ACALABRUTINIB PLUS PEMBROLIZUMAB IN RELAPSED/REFRACTORY DIFFUSE LARGE B‐CELL LYMPHOMA: A PHASE 1/2 STUDY

Background: Acalabrutinib, a highly selective, potent, covalent Bruton tyrosine kinase inhibitor, has a 24% overall response rate as a single agent in relapsed/refractory diffuse large B-cell lymphomas (DLBCL). Pembrolizumab targets PD-1, an immune checkpoint that limits anticancer responses. Pembrolizumab showed responses in patients with Richter transformation who failed ibrutinib and can augment acalabrutinib activity in vitro. This study assessed acalabrutinib plus pembrolizumab in relapsed/refractory DLBCL. Methods: Patients with DLBCL, ≥1 prior chemoimmunotherapy and no prior allogeneic transplant received oral acalabrutinib 100 mg twice daily until progressive disease plus pembrolizumab 200 mg/kg intravenously every 3 weeks for up to 2 years. Germinal center B-cell (GCB) vs non-GCB subtype was assessed by immunohistochemistry. Primary endpoint was safety. Results: Sixty-one patients (30 GCB; 31 non-GCB) were accrued, with a median age of 67 years (range, 30 to 85) and a median of 3 (range, 1 to 8) prior therapies; 1 patient had prior autologous transplant. The most common grade 3/4 adverse events were neutropenia (15%) and anemia (11%). Grade 5 adverse events were respiratory failure (n = 3), sepsis, septic shock, and abdominal abscess (n = 1 each). All-grade atrial fibrillation was 5% (n = 3), and major hemorrhage (≥ Grade 3) was 11% (4 gastrointestinal, 1 pulmonary, 1 epistaxis, 1 hematuria). Grade 3/4 immune-mediated events were elevated alanine aminotransferase (n = 4), pneumonitis (n = 2), and colitis (n = 1). The overall response rate was 26% (Table) and was similar in GCB (27%) and non-GCB (26%) tumors. The median time on study was 5.2 months (0.4 to 30.4+). Acalabrutinib/pembrolizumab discontinuations were due to progressive disease (62%/56%) and adverse events (15%/26%). As of June 2018, 10 patients remain on study; 6 on active therapy and 7 without progressive disease. Conclusions: Acalabrutinib plus pembrolizumab was well tolerated, with meaningful activity and some exceptional responders (>24 months) in these relapsed/refractory DLBCL patients. Randomized trials of the combination vs single agent are needed. Keywords: acalabrutinib; diffuse large B-cell lymphoma (DLBCL); Pembrolizumab. Disclosures: Witzig, T: Honoraria: Sandoz; Immune Design; Research Funding: Acerta; Celgene; Novartis; Spectrum. Maddocks, K: Consultant Advisory Role: AstraZeneca, Pharmacyclics, Bayer, Teva, Sandoz; Honoraria: AstraZeneca, Pharmacyclics, Bayer, Teva, Sandoz; Research Funding: Pharmacyclics, BMS, Novartis, Merck. Lyons, R: Employment Leadership Position: Texas Oncology; Stock Ownership: Texas Oncology; Research Funding: avvie, Celgene, Gilead, GenetechIncye, Rigel, Takeda. Sharman, J: Consultant Advisory Role: Celgene, Pfizer, Genentech, TG therapeutics, AbbVie, pharmacyclics GILEAD; Research Funding: Celgene, Pfizer, Genentech, TG therapeutics, AbbVie, pharmacyclics GILEAD. Yimer, H: Consultant Advisory Role: Seattle Genetics, AstraZeneca, Jenssen. Wei, H: Employment Leadership Position: Acerta Pharma. Chan, E: Employment Leadership Position: Acerta Pharma, Genentech/Roche; Stock Ownership: Acerta Pharma, Genentech/Roche, Eli Lilly & Company. Patel, P: Employment Leadership Position: Acerta/AstraZeneca; Stock Ownership: Acerta/AstraZeneca. Kolibaba, K: Employment Leadership Position: Compass Oncology; Consultant Advisory Role: Gilead; Honoraria: TG Therapeutics; Research Funding: Acerta; Celgene; CTI; Genentech; Gilead; Pharmacyclics; Novartis; Seattle Genetics; TG Therapeutics; Other Remuneration: TG Therapeutics. Cheson, B: Consultant Advisory Role: Abbvie, AstraZeneca, Bayer, Celgene, Roche Genentech, TG Therapeutics, Epizyme, GIlead, Karyopharm, Morphosys, Pharmacyclics; Research Funding: Abbvie, AstraZeneca, Roche Genentech, TG Therapeutics, Epizyme, GIlead, Trillium.