Immune priming with single-agent nivolumab followed by combined nivolumab & rituximab is safe and efficacious for first-time treatment of follicular lymphoma; interim analysis of the "1st FLOR" study.

Abstract

Background: The effectiveness of anti-tumour T and NK cells in malignancy is mitigated by the engagement of the immune check point pathway with PD-1/PDL-1 interaction.1,2 Immune manipulation with PD-1 inhibition, in combination with rituximab, can increase T cell anti-tumour effect and enhance NK cell antibody dependent cell cytotoxicity (ADCC), with this combination proving efficacious in rituximab-refractory follicular lymphoma (FL).3 The concept of ‘priming’ the immune system with nivolumab, a PD-1 inhibitor, prior to tumour-directed therapy has rationale and evidence, but the safety of this approach in previously untreated FL is not described.4 We are conducting a phase II Simon's two stage study to assess the feasibility and safety of combination nivolumab and rituximab in these patients and present the pre-planned interim analysis results.

Methods: The 1st FLOR study (NCT03245021) is an ongoing open-label, multi-centre, phase 2 study of nivolumab and rituximab in patients with previously untreated stage III-IV grade 1-3A FL requiring systemic therapy. Eligible patients are ECOG ≤ 2 and do not require urgent debulking therapy. All patients receive induction nivolumab 240mg intravenously (IV) every 2 weeks for 4 cycles. Patients achieving complete response (CR) based on PET/CT Lugano criteria receive a further 4 cycles of 240mg IV nivolumab monotherapy then maintenance nivolumab 480mg IV every 4 weeks for 12 cycles. Patients achieving less than CR received 240mg nivolumab plus 375mg/m2 IV rituximab every 2 weeks for 4 cycles. Those achieving a response at the end of 8 cycles of nivolumab and rituximab continue maintenance nivolumab 480mg IV every 4 weeks for 12 cycles PLUS rituximab 375mg/m2 every 12 weeks for 8 cycles. PET/CT assessment is performed at baseline, after 4 cycles of nivolumab, after 8 cycles of nivolumab +/-rituximab and prior to maintenance cycle 6. The primary end point is safety, with a pre-planned analysis after the first 19 patients completed induction treatment with 8 cycles of nivolumab +/- rituximab. Secondary endpoints included response rates and time to treatment failure (TTF). The planned total study population is 39 patients, with a Simon's two-stage design. We report the results of the pre-planned interim analysis.

Results: Baseline characteristics are summarised in Table 1. Treatment-related adverse events (AEs) were predominantly grade 1-2 with fatigue (74%), infection (59%), nausea/vomiting (36%) and abdominal pain (36%) being the most common (Table 2). Immune-related (IR) AEs were reported in 79% of all patients. Grade 3-4 IRAEs were uncommon and included; pancreatitis plus hepatitis (1 patient); transaminitis (n=1), hyperglycaemia (n=2) and asymptomatic lipase increase (n=2) (Table 3).

Median follow-up was 17 months. The overall response rate (ORR) was 84% (16/19) with 47% (9/19) achieving CR, 37% (7/19) partial response (PR), 5% (1/19) stable disease and 11% (2/19) progressive disease (PD) as best response (Figure 1A and 1B). Median time to CR was 5 months. Median TTF was 3.4 months. Three pts (16%) discontinued study treatment; 2 due to early disease progression (1 with suspicion of transformation in cycle 2) and 1 due to development of constitutional symptoms with stable disease.

Conclusion: In this planned interim analysis, the combination of nivolumab and rituximab in treatment naive follicular lymphoma is associated with a favourable toxicity profile and high overall and complete response rates potentially providing patients an alternative to traditional chemotherapy.