Safety and efficacy of pembrolizumab in combination with acalabrutinib in advanced head and neck squamous cell carcinoma: Phase 2 proof-of-concept study

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\u27s tyrosine kinase (BTK) induces myeloid cell reprogramming that subsequently bolsters CD8+ 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 = 39; pembrolizumab + acalabrutinib, n = 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 CD45+ leukocyte infiltration of tumors from baseline at day 43 with pembrolizumab (monotherapy, n = 5; combination, n = 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

Increased platelet activation and fibrinogen in Asian Indians. Potential implications for coronary risk

AIMS: To determine whether Asian Indians (Indians), a group known to have high rates of coronary heart disease, have increased platelet activation and fibrinogen levels relative to white Americans of European origin (whites). METHODS AND RESULTS: Forty healthy, non-smoking Indians, aged 25-45, were matched with 40 healthy whites for age (within 3 years) and gender. Platelet activation was tested in blood exiting a bleeding time wound at 1 and 2 min post-incision (wound-induced activation), as well as in venous blood stimulated in vitro with collagen, using whole blood flow cytometry. Other risk factors, including fibrinogen levels, family history of diabetes or coronary heart disease, fasting insulin and lipid levels, and Lp(a) were also assessed. Fibrinogen levels were higher among Indians than whites, even after adjustment for gender or family history of coronary heart disease (P \u3c 0.05). Indians had higher levels of wound-induced glycoprotein IIb/IIIa binding and platelet secretion (P-selectin expression) than whites, with the greatest differences found when comparing the upper quintile of activation for each group (Ps \u3c 0.05). Indians with a family history of coronary heart disease (n = 15) had higher levels of platelet secretion (wound-induced and in vitro) than Indians without a family history (Ps \u3c 0.05), while the relationship was reversed among whites. Platelet activation measures were not consistently related to other coronary risk factors, while fibrinogen was related to triglyceride and insulin levels among Indians. CONCLUSION: Indians have elevated fibrinogen and platelet activation levels relative to whites. These factors may contribute to the increased coronary risk observed in Indians

Safety and Efficacy of Pembrolizumab in Combination with Acalabrutinib in Advanced Head and Neck Squamous Cell Carcinoma: Phase 2 Proof-of-Concept Study.

PurposeProgrammed 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 CD8+ 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 methodsPatients 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.ResultsSeventy-six patients were evaluated (pembrolizumab, n = 39; pembrolizumab + acalabrutinib, n = 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 CD45+ leukocyte infiltration of tumors from baseline at day 43 with pembrolizumab (monotherapy, n = 5; combination, n = 2), which appeared to be higher in combination-treated patients; however, definitive conclusions could not be drawn due to limited sample size.ConclusionsDespite 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

Brief Report: Randomized Phase 2 Studies of Checkpoint Inhibitors Alone or in Combination with Pegilodecakin in Patients with Metastatic Non-Small-Cell Lung Cancer (CYPRESS-1 and CYPRESS-2)

INTRODUCTION: Checkpoint inhibitors (CPI) have been approved to treat metastatic NSCLC. Pegilodecakin+CPI suggested promising efficacy in phase 1 IVY, providing rationale for randomized phase 2 trials CYPRESS-1 and CYPRESS-2. METHODS: CYPRESS-1 (N=101) and CYPRESS-2 (N=52) included ECOG 0-1, 1L/2L metastatic NSCLC, respectively, without known EGFR/ALK mutations. Patients were randomized 1:1; control arms received pembrolizumab (CYPRESS-1) or nivolumab (CYPRESS-2); experimental arms received pegilodecakin+CPI. Patients had PD-L1 tumor proportion score (TPS) ≥50% (CYPRESS-1) or 0-49% (CYPRESS-2). Primary endpoint was ORR per investigator. Secondary endpoints included PFS, OS, and safety. Exploratory endpoints included immune activation biomarkers. RESULTS: Median follow-up for CYPRESS-1 and CYPRESS-2 was 10.0 and 11.6 months, respectively. Results for pegilodecakin+pembrolizumab versus pembrolizumab were: ORR per investigator 47%vs.44% (Odds ratio:1.1;95%CI[0.5,2.5]); mPFS 6.3vs.6.1 months (HR:0.937;95%CI[0.541,1.625]); and mOS 16.3 months vs. not reached (HR:1.507;95%CI[0.708,3.209]). Results per blinded independent central review (BICR) were consistent. Treatment discontinuation rate due to AEs doubled in the experimental arm (32%vs.15%). Gr≥3 treatment related adverse events (TRAEs)(62%vs.19%) included anemia(20%vs.0%) and thrombocytopenia(12%vs.2%). Results for pegilodecakin+nivolumab versus nivolumab were: ORR per investigator 15%vs.12% (Odds ratio:1.2;95%CI[0.3,5.9]); mPFS 1.9vs.1.9 months (HR:1.006;95%CI[0.519,1.951]); and mOS 6.7vs.10.7 months (HR:1.871;95%CI[0.772,4.532]). Gr≥3 TRAEs (70.4%vs.16.7%) included anemia(40.7%vs.0%), fatigue(18%vs.0%), and thrombocytopenia(14.8%vs.0%). Biomarker data suggested activation of immunostimulatory signals of IL-10R pathway in pegilodecakin-containing arms. CONCLUSION: Despite evidence of biological effect in peripheral blood, adding pegilodecakin to CPI did not improve ORR, PFS, or OS, in 1L/2L NSCLC. Pegilodecakin+CPI demonstrated overall higher toxicity compared to CPI alone, leading to doubling of treatment discontinuation rate due to AEs