Nivolumab-Based, Response-Adapted Approach Yields Durable Responses in Frontline Follicular Lymphoma

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A response-adapted treatment strategy incorporating nivolumab (Opdivo) with or without rituximab (Rituxan) led to high response rates and durable clinical benefit in patients with treatment-naive follicular lymphoma, according to results from the phase 2 1stFLOR study (NCT03245021) published in Blood.

During the study, patients started with 4 cycles of nivolumab monotherapy, and patients with a complete response (CR) after 4 doses received rituximab in addition to continued nivolumab. Findings showed that evaluable patients (n = 39) achieved an overall response rate (ORR) of 92%, including a complete response (CR) rate of 59%. The median time to CR was 6.5 months (range, 1-25), and 7 patients (18%) who initially achieved a partial response (PR) during induction later converted to CR during maintenance therapy. At data cutoff, 70% of patients with CR had ongoing responses.

Following 4 cycles of priming nivolumab, 5% of patients achieved a CR, 26% had a PR, 28% had stable disease, and 41% had progressive disease. The 2 patients who achieved CR on nivolumab alone had high- and intermediate-risk disease, respectively, per Follicular Lymphoma International Prognostic Index (FLIPI) criteria. The high-risk patient had advanced age, stage IV disease, more than 4 nodal sites, and elevated lactate dehydrogenase (LDH) levels; the intermediate-risk patient had stage IV disease and elevated LDH levels.

Regarding safety, the study met its primary end point with only 33% of patients (n = 39) experienced grade 3 or higher adverse effects (AEs) during induction. Overall, any-grade AEs occurred in all patients, grade 3 or higher AEs were observed in 59% of patients, and 46% had serious AEs. No deaths due to toxicity were reported.

“To our knowledge, our phase 2 immune-priming study is the first to explore the synergy of B-cell targeting with natural killer cell–mediated antibody-dependent cell-mediated cytotoxicity from rituximab, partnered with nivolumab-induced T-cell stimulation in treatment-naive follicular lymphoma,” lead study author Allison Barraclough, MD, and colleagues wrote in the publication of the data. “We demonstrated this combination to be efficacious with a favorable toxicity profile.”

Barraclough is a member of the Department of Hematology at Fiona Stanley Hospital, in Murdoch, the Department of Hematology at Olivia Newton John Cancer Research Institute at Austin Health in Heidelberg, and Melbourne Medical School at The University of Melbourne in Australia. She is also a PhD candidate at the University of Melbourne.

At a median follow-up of 51 months (range, 2-72), the median duration of response (DOR) was 59 months (range, 0-68). Progression occurred in 14 patients (36%) requiring treatment discontinuation, and an additional 5 patients (13%) experienced disease progression during follow-up. Ten total patients experienced progression within 24 months of initiating therapy, and of the 19 patients with disease progression, 14 required subsequent treatment.

The median progression-free survival (PFS) was 61 months (95% CI, 2-72), and the median overall survival (OS) was not reached (95% CI, 18-72). The 4-year PFS and OS rates were 58% (95% CI, 41%-72%) and 95% (95% CI, 81%-99%), respectively.

1stFLOR Trial Design

The 1stFLOR trial was a single-arm, investigator-initiated study that enrolled patients at least 18 years of age with treatment-naive, grade 1 to 3A follicular lymphoma that was stage II to IV. Patients with stage II disease were eligible if the disease was able to be encompassed within a single radiotherapy field. An ECOG performance status of 0 to 2 and adequate organ function were required.

Key exclusion criteria included prior exposure to immune checkpoint inhibitors or T-cell–redirecting therapies; active autoimmune disease; immunosuppressive therapy; interstitial lung disease; central nervous system involvement; active hepatitis B or C; or HIV.

Induction treatment consisted of nivolumab at 240 mg intravenously every 2 weeks for 4 cycles. Patients who achieved a complete metabolic response (CMR) based on PET/CT imaging continued on single-agent nivolumab. Those with less than a CMR proceeded to combination therapy with nivolumab plus rituximab at 375 mg/m² for 4 cycles. All patients achieving a response were then eligible for maintenance therapy with nivolumab at 480 mg every 4 weeks for 12 months. Patients who had received rituximab during induction continued maintenance rituximab every 12 weeks for 2 years.

The primary end point was the incidence of grade 3 or higher treatment-related adverse effects during the induction phase. The study followed a Simon 2-stage design, with 39 patients enrolled overall. Among the first 19 patients enrolled, if 7 or more experienced grade 3 or higher toxicities during induction, the study would end; otherwise, accrual would continue to 39 patients. Secondary end points included overall treatment-emergent toxicity, ORR per Lugano 2014 PET/CT criteria, PFS, and OS.

‌Baseline Patient Demographics

Enrolled patients had a median age of 54 years (range, 28-79). The study population was balanced by sex, with 49% female and 51% male participants. Most patients presented with advanced-stage disease, with 33% having Ann Arbor stage III and 67% having stage IV disease.

The majority of patients (74%) had an ECOG performance status of 0, and the remaining 26% had a performance status of 1. B symptoms were reported in 23% of patients, and bulky disease (≥7 cm) was observed in 23%. Additionally, 74% of patients had at least 1 extranodal disease site.

Histologic subtypes included grade 1 to 2 follicular lymphoma in 77% of patients and grade 3A in 21%. Most patients (80%) met GELF criteria for treatment initiation. Other eligibility criteria included rapid disease progression in the prior 3 months (15%) and symptomatic lymphadenopathy or painful bone lesions (5%). FLIPI risk stratification showed that 26% of patients were classified as low risk (score 0-1), 56% as intermediate risk (score 2), and 18% as high risk (score 3).

Biomarker Analysis and Additional Safety Data

Gene expression profiling was conducted on 34 pretreatment tumor biopsy samples collected from patients enrolled in the study. Among the biomarkers analyzed, elevated CD8A expression in tumor tissue prior to treatment was significantly associated with favorable outcomes.

Patients who achieved a CR or PR following nivolumab monotherapy (n = 11) exhibited significantly higher CD8A expression compared with those who experienced stable disease or progressive disease (n = 22; P = .02). This trend was also observed among patients who remained relapse-free throughout the follow-up period (no relapse, n = 16) compared with those who experienced relapse (n = 18; P = .02).

Importantly, CD8A expression was significantly higher in patients whose best evaluable response during the study was a CR (n = 19), relative to those who achieved a PR or experienced PD (n = 15; P = .03). Furthermore, patients with high pretreatment CD8A expression (n = 17) experienced significantly longer PFS compared with those with lower expression levels (n = 17; P = .03).

Expression levels of other immune-related markers—including CD4, PD-1, PD-L1, PD-L2, LAG3, TIGIT, and TIM3—did not correlate with treatment response or survival outcomes. These findings suggest that tumor-infiltrating CD8-positive T-cell activity, as reflected by CD8A gene expression, may serve as a predictive biomarker for response and durable benefit in patients with follicular lymphoma receiving nivolumab-based therapy.

Further safety data demonstrated that the most common any-grade AEs reported in more than 15% of patients included infection (82%), fatigue/lethargy (62%), musculoskeletal (62%), rash (60%), elevated liver enzymes (44%), abdominal pain (41%), nausea/vomiting (41%), diarrhea (34%), rituximab infusion-related reaction (IRR; 31%), headache (28%), dyspnea (23%), nivolumab IRR (23%), anorexia/weight loss (23%), increased amylase/lipase levels (21%), insomnia (21%), mood disturbance (21%), gastroesophageal reflux disease (18%), hyperglycemia (18%), cough (18%), and pruritus (18%).

Reference

Barraclough A, Lee ST, Burgess M, et al. Nivolumab and rituximab in treatment-naïve follicular lymphoma: the phase 2 1st FLOR study. Blood.2025:9(6):1432-1441. doi:10.1182/bloodadvances.2024015487