S866 PHASE 1/2 TRIAL OF ACALABRUTINIB PLUS PEMBROLIZUMAB IN PATIENTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B‐CELL LYMPHOMA

Background: Acalabrutinib, a highly selective, potent, covalent Bruton tyrosine kinase inhibitor, has demonstrated a 24% overall response rate as a single agent in relapsed/refractory diffuse large B‐cell lymphoma. 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. Aims: To assess the efficacy and safety of the combination of acalabrutinib plus pembrolizumab for patients with relapsed/refractory diffuse large B‐cell lymphoma. Methods: Patients with diffuse large B‐cell lymphoma, ≥1 prior chemoimmunotherapy, and no prior allogeneic transplant received acalabrutinib 100 mg orally twice daily until progressive disease plus pembrolizumab 200 mg/kg intravenously every 3 weeks for up to 2 years. Germinal center B‐cell versus non‐germinal center B‐cell subtype was assessed by immunohistochemistry. The primary endpoint was safety. Secondary endpoints included investigator‐assessed overall response rate per Lugano criteria, duration of response, and progression‐free survival. Results: Sixty‐one patients (30 germinal center B cell; 31 non‐germinal center B cell) 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) and 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, and 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 germinal center B‐cell (27%) and non‐germinal center B‐cell (26%) tumors. The median time on study was 5.2 months (range, 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. Summary/Conclusion: The combination of acalabrutinib plus pembrolizumab was well tolerated, with meaningful activity and some exceptional responders (>24 months) in these patients with relapsed/refractory diffuse large B‐cell lymphoma. Randomized trials of the combination versus single agent are needed.