GALEN trial phase II results: obinutuzumab + lenalidomide for relapsed/refractory follicular lymphoma

There is currently no standard-of-care treatment for patients with relapsed/refractory (R/R) follicular lymphoma (FL), although therapeutic options include rituximab, rituximab plus chemotherapy and autologous stem cell transplant. Therefore, there is an unmet need to provide efficacious new treatment options.¹

Rituximab is a type I chimeric IgG1 anti-CD20 monoclonal antibody (mAb) which, in combination with the immunomodulatory agent, lenalidomide, has proven efficacy in patients with R/R FL. This chemotherapy-free regimen, termed R², was approved by the United States (US) Food & Drug Administration in May 2019 for patients with previously treated FL and marginal zone lymphoma (MZL).²

Obinutuzumab (GA101), a type II humanized IgG1 anti-CD20 mAb, displays greater antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis, as well as B-cell killing effects compared to rituximab.³ Studies in patients with previously untreated FL comparing rituximab to obinutuzumab, have shown that obinutuzumab prolongs progression-free survival (PFS), regardless of the chemotherapy backbone it is combined with.⁴ It was, therefore, hypothesized that obinutuzumab in combination with lenalidomide (GALEN) could improve the outcome of patients with R/R FL.¹

The phase Ib results of the GALEN study were previously published in Blood in 2018. The investigators established the recommended phase II doses of lenalidomide (20mg), and obinutuzumab (1000mg fixed dose), and showed GALEN had a satisfactory safety profile.⁵ Furthermore, Frank Morschhauser, University of Lille, Lille, FR, and colleagues, recently published the results of the phase II portion of the GALEN study (NCT01582776) in Lancet Hematology, which investigated the efficacy and safety of GALEN in patients with R/R FL.¹

Study design and patient characteristics

• Multicenter, single-arm, phase II study in France
• Adult patients had CD20⁺ R/R FL (N= 89) and had:
  • World Health Organization (WHO) grade 1, 2 or 3a disease
  • An Eastern Cooperative Oncology Group (ECOG) score of 0–2
  • ≥ one lesion by CT scan
  • A life expectancy ≥ three months
  • Received a prior rituximab-containing therapy
  • No other efficacious treatment options available

• A percentage of planned doses taken (total dose taken [mg] x 100 / total dose expected [mg]) was calculated (given as lenalidomide versus obinutuzumab):
  • During induction: 61% vs 84%
  • At least 90% of doses taken, by end of year one maintenance: 70% vs 95%
  • At least 90% of doses taken, by end of year two maintenance (obinutuzumab): 77%

Patient characteristics of the safety population (n= 88) are shown in Table 2.

• Primary endpoint: overall response at induction
  • Investigator assessed using the 1999 international working group criteria
  • Hypothesis: overall response would increase from 50% to 70% after six treatment cycles
• Secondary endpoints: event-free survival (EFS), PFS, overall survival (OS) and safety
• Median follow-up: 2.6 years (interquartile range: 2.2–2.8)
• In total, 43 patients completed full maintenance therapy and 43 discontinued therapy (Table 3)

Permanent discontinuations due to drug toxicity:

• Lenalidomide: 8
• Obinutuzumab: 1
• GALEN: 5

Efficacy

• Evaluated in patients who received ≥ one dose of obinutuzumab and lenalidomide (n= 86)
• Median PFS, duration of response (DOR) and OS were not reached (NR)
• Post-hoc analysis found that patients who experienced early PD within 24 months had similar responses, PFS and OS rates as those who relapsed later
• The study met the primary endpoint of overall response post-induction

Safety

• Evaluated in patients who received one dose of either obinutuzumab or lenalidomide (n= 88)
• Adverse events (AEs) of special interest of all grades:
  • Infusion-related reactions (IRRs): 14 (16%)
  • Serious infections: 13 (15%)
  • Secondary primary malignancy: 8 (9%)
  • Tumor flare: 2 (2%)
  • Tumor lysis syndrome: 2 (2%)
• In total, 57 serious AEs (SAEs) were reported in 30 of 88 (34%) evaluable patients
  • Twenty-eight of these were SAEs during the induction phase
• Deaths: 18 (21%)
  • Progressive lymphoma: 10
  • Infection: 4
    • Including one patient who died due to treatment-related febrile neutropenia
  • Related cancer: 1
  • Unknown cause: 3

Conclusion

The phase II GALEN study met its primary endpoint with an ORR of 79% and showed activity in all subgroups, including those with disease progression within 24 months of diagnosis. The safety profile of GALEN was deemed to be acceptable and in line with other studies using the same combination therapies. Studies comparing GALEN, or combinations using GALEN as a backbone, versus R² are warranted.

Other ongoing trials involving GALEN include:

• GALEN + atezolizumab (NCT02631577)
• GALEN versus umbralisib + obinutuzumab versus obinutuzumab + chemotherapy (NCT03269669)