Lenalidomide-Obinutuzumab Combo Yields Promising Results in Relapsed NHL

A recent phase 1/2 clinical trial, published in eClinicalMedicine, investigates the safety and efficacy of lenalidomide (Revlimid) in combination with obinutuzumab (Gazvya) for patients with relapsed indolent non-Hodgkin lymphoma (NHL).¹ The study aimed to determine the recommended phase 2 dose and evaluate the combination therapy's safety and overall response rate after 6 months of induction therapy.

NHL cells | image credit: sovova - stock.adobe.com

The trial, conducted at MD Anderson Cancer Center between June 2014 and March 2019, was a single-arm open-label trial that enrolled 66 patients with relapsed or refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), and small lymphocytic lymphoma (SLL), noting that approximately 85% of patients had FL. Patients received lenalidomide at varying doses, combined with a fixed dose of intravenous obinutuzumab (1000 mg), to establish the optimal dose for phase 2 trials. Lenalidomide was ultimately dosed at 20 mg combined with a fixed dose of obinutuzumab at 1000 mg, based on the phase 1 dose-escalation results. The patients underwent 6 total 28-day cycles of this combination therapy, with the possibility of receiving up to 6 additional cycles depending on their response to treatment.

After completing 6 cycles of induction therapy, 90% of the patients (n = 54; 95% CI, 79-96) achieved an overall response, meeting the trial's primary efficacy endpoint. Additionally, 33% of the patients (n = 20; 95% CI, 22-47) achieved a complete response. The study did not reach median progression-free survival (PFS), time to progression (TTP), or overall survival (OS), even after a median follow-up of 41.7 months. The estimated 4-year PFS rate was 55% (95% CI, 42-73), with a TTP of 56% (95% CI, 43-74) and OS of 84% (95% CI, 74-95). "Despite 42% of our efficacy cohort only receiving a 6-month duration of lenalidomide, we report high overall response rates. Interestingly, there were no significant differences in PFS or TTP by whether there were 6 cycles compared to >6 cycles of lenalidomide completed with median survival times not reached for both groups," the researchers noted.

The safety profile of lenalidomide and obinutuzumab was consistent with the reported toxicities of lenalidomide and rituximab in the AUGMENT trial.² The most common Grade 3 or 4 hematological toxicities observed were neutropenia in 21% of patients and thrombocytopenia in 11%. No cases of febrile neutropenia were reported. The most common non-hematological adverse events were mainly Grade 1 or 2, with 83% of patients experiencing fatigue, 58% having a rash, and 53% with a cough. Non-hematological Grade 3 or 4 toxicities included lung infections and fatigue, each affecting 8% of patients. Severe adverse events were seen in 27% of patients, including lung infections (8%), sepsis (5%), and sinus bradycardia (3%).¹

High-risk subgroups of patients were also evaluated, including those who had experienced disease progression within 24 months of diagnosis (POD24) or were refractory to their last line of therapy. Nearly a quarter of patients were noted to be refractory to rituximab. Among patients with POD24, the overall response rate was 93% (95% CI, 76-99), with 33% achieving complete responses. The median PFS in this group was 44.2 months (95% CI, 22.5–NA).

While the authors conclude that "oral lenalidomide with obinutuzumab is safe and highly active in patients with relapsed and refractory indolent B cell non-Hodgkin lymphoma and is associated with prolonged remission duration," they also note the study is limited by the lack of a control arm, which makes it difficult to directly compare outcomes to current standard treatments, such as rituximab and lenalidomide.

References:

1. Gurumurthi A, Chin CK, Feng L, et al. Safety and activity of lenalidomide in combination with obinutuzumab in patients with relapsed indolent non-Hodgkin lymphoma: a single group, open-label, phase 1/2 trial. EClinicalMedicine. 2024;74:102747. doi:10.1016/j.eclinm.2024.102747
2. Leonard JP, Trneny M, Izutsu K, et al. AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol. 2019;37(14):1188-1199. doi:10.1200/JCO.19.00010