Follicular lymphoma: Efficacy and safety updates

In the context of follicular lymphoma treatment, there is a clear unmet need for patients who have experienced early progression (progression within 24 months of front-line therapy, POD24), as well as those who are refractory to treatment and present with other high-risk features. At ASH 2024, promising efficacy and safety data were reported for the five molecules nemtabrutinib, zanubrutinib, BGB-16673, epcoritamab, and mosunetuzumab [1-6].

Nemtabrutinib: Promising antitumor activity

Covalent Bruton tyrosine kinase inhibitors (BTKi) have demonstrated efficacy in relapsed/refractory follicular lymphoma (R/R FL). However, response rates and efficacy results are limited. Jurczak et al. presented safety and efficacy results for nemtabrutinib, a once daily, potent, reversible, non-covalent BTKi with a distinct kinase profile [1].

The multicenter, open-label, single-arm phase II BELLWAVE-003 study enrolled a total of 36 patients with R/R FL who had received a median of four prior therapies (range 1-11) and had a median follow-up of 6.1 months. Patients were treated with single-agent nemtabrutinib 65 mg once daily until unacceptable toxicity, disease progression, or withdrawal. The primary endpoint was the objective response rate (ORR).

At the data cut-off in April 2024, 29 patients were evaluable for the efficacy endpoints. The ORR was 41 % (95 % CI: 24–61 %) and included one patient with complete response (CR). The median duration of response (DOR) was 5.8 months (95 % CI: 1.5–not reached), median progression-free survival (PFS) was 5.5 months (95 % CI: 2.8–not reached), and median overall survival (OS) had not been reached (95 % CI: 10.4–NR).

Adverse events (AEs) were reported in 86 % of patients, 31 % of which were grade 3 or 4. The most common AEs were neutropenia (25 %) and decreased platelet count (19 %). Only three patients discontinued nemtabrutinib due to AEs.

Taken together, nemtabrutinib demonstrated promising antitumor activity with no new safety signals in this phase II study.

Zanubrutinib: Comparative efficacy versus prior treatment

Trotman et al. evaluated the efficacy of zanubrutinib plus obinutuzumab (ZO) with obinutuzumab (O) by comparing PFS duration with prior treatments in a post-hoc analysis of data from the global, randomized, open-label, phase II ROSEWOOD trial [2]. Growth Modulation Index (GMI) scores ≥1.33 were considered significant clinical activity compared with the previous treatment.

In the ZO arm of the study, median PFS was longer compared with the prior treatment (28.0 vs 12.1 months), resulting in a median GMI score of 2.7 (95 % CI: 1.6–4.9). Over 60 % of patients treated with ZO achieved median GMI scores ≥1.33 across all subgroups analyzed. Obinutuzumab alone did not lead to longer PFS compared with the prior line of therapy (10.4 vs 11.5 months), resulting in a non-significant GMI score of 0.9 (95 % CI: 0.5–1.7).

Overall, patients with R/R FL who received ZO showed significant improvement of PFS compared with their prior lines of therapy.

BGB-16673: Preliminary efficacy and safety data of a BTK degrader

BGB-16673, a bivalent small molecule that binds specifically to BTK and the E3 ligase, induces the degradation of BTK, thus circumventing disease progression of B-cell malignancies due to BTK mutations. Tam et al. presented updated results in patients with FL and marginal zone lymphoma (MZL) from the open-label, dose-escalation and dose-expansion phase I/II study CaDAnCe-101 [3]. The primary endpoints of the study comprised safety/tolerability, maximum tolerated dose (MTD), and recommended phase II dose. Eligible patients received oral doses of BGB-16673 100 mg, 200 mg, or 350 mg once daily in 28-day cycles for the treatment of R/R FL (n = 8) or MZL (n = 17). All of them were pretreated with two or more therapies.

As of September 2024, no dose-limiting toxicities occurred during the study, and the MTD was not reached. Any-grade treatment-emergent AEs (TEAEs) were reported in 100 % of patients with FL and 94.1 % of those with MZL. Twenty-five percent and 41.2 %, respectively, were grade ≥3. Three patients with MZL discontinued treatment because of TEAEs. A detailed list of TEAEs in patients of either group can be found in Table 1.

The ORRs for evaluable patients were 50 % for FL and 64.3 % for MZL. One patient each achieved CR.

As the authors noted, data from this first-in-human study showed a tolerable safety profile and clinically meaningful responses with BGB-16673 in heavily pretreated patients with FL and MZL.

Table 1

Epcoritamab: Deep and durable response during two years

Epcoritamab is a CD3xCD20 bispecific antibody approved in patients with FL after at least 2 treatment lines. It has shown encouraging antitumor activity and a manageable safety profile in arm 2 of the EPCORE-NHL-2 trial. Falchi et al. presented follow-up results beyond 2 years with a first-time analysis of minimal residual disease (MRD) data [4].

A total of 111 patients with R/R FL received subcutaneous epcoritamab 48 mg in combination with rituximab and lenalidomide (R²) for up to 12 cycles of 28 days, followed by R² maintenance for the subsequent 12 months. The primary endpoint was the ORR. At prespecified time points, peripheral mononuclear cell samples were collected and analyzed for MRD.

Patients receiving epcoritamab + R² achieved an ORR of 96 %, with 87 % achieving CR. Similar CR rates resulted in the presence of high-risk features (Figure 1). During the study, MRD negativity developed in 66 out of 75 evaluable patients. At a median follow-up of 21-months, 86 % of patients maintained CR, and 78 % maintained overall objective responses.

The most common TEAEs comprised neutropenia (62 %), COVID-19 (57 %) and cytokine release syndrome (CRS, 52 %). Five patients suffered grade 5 COVID-19-related events.

These results underline the deep and durable response of epcoritamab + R² over a 2-year time frame and the fact that the safety profile is consistent with earlier reports.

Figure 1: Forest-plot of patients with R/R FL and high-risk features who received epcoritamab + R² in the long-term follow-up of the Epcore NHL-2 trial

Mosunetuzumab: Subcutaneous administration is non-inferior

Mosunetuzumab is a CD20xCD3 T-cell engaging bispecific antibody approved for the treatment of R/R FL as an intravenous formulation. The efficacy of fixed-duration intravenous treatment was confirmed by the four-year follow-up results of the pivotal phase II study reported at ASH 2024 [5]. Mosunetuzumab continued to demonstrate clinically meaningful outcomes after ≥ 2 prior therapies. Furthermore, the findings confirmed a relatively low incidence of infections, and no mortality related to the SARS-CoV-2 virus.

Bartlett et al. presented data from a phase II study with mosunetuzumab as a subcutaneous formulation to improve the safety and convenience for patients with R/R FL [6]. The primary endpoint was the pharmacokinetic non-inferiority (PKNI) of subcutaneous mosunetuzumab compared with the approved intravenous mosunetuzumab formulation as a historical control. PKNI was defined as the lower bounds of the geometric mean ratios (GMRs) above 0.8 in the co-primary pharmacokinetic endpoints serum C_trough(C3) and model-predicted cumulative serum AUC_0-84.

At the data cut-off in July 2024, 94 patients were enrolled and received a single subcutaneous injection every 21 days, with step-up dosing of up to 45 mg.

The study met both co-primary endpoints, with a C_trough(C3) GMR of 1.39 (95 % CI: 1.2–1.6) and an AUC_0-84 GMR of 1.06 (95 % CI: 0.9–1.2). ORR and CR were 76.6% and 61.7%, respectively. The estimated 18-month DOR was 64.1% (95% CI, 52.1–6.1).

The most common adverse events (all grades) were injection-site reactions (ISRs, 61 %), fatigue (35 %), and CRS (30 %). All ISRs were non-serious, and no patient discontinued treatment because of ISRs.

The authors concluded that subcutaneous injections of mosunetuzumab are non-inferior to intravenous formulations and could improve convenience for the patients.

REFERENCES

1. Jurczak W et al., Nemtabrutinib, a noncovalent reversible BTK inhibitor in relapsed or refractory follicular lymphoma: Results from the phase 2 Bellwave-003 Study. ASH 2024, abstract 1634
2. Trotman J et al., Comparative efficacy of zanubrutinib plus obinutuzumab versus last prior treatment in relapsed/refractory follicular lymphoma: Growth modulation index analysis from ROSEWOOD study. ASH 2024, abstract 3029
3. Tam CS et al., Preliminary efficacy and safety of the Bruton tyrosine kinase degrader BGB-16673 in patients with relapsed or refractory (R/R) indolent NHL: Results from the phase 1 CaDAnCe-101 study. ASH 2024, abstract 1649
4. Falchi L et al., Fixed-duration epcoritamab + R2 drives deep and durable responses in patients with relapsed or refractory follicular lymphoma: 2-Year follow-up from arm 2 of the Epcore NHL-2 Trial. ASH 2024, abstract 342
5. Shadman M et al., Mosunetuzumab continues to demonstrate clinically meaningful outcomes in patients with relapsed and/or refractory follicular lymphoma after ≥ prior therapies including those with a history of POD24: 4-Year follow-up of a pivotal phase II study. ASH 2024, abstract 4407
6. Bartlett NL et al., Subcutaneous mosunetuzumab leads to high rates of durable responses, low rates of cytokine release syndrome, and non-inferior exposure compared with intravenous administration in patients with relapsed/refractory follicular lymphoma: Primary analysis of a pivotal phase II. ASH 2024, abstract 1645

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