Background: Novel strategies are needed to improve upon the 60% cure rate of upfront R-CHOP in advanced DLBCL. Single-agent immune checkpoint inhibition (ICI) has limited efficacy in heavily pre-treated DLBCL (response rate <10%, Ansell JCO 2019), potentially due to residual immunocompromise from prior therapy. Frontline ICI, given when host immunity is relatively intact, may improve these outcomes. Concurrent ICI with R-CHOP is safe (Smith BJH 2020) but corticosteroid-related immunosuppression may negate ICI efficacy. These factors, along with evidence that ICI sensitises non-Hodgkin lymphoma to subsequent chemotherapy (Carreau BJH 2020), support a sequential treatment strategy. Avelumab (Av) is an anti-PDL1 monoclonal antibody with antibody dependent cell cytotoxicity (ADCC) activity which acts synergistically with rituximab (R) in vitro. We report the results of a phase II single arm study assessing safety of 1st line sequential AvR induction, R-CHOP & Av maintenance for DLBCL. Methods: Patients aged ≥18 years, ECOG 0-2 with untreated stage II-IV DLBCL and no active autoimmune disease were treated with AvR induction x2 cycles q2-weekly (Av 10mg/kg IV + R 375mg/m2 IV), followed by R-CHOP21 x 6 cycles then Av 10mg/kg x 6 cycles q2-weekly if in complete metabolic response (CMR) post R-CHOP. The primary endpoint was the rate of grade 3/4 immune-related adverse events (irAE). Secondary endpoints included overall response rate (ORR), failure free survival (FFS), overall survival (OS) and overall toxicity. Response was determined centrally by PET-CT (Lugano 2014 criteria). CMR rates by PET-CT post AvR induction and post C2 R-CHOP were exploratory endpoints. Genomic analysis was performed including next generation sequencing (NGS) based sequence variant detection, copy number analysis and structural variant detection. Results: 28 pts were enrolled from Dec 2017 to Oct 2019. Key baseline characteristics included median age 54 yrs (range 20-79); stage III/IV disease 68%; elevated LDH 61%; IPI ≥2 25%. Histology included 21 DLBCL NOS (75%; 14 GCB, 7 non-GCB by Hans algorithm), 6 primary mediastinal B-cell lymphoma (PMBCL; 21%) and 1 EBV positive DLBCL (4%). The study met its pre-specified primary endpoint of G3/4 irAE <30%. Grade 3/4 irAEs included hepatitis (n=1) and rash (n=2). G1/2 irAEs occurred in 71% (20/28) as follows: rash 53%, liver dysfunction 26%, hyper/hypothyroidism 29% and diarrhoea 21%. 79% had G3/4 toxicity, predominantly haematological, related to RCHOP with febrile neutropenia/infection in 28% of pts. ORR post R-CHOP was 89% (all CR) (Figure 1). The ORR to 2 cycles of induction AvR was 60%, including 6 CMR (21%) across all diagnostic/histologic subgroups (n=1 PMBCL, n=2 non-GCB DLBCL, n=3 GCB DLBCL; Figures 1 and 2). Six pts (21%) progressed during AvR induction (with 1 pt completing only 1 x AvR cycle); all subsequently responded to R-CHOP. With a median follow-up of 16 months, 1-year FFS was 76% and OS 89%. Treatment was discontinued early in 5 pts; 2 during R-CHOP due to progressive disease and 3 during Av maintenance (n=1 immune hepatitis; n=1 pulmonary embolism initially reported as pneumonitis; n=1 progressive disease). Alterations in the CD274/PDCDLG2 locus were identified by NGS in 3 of 27 evaluable pts (n=2 PMBCL, n=1 EBV+ DLBCL). Full genomic analysis to identify factors associated with response will be presented. Conclusion: Sequential AvR induction, R-CHOP and Av maintenance in pts with newly diagnosed DLBCL is feasible with a manageable toxicity profile and a high CR rate. Responses to AvR alone were higher than expected based on the relapsed/refractory population and may suggest superior efficacy of ICI in the frontline setting. These results support ongoing sequential studies of immune priming with PD1/PDL1 inhibition prior to R-CHOP in DLBCL. Acknowledgements: Merck KgA for avelumab plus funding. Tour de Cure Scott Canning Early Career Grant (E Hawkes) and Wilson Centre for Lymphoma Genomics for biomarker testing. Disclosures Hawkes: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding, Speakers Bureau; BMS celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Merck Sharpe &Dohme: Membership on an entity's Board of Directors or advisory committees, Research Funding; takeda: Speakers Bureau; Merck KgA: Research Funding. Chong:Merck Serono: Research Funding; Bristol-Myers Squibb: Research Funding; Hutchison Medipharma: Research Funding; Bayer: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Servier: Research Funding; Isofol: Research Funding. Blombery:Novartis: Consultancy; Janssen: Honoraria; Amgen: Consultancy; Invivoscribe: Honoraria. Barraclough:Roche: Other: Conference sponsorship. Keane:Celgene: Honoraria, Other: Travel; BMS: Research Funding; Roche: Honoraria, Other: Travel, Speakers Bureau; MSD Oncology: Honoraria, Other: Travel; Gilead: Honoraria, Other: Travel, Speakers Bureau. Fong:Pfizer: Honoraria; Astellas: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria; AbbVie: Honoraria. Manos:Bristol-Myers Squibb: Other: Conference sponsorship. OffLabel Disclosure: Avelumab is an anti-PDL1 monoclonal antibody. Inhibition of the PD1/PDL1 pathway stimulates anti-tumour immunity.
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. Acknowledgements: Bristol-myers Squibb provided funding and nivolumab for this study. References: 1. Salmaninejad A, et al. PD-1/PD-L1 pathway: Basic biology and role in cancer immunotherapy. J Cell Physiol. 2. Ferris RL, et al. Rationale for combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors: Harnessing innate and adaptive immunity through IgG1 isotype immune effector stimulation. Cancer Treat Rev. 3. Nastoupil LJ, et al. Response rates with pembrolizumab in combination with rituximab in patients with relapsed follicular lymphoma: Interim results of an on open-label, phase II study. J Clin Oncol. 4. Park SE, et al. Increased Response Rates to Salvage Chemotherapy Administered after PD-1/PD-L1 Inhibitors in Patients with Non-Small Cell Lung Cancer. J Thorac Oncol. Disclosures Chong: Novartis: Research Funding; Hutchison Medipharma: Research Funding; Pharmacyclics: Research Funding; Bayer: Research Funding; Merck Serono: Research Funding; BMS: Research Funding. Gilbertson:Roche: Speakers Bureau; Roche: Honoraria. Grigg:Janssen: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel. Ritchie:Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Takeda: Research Funding; Beigene: Research Funding; Imago: Research Funding; Novartis: Honoraria; Sanofi: Honoraria. Koldej:NanoString Technologies: Other: Travel grant. Manos:Novo Nordisk Pharmaceuticals: Other: Travel; Janssen: Honoraria. Hawkes:Astra Zeneca: Research Funding; BMS: Research Funding, Speakers Bureau; Merck KgA: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Mundi pharma: Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Merck Sharpe & Dohme: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Takeda: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Nivolumab is a fully human IgG4 monoclonal antibody against programmed cell death 1 (PD-1). The PD-1 pathway is an immune system checkpoint that may be exploited by tumour cells to escape immune surveillance. By blocking the binding of the PD-1 receptor to the PD-1 and PD- 2 ligands, nivolumab reactivates tumour-specific cytotoxic T-lymphocytes in the tumour microenvironment to restimulate anti-tumour immunity.
7560 Background: Standard of care immunochemotherapy in front-line (1L) follicular lymphoma (FL) is highly efficacious but not without significant toxicity. High rates of grade 3-5 adverse events (AEs), primarily infection and bone marrow suppression, are experienced in up to 75% of patients. A more tolerable but equally effective approach is required. PD-1 inhibition, in combination with rituximab (R), increases T cell anti-tumour effect & enhances NK cell antibody dependent cell cytotoxicity, with proven efficacy in relapsed FL. The concept of ‘priming’ the immune system with nivolumab (N) prior to tumour-directed therapy has rationale and evidence, but the safety of this approach in 1L FL is not described. Methods: ‘1st FLOR’ (NCT03245021) is an open-label, multi-centre, phase 2, Simon’s 2-stage study of N + R (N = 39). Key eligibility were stage III-IV grade 1-3A FL requiring 1L systemic therapy; ECOG ≤2; adequate organ function. All patients (pts) receive induction N 240mg IV 2-weekly for 4 cycles. Pts with complete response (CR) receive 4 further cycles of 240mg IV N monotherapy then 12 cycles of maintenance N 480mg IV 4-weekly. Pts with < CR had 240mg N plus 375mg/m2 IV R 2-weekly for 4 cycles followed by maintenance N+R (N 480mg 4 weekly for 12 cycles; R 12 weekly for 8 cycles). Primary endpoint (EP) was ≥ G3 toxicity rate during induction. Secondary EPs; response rate by Lugano response criteria, overall toxicity, PFS, OS. Results: Between September 2017 to March 2020, 39 pts were enrolled. Baseline characteristics included median age of 54 (range: 28-79). stage IV disease in 67%, B Symptoms & bulk (≥7cm) in 23% each, intermediate-high risk FLIPI in 74%. The primary EP was met, with only 16 pts (41%) having ≥G3 toxicity at end of induction. Non-immune AEs were predominantly G1-2; most commonly infection (67%) & fatigue (64%). G3-4 Immune-related AEs were infrequent and included pancreatitis plus hepatitis (N = 1), pancreatitis alone (N = 1), rash (N = 1), transaminitis (N = 2), hypocortisolism (N = 1), hyperglycaemia (N = 3) and asymptomatic lipase/amylase increase (N = 3). Median follow-up was 17.5 months (range: 7-39). Overall response rate was 92% (36/39) with CR in 54% (21/39). Median time to CR was 5 months (m) (range: 2-25). Nine pts (23%) discontinued treatment; 7 due to progressive disease (1 pt died of transformed FL), 2 developed constitutional symptoms (1 stable disease, 1 partial response). In 25 evaluable pts, 12m PFS & OS is 72% (CI 51-88) & 96% (CI 80-100). Biomarker analysis is in progress. Conclusions: Immune-priming with single-agent N, then combination N+R in 1L FL is associated with favourable toxicity and high ORR & CR rates potentially providing an alternative to chemotherapy. Acknowledgements: Bristol-myers Squibb provided funding and nivolumab for this study. Clinical trial information: NCT03245021.
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