Frontline Nivolumab and Rituximab Shows Efficacy With Manageable Safety in Follicular Lymphoma

Eliza A. Hawkes, MD

A large number of responses were observed in patients with advanced-stage follicular lymphoma who were treated with frontline nivolumab (Opdivo) plus rituximab (Rituxan), according to results from the phase 2 1st FLOR trial (NCT03245021).

Additionally, the combination showed a manageable safety profile, according to Eliza A. Hawkes, MD, who presented the results during the 2021 International Conference on Malignant Lymphoma.¹

Hawkes, a senior clinical research fellow and medical lead in lymphoma at the Olivia Newton- John Cancer Research Institute in Heidelberg, Australia, noted that standard frontline combination therapies have high response rates (75%-89%) but also high toxicity rates.

“Noting that these roughly compare to some chemotherapy combinations, the high efficacy compared [with] similar checkpoint inhibitor combinations in relapsed [disease] suggests adequate immune function is crucial to the success of these agents,” Hawkes said.

She suggested that due to the tumor microenvironment composition in follicular lymphoma, there is a possible role for immune manipulation with checkpoint inhibition. However, prior trials of PD-1/PD-L1 inhibitors have shown limited efficacy in heavily pretreated follicular lymphoma. In the phase 2 Check-Mate 140 trial (NCT02038946), nivolumab monotherapy led to an objective response rate (ORR) of 4% and a median progression-free survival (PFS) of 2.2 months in patients with relapsed/refractory disease.²

Combination pembrolizumab (Keytruda) and rituximab led to an ORR of 65% and a complete response (CR) rate of 50% in patients with relapsed/refractory follicular lymphoma, suggesting that there is synergy between the 2 agents.³

Investigators believed that PD-1 inhibitors could sensitize patients with relapsed non-Hodgkin lymphoma to subsequent chemotherapy. As such, the study investigators sought to determine if immune priming with nivolumab prior to combination therapy of nivolumab and rituximab could improve outcomes for patients with treatmentnaive follicular lymphoma.

The 1st FLOR study enrolled 39 patients with grade 1 to 3a, stage III/IV follicular lymphoma requiring therapy who were given treatment in an induction and a maintenance phase. Treatment was first given with nivolumab 240 mg/kg intravenously (IV) every 2 weeks for 4 cycles. If patients achieved a CR, they received nivolumab every 2 weeks for 4 cycles then nivolumab at 480 mg/kg IV every 4 weeks for 12 cycles as maintenance. If not, patients received nivolumab 240 mg/kg IV plus rituximab 375 mg/m² IV every 2 weeks for 4 cycles. If patients achieved a response after induction therapy, they received maintenance with rituximab every 12 weeks for 8 cycles and nivolumab 480 mg/kg every 4 weeks for 12 cycles.

The primary end point was safety in terms of grade 3 or higher adverse events (AEs). Secondary end points included overall toxicity rate, ORR, PFS, and overall survival (OS).

Patients had a median age of 54 years (range, 28-79). The majority were men (51%), had Ann Arbor stage IV disease (67%), an ECOG performance status of 0 (74%), at least 1 extranodal site (74%), grade 1-2 follicular lymphoma (79%), and/or had intermediate-risk disease (56%).

The ORR was 93%, which consisted of CRs in 56% of patients and partial responses in 36%. Twenty-eight percent of patients had a response on nivolumab alone. Sixteen patients had a partial response during the induction phase, and 6 of them converted to a CR during maintenance.

The median duration of response was not reached after a median follow-up of 22 months both in the overall population of patients as well as in the patients who had a response to therapy. The median time to CR was 5 months (range, 1-25).

At 1 year, the OS rate was 97% (95% CI, 85%- 100%) and the failure-free survival rate was 68% (95% CI, 49%-83%). There were 11 progression events and 1 death during the study. The median time to progression was 10 months.

The primary end point of this study was met with only 41% of patients experiencing a grade 3 or higher AE during induction. Grade 3 or higher toxicities were reported in 64% of patients overall. Only 1 case of grade 4 toxicity of lymphopenia was reported during the maintenance phase, and 1 death was reported from transformed disease that was refractory to chemotherapy.

The most common grade 3 AEs observed during induction were lipase/amylase increase (8%), infection (8%), hyperglycemia (5%), and infusion reaction to either agent (5%). Grade 3 or higher AEs overall reported in 2 or more patients were infection (13%), lipase/amylase increase (8%), hyperglycemia (8%), hypotension (5%), infusion reaction (5%), and transaminitis.

Common immune-related AEs were rash, myalgia/arthralgia, dry mouth/eyes/skin, diarrhea, and transaminitis. One patient stopped nivolumab at the end of induction therapy due to grade 3 immune-related AEs. The majority of AEs were reversible.

Hawkes suggested that further studies of immunotherapy-based combinations showed be explored in patients with immunologically intact follicular lymphoma.

_REFERENCES:

_{1. Hawkes EA, Lee ST, Chong G, et al. Immune priming with nivolumab followed by nivolumab & rituximab in 1st line treatment of follicular lymphoma: the phase II ‘1st FLOR’ study. Presented at: 16th International Conference on Malignant Lymphoma; June 18-22, 2021; virtual. Abstract 081.}

_{2. Armand P, Janssens A, Gritti G, et al. Efficacy and safety results from CheckMate 140, a phase 2 study of nivolumab for relapsed/refractory follicular lymphoma. Blood. 2021;137(5):637-645. doi:10.1182/blood.2019004753}

_{3. Nastoupil LJ, Westin J, Fowler N, at al. High response rates with pembrolizumab in combination with rituximab in patients with relapsed follicular lymphoma: interim results of an on open-label, phase II study. Hematol Oncol. 2017;35(S2):120-121. doi:10.1002/hon.2437_108}