Nivolumab in Combination with Gemcitabine and Oxaliplatin (GemOx) in Relapse/Refractory T-Cell Lymphoma: Preliminary Results of the Experimental Arm of the Niveau Trial
Authors: Houot Roch , Poeschel Viola , Altmann Bettina , Illmer Thomas , André Marc , Dreyling Martin , Maisonneuve Herve , Tilly Herve , Mayer Stephanie , Casasnovas Rene-Olivier , Le Gouill Steven , Offner Fritz C. , Cartron Guillaume , Kerkhoff Andrea , Weber Thomas , Hoffmann Joerg , Ziepert Marita , Klapper Wolfram , Itti Emmanuel , Hellwig Dirk , De Leval Laurence , Rosenwald Andreas , Haioun Corinne , Dercle Laurent , Gaulard Philippe , Held Gerhard 
Published: November 2020

Introduction
Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of aggressive lymphomas, which usually carry a poor prognosis. Malignant T-cells may overexpress programmed death ligand 1 (PD-L1), which signals via programmed death-1 (PD-1) receptor, and provides an inhibitory signal on normal T-cells further suppressing antitumor immunity. They can also express PD1 which may act as a tumor suppressor on malignant T-cells (Wartewig et al, Nature 2017). Thus, blocking the PD1/PDL1 synapse in PTCL may lead to tumor regression or progression.
The NIVEAU trial is an ongoing international, multicenter, randomized, open label, phase 3 study testing Nivolumab (Nivo) in combination with (Rituximab), Gemcitabine, Oxaliplatin ((R-)GemOx) for patients with aggressive (B and T-cell) Non-Hodgkin Lymphoma in first relapse or progression not eligible for High-Dose Chemotherapy (NCT03366272). Here, we performed a preliminary analysis of the experimental arm (Nivo-GemOx) of the PTCL cohort to assess the safety and efficacy of this regimen in this population.
Methods
Key eligibility criteria include: first relapse or progression of peripheral T-cell lymphoma (PTCL), ineligibility for high dose therapy (defined as &gt;65 years of age or older than 18 years if HCT-CI score &gt; 2), only one prior chemotherapy regimen including an anthracycline. Pts were planned to receive 8 cycles Nivolumab (3mg/kg) plus Gemcitabine and Oxaliplatin in 2-wk intervals followed by additional 18 Nivolumab (3mg/kg) biweekly as consolidation or until progression. Response was evaluated after 4 and 8 cycles of GemOx. Each progression/relapse of PTCL had to be reported as a SAE.
Results
The analysis (data cut-off 13-July-2020) included 12 PTCL pts enrolled in the experimental arm (Table 1): 4 (33%) PTCL NOS, 3 (25%) AITL, 1 (8%) PTCL TFH-type, 2 (17%) ALCL ALK-, 1 (8%) EATL, and 1 (8%) MEITL. Median age was 69.5 years (range, 53-80), 7 (58%) patients were male, 2 (17%) had received a prior autologous stem cell transplantation, and 5 (42%) were refractory to first line therapy. At enrollment, performance status was 0-1 in 9 (75%) pts and 2 in 3 (25%) pts, 11 (92%) had Ann Arbor stage III-IV, 2 (17%) had B-symptoms, 7 (58%) had more than one extra-nodal site and 4 (33%) had elevated LDH. PD1 and PD-L1 were expressed by the tumor cells in 6/10 (60%) and 2/11 (18%) patients, respectively (Table 1). Pts have received a median of 6 (1-8) cycles of GemOx and 7 (1-26) infusions of nivolumab. Treatment was prematurely discontinued in 9 pts (7 during induction and 2 during consolidation), due to lymphoma progression (n=6), toxicity (n=2) and an intercurrent disease (n=1). There were 26 SAE in 10 patients, including 8 progressive diseases. Nine (75%) patients achieved an objective response (4 CR and 5 PR). Two patients (pt 9: MEITL PD1-negative; and pt 12: PTCL-NOS strongly PD1-positive) experienced primary progression upon Nivo-GemOx (Table 1). Median PFS2 (time from randomisation to 2nd rel/prog/death) was 6.9 months (95% CI: 1.9-11.9) vs 7.7 months (95% CI: 7.2-8.2) for PFS1 (time from diagnosis to 1st rel/prog). PFS2 was superior to PFS1 in 2 out of 8 patients (25%), and not informative in 4 pts: 3 who are still on therapy (ongoing PFS) and 1 who died prematurely due to infection (pt 8) (Figure 1). Median OS was 24.8 months (95% CI: 0-49.8). After a median follow-up of 22.8 months, 7 patients have died (5 from lymphoma and 2 from infection (1 COVID-19 infection and 1 yeast septicemia)), and 5 remain alive.
Conclusions
Nivolumab in combination with GemOx was well tolerated in PTCL. The response rate and PFS2 (compared to PFS1) are encouraging. Marked differences in PFS2 might reflect heterogeneity of biology and susceptibility to PD-1 blockade in combination with GemOx chemotherapy. Furthermore, the translational research program of the study might help to identify markers which are predictive for efficacy of PD-1 blockade in PTCL. This phase 3 trial is actively enrolling patients and an update of these results will be presented at the meeting.
Disclosure: ISR financially supported by Bristol Myers Squibb.

Disclosures
Houot: Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Kite: Honoraria; Gilead: Honoraria; MSD: Honoraria; Bristol-Myers Squibb: Honoraria. Poeschel:Roche: Other: Travel, Accommodations, Expenses; Amgen: Other: Travel, Accommodations, Expenses; Abbvie: Other: Travel, Accommodations, Expenses. André:Abbvie: Consultancy; Celgene: Other, Research Funding; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Takeda: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Karyopharm: Consultancy; CHU UCL Namur, site Godinne, Yvoir, Belgium: Current Employment; Seattle Genetics: Consultancy; Gilead: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Johnson & Johnson: Research Funding; Novartis: Consultancy, Research Funding; Amgen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Dreyling:Beigene: Consultancy; Bayer: Consultancy, Speakers Bureau; Astra Zeneca: Consultancy; Abbvie: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau. Tilly:BMS: Honoraria. Casasnovas:Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Amgen: Consultancy, Honoraria; MSD: Consultancy, Honoraria. Le Gouill:Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria; Loxo Oncology at Lilly: Consultancy. Cartron:Celgene: Consultancy, Honoraria; Gilead: Honoraria; Abbvie: Honoraria; Jansen: Honoraria; Sanofi: Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria. Kerkhoff:BMS: Honoraria. De Leval:Lausanne University Hospital & Lausanne University Institute of Pathology: Current Employment; Lunaphore Technologies SA: Consultancy, Honoraria; Abbvie: Honoraria; Roche Diagnostics: Honoraria. Gaulard:takeda: Honoraria, Research Funding; innate pharma: Research Funding. Held:Roche: Consultancy, Other: travel grants, Research Funding; MSD: Consultancy; Acrotech, Spectrum: Research Funding; Amgen: Research Funding; BMS: Consultancy, Other: Travel Grants, Research Funding.

OffLabel Disclosure:
Nivolumab in peripheral T-cell lymphoma