status at the first full dose, 77 % of patients with CRS following the first full dose had CRS onset in the outpatient setting; all of them were able to identify CRS signs and symptoms in a timely manner and to receive adequate treatment. Overall, no grade 5 AEs were reported. Other common AEs included injection-site reactions, COVID-19, fatigue, neutropenia, diarrhea and pyrexia. No clinical tumor lysis syndrome occurred in either cohort.

The modified step-up in the C1 OPT cohort had no impact on the efficacy of treatment. In both cohorts, median time to response and median time to CR were 1.4 and 1.5 months, respectively. The ORRs were 83 % and 86 % for the pivotal and C1 OPT cohorts, respectively, and the MRD negativity rates were 67 % and 64 %, respectively. MRD negativity was associated with favorable PFS at all times. Taken together, cycle 1 optimization with three dosing steps prior to the full dose in addition to simple prophylactic measures substantially reduced the incidence and severity of CRS and ICANS. The treatment showed robust, clinically meaningful efficacy including deep responses in the largest relapsed/refractory FL dataset for a T-cell–engaging therapy to date. These data further support the feasibility and safety of epcoritamab as a potential outpatient treatment option in the setting of relapsed/refractory FL.

Sequences of treatment

Using data from the Optum^® Clinformatics^® Data Mart database, Gaballa et al. evaluated treatment patterns, time to next treatment (TTNT), healthcare resource utilization and cost of care for US residents with FL [8]. Patients were included who had received ≥ 1 line of treatment during the index period. A total of 4,525 individuals initiated first-line treatment; second-, third- and fourth-line therapies were started by 1,053, 304, and 97 patients, respectively. Rituxumab monotherapy (R-mono) was the most commonly used regimen in the first, second and third lines, followed by bendamustine/rituximab (BR) and R-CHOP. In the fourth line, BR and R-mono were most commonly prescribed, followed by R-CHOP.

Bendamustine plus obinutuzumab gave rise to the longest TTNT in the first line; in the second and third lines, this applied to BR and lenalidomide plus rituximab, respectively. R-mono demon­strated the longest TTNT in the fourth line. While median TTNT decreased by line of therapy across all regimens, inpatient admissions and outpatient visits increased with each subsequent line, as did the mean total cost of care that ranged from $ 40,538 to $ 74,466. The authors emphasized that these findings suggest a high disease burden and the need for better treatment options for patients with FL, especially in the third and fourth lines.

The randomized, phase II ROSEWOOD trial has shown superior efficacy of the combination of zanubrutinib and obinutuzumab compared to obinutuzumab monotherapy in patients with relapsed/refractory FL after ≥ 2 lines [9]. A post-hoc analysis assessed the efficacy of the combination in the sequence of treatments administered in ROSEWOOD based on the Growth Modulation Index. This allowed for the generation of comparative efficacy evidence by comparing PFS durations with successive treatments, using each patient as their own control.

According to this analysis, the majority of patients receiving zanubrutinib plus obinutuzumab had significant improvement in PFS vs. PFS on their last prior regimen, irrespective of the number of previous treatments [10]. The median Growth Modulation Index of 2.7 in the overall population of the combination arm was more than double the 1.33 threshold for meaningful clinical activity versus the last prior line. In their summary, the authors noted that these data confirm the benefit of zanubrutinib plus obinutuzumab as a novel option for patients with relapsed/refractory FL.

REFERENCES

1. Batlevi CL et al., Follicular lymphoma in the modern era: survival, treatment outcomes, and identification of high-risk subgroups. Blood Cancer J 2020; 10(7): 74
2. Taszner M et al., Primary analysis of the phase 2 ELM-2 study: Odronextamab in patients with relapsed/refractory follicular lymphoma. EHA 2024, abstract S232
3. Budde LE et al., Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study. Lancet Oncol 2022; 23(8): 1055-1065
4. Schuster SJ et al., Mosunetuzumab monotherapy continues to demonstrate durable responses in patients with relapsed and/or refractory follicular lymphoma after ≥ 2 prior therapies: 3-year follow-up from a pivotal phase II study. Blood 2023; 142 (Supplement 1): 603
5. Assouline S et al., Mosunetuzumab demonstrates clinically meaningful outcomes in high-risk patients with heavily pretreated R/R FL after ≥ 3 years of follow-up: Subgroup analysis of a pivotal phase II study. EHA 2024, abstract S233
6. Linton KM et al., Epcoritamab sc monotherapy leads to deep and durable responses in patients with relapsed or refractory follicular lymphoma: First data disclosure from the EPCORE NHL-1 follicular lymphoma dose-expansion cohort. ASH 2024, abstract 1655
7. Vitolo U et al., Epcoritamab induces deep responses in relapsed or refractory follicular lymphoma: Safety and pooled efficacy data from EPCORE NHL-1 pivotal and cycle 1 optimization FL cohorts. EHA 2024, abstract S234
8. Gaballa SR et al., Real-world evaluation of treatment pattern, time to next treatment, healthcare resource utilization, and cost of care in follicular lymphoma. EHA 2024, abstract P1124
9. Zinzani PL et al., ROSEWOOD: A phase II randomized study of zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy in patients with relapsed or refractory follicular lymphoma. J Clin Oncol 2023; 41(33): 5107-5117
10. Bouabdallah K et al., Intrapatient comparative analysis of zanubrutinib plus obinutuzumab efficacy in relapsed/refractory follicular lymphoma using the Growth Modulation Index. EHA 2024, abstract P1143

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