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Purpose:The prognosis for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is poor, and only a minority of patients benefit from checkpoint immunotherapy. Talimogene laherparepvec (T-VEC), an oncolytic immunotherapy approved for advanced melanoma, in combination with pembrolizumab may yield enhanced antitumor activity over either agent alone.Patients and Methods:This was a phase Ib/III, multicenter trial testing intratumoral T-VEC combined with intravenous pembrolizumab in R/M HNSCC refractory to platinum-based chemotherapy. For phase Ib, primary endpoint was incidence of dose-limiting toxicity (DLT). Key secondary endpoints included objective response rate and progression-free survival per irRECIST, overall survival, and safety.Results:Thirty-six patients were enrolled into the phase Ib study. The data cut-off date was August 28, 2018. Median follow-up was 5.8 months (range, 0.3–24.2). One DLT of T-VEC–related fatal arterial hemorrhage was reported. Twenty (55.6%) and 21 (58.3%) patients experienced adverse events (AE) related to T-VEC and pembrolizumab, respectively. Besides the DLT, there were no treatment-related fatal AEs. A confirmed partial response was observed in 5 (13.9%) patients. Ten (27.8%) patients were unevaluable for response due to early death. Median PFS and OS were 3.0 months [95% confidence interval (Cl), 2.0–5.8] and 5.8 months (95% Cl, 2.9–11.4), respectively.Conclusions:The combination of T-VEC and pembrolizumab demonstrated a tolerable safety profile in R/M HNSCC. The efficacy with the combination was similar to that with pembrolizumab monotherapy in historical HNSCC studies. Phase III part of this study was not further pursued (ClinicalTrials.gov Identifier: NCT02626000).

Confirmed best overall response per irRECIST by baseline PD-L1 CPS of {greater than or equal to} 1, {greater than or equal to} 20, and {greater than or equal to} 50

Change from baseline in tumor burden of target lesions at patient level

Introduction Pembrolizumab provided durable responses and acceptable safety in recurrent or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC) in the KEYNOTE-629 study. In this elderly, fragile population with disfiguring tumours, preservation of health-related quality of life (HRQoL) is critical. Here, we present pre-specified exploratory HRQoL analyses from the first interim analysis of KEYNOTE-629. Methods Patients with R/M cSCC not amenable to surgery or radiation therapy received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. HRQoL end points included change from baseline to week 12 in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) global health status (GHS)/QoL, functioning, symptom and European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) scores and change from baseline through week 48 in EORTC QLQ-C30 GHS/QoL and physical functioning scores. Improvement (≥ 10-point increase post-baseline with confirmation) was assessed using the exact binomial method. Results Analyses included 99 patients for EORTC QLQ-C30 and 100 for EQ-5D-5L. Compliance was > 80% at week 12. Mean scores were stable from baseline to week 12 for GHS/QoL (4.95 points; 95% confidence interval, −1.00 to 10.90) and physical functioning (−3.38 points; 95% confidence interval, −8.80 to 2.04). EORTC-QLQ-C30 functioning, symptom, and EQ-5D-5L scores remained stable at week 12. Post-baseline scores were improved in 29.3% of patients for GHS/QoL, 17.2% for physical functioning, and in a numerically higher proportion of responders versus non-responders (GHS/QoL, 55.6% versus 16.1%; physical functioning, 36.1% versus 7.1%). Conclusions In elderly patients with R/M cSCC, the clinical efficacy of pembrolizumab translates into a benefit validated by HRQoL preservation or improvement during treatment. Trial Registration ClinicalTrials.gov identifier: NCT03284424. Supplementary Information The online version contains supplementary material available at 10.1007/s13555-021-00598-6., Plain Language Summary Cutaneous squamous cell carcinoma (cSCC) is the second most common type of non-melanoma skin cancer. cSCC is usually caused by cumulative exposure to sunlight and often occurs in exposed parts of the body such as the head and neck. cSCC is most often seen in older people. If cSCC is detected early, it can be removed by surgery; however, if left untreated, the cancer can spread throughout the body and cause death. The disease itself and its treatment can be painful, cause scarring, or change the patient’s physical appearance. Hence, people with cSCC often have poor quality of life. It is therefore important to develop new drugs to help patients with cSCC live longer without worsening their quality of life. The phase 2 KEYNOTE-629 study investigated how well the drug pembrolizumab treated cSCC and whether it was safe. KEYNOTE-629 included patients who were mostly older and had advanced cSCC. The results showed that pembrolizumab was effective and safe. Here, we investigated how pembrolizumab affected the quality of life of these patients. To do this, we asked patients to answer questionnaires on important aspects of their experience, such as their general health status, physical functioning, emotional wellbeing, and symptoms. We found that patients who were treated with pembrolizumab had stable quality of life during treatment. Furthermore, patients whose cancer responded well to pembrolizumab were more likely to have an improved quality of life. These results support the use of pembrolizumab in patients with advanced cSCC. Supplementary Information The online version contains supplementary material available at 10.1007/s13555-021-00598-6.

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.

Quimioteràpia; Carcinoma de cèl·lules escamoses de cap i coll Quimioterapia; Carcinoma de células escamosas de cabeza y cuello Chemotherapy; Head and neck squamous cell carcinoma 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. Funding for this research was provided by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co Inc, Kenilworth, NJ.

Objectives: FDA approval of PD-L1 IHC 22C3 pharmDx for use as an aid in identifying head and neck squamous cell carcinoma (HNSCC) patients for treatment with pembrolizumab was based on the results of rigorous analytical and clinical validation testing. Methods: For the HNSCC indication, the device was validated at Agilent Technologies on the performance of sensitivity and precision using the Combined Positive Score (CPS) ≥ 1 and CPS ≥ 20 cutoffs; external validation studies were performed at three external laboratories. CPS ≥ 1 and CPS ≥ 20 cutoffs were evaluated in KEYNOTE-048, a phase 3 clinical trial. Results: Analytical validation studies supporting the companion diagnostic indication (CPS ≥ 1) achieved point estimates of > 85% for negative, positive, and overall percent agreement. Clinical validation studies show that HNSCC patients treated with pembrolizumab as a single agent had an overall survival (OS) of 12.3 months at CPS ≥ 1 (95% CI, 10.8-14.9) compared with patients receiving cetuximab, platinum, and 5-fluorouracil (CPS ≥ 1 OS of 10.3 months (95% CI, 9.0-11.5)). Conclusion: Analytical and clinical validation studies demonstrate that PD-L1 IHC 22C3 pharmDx is a precise companion diagnostic assay, allowing for selection of eligible HNSCC patients for treatment with pembrolizumab.

Background Here, we report the results of the Japanese subgroup of the phase 3 KEYNOTE-048 study of pembrolizumab alone, pembrolizumab plus platinum and 5-fluorouracil (pembrolizumab–chemotherapy), or cetuximab plus platinum and 5-fluorouracil (EXTREME) in previously untreated recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Methods Primary end points were overall survival (OS) and progression-free survival (PFS). Efficacy was evaluated in patients with PD-L1 combined positive score (CPS) ≥ 20 and ≥ 1 and the total Japanese subgroup (n = 67). Results At data cutoff (25 February 2019), pembrolizumab led to longer OS versus EXTREME in the PD-L1 CPS ≥ 20 subgroup (median, 28.2 vs. 13.3 months; HR, 0.29 [95% CI 0.09–0.89]) and to similar OS in the total Japanese (23.4 vs. 13.6 months; HR, 0.51 [95% CI 0.25–1.05]) and CPS ≥ 1 subgroups (22.6 vs. 15.8 months; HR, 0.66 [95% CI 0.31–1.41]). Pembrolizumab–chemotherapy led to similar OS versus EXTREME in the PD-L1 CPS ≥ 20 (median, 18.1 vs. 15.8 months; HR, 0.72 [95% CI 0.23–2.19]), CPS ≥ 1 (12.6 vs. 15.8 months; HR, 1.19 [95% CI 0.55–2.58]), and total Japanese subgroups (12.6 vs. 13.3 months; unadjusted HR, 1.10 [95% CI 0.55–2.22]). Median PFS was similar for pembrolizumab and pembrolizumab–chemotherapy versus EXTREME in all subgroups. Grades 3–5 treatment-related adverse events occurred in 5 (22%), 19 (76%), and 17 (89%) patients receiving pembrolizumab, pembrolizumab–chemotherapy, and EXTREME, respectively. One patient receiving pembrolizumab–chemotherapy died because of treatment-related pneumonitis. Conclusion These results support the use of first-line pembrolizumab and pembrolizumab–chemotherapy for Japanese patients with R/M HNSCC. Clinical trial registry ClinicalTrials.gov, NCT02358031.

Aim: Real-world treatment patterns and clinical outcomes in advanced cutaneous squamous cell carcinoma were evaluated. Methods: Adults receiving their first systemic therapy for unresectable, locally advanced or recurrent/metastatic cutaneous squamous cell carcinoma from 4 September 2014 to 30 June 2017, were evaluated. The primary end point was real-world overall response rate per Response Evaluation Criteria in Solid Tumors or physician assessment. Time-to-event outcomes were assessed using the Kaplan–Meier method. Results: Of 51 eligible patients, the median age was 76 years, 80% were male and 65% had an Eastern Cooperative Oncology Group score of 0–1. The most common regimens were cetuximab (51%) and carboplatin + paclitaxel (22%). Median real-world overall response rate ranged from 9.8% per Response Evaluation Criteria in Solid Tumors to 43.1% when supplemented by physician assessment. Median overall survival was 10.7 months, and median time to next treatment was 7.5 months. Conclusion: Survival in advanced cutaneous squamous cell carcinoma was short. Real-world overall response rate was lower with Response Evaluation Criteria in Solid Tumors than physician assessment.

Purpose: The prognosis for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is poor, and only a minority of patients benefit from checkpoint immunotherapy. Talimogene laherparepvec (T-VEC), an oncolytic immunotherapy approved for advanced melanoma, in combination with pembrolizumab may yield enhanced antitumor activity over either agent alone. Patients and Methods: This was a phase Ib/III, multicenter trial testing intratumoral T-VEC combined with intravenous pembrolizumab in R/M HNSCC refractory to platinum-based chemotherapy. For phase Ib, primary endpoint was incidence of dose-limiting toxicity (DLT). Key secondary endpoints included objective response rate and progression-free survival per irRECIST, overall survival, and safety. Results: Thirty-six patients were enrolled into the phase Ib study. The data cut-off date was August 28, 2018. Median follow-up was 5.8 months (range, 0.3–24.2). One DLT of T-VEC–related fatal arterial hemorrhage was reported. Twenty (55.6%) and 21 (58.3%) patients experienced adverse events (AE) related to T-VEC and pembrolizumab, respectively. Besides the DLT, there were no treatment-related fatal AEs. A confirmed partial response was observed in 5 (13.9%) patients. Ten (27.8%) patients were unevaluable for response due to early death. Median PFS and OS were 3.0 months [95% confidence interval (Cl), 2.0–5.8] and 5.8 months (95% Cl, 2.9–11.4), respectively. Conclusions: The combination of T-VEC and pembrolizumab demonstrated a tolerable safety profile in R/M HNSCC. The efficacy with the combination was similar to that with pembrolizumab monotherapy in historical HNSCC studies. Phase III part of this study was not further pursued (ClinicalTrials.gov Identifier: NCT02626000).

BACKGROUND: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.METHODS: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031.FINDINGS: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], pINTERPRETATION: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.FUNDING: Merck Sharp & Dohme.

Background Pembrolizumab demonstrated clinically meaningful and durable antitumor activity with a manageable safety profile in recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC). Patients and methods KEYNOTE-629 was a global, open-label, nonrandomized, phase II trial of patients with locally advanced (LA) or R/M cSCC conducted at 59 centers. Eligible patients received intravenous pembrolizumab 200 mg every 3 weeks for up to 35 cycles. Primary endpoint was objective response rate (ORR), defined as the percentage of patients with a complete (CR) or partial response (PR), by blinded independent central review as per Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints included duration of response (DOR), disease control rate, progression-free survival, overall survival, and safety and tolerability. Efficacy and safety were analyzed in patients who were treated with at least one dose of pembrolizumab. Results Between 29 November 2017 and 25 September 2019, 159 patients were enrolled and treated with pembrolizumab (LA cohort, n = 54; R/M cohort, n = 105). The median time from the first dose to data cut-off date (29 July 2020) was 14.9 [interquartile range (IQR), 12.6-17.2] months for the LA cohort and 27.2 (IQR, 25.6-29.2) months for the R/M cohort. In the LA cohort, ORR was 50.0% [95% confidence interval (CI), 36.1% to 63.9%], including 16.7% of patients with a CR and 33.3% with a PR. In the R/M cohort, ORR was 35.2% (95% CI, 26.2% to 45.2%), including 10.5% of patients with a CR and 24.8% with a PR. Median DOR was not reached in either cohort. Grade 3-5 treatment-related adverse events occurred in 11.9% of patients. Conclusions The robust antitumor activity of pembrolizumab in both LA and R/M cSCC was confirmed and demonstrated to be durable without unexpected safety signals. Our findings establish pembrolizumab as a promising treatment option for cSCC.

PURPOSE Treatment options are limited for patients with recurrent and/or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC); mortality rates exceed 70% in patients with distant metastases. Here, we present the first interim analysis of the R/M cSCC cohort from the 2-cohort—locally advanced and R/M—phase II KEYNOTE-629 study. PATIENTS AND METHODS Patients with R/M cSCC not amenable to surgery or radiation received pembrolizumab 200 mg every 3 weeks. The primary end point was objective response rate per RECIST v1.1. Secondary end points were duration of response, disease control rate, progression-free survival, overall survival, and safety. RESULTS At data cutoff (April 8, 2019), median follow-up of 105 enrolled patients in the R/M cohort was 11.4 months (range, 0.4 to 16.3 months). Objective response rate was 34.3% (95% CI, 25.3% to 44.2%; 4 complete responses, 32 partial responses), and disease control rate was 52.4% (95% CI, 42.4% to 62.2%). Median duration of response was not reached (range, 2.7 to 13.1+ months; ‘+’ refers to ongoing response at data cutoff). Median progression-free survival was 6.9 months (95% CI, 3.1 months to 8.5 months). Median overall survival was not reached (95% CI, 10.7 months to not reached). Treatment-related adverse events occurred in 66.7% of patients (n = 70), the most common of which were pruritus (n = 15; 14.3%), asthenia (n = 14; 13.3%), and fatigue (n = 13; 12.4%). Grade 3 to 5 treatment-related adverse events occurred in 5.7% (n = 6) of patients. One patient died of treatment-related cranial nerve neuropathy. CONCLUSION Pembrolizumab demonstrated effective antitumor activity; clinically meaningful, durable responses; and acceptable safety in primarily elderly patients with R/M cSCC, supporting its use in clinical practice. Pembrolizumab adverse events in this study were consistent with its established safety profile.

Background: In the multicenter, open-label, nonrandomized, phase 2 KEYNOTE-629 trial, pembro has demonstrated clinically meaningful and durable antitumor activity with a manageable safety profile for R/M cSCC based on the first interim analysis (IA). Here, we present the second IA of KEYNOTE-629, which reports the initial efficacy and safety data for the LA cohort and updated data for the R/M cohort in cSCC.Methods: Eligible patients (pts) were ≥18 years old, had histologically confirmed cSCC (LA or R/M) with measurable disease per RECIST 1.1 by blinded independent central review (BICR), an ECOG PS score of 0 or 1, and adequate organ function. Pts received intravenous pembro 200 mg every 3 weeks for up to 35 infusions (~ 2 years) or until protocol-specified treatment discontinuation criteria were met. The primary endpoint was ORR per RECIST 1.1 by BICR. Secondary endpoints were DOR, DCR, and PFS, all per RECIST 1.1 by BICR; OS; and safety and tolerability. Results: A total of 159 pts were enrolled and treated with pembro (LA, n=54; R/M, n=105). The median time from the first dose to data cutoff (July 29, 2020) was 14.9 (range, 10.1-19.4) mo for the LA cohort and 27.2 (range, 24.6-32.0) mo for the R/M cohort. In the LA cohort, 22.2% of pts were treated with prior systemic therapy with curative intent. In the R/M cohort, 86.7% of pts received ≥1 prior systemic therapy. Updated efficacy outcomes are summarized in the table. Across cohorts, grade 3-5 treatment-related AEs occurred in 11.9% of pts. Grade 3-5 immune-related AEs occurred in 8.2% of pts. Conclusions: Pembro confirmed robust and durable antitumor activity, with promising survival in LA and R/M cSCC. AEs with pembro in this study were generally consistent with its established safety profile. These data support the use of pembro for cSCC. LA cSCC(N=54)R/M cSCC(N=105)Total(N=159)ORR, % (95% CI)50.0 (36.1-63.9)35.2 (26.2-45.2)40.3 (32.6-48.3)DCR (SD ≥12 wks + ORR), % (95% CI)64.8 (50.6-77.3)52.4 (42.4-62.2)56.6 (48.5-64.4)Best overall response, n (%)CR9 (16.7)11 (10.5)20 (12.6)PR18 (33.3)26 (24.8)44 (27.7)SD13 (24.1)30 (28.6)43 (27.0)SD≥12 wks8 (14.8)18 (17.1)26 (16.4)PD9 (16.7)28 (26.7)37 (23.3)NE1 (1.9)2 (1.9)3 (1.9)No assessment4 (7.4)8 (7.6)12 (7.5)DOR, median (range), moNR (1.0+-17.2+)NR (2.7-30.4+)NR (1.0+-30.4+)Patients with extended responses≥12 months, n (%)10 (84.1)25 (77.8)35 (80.3)PFS, median (95% CI), moNR (5.5-NR)5.7 (3.1-8.5)7.8 (5.3-12.3)12-mo PFS rate, % (95% CI)54.4 (39.6-67.0)36.4 (27.0- 45.9)42.4 (34.3-50.2)OS, median (95% CI), moNR (NR-NR)23.8 (13.4-29.8)26.4 (19.5-NR)12-mo OS rate, % (95% CI)73.6 (59.5-83.4)61.0 (50.9-69.5)65.1 (57.1-72.0) Citation Format: Brett G.M. Hughes, Eva Munoz-Couselo, Laurent Mortier, Åse Bratland, Ralf Gutzmer, Osama Roshdy, Rene González Mendoza, Jacob Schachter, Ana Arance, Florent Grange, Nicolas Meyer, Abhishek Joshi, Salem Billan, Pingye Zhang, Burak Gumuscu, Ramona F. Swaby, Jean-Jacques Grob. Phase 2 study of pembrolizumab (pembro) for locally advanced (LA) or recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC): KEYNOTE-629 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT006.

Introduction: In the phase 3 KEYNOTE-048 trial (NCT02358031) in R/M HNSCC, first-line pembrolizumab (P) monotherapy vs EXTREME (E; chemotherapy [C] + cetuximab) improved overall survival (OS) in PD-L1 combined positive score (CPS) ≥20 and CPS ≥1 populations and led to noninferior OS in the total population with favorable safety; first-line P+C vs E had superior OS in CPS ≥20, CPS ≥1, and total populations with comparable safety. Outcomes in CPS Table.Efficacy in subgroups of patients with PD-L1 CPS Citation Format: Barbara Burtness, Danny Rischin, Richard Greil, Denis Soulières, Makoto Tahara, Gilberto de Castro, Amanda Psyrri, Neus Basté, Prakash Neupane, Åse Bratland, Thorsten Fuereder, Brett G. Hughes, Ricard Mesia, Nuttapong Ngamphaiboon, Tamara Rordorf, Wan Zamaniah Wan Ishak, Joy Ge, Ramona Swaby, Burak Gumuscu, Kevin Harrington. Efficacy of first-line (1L) pembrolizumab by PD-L1 combined positive score

Background: Local recurrence occurs within 5 years in ~20% of patients with high-risk locally advanced cutaneous squamous cell carcinoma treated with current standard-of-care surgical resection and adjuvant radiotherapy. Recent data with programmed death 1 inhibitors have demonstrated antitumor activity and an acceptable safety profile in patients with locally advanced or metastatic disease. The randomized, double-blind, placebo-controlled phase 3 KEYNOTE-630 trial (NCT03833167) will evaluate the efficacy and safety of adjuvant pembrolizumab monotherapy in patients with high-risk locally advanced cutaneous squamous cell carcinoma. Trial design: Patients with resectable high-risk locally advanced cutaneous squamous cell carcinoma who have undergone surgical resection and radiotherapy will be randomly assigned 1:1 to intravenous pembrolizumab (400 mg every 6 weeks) or placebo for up to 9 cycles (~1 year) or until disease recurrence, unacceptable toxicity, or withdrawal by the investigator or the patient. Randomization will be stratified by extracapsular extension (yes vs no), cortical bone invasion (yes vs no), and prior systemic therapy (yes vs no). Key eligibility criteria include histologically confirmed locally advanced cutaneous squamous cell carcinoma with ≥1 high-risk feature as the primary site of malignancy and complete macroscopic resection of all known cutaneous squamous cell carcinoma disease, with or without microscopic positive margins, who completed ≥45 Gy adjuvant radiotherapy, were disease free ≤28 days from randomization, and have Eastern Cooperative Oncology Group performance status 0 or 1. The primary end point is recurrence-free survival based on investigator assessment with biopsy confirmation. Secondary end points are overall survival, health-related quality of life, and safety. Radiographic imaging will be performed at least every 12 weeks in years 1 and 2, then every 6 months until the end of year 5 to assess treatment response. Patients who are ineligible for surgical resection following documented disease recurrence may cross over to receive re-treatment with open-label intravenous pembrolizumab 400 mg every 6 weeks for up to 18 cycles (~2 years). Adverse events will be recorded until 30 days (90 days for serious adverse events) after study end and will be graded per NCI CTCAE v4.0. Enrollment of ~570 patients is planned, and recruitment is ongoing in 20 countries. Citation Format: Anne Lynne S. Chang, Gregory A. Daniels, Ezra E. Cohen, Joy Yang Ge, Burak Gumuscu, Ramona F. Swaby, Jessica L. Geiger. Adjuvant pembrolizumab or placebo in patients with high-risk, locally advanced cutaneous squamous cell carcinoma: Phase 3 KEYNOTE-630 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-138.

Background KEYNOTE-048 (NCT02358031) is a randomized, open-label, phase 3 trial of pembrolizumab (pembro) or pembro + chemotherapy (chemo) vs EXTREME (E) as first-line therapy for recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). At the second interim analysis, overall survival (OS) was significantly longer with pembro than E in patients with PD-L1 combined positive score (CPS) ≥20 (P = 0.0007) and CPS ≥1 (P = 0.0086) and was noninferior in the total population (pop). Pembro + chemo significantly improved OS vs E in the total pop (P = 0.0034). Safety was favorable or similar to that of E. Methods Patients with R/M HNSCC not curable by local therapy and with no prior systemic therapy were randomized (1:1:1) to pembro 200 mg Q3W, pembro + chemo (cisplatin 100 mg/m2 or carboplatin AUC 5 Q3W + 5-FU 1000 mg/m2/day for 4 days Q3W), or E (cetuximab 400 mg/m2 loading dose with 250 mg/m2 subsequent infusion QW + chemo) until progressive disease, unacceptable toxicity, 6 cycles of chemo, or 24 months of pembro. Primary end points were progression-free survival and OS. Data cutoff date was June 13, 2018. Results Efficacy is reported in the table. Gr 3-5 drug-related AE rates with pembro vs E were 28.6% vs 76.9% in the Asia subgroup and 13.9% vs 67.2% in the non-Asia subgroup; rates with pembro + chemo vs E were 71.9% vs 76.9% in the Asia subgroup and 70.8% vs 67.2% in the non-Asia subgroup. Table: 286O Asia CPS ≥20 Asia CPS ≥1 Asia Tot Pop Non-Asia CPS ≥20 Non-Asia CPS ≥1 Non-Asia Tot Pop HR; 95% CI P vs E 22 v 23 P+C v E 22 v 21 P v E 48 v 46 P+C v E 45 v 43 P v E 56 v 53 P+C v E 57 v 49 P v E 111 v 99 P+C v E 104 v 89 P v E 209 v 209 P+C v E 197 v 192 P v E 245 v 247 P+C v E 224 v 229 OS 0.39; 0.19-0.80 0.80; 0.41-1.58 0.80; 0.51-1.27 1.13; 0.71-1.79 0.74; 0.48-1.13 1.03; 0.68-1.58 0.75; 0.54-1.04 0.68; 0.48-0.96 0.76; 0.61-0.95 0.65; 0.51-0.82 0.87; 0.71-1.06 0.71; 0.57-0.88 PFS 1.16; 0.63-2.11 1.07; 0.58-1.99 1.25; 0.82-1.91 1.14; 0.74-1.76 1.39; 0.94-2.05 1.12; 0.75-1.66 0.95; 0.70-1.28 0.65; 0.47-0.89 1.10; 0.89-1.35 0.74; 0.60-0.92 1.27; 1.05-1.54 0.82; 0.67-1.00 HRs, Kaplan-Meier method; 95% CIs, Cox regression model. Conclusions Pembro vs E showed favorable OS in Asia and non-Asia subgroups, regardless of PD-L1 status; responses were durable, particularly among all non-Asia subgroups; safety was favorable. Pembro + chemo vs E showed favorable OS in patients with CPS ≥20 in Asia and non-Asia subgroup regardless of PD-L1 status, durable responses, and similar safety. Clinical trial identification NCT02358031. Editorial acknowledgement Medical writing and/or editorial assistance was provided by Doyel Mitra, PhD, CMPP, and Holly Cappelli, PhD, CMPP, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure N. Ngamphaiboon: Honoraria (self): Roche, AstraZeneca, Eisai, Amgen, MSD, Novartis; Advisory / Consultancy: MSD, Amgen, Novartis, Boehringer Ingelheim, AstraZeneca; Speaker Bureau / Expert testimony: Roche, AstraZeneca, Eisai, Amgen, MSD, Novartis; Travel / Accommodation / Expenses: Roche, MSD, Amgen, Novartis, Merck, Eisai, Taiho; Research grant / Funding (institution): MSD, Pfizer, Roche, AstraZeneca. K. Tanaka: Honoraria (self): Merck Serono, Bristol-Myers Squibb, Eisai, Ono Pharmaceutical, MSD, AstraZeneca; Advisory / Consultancy: Merck Serono, Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Rakuten Medical, Celgene, Amgen; Research grant / Funding (institution): Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Rakuten Medical, Novartis, Loxo, AstraZeneca, Rakuten Medical. R-L. Hong: Research grant / Funding (institution): MSD. W.Z. Wan Ishak: Honoraria (self): Eli Lilly Malaysia, Roche Malaysia, Pfizer Malaysia, MSD Ltd, Eisai Korea, Eisai Malaysia, Mundipharma, Merck Serono, Roche Myanmar; Advisory / Consultancy: Boehringer Ingelheim (M), Merck Serono (M), Roche (M), Eli Lilly (M), Amgen (M); Speaker Bureau / Expert testimony: Eli Lilly Inc; Research grant / Funding (self): Amgen Inc, MSD, Roche & Genetech, AstraZeneca; Travel / Accommodation / Expenses: Eisai (M), Eli Lilly (M), AstraZeneca (M), MSD Inc, Roche (M), Merck Serono (M), Mundipharma (M), Novartis (M), Pfizer (M), Amgen (M), Menarini (M). V. Sriuranpong: Honoraria (self): MSD; Advisory / Consultancy: MSD. S. Takahashi: Honoraria (self): Novartis, MDS, Eisai, Taiho, Chugai, Daiichi-Sankyo, Bayer, AstraZeneca; Research grant / Funding (self): MSD, Eisai, Taiho, Chugai, Daiichi-Sankyo, Bayer, AstraZeneca, Quintiles. N. Nohata: Shareholder / Stockholder / Stock options: Merck; Full / Part-time employment: MSD KK. A. Roy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. B. Gumuscu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. R. Swaby: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. M. Tahara: Honoraria (self): Merck Serono, Bristol-Myers Squibb, Eisai, Ono Pharmaceutical, MSD, AstraZeneca; Advisory / Consultancy: Merck Serono, Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Rakuten Medical, Celgene, Amgen; Research grant / Funding (institution): Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Rakuten Medical, Novartis, Loxo, AstraZeneca, Rakuten Medical. All other authors have declared no conflicts of interest.

Background The global, single-arm, phase II KEYNOTE-629 trial (NCT03284424) studied the safety and efficacy of pembrolizumab in patients with recurrent/metastatic (R/M) cSCC. Methods Patients with R/M cSCC received pembrolizumab 200 mg Q3W for up to 35 infusions (Grob JJ et al. J Clin Oncol. 2019;37(suppl; abstr TPS9598)). The primary end point was ORR by blinded independent central review per RECIST v1.1. Secondary end points were DOR, DCR, PFS, OS, and safety. DOR, PFS, and OS were estimated using the Kaplan-Meier method. Results of an interim analysis are presented. Results Of 105 patients, 76.2% were male, median age was 72 years, 86.7% had previously received ≥1 line of systemic therapy, and 74.3% had previously undergone radiation. At data cutoff (April 8, 2019), median duration of follow-up was 9.5 months (range, 0.4-16.3 months). ORR was 34.3% (95% CI, 25.3%-44.2%); 4 patients (3.8%) achieved CR (95% CI, 1.0%-9.5%), and 32 patients (30.5%) achieved PR (95% CI, 21.9%-40.2%). Median DOR was not reached (range, 2.7-13.1+ months). Of the 36 responders, 31 patients and 7 patients had a minimum follow-up of 6 months and 12 months, respectively, after achieving response; 25 (79.5%) and 1 (65.6%) were estimated to have ongoing responses at > 6 months and >12 months, respectively. DCR (CR + PR + stable disease ≥12 weeks) was 52.4% (95% CI, 42.4%-62.2%). Median PFS was 6.9 months (95% CI, 3.1-8.5 months); 12-month PFS rate was 32.4%. Median OS was not reached (95% CI, 10.7 months-not reached); 12-month OS rate of 60.3%. Treatment-related adverse events (TRAEs) occurred in 70 patients (66.7%), and 6 patients (5.7%) had grade 3-5 TRAEs; 1 patient died of treatment-related cranial nerve neuropathy. The most common TRAEs were pruritus (14.3%), asthenia (13.3%), and fatigue (12.4%). Conclusions Pembrolizumab demonstrated a clinically meaningful ORR (34.3%), durable responses, and remarkable PFS and OS in patients with R/M cSCC, most of whom were heavily pretreated. Treatment was well tolerated, and the safety profile was generally consistent with that of other pembrolizumab monotherapy studies; no new safety signals were identified. These data support pembrolizumab for the treatment of R/M cSCC. Clinical trial identification NCT03284424, October 26, 2017. Editorial acknowledgement Medical writing and/or editorial assistance was provided by Holly Cappelli, PhD, and Dana Francis, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA). Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure J.J. Grob: Honoraria (self): Roche, Novartis, BMS, MSD, Pierre Fabre, Amgen, Sunpharma, Sanofi, Merck, Pfizer; Advisory / Consultancy: Roche, Novartis, BMS, MSD, Pierre Fabre, Amgen, Sunpharma, Sanofi, Merck, Pfizer; Travel / Accommodation / Expenses: Novartis, BMS, MSD, Pierre Fabre. N. Basset-Seguin: Research grant / Funding (institution), Financial contract with St Louis Hospital for the clinical trial: MSD. O. Vornicova: Honoraria (self), Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Travel / Accommodation / Expenses: Roche. J. Schachter: Honoraria (self): BMS; Honoraria (self): Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD. N. Meyer: Advisory / Consultancy, Research grant / Funding (institution), Personal fees: MSD; Advisory / Consultancy, Research grant / Funding (institution), Personal fees: BMS; Advisory / Consultancy, Personal fees: Roche; Advisory / Consultancy, Personal fees: Novartis; Advisory / Consultancy: Incyte; Non-remunerated activity/ies, Personal fees: Sun pharma; Advisory / Consultancy, Personal fees: Pierre Fabre. F. Grange: Advisory / Consultancy: MSD. J.M. Piulats: Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Janssen. J. Bauman: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Bayer. P.(. Zhang: Full / Part-time employment: Merck & Co., Inc.. B. Gumuscu: Full / Part-time employment: MSD. R.F. Swaby: Full / Part-time employment: Merck & Co., Inc.. B.G.M. Hughes: Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Boehringer. All other authors have declared no conflicts of interest.

Background KEYNOTE-048 (NCT02358031) is a randomized, open-label, phase 3 trial of P or P + chemotherapy (C) vs EXTREME (E) as 1L therapy for R/M HNSCC. At 2nd interim analysis, overall survival (OS) was significantly longer with P than E in patients (pts) with PD-L1 combined positive score (CPS) ≥20 (P = 0.0007) and CPS ≥1 (P = 0.0086) and was noninferior in the total population (pop). P+C significantly improved OS vs E in the total pop (P = 0.0034). Safety was favorable or similar to that of E. Methods Pts with R/M HNSCC not curable by local therapy and with no prior systemic therapy were randomized (1:1:1) to P 200 mg Q3W, P+C (cisplatin 100 mg/m2 or carboplatin AUC 5 Q3W + 5-FU 1000 mg/m2/day for 4 days Q3W), or E (cetuximab 400 mg/m2 loading dose with 250 mg/m2 subsequent infusion QW + C) until progressive disease, unacceptable toxicity, 6 cycles of C, or 24 months of P. Primary end points were progression-free survival and OS. Data cutoff date was June 13, 2018. Results Efficacy is reported in the table. Gr 3-5 drug-related AE rates with P vs E were 28.6% vs 76.9% in the Asia subgrp and 13.9% vs 67.2% in the non-Asia subgrp; rates with P+C vs E were 71.9% vs 76.9% in the Asia subgrp and 70.8% vs 67.2% in the non-Asia subgrp. Conclusions P vs E showed favorable OS in Asia and non-Asia subgrps, regardless of PD-L1 status; responses were durable, particularly among all non-Asia subgrps; safety was favorable. P+C vs E showed favorable OS in pts with CPS ≥20 in Asia and non-Asia subgrps regardless of PD-L1 status, durable responses, and similar safety. Clinical trial identification NCT02358031. Editorial acknowledgement Doyel Mitra, PhD, and Dana Francis, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA), funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Table: 1136P . Asia, CPS ≥20 Asia, CPS ≥1 Asia, Total Population Non-Asia, CPS ≥20 Non-Asia, CPS ≥1 Non-Asia, Total Population P vs E n = 22 vs 23 P+C vs E n = 22 vs 21 P vs E n = 48 vs 46 P+C vs E n = 45 vs 43 P vs E n = 56 vs 53 P+C vs E n = 57 vs 49 P vs E n = 111 vs 99 P+C vs E n = 104 vs 89 P vs E n = 209 vs 209 P+C vs E n = 197 vs 192 P vs E n = 245 vs 247 P+C vs E n = 224 vs 229 OS: HR (95% CI ) 0.39 (0.19-0.80) 0.80 (0.41-1.58) 0.80 (0.51-1.27) 1.13 (0.71-1.79) 0.74 (0.48-1.13) 1.03 (0.68-1.58) 0.75 (0.54-1.04) 0.68 (0.48-0.96) 0.76 (0.61-0.95) 0.65 (0.51-0.82) 0.87 (0.71-1.06) 0.71 (0.57-0.88) PFS: HR (95% CI) 1.16 (0.63-2.11) 1.07 (0.58-1.99) 1.25 (0.82-1.91) 1.14 (0.74-1.76) 1.39 (0.94-2.05) 1.12 (0.75-1.66) 0.95 (0.70-1.28) 0.65 (0.47-0.89) 1.10 (0.89-1.35) 0.74 (0.60-0.92) 1.27 (1.05-1.54) 0.82 (0.67-1.00) ORR, % 22.7 vs 30.4 45.5 vs 33.3 16.7 vs 37.0 31.1 vs 37.2 14.3 vs 41.5 31.6 vs 40.8 23.4 vs 37.4 42.3 vs 39.3 19.6 vs 34.4 37.6 vs 35.4 17.6 vs 34.8 36.6 vs 35.4 Median DOR, mo 5.7 vs 4.3 6.1 vs 4.3 12.6 vs 4.3 6.1 vs 4.2 12.6 vs 4.1 5.7 vs 4.1 23.4 vs 4.1 8.5 vs 4.1 20.9 vs 4.5 6.9 vs 4.4 20.9 vs 5.0 6.9 vs 5.0 C, chemotherapy; CI, confidence interval; CPS, combined positive score; DOR, duration of response; E, EXTREME; HR, hazard ratio; mo, months; ORR, objective response rate; OS, overall survival; P, pembrolizumab; PFS, progression-free survival. HRs are from product-limit (Kaplan-Meier) method for censored data; 95% CIs are based on Cox regression model with Efron’s method of tie handling with treatment as a covariate. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure M. Tahara: Honoraria (self): Merck Serono, Bristol-Myers Squibb, Eisai, Ono Pharmaceutical, MSD, AstraZeneca; Advisory / Consultancy: Merck Serono, Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Rakuten Medical, Celgene, Amgen; Research grant / Funding (institution): Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Rakuten Medical, Novartis, Loxo, AstraZeneca, Rakuten Medical. R. Hong: Research grant / Funding (institution): MSD. W.Z. Wan Ishak: Honoraria (self): Eli Lilly Malaysia, Roche Malaysia, Pfizer Malaysia MSD Ltd, Eisai Korea, Eisai Malaysia, Mundipharma, Merck Serono, Roche Myanmar; Advisory / Consultancy: Boehringer Ingelheim, Merck Serono, Roche, Eli Lilly, Amgen; Speaker Bureau / Expert testimony: Eli Lilly; Research grant / Funding (self): Amgen Inc, MSD, Roche, Genentech, AstraZeneca; Travel / Accommodation / Expenses: Eisai, Eli Lilly, AstraZeneca, MSD Inc, Roche, Merck Serono, Mundipharma, Novartis, Pfizer, Amgen, Menarini. S. Takahashi: Honoraria (self): Novartis, MDS, Eisai, Taiho, Chugai, Daiichi-Sankyo, Bayer, AstraZeneca; Research grant / Funding (self): MSD, Eisai, Taiho, Chugai, Daiichi-Sankyo, Bayer, AstraZeneca, Quintiles. K. Tanaka: Honoraria (self): AstraZeneca, ONO Pharmaceutical, MSD, Eisai, Merck Serono, Bristol-Myers Squibb. N. Nohata: Shareholder / Stockholder / Stock options: Merck & Co., Inc.; Full / Part-time employment: MSD K.K. A. Roy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. B. Gumuscu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. R.F. Swaby: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. N. Ngamphaiboon: Honoraria (self): Roche, AstraZeneca, Eisai, Amgen, MSD, Novartis; Advisory / Consultancy: MSD, Amgen, Novartis, Boehringer Ingelheim, AstraZeneca; Speaker Bureau / Expert testimony: Roche, AstraZeneca, Eisai, Amgen, MSD, Novartis; Travel / Accommodation / Expenses: Roche, MSD, Amgen, Novartis, Merck, Eisai, Taiho; Research grant / Funding (institution): MSD, Pfizer, Roche, AstraZeneca. All other authors have declared no conflicts of interest.

Background: Findings from Phase I and II clinical trials suggest that treatment with an anti-programmed death 1 (PD-1) antibody is well tolerated and provides durable antitumor activity in patients with local/regionally advanced or metastatic cutaneous squamous cell carcinoma (cSCC). Encouraging efficacy and safety findings have also been reported from an expansion cohort in the phase 1 KEYNOTE-012 trial with the PD-1 inhibitor pembrolizumab. KEYNOTE-012 demonstrated that pembrolizumab 200 mg administered once every 3 weeks was well tolerated and yielded a clinically meaningful overall response rate with evidence of durable responses in patients with recurrent and/or metastatic head and neck cSCC. To test the clinical activity of pembrolizumab, the open-label, single-arm, phase 2 KEYNOTE-629 trial (NCT03284424) will be carried out in patients with locally advanced, unresectable, and recurrent or metastatic cSCC. Trial design: Patients will receive intravenous pembrolizumab 200 mg every 3 weeks for up to 35 infusions (≤24 months) or until protocol-specified treatment discontinuation. Treatment will not be stratified in this study. Eligibility criteria include age ≥18 years; locally advanced cSCC that is ineligible for surgical resection or radiotherapy (RT) or that previously underwent RT to the index site or systemic therapy for curative intent; presence of measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; and Eastern Cooperative Oncology Group performance status 0 or 1. Treatment will be discontinued for progressive disease, unacceptable toxicity, intercurrent illness preventing study treatment administration, investigator’s decision, patient withdrawal of consent, pregnancy, or cessation for administrative reasons. Response will be assessed by computed tomography or magnetic resonance imaging 6 weeks after treatment initiation, every 6 weeks through year 1, then every 9 weeks thereafter or more frequently if clinically indicted. After a patient experiences disease progression or starts new anticancer therapy, the patient will be followed up and contacted every 12 weeks until death, consent withdrawal, or study end, whichever occurs first. Safety will be monitored throughout the study treatment and for 30 days after treatment end and for 90 days for serious adverse events after the end of treatment. The primary end point is objective response rate (RECIST v1.1). Secondary end points include duration of response, disease control rate, progression-free survival, overall survival, and safety. Recruitment is ongoing in 10 countries and will continue until approximately 50 additional patients with locally advanced unresectable cSCC are enrolled. Citation Format: Jean-Jacques Grob, Rene Gonzalez Mendoza, Nicole Basset-Seguin, Jacob Schachter, Olga Vornicova, Jessica Bauman, Florent Grange, Nicolas Meyer, Josep Piulats, Pingye (Eric) Zhang, Burak Gumuscu, Ramona Swaby, Brett GM Hughes. KEYNOTE-629: Phase II study of pembrolizumab for recurrent/metastatic or locally advanced unresectable cutaneous squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT170.

Hemophilia A, a deficiency in the activity of coagulation factor (F) VIII, is an X-linked bleeding disorder with an approximate incidence of one in 5,000 male infants. Bleeding-related complications often result in greater severity of disease, poor quality of life, surgical interventions for severe joint destruction, and shortened life span. With the availability of plasma-derived and recombinant FVIII products, the benefits of primary prophylaxis were demonstrated and is now the standard of care for patients with severe factor deficiencies. Current hemophilia research is focusing on the creation of new factor replacement therapies with longer half-lives; accessing alternative mechanisms to achieve desired hemostasis and enhance bypassing activity; and limiting the immunogenicity of the protein. PEGylation involves the covalent attachment of polyethylene glycol (PEG) to a protein, peptide, or a small molecule drug. PEG effectively increases the molecular weight and size of the protein by creating a hydrophilic cloud around the molecule. This molecular change may reduce susceptibility of the molecule to proteolytic activity and degradation. It is also believed that PEGylation changes the surface charge of the protein that ultimately interferes with some receptor-mediated clearance processes. The half-life of PEGylated factor is more prolonged when compared to non-PEGylated full-length recombinant FVIII. The dawn of a new era in the care of hemophilia patients is upon us with the release of recombinant FVIII products with extended half-lives, and products with even more extended half-life will become available in a very short time. With all the promise of these new agents, many questions still remain.

The number of proliferating cells in the rodent retina declines dramatically after birth. To determine if extrinsic factors in the retinal micro-environment are responsible for this decline in proliferation, we established cultures of retinal progenitors or Muller glia, and added dissociated retinal neurons from older retinas. The older cells inhibited proliferation of progenitor cells and Muller glia. When these experiments were performed in the presence of TGF(beta)RII-Fc fusion protein, an inhibitor of TGF(beta) signaling, proliferation was restored. This suggests a retina-derived TGF(beta) signal is responsible for the developmental decline in retinal proliferation. TGFbeta receptors I and II are expressed in the retina and are located in nestin-positive progenitors early in development and glast-positive Muller glia later in development. RT-PCR and immunofluorescence data show TGF(beta)2 is the most highly expressed TGF(beta)ligand in the postnatal retina, and it is expressed by inner retinal neurons. Addition of either TGF(beta)1 or TGF(beta)2 to postnatal day 4 retinas significantly inhibited progenitor proliferation, while treatment of explanted postnatal day 6 retinas with TGF(beta) signaling inhibitors resulted in increased proliferation. Last, we tested the effects of TGF(beta) in vivo by injections of TGF(beta) signaling inhibitors: when TGF(beta) signaling is inhibited at postnatal day 5.5, proliferation is increased in the central retina; and when co-injected with EGF at postnatal day 10, TGF(beta)inhibitors stimulate Muller glial proliferation. In sum, these results show that retinal neurons produce a cytostatic TGF(beta) signal that maintains mitotic quiescence in the postnatal rat retina.