Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study.

PURPOSE: Pembrolizumab and pembrolizumab-chemotherapy demonstrated efficacy in recurrent/metastatic head and neck squamous cell carcinoma in KEYNOTE-048. Post hoc analysis of long-term efficacy and progression-free survival on next-line therapy (PFS2) is presented. METHODS: Patients were randomly assigned (1:1:1) to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Efficacy was evaluated in programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20, CPS ≥ 1, and total populations, with no multiplicity or alpha adjustment. RESULTS: The median study follow-up was 45.0 months (interquartile range, 41.0-49.2; n = 882). At data cutoff (February 18, 2020), overall survival improved with pembrolizumab in the PD-L1 CPS ≥ 20 (hazard ratio [HR], 0.61; 95% CI, 0.46 to 0.81) and CPS ≥ 1 populations (HR, 0.74; 95% CI, 0.61 to 0.89) and was noninferior in the total population (HR, 0.81; 95% CI, 0.68 to 0.97). Overall survival improved with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.62; 95% CI, 0.46 to 0.84), CPS ≥ 1 (HR, 0.64; 95% CI, 0.53 to 0.78), and total (HR, 0.71; 95% CI, 0.59 to 0.85) populations. The objective response rate on second-course pembrolizumab was 27.3% (3 of 11). PFS2 improved with pembrolizumab in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.84) and CPS ≥ 1 (HR, 0.79; 95% CI, 0.66 to 0.95) populations and with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.86), CPS ≥ 1 (HR, 0.66; 95% CI, 0.55 to 0.81), and total (HR, 0.73; 95% CI, 0.61 to 0.88) populations. PFS2 was similar after pembrolizumab and longer after pembrolizumab-chemotherapy on next-line taxanes and shorter after pembrolizumab and similar after pembrolizumab-chemotherapy on next-line nontaxanes. CONCLUSION: With a 4-year follow-up, first-line pembrolizumab and pembrolizumab-chemotherapy continued to demonstrate survival benefit versus cetuximab-chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma. Patients responded well to subsequent treatment after pembrolizumab-based therapy

Pembrolizumab Alone or With Chemotherapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma in KEYNOTE-048: Subgroup Analysis by Programmed Death Ligand-1 Combined Positive Score.

PURPOSE: The phase III KEYNOTE-048 (ClinicalTrials.gov identifier: NCT02358031) trial of pembrolizumab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) included planned efficacy analyses in the total population and in participants with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 1 and CPS ≥ 20. To further characterize the predictive value of PD-L1 expression on outcome, we conducted efficacy analyses in the PD-L1 CPS < 1 and CPS 1-19 subgroups in KEYNOTE-048. METHODS: Participants with R/M HNSCC and no prior systemic therapy for R/M disease were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Post hoc efficacy analyses of the PD-L1 CPS < 1 and CPS 1-19 subgroups were performed. RESULTS: Of 882 participants enrolled, 128 had PD-L1 CPS < 1 and 373 had CPS 1-19. For pembrolizumab versus cetuximab-chemotherapy, the median overall survival was 7.9 versus 11.3 months in the PD-L1 CPS < 1 subgroup (hazard ratio [HR], 1.51 [95% CI, 0.96 to 2.37]) and 10.8 versus 10.1 months in the CPS 1-19 subgroup (HR, 0.86 [95% CI, 0.66 to 1.12]). For pembrolizumab-chemotherapy versus cetuximab-chemotherapy, the median overall survival was 11.3 versus 10.7 months in the PD-L1 CPS < 1 subgroup (HR, 1.21 [95% CI, 0.76 to 1.94]) and 12.7 versus 9.9 months in the CPS 1-19 subgroup (HR, 0.71 [95% CI, 0.54 to 0.94]). CONCLUSION: Increased efficacy of pembrolizumab or pembrolizumab-chemotherapy was observed with increasing PD-L1 expression. PD-L1 CPS < 1 subgroup analysis was limited by small participant numbers. Results from the PD-L1 CPS 1-19 subgroup support previous findings of treatment benefit with pembrolizumab monotherapy and pembrolizumab-chemotherapy in patients with PD-L1 CPS ≥ 1 tumors. Although PD-L1 expression is informative, exploration of additional predictive biomarkers is needed for low PD-L1-expressing HNSCC

HPV Prevalence and Prognostic Value in a Prospective Cohort of 255 Patients with Locally Advanced HNSCC: A Single-Centre Experience

Background. HPV is a positive prognostic factor in HNSCC. We studied the prevalence and prognostic impact of HPV on survival parameters and treatment toxicity in patients with locally advanced HNSCC treated with concomitant chemoradiation therapy. Methods. Data on efficacy and toxicity were available for 560 patients. HPV was detected by PCR. Analysis was performed using Kaplan-Meier survival curves, Fisher’s test for categorical data, and log-rank statistics for failure times. Results. Median follow-up was 4.7 years. DNA extraction was successful in 255 cases. HPV prevalence was 68.6%, and 53.3% for HPV 16. For HPV+ and HPV−, median LRC was 8.9 and 2.2 years (P=0.0002), median DFS was 8.9 and 2.1 years (P=0.0014), and median OS was 8.9 and 3.1 years (P=0.0002). Survival was different based on HPV genotype, stage, treatment period, and chemotherapy regimen. COX adjusted analysis for T, N, age, and treatment remained significant (P=0.004). Conclusions. Oropharyngeal cancer is increasingly linked to HPV. This study confirms that HPV status is associated with improved prognosis among H&N cancer patients receiving CRT and should be a stratification factor for clinical trials including H&N cases. Toxicity of CRT is not modified for the HPV population

Sunitinib combined with pemetrexed and carboplatin in patients with advanced solid malignancies—results of a phase I dose-escalation study

Objectives The maximum tolerated dose (MTD) and overall safety of sunitinib plus pemetrexed and carboplatin was determined in patients with advanced solid malignancies. Methods In this phase I dose-escalation study, patients received oral sunitinib on a continuous daily dosing (CDD) schedule (37.5 mg/day) or Schedule 2/1 (2 weeks on treatment, 1 week off treatment; 37.5 or 50 mg/day). Pemetrexed (400–500 mg/m(2) IV) and carboplatin (AUC = 5 mg·min/ml IV) were administered q3w. At the MTD for the chosen schedule, a cohort of patients with non-small cell lung cancer (NSCLC) or mesothelioma was further evaluated. Results Twenty-one patients were enrolled on Schedule 2/1 (expansion cohort included) and 3 patients on the CDD schedule. The MTD on Schedule 2/1 was sunitinib 37.5 mg/day with pemetrexed 500 mg/m(2) and carboplatin AUC = 5 mg·min/ml; MTD on the CDD schedule was not established. Dose-limiting toxicities included grade 3/4 neutropenia, grade 3 thrombocytopenia, and grade 3 hand–foot syndrome. The most common grade 3/4 drug-related non-hematologic adverse events at Schedule 2/1 MTD were fatigue/asthenia and diarrhea (both n = 4). Grade 3/4 hematologic abnormalities included neutropenia (83 %) and leukopenia (83 %). Pharmacokinetic data revealed no clinically significant drug–drug interactions. Best response at the Schedule 2/1 MTD was stable disease ≥8 weeks in 3/5 evaluable patients (60 %). Conclusions With this combination, in patients with advanced solid malignancies, sunitinib MTD on Schedule 2/1 was 37.5 mg/day. Sunitinib plus pemetrexed and carboplatin were tolerable at the MTD, although sunitinib dose delays and reductions were often required due to myelosuppression

Subsequent therapy following pembrolizumab + axitinib or sunitinib treatment for advanced renal cell carcinoma (RCC) in the phase III KEYNOTE-426 study

Background: In the phase III KEYNOTE-426 study, pembrolizumab + axitinib showed significant improvement in OS, PFS, and ORR vs sunitinib in patients with RCC. This analysis assessed subsequent treatment in patients enrolled in KEYNOTE-426. Methods: Treatment-naive patients with clear cell RCC, KPS score �70%, and measurable disease (RECIST v1.1) were randomly assigned 1:1 to receive pembrolizumab 200 mg IV every 3 weeks for up to 35 doses + axitinib 5 mg orally twice daily or sunitinib 50 mg once daily (4 weeks on/2 weeks off) until progression, toxicity, or withdrawal. Type of and time to subsequent therapy were assessed. Results: Of patients in the pembrolizumab + axitinib arm and in the sunitinib arm, 81.4% (349/432) and 90.6% of patients (385/429), respectively, discontinued treatment; radiologic or clinical PD was the most common reason for discontinuation in both (pembrolizumab + axitinib: 65.0% [227/349]; sunitinib: 68.1% [262/385]). Of patients who discontinued, 58.5% of patients (204/349) in the pembrolizumab + axitinib arm and 73.0% (281/385) in the sunitinib arm received subsequent therapy (Table). Although a similar proportion of patients in both arms received subsequent therapy with a VEGF/VEGFR inhibitor (pembrolizumab + axitinib: 88.2% [180/204]; sunitinib: 68.7% [193/281]), a greater proportion of patients in the sunitinib arm (74.4% [209/281]) received subsequent PD-1/PD-L1 inhibitor therapy than in the pembrolizumab + axitinib arm (21.6% [44/204]). Of patients in the pembrolizumab + axitinib arm and the sunitinib arm, 32.4% (66/204) and 22.8% (64/281), respectively, received other therapies

Health-related Quality of Life Analysis from KEYNOTE-426: Pembrolizumab plus Axitinib Versus Sunitinib for Advanced Renal Cell Carcinoma

The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma