Next-generation therapy for follicular lymphoma

In this issue of Blood, Morschhauser et al report the safety and efficacy of lenalidomide in combination with obinutuzumab and establish the recommended phase 2 dose (RP2D).¹  Rituximab in combination with lenalidomide (R²) has favorable efficacy and toxicity in relapsed and untreated follicular lymphoma (FL) and is now entering the treatment landscape of FL.^2-4  Obinutuzumab, a glycoengineered type II anti-CD20 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC), may be an attractive partner to lenalidomide that can exert immunomodulatory effects via natural killer (NK) and T cells for the treatment of relapsed or refractory (R/R) FL. The question is whether the potentially enhanced ADCC activity of obinutuzumab will translate into enhanced synergism with lenalidomide and result in an improved next-generation R².

Outcomes for FL have improved over the past few decades, and many patients diagnosed in the modern era can anticipate a normal life expectancy.⁵  However, FL remains a disease associated with continued risk for relapse. Currently, the greatest unmet need in new drug development is to alter the natural history among those who experience early relapse (<24 months) following frontline chemoimmunotherapy.⁶  Identifying effective, well-tolerated therapies that result in meaningful remission duration without negatively impacting quality of life remains fundamental to clinical research in this field. Providing insight into treatment selection and sequencing of therapy is also desirable given the list of therapeutic approaches is nearly as long as the natural history of this disease. With those ground rules, how do we interpret/incorporate the findings of this phase 1b dose-escalation study into the ever-expanding treatment landscape of FL?

Obinutuzumab is US Food and Drug Administration (FDA) approved for R/R patients with FL based on the GADOLIN study, which compared obinutuzumab in combination with bendamustine followed by obinutuzumab maintenance to bendamustine alone in patients with rituximab-refractory indolent lymphoma. With a median progression-free survival (PFS) of 25.8 months vs 14.1 months, the obinutuzumab-containing arm was superior to chemotherapy alone.⁷  Neutropenia, an adverse event associated with obinutuzumab was one of the most common grade 3 or higher adverse events observed at 27.5%. GADOLIN provides a snapshot of the efficacy and safety of obinutuzumab in combination with bendamustine in rituximab-refractory. Though superior to chemotherapy alone, it is less clear whether obinutuzumab is superior to rituximab in this setting based on the study design.

Targeted therapies have been promising in R/R FL. Idelalisib, a phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor, and copanlisib, a pan-PI3K inhibitor with predominant activity against α and δ isoforms, are both approved for the treatment of R/R FL patients who have failed at least 2 prior lines of therapy. Idelalisib was associated with a 57% objective response rate (ORR) and 11-month PFS among patients refractory to rituximab and an alkylating agent.⁸  Copanlisib was associated with an ORR of 59% and median PFS of 11 months.⁹  Though similar in efficacy, the safety profile of these 2 PI3K inhibitors is different, with less gastrointestinal toxicity and higher rates of hyperglycemia and hypertension associated with copanlisib. The toxicity profile of PI3K inhibitors (ie, pneumonitis, colitis, transaminitis, rash, and infection) has likely impacted the uptake of these drugs despite their efficacy profile in poor-risk patients.

R² is under active exploration for relapsed indolent lymphoma. The phase 3 AUGMENT study met its primary end point of superior PFS of R² compared with rituximab monotherapy in relapsed follicular and marginal zone lymphoma. The details are forthcoming but will likely lead to FDA approval of R² for R/R FL. The control arm is likely to impact the excitement surrounding this study, but it is important nonetheless to allow exploration of the impact of combination over R monotherapy. The MAGNIFY study is examining 12 cycles of R² followed by R² maintenance vs rituximab maintenance in indolent and mantle cell lymphoma. Preliminary efficacy has been reported for the FL subgroup including cohorts of early-relapse or double-refractory (CD20 monoclonal antibody and alkylating agent) patients.⁴  R² was associated with an ORR of 66% and 1-year PFS estimates of 70% for R/R FL. The early-relapse and double-refractory cohorts had less favorable but meaningful outcomes, with ORRs of 47% and 45% and 1-year PFS estimates of 49% and 65%, respectively. Neutropenia was one of the most common grade 3 or 4 adverse events at 29%. R² appears to be an effective, manageable strategy for R/R FL. It remains unknown whether the greatest uptake will be in third-line or earlier lines of therapy.

This leads us to the current study: obinutuzumab in combination with lenalidomide in R/R FL. This dose-escalation study established the RP2D of lenalidomide at 20 mg in combination with a fixed dose of obinutuzumab (1000 mg). Only 19 patients were evaluable for safety and efficacy and had favorable features. Mean age was 61.5 years, and most had excellent performance status (80% Eastern Cooperative Oncology Group 0), responded to prior rituximab (60%) or prior lymphoma therapy (80%), and had nonbulky disease (75% with lymph nodes <5 cm in size). With a median follow-up of 38.1 months, the 3-year PFS was 52% and ORR was 63%. The most common grade 3 or higher adverse event was neutropenia at 26%. Therefore, the combination appears effective and manageable, with no new safety signals. Commendable is the schedule (6 cycles of therapy). In an era where longer duration of therapy is commonly pursued, this is an important distinction for this study. Larger studies are necessary to understand whether this is a superior option to the available therapies, most importantly, its predecessor (R²).

Where do we go from here? The importance of this study is establishing the RP2D for the potentially practice-changing trials. An important study, SWOG S1608, is a randomized phase 2 study exploring 3 arms for early-relapsing FL. One arm is obinutuzumab and lenalidomide. The other arms include a PI3Kδ inhibitor in combination with obinutuzumab and a chemoimmunotherapy arm. Understanding how to approach early-relapse FL is critical and will address the greatest unmet need. Obinutuzumab and lenalidomide have a critical role in one of the most important modern-day FL studies.