Ibrutinib and Venetoclax in Relapsed and Refractory Follicular Lymphoma

Abstract

Background: Ibrutinib (I) and venetoclax (V) have modest single-agent activity in relapsed/refractory follicular lymphoma (FL) (Gopal A, JCO 2018; Davids M, JCO 2017). Preclinical data have shown synergy I and V (Kuo H, Mol Cancer Ther 2017). Based on these data, we conducted the first phase I/II trial to combine I and V in FL (NCT02956382). We previously presented results from the phase Ib portion of this multi-institutional trial (Ujjani C, Blood 2020). Here, we present data from the phase II study. Methods: Enrolling sites include Fred Hutch CC, Lombardi CCC, and John Theurer CC. Eligibility criteria were WHO grade 1-3a FL, >1 prior systemic therapy, measurable disease warranting therapy by standard criteria or physician discretion, ECOG PS ≤2, adequate marrow, hepatic, renal function. In the phase II study, patients (pts) received I 560 mg and V 600 mg daily. There was no dose ramp up of V based on experience in FL. Pts at high risk for tumor lysis syndrome (TLS) (node ≥8 cm and/or significant lymphocytosis) were hospitalized for initial dose. Pts received therapy until progression or unacceptable toxicity. Response was assessed by Lugano criteria. Results: Fourteen pts received treatment at the RP2D between May 2019 and April 2021. Patient characteristics are listed in Table 1. One pt was considered high risk for TLS. Pts received a median of 1 prior therapy (range 1–8). Grade 3/4 adverse events (AE) included neutropenia (NTP) (21%), febrile NTP (14%), diarrhea (21%), nausea (14%), hypertension (14%), thrombocytopenia (7%), atrial fibrillation (7%), vomiting (7%), ALT/AST elevation (7%), COVID pneumonia (7%). Grade 1/2 AE occurring in > 30% of pts were rash (64%), diarrhea (57%), bruising (50%), abdominal pain (36%), fatigue (36%), nausea (35%), and mucositis (35%). There were 2 SAEs: febrile NTP and COVID. There was no clinical TLS. The ORR amongst the 14-patient cohort was 64% (0.35, 0.87); CR 21%. One of these 14 developed a prolonged, severe COVID infection resulting in study withdrawal before a response evaluation could be performed. One other pt also discontinued for toxicity (mucositis, malaise, arthralgia). Nine discontinued for progression. Two responding pts chose to discontinue further treatment. Median PFS was 8.6 months (2.73, NA) (Figure 1). Duration of response is displayed in Figure 2. Median DOR for 6 pts with PR was 5.7 months; 3 pts with CR was NA. The study closed early due to poor accrual during the COVID pandemic. Conclusion: In the first trial to combine a BTK and BCL-2 inhibitor in relapsed/refractory FL, we found the I-V doublet to demonstrate a toxicity profile similar to that seen in CLL. Importantly, there was no evidence of clinical TLS, despite omission of the V ramp up. Preliminary results of anti-tumor activity are encouraging. The combination of BTK and BCL2 inhibitor may provide an effective option for FL, utilizing a targeted approach distinct from other approved novel agents. The research was funded by: Pharmacyclics and Abbvie Keywords: Combination Therapies, Indolent non-Hodgkin lymphoma, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. C. Ujjani Consultant or advisory role: Abbvie, Janssen, Pharmacyclics, Beigene, Lilly, Astrazeneca, Epizyme, Atara, Incyte, Genentech Research funding: Abbvie, Pharmacyclics, Astrazeneca, Lilly A. Gopal Consultant or advisory role: Incyte, Kite, Morphosys/Incyte, ADCT, Acrotech, Merck, Karyopharm, Servier, Beigene, Cellectar, Janssen, SeaGen, Epizyme, I-Mab bio, Gilead, Genentech, Lilly, Caribou, Fresenius-Kabi Stock ownership: Compliment Corporation Research funding: Merck, I-Mab bio, IgM Bio, Takeda, Gilead, Astra-Zeneca, Agios, Janssen, BMS, SeaGen, Teva, Genmab C. Lai Consultant or advisory role: BMS, Jazz Pharma, Genentech, Novartis, Abbvie, Daiichi, Astellas, Macrogenics, Servier, Taiho M. Shadman Consultant or advisory role: abbvie S. D. Smith Consultant or advisory role: ADC Therapeutics, Astrazeneca, Beigene, Epizyme, Karyopharm, KITE pharma, Incyte, Numab Therapeutics AG, Abbvie, Coherus Biosciences, advisory board (spouse), Genentech Research funding: ADC Therapeutics, Astrazeneca, Ayala (spouse), Bayer, Beigene, Bristol Myers Squibb (spouse) De Novo Biopharma Enterome Genentech Ignyta (spouse), Incyte Corporation, Kymera Therapeutics, Merck, Sharp and Dohme Corp, MorphoSys, Nanjing Pharmaceuticals Co., Ltd., Portola Pharmaceuticals, Viracta Therapeutics B. D. Cheson Consultant or advisory role: Abbvie, Pharmacyclics, Morphosys, Lilly, Beigene, Reddy Biosimilar, Genmab K. Dunleavy Consultant or advisory role: Astra Zeneca, Abbvie, ADC Therapeutics, Cellectar, Beigene, ONO, Incyte Research funding: Genentech, ONO, Kymera