Polatuzumab vedotin + obinutuzumab + venetoclax in patients with relapsed/refractory (r/r) follicular lymphoma (fl): primary analysis of a phase 1b/2 trial

Introduction: Polatuzumab vedotin (Pola) + obinutuzumab (G) demonstrated activity and tolerability in a Phase 1b/2 trial of patients (pts) with R/R FL (Phillips, et al. Blood 2016). Preclinical studies with venetoclax (Ven) showed that concurrent treatment with Pola promotes MCL-1 degradation, a known mechanism of resistance to Ven, and enhances in vivo anti-tumor efficacy (Amin, et al. AACR 2020). Here, we report the primary safety/efficacy analysis with Pola-G-Ven in a Phase 1b/2 study of pts with R/R FL (GO29833; NCT02611323). Methods: Pts received induction treatment every 21 days (D) x six cycles (C) of: Pola 1.4–1.8mg/kg intravenously (IV) in dose escalation (DE) or recommended Phase II dose (RP2D) on D1; G 1000mg IV (C1: D1, D8, D15; C2–6: D1); and oral Ven 200–800mg (DE or RP2D; D1–21). Pts with complete response/partial response/stable disease (CR/PR/SD) at end of induction (EOI) received maintenance with G (1000mg on D1 every 2 months [mo] for 24 mo) and Ven (200–800mg daily) for 8 mo. Primary endpoints were safety/tolerability and positron emission tomography (PET)-CR rate at EOI by independent review committee (IRC) using modified Lugano criteria. Results: At the primary analysis (Oct 05, 2020), 74 pts were enrolled. Median pt age was 64 years (range 36–78); male (57%); Ann Arbor Stage III–IV (86%); FL International Prognostic Index high risk ≥3 (55%); bulky disease ≥7cm (16%); prior lines of therapy ≥2 (74%); refractory to: last prior therapy (51%), any prior anti-CD20 therapy (55%), both anti-CD20 therapy and an alkylating agent (double refractory; 55%). Grade 3–4 adverse events (AEs) were experienced by 73% of pts; most commonly, neutropenia (39%), thrombocytopenia (19%), and infections (16%; mainly pneumonia). AEs led to dose reduction in 38% and interruption in 68% of pts (mainly modifications to Ven). One fatal AE was reported (pneumonia). In total, 49 pts were treated at RP2D (Pola 1.8mg/kg + Ven 800mg) and were evaluable for efficacy. PET-CR rate at EOI by IRC was 57% (Table). With a median follow-up of 14.4 mo (range 8.2–28.4), the 12-mo progression-free survival (PFS) was 73% (95% confidence interval: 59.4–86.9). Median PFS was not reached. Conclusions: The safety profile of Pola-G-Ven is consistent with the known profiles of the individual drugs. Response rates at EOI with Pola-G-Ven are encouraging in this R/R FL patient population. Additional follow-up is needed to assess PFS benefit during maintenance treatment and beyond. EA – previously submitted to ASCO 2021. The research was funded by: F. Hoffmann-La Roche Ltd/Genentech, Inc. Third party medical writing assistance, under the direction of the authors, was provided by Carla Smith, MSc, of Ashfield MedComms, an Ashfield Health company, and was funded by F. Hoffmann-La Roche Ltd. Keywords: Indolent non-Hodgkin lymphoma, Molecular Targeted Therapies, Combination Therapies Conflicts of interests pertinent to the abstract R. Bannerji Employment or leadership position: Sanofi Pasteur Research funding: Abbvie, Genentech, Inc., F. Hoffmann-La Roche Ltd, Regeneron, Abbvie/Pharmacyclics S. Yuen Educational grants: Genentech, Inc. T. Phillips Consultant or advisory role: ADCT, Genentech, Inc., Abbvie, Pharmacyclics, Bayer, BMS, Incyte, TG Therapeutics, Gilead, Astra Zeneca Honoraria: Lymphoma connect Research funding: Bayer, Abbvie, BMS, Incyte I. Isufi Consultant or advisory role: Astra Zeneca, Celgene, Kite, Novartis, Epizyme Honoraria: Bayer Taiwan P. Marlton Consultant or advisory role: F. Hoffmann-La Roche Ltd, AbbVie, Janssen, Astellas, Gilead, AstraZeneca, BeiGene, Jazz Pahrmaceuticals Educational grants: F. Hoffmann-La Roche Ltd Other remuneration: Speakers' bureau: AbbVie J. F Seymour Consultant or advisory role: Abbvie, Acerta Pharma, Janssen, F. Hoffmann-La Roche Ltd, Sunesis Pharmaceuticals, Takeda, AstraZeneca, Bristol-Myers Squibb, Gilead Sciences, MEI Pharma, MorphoSys Honoraria: Abbvie, Acerta Pharma, Janssen, F. Hoffmann-La Roche Ltd, Sunesis Pharmaceuticals, Takeda Research funding: Abbvie, Celgene, Janssen, F. Hoffmann-La Roche Ltd Educational grants: Abbvie, F. Hoffmann-La Roche Ltd Other remuneration: Speakers' bureau: Abbvie, F. Hoffmann-La Roche Ltd; Expert Testimony: F. Hoffmann-La Roche Ltd P. Corradini Consultant or advisory role: AbbVie, ADC Therapeutics, Amgen, Celgene, Daiichi Sankyo, Gilead, Incyte, Janssen, Kite, KyowaKirin, Novartis, F. Hoffmann-La Roche Ltd, Sanofi, Servier, Takeda Honoraria: AbbVie, ADC Therapeutics, Amgen, Celgene, Daiichi Sankyo, Gilead, Incyte, Janssen, Jazz Pharmaceutics, Kite, KyowaKirin, Novartis, F. Hoffmann-La Roche Ltd, Sanofi, Servier, Takeda G. Gritti Consultant or advisory role: Autolus, Gilead, IQvia, Amgen, F. Hoffmann-La Roche Ltd, Takeda Honoraria: Takeda Educational grants: F. Hoffmann-La Roche Ltd, AbbVie, Gilead, Janssen, Takeda J. Hirata Employment or leadership position: Genentech, Inc. Stock ownership: F. Hoffmann-La Roche Ltd L. Musick Employment or leadership position: Genentech, Inc. Stock ownership: F. Hoffmann-La Roche Ltd/GNE S. Saha Employment or leadership position: Genentech, Inc. B. Croft Employment or leadership position: Genentech, Inc. Stock ownership: Genentech, Inc./F. Hoffmann-La Roche Ltd C. Flowers Consultant or advisory role: Abbvie, Bayer, BeiGene, Celgene, Denovo Biopharma, Genentech/Roche, Gilead, Karyopharm, Pharmacyclics/Janssen, Spectrum Research funding: 4D, Abbvie, Acerta, Adaptimmune, Allogene, Amgen, Bayer, Celgene, Cellectis, EMD, Gilead, Genentech/Roche, Guardant, Iovance, Janssen Pharmaceutical, Kite, Morphosys, Nektar, Novartis, Pfizer, Pharmacyclics, Sanofi, Takeda, TG Therapeutics, Xencor, Ziopharm, Burroughs Wellcome Fund, Eastern Cooperative Oncology Group, National Cancer Institute, V Foundation, Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research