TY - JOUR
T1 - Safety and Efficacy of Pembrolizumab in Combination with Acalabrutinib in Advanced Head and Neck Squamous Cell Carcinoma
T2 - Phase 2 Proof-of-Concept Study
AU - Taylor, Matthew H.
AU - Betts, Courtney B.
AU - Maloney, Lauren
AU - Nadler, Eric
AU - Algazi, Alain
AU - Guarino, Michael J.
AU - Nemunaitis, John
AU - Jimeno, Antonio
AU - Patel, Priti
AU - Munugalavadla, Veerendra
AU - Tao, Lin
AU - Adkins, Douglas
AU - Goldschmidt, Jerome H.
AU - Cohen, Ezra E.W.
AU - Coussens, Lisa M.
N1 - Publisher Copyright:
©2021 The Authors; Published by the American Association for Cancer Research
PY - 2022/3/1
Y1 - 2022/3/1
N2 - Purpose: Programmed cell death-1 (PD-1) receptor inhibitors have shown efficacy in head and neck squamous cell carcinoma (HNSCC), but treatment failure or secondary resistance occurs in most patients. In preclinical murine carcinoma models, inhibition of Bruton’s tyrosine kinase (BTK) induces myeloid cell reprogramming that subsequently bolsters CD8þ T cell responses, resulting in enhanced antitumor activity. This phase 2, multicenter, open-label, randomized study evaluated pembrolizumab (anti–PD-1 monoclonal antibody) plus acalabrutinib (BTK inhibitor) in recurrent or metastatic HNSCC. Patients and Methods: Patients received pembrolizumab 200 mg intravenously every 3 weeks, alone or in combination with acalabrutinib 100 mg orally twice daily. Safety and overall response rate (ORR) were co-primary objectives. The secondary objectives were progression-free survival (PFS) and overall survival. Results: Seventy-six patients were evaluated (pembrolizumab, n ¼ 39; pembrolizumab þ acalabrutinib, n ¼ 37). Higher frequencies of grade 3–4 treatment-emergent adverse events (AE; 65% vs. 39%) and serious AEs (68% vs. 31%) were observed with combination therapy versus monotherapy. ORR was 18% with monotherapy versus 14% with combination therapy. Median PFS was 2.7 [95% confidence interval (CI), 1.4–6.8] months in the combination arm and 1.7 (95% CI, 1.4–4.0) months in the monotherapy arm. The study was terminated due to lack of clinical benefit with combination treatment. To assess how tumor immune contexture was affected by therapy in patients with pre- and post-treatment biopsies, spatial proteomic analyses were conducted that revealed a trend toward increased CD45þ leukocyte infiltration of tumors from baseline at day 43 with pembrolizumab (monotherapy, n ¼ 5; combination, n ¼ 2), which appeared to be higher in combination-treated patients; however, definitive conclusions could not be drawn due to limited sample size. Conclusions: Despite lack of clinical efficacy, immune subset analyses suggest that there are additive effects of this combination; however, the associated toxicity limits the feasibility of combination treatment with pembrolizumab and acalabrutinib in patients with recurrent or metastatic HNSCC.
AB - Purpose: Programmed cell death-1 (PD-1) receptor inhibitors have shown efficacy in head and neck squamous cell carcinoma (HNSCC), but treatment failure or secondary resistance occurs in most patients. In preclinical murine carcinoma models, inhibition of Bruton’s tyrosine kinase (BTK) induces myeloid cell reprogramming that subsequently bolsters CD8þ T cell responses, resulting in enhanced antitumor activity. This phase 2, multicenter, open-label, randomized study evaluated pembrolizumab (anti–PD-1 monoclonal antibody) plus acalabrutinib (BTK inhibitor) in recurrent or metastatic HNSCC. Patients and Methods: Patients received pembrolizumab 200 mg intravenously every 3 weeks, alone or in combination with acalabrutinib 100 mg orally twice daily. Safety and overall response rate (ORR) were co-primary objectives. The secondary objectives were progression-free survival (PFS) and overall survival. Results: Seventy-six patients were evaluated (pembrolizumab, n ¼ 39; pembrolizumab þ acalabrutinib, n ¼ 37). Higher frequencies of grade 3–4 treatment-emergent adverse events (AE; 65% vs. 39%) and serious AEs (68% vs. 31%) were observed with combination therapy versus monotherapy. ORR was 18% with monotherapy versus 14% with combination therapy. Median PFS was 2.7 [95% confidence interval (CI), 1.4–6.8] months in the combination arm and 1.7 (95% CI, 1.4–4.0) months in the monotherapy arm. The study was terminated due to lack of clinical benefit with combination treatment. To assess how tumor immune contexture was affected by therapy in patients with pre- and post-treatment biopsies, spatial proteomic analyses were conducted that revealed a trend toward increased CD45þ leukocyte infiltration of tumors from baseline at day 43 with pembrolizumab (monotherapy, n ¼ 5; combination, n ¼ 2), which appeared to be higher in combination-treated patients; however, definitive conclusions could not be drawn due to limited sample size. Conclusions: Despite lack of clinical efficacy, immune subset analyses suggest that there are additive effects of this combination; however, the associated toxicity limits the feasibility of combination treatment with pembrolizumab and acalabrutinib in patients with recurrent or metastatic HNSCC.
UR - http://www.scopus.com/inward/record.url?scp=85125803492&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-21-2547
DO - 10.1158/1078-0432.CCR-21-2547
M3 - Article
C2 - 34862248
AN - SCOPUS:85125803492
SN - 1078-0432
VL - 28
SP - 903
EP - 914
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 5
ER -