Obinutuzumab combined with lenalidomide for relapsed or refractory follicular B-cell lymphoma (GALEN): a multicentre, single-arm, phase 2 study

Summary

Background

Lenalidomide plus rituximab is approved to treat patients with relapsed or refractory follicular lymphoma. Obinutuzumab has been shown to enhance antibody-dependent cellular cytotoxicity, phagocytosis, and direct B-cell killing better than rituximab. Our aim was to determine the activity and safety of lenalidomide plus obinutuzumab in previously treated patients with relapsed or refractory follicular lymphoma.

Methods

In this multicentre, single-arm, phase 2 study, patients were enrolled from 24 Lymphoma Academic Research Organisation centres in France. Eligible patients (age ≥18 years) had histologically confirmed CD20-positive relapsed or refractory follicular lymphoma of WHO grade 1, 2, or 3a; an ECOG performance status of 0–2; and received at least one previous rituximab-containing therapy. Patients received oral lenalidomide (20 mg) plus intravenously infused obinutuzumab as induction therapy (1000 mg; six 28-day cycles), 1-year maintenance with lenalidomide (10 mg; 12 28-day cycles; days 2–22) plus obinutuzumab (1000 mg; alternate cycles), and 1-year maintenance with obinutuzumab (1000 mg; six 56-day cycles; day 1). The primary endpoint was the proportion of patients who achieved an overall response at induction end as per investigator assessment using the 1999 international working group criteria. The secondary endpoints were event-free survival, progression-free survival, overall survival, and safety. Analyses were per-protocol; the efficacy population included all patients who received at least one dose of both obinutuzumab and lenalidomide, and the safety population included all patients who received one dose of either investigational drug. The study is registered with ClinicalTrials.gov, number NCT01582776, and is ongoing but closed to accrual.

Findings

Between June 11, 2014, and Dec 18, 2015, 89 patients were recruited and 86 patients were evaluable for efficacy and 88 for safety. Median follow-up was 2·6 years (IQR 2·2–2·8). 68 (79%) of 86 evaluable patients (95% CI 69–87) achieved an overall response at induction end, meeting the prespecified primary endpoint. At 2 years, event-free survival was 62% (95% CI 51–72), progression-free survival 65% (95% CI 54–74), duration of response 70% (95% CI 57–79), and overall survival 87% (95% CI 78–93). Complete response was achieved by 33 (38%, 95% CI 28–50) of 86 patients at induction end, and the proportion of patients achieving a best overall response was 70 (81%, 95% CI 72–89) and 72 (84%, 74–91) of 86 patients during induction and treatment, respectively. The most common adverse events were asthenia (n=54, 61%), neutropenia (n=38, 43%), bronchitis (n=36, 41%), diarrhoea (n=35, 40%), and muscle spasms (n=34, 39%). Neutropenia was the most common toxicity of grade 3 or more; four (5%) patients had febrile neutropenia. 57 serious adverse events were reported in 30 (34%) of 88 patients. The most common serious adverse events were basal cell carcinoma (n=5, 6%), febrile neutropenia (n=4, 5%), and infusion-related reaction (n=3, 3%). One patient died due to treatment-related febrile neutropenia.

Interpretation

Our data shows that lenalidomide plus obinutuzumab is active in previously treated patients with relapsed or refractory follicular lymphoma, including those with early relapse, and has a manageable safety profile. Randomised trials of new immunomodulatory regimens, such as GALEN or using GALEN as a backbone, versus lenalidomide plus rituximab, are warranted.

Funding

Lymphoma Academic Research Organisation, and Celgene and Roche

Introduction

Follicular lymphoma is characterised by a defective immune microenvironment that suppresses normal T-cell and natural killer (NK)-cell activity, and by a long natural history of disease with repeated relapses in many patients. There is no standard of care for relapsed or refractory follicular lymphoma; systemic treatments commonly used include rituximab or rituximab–chemotherapy and autologous stem transplantation whereas radioimmunotherapy has been underused over the past decade. New treatment options include immunomodulatory agents1, 2, 3, 4, 5 and phosphoinositide 3′-kinase (PI3K) inhibitors.6, 7 Lenalidomide is an immunomodulatory drug that has direct antiproliferative activity on lymphoma cells, enhances T-cell and NK-cell function, and improves antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis.⁸ When combined with rituximab, a CD20 type 1 antibody, lenalidomide has synergistic effects in preclinical lymphoma models.9, 10, 11 This immunomodulatory lenalidomide-rituximab combination showed promising activity in patients with relapsed or refractory follicular lymphoma, and was approved by the US Food and Drug Administration for this use in May 2019.1, 2, 3, 4

Research in context

Evidence before this study

Before undertaking this study, we considered the fact that there is no clear standard of care, but there are new immunomodulatory treatment options, for patients with relapsed or refractory follicular lymphoma. Conventional treatment options include autologous stem cell transplantation in patients with early relapsed follicular lymphoma (progression of disease <2 years after diagnosis) and immunochemotherapy regimens such as obinutuzumab plus bendamustine in patients with refractory disease. For the past decade, patients with relapsed or refractory follicular lymphoma have been successfully treated in clinical trials with an immunomodulatory regimen combining lenalidomide plus rituximab, which was approved in May 2019, for this use.

Added value of this study

Our data suggest that lenalidomide plus obinutuzumab–a glycoengineered type 2 anti-CD20 monoclonal antibody that has shown greater antibody-dependent cellular cytotoxicity, phagocytosis, and direct B-cell killing effects than rituximab–might have greater activity than lenalidomide plus rituximab in patients with disease progression within 24 months of initial diagnosis, and might be similarly efficient to autologous stem cell transplantation and approved phosphoinositide 3′-kinase inhibitors in this setting, and obinutuzumab plus bendamustine in patients with refractory disease.

Implications of all the available evidence

Results of this study evaluating the activity and safety of combining lenalidomide with obinutuzumab for induction therapy and using lenalidomide for maintenance provide supporting evidence to expand immunomodulatory treatment options for previously treated patients with relapsed or refractory follicular lymphoma, including subgroups of patients with disease progression within 24 months of initial diagnosis and refractory disease. This regimen might also constitute a potential backbone for new regimens as investigated in the combination triplet including atezolizumab.

Obinutuzumab is a glycoengineered, type 2 anti-CD20 monoclonal antibody, which, when compared with rituximab, has lower complement-dependent cytotoxicity, but greater ADCC and phagocytosis, and direct B-cell killing effects.12, 13 Obinutuzumab with lenalidomide also has an additive effect in triggering NK-cell activation in vivo, as shown in vitro on patient samples from a phase 1 study.¹⁴ Clinically, obinutuzumab-based immunochemo therapy and maintenance therapy are effective in patients with rituximab-refractory, indolent non-Hodgkin lymphoma.5, 15, 16

We hypothesised that obinutuzumab plus lenalidomide would have greater activity than lenalidomide plus rituximab, and in 2012, we initiated the GALEN trial, a phase 1b/2 study to assess the safety and antitumour activity of obinutuzumab plus lenalidomide in patients with relapsed or refractory follicular lymphoma. The phase 1b study¹⁷ showed satisfactory safety of the combination given for 6 months as induction therapy and established the recommended phase 2 dose of lenalidomide as 20 mg, for use in combination with a fixed dose of obinutuzumab of 1000 mg. We report the results of the phase 2 part of the study assessing activity and safety of the GALEN regimen in patients with relapsed or refractory follicular lymphoma.