Supplementary Data from Adjuvant Pembrolizumab versus IFNα2b or Ipilimumab in Resected High-Risk Melanoma

Fig S1. Kaplan-Meier plots of overall survival, stratified by pembrolizumab dose, demonstrate similarity of efficacy across a 5-fold dose range (2 to 10 mg/kg Q3W) in A) advanced ipilimumab-refractory melanoma, KEYNOTE-002 (Cox HR 0.98; 95% CI 0.94-1.02) and B) advanced, previously-treated PD-L1 positive NSCLC, KEYNOTE-010 (Cox HR 0.98; 95%CI 0.95-1.01). Subjects with at least one available PK measurement were included. Fig S2. Overall pooled exposure-response patterns demonstrate trends incongruent with similarity in dose-response patterns across 2 to 10 mg/kg in A) advanced ipilimumab-refractory melanoma, KEYNOTE-002 and B) advanced, previously-treated PD-L1 positive NSCLC, KEYNOTE-010. Fig S3. Similarity in OS between respective within-dose exposure quartiles at 2 and 10 mg/kg shows E-R patterns from pooled data (Fig S2 above) to be misleading in A-B) advanced ipilimumab-refractory melanoma, KEYNOTE-002 and C-D) advanced, previously-treated PD-L1 positive NSCLC, KEYNOTE-010. Fig S4. Kaplan-Meier plots of OS by all CL0 quartiles in KEYNOTE-002 (melanoma; left) and KEYNOTE-010 (previously-treated NSCLC; right) using the complete case datasets. Fig S5. Kaplan-Meier plots of OS by baseline clearance (CL0) quartiles in advanced, previously-untreated NSCLC with PD-L1 expression at least 50 percent. Pembrolizumab administered at 200 mg Q3W (KEYNOTE-024; n=152). Subjects with at least one available PK measurement were included. Fig S6. Forest plot of Docetaxel-treated NSCLC Cox proportional hazards model-estimated overall survival hazard ratios (n=249). Complete case dataset was used. Supplementary Table S1. Source Profile of PK - Overall Survival Analysis Datasets (KEYNOTE-002 and -010) Used in Multivariate Cox Models. Supplementary Table S2. Demographics and Baseline Characteristics for Subjects with {greater than or equal to} 1 Pembrolizumab PK Measurement (KEYNOTE-010/-024 and -002). Supplementary Table S3. Comparison of Univariate HR Results using Baseline Clearance from Time-dependent PK Model Versus a Steady-state Clearance from a Static PK Model Shows the Choice of Exposure Interval is Not Expected to Impact Rank Order of Exposure Estimates and that a Modest, Time-dependent Change in Pembrolizumab Clearance Does Not Meaningfully Alter Interpretations Described in this Study. Supplementary Table S4. Protocol-specified Pharmacokinetic Sampling Strategy.

Supplementary Table 1. Hits from the dalotuzumab enhancer screen. Supplementary Table 2. Patient and disease characteristics. Supplementary Table 3. Summary of dose-limiting toxicities. Supplementary Table 4. Summary of clinical efficacy in breast cancer patients.

Supplementary Figure 4. Responder biomarker hypothesis for ridaforolimus and dalotuzumab?based therapy

Supplementary Figure 3. Change in Ki67 levels with ridaforolimus and dalotuzumab combination therapy

Supplementary Figure 2. Combination therapy with ridaforolimus and dalotuzumab potentiates PI3K pathway inhibition and blocks cancer cell proliferation

Supplementary Figure 1. Treatment and pharmacodynamic assessment schedules.

With multiple PD-(L)1 inhibitors approved across dozens of indications by the US Food and Drug Administration, the number of patients exposed to these agents in adjuvant, first-line metastatic, second-line metastatic, and refractory treatment settings is increasing rapidly. Although some patients will experience durable benefit, many have either no clinical response or see their disease progress following an initial response to therapy. There is a significant need to identify therapeutic approaches to overcome resistance and confer clinical benefits for these patients. PD-1 pathway blockade has the longest history of use in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). Therefore, these settings also have the most extensive clinical experience with resistance. In 2021, six non-profit organizations representing patients with these diseases undertook a year-long effort, culminating in a 2-day workshop (including academic, industry, and regulatory participants) to understand the challenges associated with developing effective therapies for patients previously exposed to anti-PD-(L)1 agents and outline recommendations for designing clinical trials in this setting. This manuscript presents key discussion themes and positions reached through this effort, with a specific focus on the topics of eligibility criteria, comparators, and endpoints, as well as tumor-specific trial design options for combination therapies designed to treat patients with melanoma, NSCLC, or RCC after prior PD-(L)1 pathway blockade.

Abstract We conducted a randomized phase III trial to evaluate whether adjuvant pembrolizumab for one year (647 patients) improved recurrence-free survival (RFS) or overall survival (OS) in comparison with high-dose IFNα-2b for one year or ipilimumab for up to three years (654 patients), the approved standard-of-care adjuvant immunotherapies at the time of enrollment for patients with high-risk resected melanoma. At a median follow-up of 47.5 months, pembrolizumab was associated with significantly longer RFS than prior standard-of-care adjuvant immunotherapies [HR, 0.77; 99.62% confidence interval (CI), 0.59–0.99; P = 0.002]. There was no statistically significant association with OS among all patients (HR, 0.82; 96.3% CI, 0.61–1.09; P = 0.15). Proportions of treatment-related adverse events of grades 3 to 5 were 19.5% with pembrolizumab, 71.2% with IFNα-2b, and 49.2% with ipilimumab. Therefore, adjuvant pembrolizumab significantly improved RFS but not OS compared with the prior standard-of-care immunotherapies for patients with high-risk resected melanoma. Significance: Adjuvant PD-1 blockade therapy decreases the rates of recurrence, but not survival, in patients with surgically resectable melanoma, substituting the prior standard-of-care immunotherapies for this cancer. See related commentary by Smithy and Shoushtari, p. 599. This article is highlighted in the In This Issue feature, p. 587

We conducted a randomized phase 3 trial to evaluate whether adjuvant pembrolizumab for one year (648 patients) improved recurrence-free survival (RFS) or overall survival (OS) in comparison to high-dose interferon alfa-2b for one year or ipilimumab for up to three years (655 patients), the approved standard-of-care adjuvant immunotherapies at the time of enrollment for patients with high-risk resected melanoma. At a median follow-up of 47.5 months, pembrolizumab was associated with significantly longer RFS than prior standard-of-care adjuvant immunotherapies (hazard ratio [HR] 0.77; 99.62% confidence interval [CI] 0.59-0.99; P=0.002). There was no statistically significant association with OS among all patients (HR, 0.82; 96.3% CI 0.61-1.09; P=0.15). Proportions of treatment-related adverse events of grades 3 to 5 were 19.5% with pembrolizumab, 71.2% with interferon alfa-2b, and 49.2% with ipilimumab. Therefore, adjuvant pembrolizumab significantly improved RFS but not OS compared to the prior standard-of-care immunotherapies for patients with high-risk resected melanoma.

Purpose: Washout periods and concomitant medication exclusions are common in cancer clinical trial protocols. These exclusion criteria are often applied inconsistently and without evidence to justify their use. The authors sought to determine how washout period and concomitant medication allowances can be broadened to speed trial enrollment and improve the generalizability of trial data to a larger oncology practice population without compromising the safety of trial participants. Experimental Design: A multistakeholder working group was convened to define problems associated with excessively long washout periods andexclusionof patients due to concomitantmedications. The group performed a literature search and evaluated study data from the Pancreatic Cancer Action Network (PanCAN), Emory University School of Medicine (Atlanta, GA), and the FDA to understand recent approaches to these eligibility criteria. The group convened to develop consensus recommendations for broadened eligibility criteria. Results: The data analysis found that exclusion criteria based on washout periods and concomitant medications are frequently inconsistent and lack scientific rationale. Scientific rationale for appropriate eligibility criteria are presented in the article; for washout periods, rationale is presented by treatment type. Conclusions: Arbitrary or blanket washout and concomitant medication exclusions should be eliminated. Where there is evidence to support them, clinically relevant washout periods and concomitant medication-related eligibility criteria may be included.

Background Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer. Methods KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668. Findings Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3). Interpretation Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Background Understanding the perceptions of patients and oncology nurses about the relative importance of benefits and risks associated with newer treatments of advanced melanoma can help to inform clinical decision-making. Objectives The aims of this study were to quantify and compare the views of patients and oncology nurses regarding the importance of attributes of treatments of advanced melanoma. Methods A discrete choice experiment (DCE) was conducted in US-based oncology nurses and patients diagnosed with advanced melanoma. Patients and nurses were enlisted through online panels. In a series of scenarios, respondents had to choose between 2 hypothetical treatments, each with 7 attributes: mode of administration (MoA), dosing schedule (DS), median duration of therapy (DoT), objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and grade 3 or 4 adverse events (AEs). Hierarchical Bayesian logistic regression models were used to estimate preference weights. Results A total of 200 patients with advanced melanoma and 150 oncology nurses participated. The relative importance estimates of attributes by patients and nurses, respectively, were as follows: OS, 33% and 28%; AEs, 29% and 26%; ORR, 25% and 27%; PFS, 12% and 15%; DS, 2% and 3%; DoT, 0% and 0%; and MoA, 0% and 0%. Conclusion Both patients and oncology nurses valued OS, ORR, and AEs as the most important treatment attributes for advanced melanoma, followed by PFS, whereas DS, DoT, and MoA were given less value in their treatment decisions. Implications for Practice Oncology nurses and patients have similar views on important treatment considerations for advanced melanoma, which can help build trust in shared decision-making.

Background: Pembro received accelerated approval for second-line therapy in pts with advanced HCC, based on the phase 2, KEYNOTE-224 trial. KEYNOTE-240 was a randomized, phase 3 study of Pembro vs BSC in pts with previously treated advanced HCC. Method: Eligible pts had radiographic or pathologic diagnoses of HCC, progression on/intolerance to sorafenib, Child-Pugh A disease and ECOG PS 0-1. Pts were randomized 2:1 to Pembro 200 mg + BSC or placebo (Pbo) + BSC IV every 3 wk, stratified by geographic region, MVI and AFP levels for ≤35 cycles or until confirmed PD/unacceptable toxicity. Response was assessed every 6 wk (RECIST v1.1, central imaging review). Co-primary endpoints were OS and PFS. Secondary endpoints were ORR, DOR and safety. Data cutoff: OS, final analysis (Jan 2 2019); PFS, first interim (Mar 26 2018) and final analyses. Results: 413 patients were randomized (278 to Pembro,135 to Pbo). After a median follow up of 13.8 mo, 10.1% of pts remained on Pembro, 3.0% on Pbo. Pembro improved OS (HR 0.781, 95% CI 0.611 − 0.998; one sided p = 0.0238) and PFS (HR 0.775, 95% CI 0.609 − 0.987; one sided p = 0.0186 [first interim] and 0.718, 95% CI 0.570 − 0.904; one sided p = 0.0022 [final analysis]) vs Pbo; differences in OS at final and PFS at first interim analyses did not meet significance per the prespecified statistical plan. ORR (95% CI) was 18.3% (14.0 − 23.4%) and 4.4% (1.6 − 9.4%) for Pembro vs Pbo at final analysis (one sided p = 0.00007); Pembro responses were durable (median DOR: 13.8 mo [1.5+ – 23.6+]). Off study, anticancer therapy use was 42% for Pembro and 47% for Pbo. Safety profile including incidence of hepatitis and other immune mediated events was generally consistent with that previously reported for Pembro; no HBV/HCV flares were identified. Conclusion: Pembro reduced the risk of death by 22% and improved PFS vs Pbo in pts with advanced HCC, but significance did not meet prespecified statistical criteria. ORR for Pembro was consistent with that of KEYNOTE-224. New anticancer therapy in the Pbo arm likely impacted OS. The safety profile was comparable to that established for Pembro monotherapy. The results are consistent with those of KEYNOTE-224, further supporting second line therapy with Pembro in HCC pts.

PURPOSEPembrolizumab demonstrated antitumor activity and safety in the phase II KEYNOTE-224 trial in previously treated patients with advanced hepatocellular carcinoma (HCC). KEYNOTE-240 evaluated the efficacy and safety of pembrolizumab in this population.PATIENTS AND METHODSThis randomized, double-blind, phase III study was conducted at 119 medical centers in 27 countries. Eligible patients with advanced HCC, previously treated with sorafenib, were randomly assigned at a two-to-one ratio to receive pembrolizumab plus best supportive care (BSC) or placebo plus BSC. Primary end points were overall survival (OS) and progression-free survival (PFS; one-sided significance thresholds, P = .0174 [final analysis] and P = .002 [first interim analysis], respectively). Safety was assessed in all patients who received ≥ 1 dose of study drug.RESULTSBetween May 31, 2016, and November 23, 2017, 413 patients were randomly assigned. As of January 2, 2019, median follow-up was 13.8 months for pembrolizumab and 10.6 months for placebo. Median OS was 13.9 months (95% CI, 11.6 to 16.0 months) for pembrolizumab versus 10.6 months (95% CI, 8.3 to 13.5 months) for placebo (hazard ratio [HR], 0.781; 95% CI, 0.611 to 0.998; P = .0238). Median PFS for pembrolizumab was 3.0 months (95% CI, 2.8 to 4.1 months) versus 2.8 months (95% CI, 2.5 to 4.1 months) for placebo at the first interim analysis (HR, 0.775; 95% CI, 0.609 to 0.987; P = .0186) and 3.0 months (95% CI, 2.8 to 4.1 months) versus 2.8 months (95% CI, 1.6 to 3.0 months) at final analysis (HR, 0.718; 95% CI, 0.570 to 0.904; P = .0022). Grade 3 or higher adverse events occurred in 147 (52.7%) and 62 patients (46.3%) for pembrolizumab versus placebo; those that were treatment related occurred in 52 (18.6%) and 10 patients (7.5%), respectively. No hepatitis C or B flares were identified.CONCLUSIONIn this study, OS and PFS did not reach statistical significance per specified criteria. The results are consistent with those of KEYNOTE-224, supporting a favorable risk-to-benefit ratio for pembrolizumab in this population.

BACKGROUND:In oncology clinical development, objective response rate, disease control rate and early tumor size changes are commonly used as efficacy metrics for early decision-making. However, for immunotherapy trials, it is unclear whether these early efficacy metrics are still predictive of long-term clinical benefit such as overall survival. The goal of this paper is to identify appropriate early efficacy metrics predictive of overall survival for immunotherapy trials.METHODS:Based on several checkpoint blockade based immunotherapy studies in metastatic melanoma, we evaluated the predictive value of early tumor size changes and RECIST-based efficacy metrics at various time points on overall survival. The cut-off values for tumor size changes to predict survival were explored via tree based recursive partitioning and validated by external data. Sensitivity analyses were performed for the cut-offs.RESULTS:The continuous tumor size change metric and RECIST-based trichotomized response metric at different landmark time points were found to be statistically significantly associated with overall survival. The predictive values were higher at Week 12 and 18 than those at Week 24. The percentage of tumor size changes appeared to have comparable or lower predictive values than the RECIST-based trichotomized metric, and a cut-off of approximately 10% tumor reduction appeared to be reasonable for predicting survival.CONCLUSIONS:An approximate 10% tumor reduction may be a reasonable cut-off for early decision-making while the RECIST-based efficacy metric remains the primary tool. Early landmark analysis is especially useful for decision making when accrual is fast. Composite response rate (utilizing different weights for PR/CR and SD) may be worth further investigation.TRIAL REGISTRATION:Clinical trials gov, NCT01295827 , Registered February 15, 2011; NCT01704287 , Registered October 11, 2012; NCT01866319 , Registered May 31, 2013.

The programmed death-1 inhibitor pembrolizumab has demonstrated efficacy and safety in clinical trials for treating advanced (unresectable/metastatic) melanoma. We investigated the real-world utilization of pembrolizumab and associated patient outcomes for advanced melanoma in US community oncology practices. This retrospective, observational study used deidentified data from electronic health records for adult patients with advanced melanoma who received pembrolizumab at The US Oncology Network sites from September 2014 through December 2015, with follow-up through September 2016. Patients enrolled in clinical trials were excluded. Overall survival (OS) and physician-stated progression-free survival (PFS) were analyzed from pembrolizumab initiation using Kaplan-Meier, and associations between pembrolizumab therapy and OS/PFS, using multivariable Cox regression. Of 168 patients studied, 110 (65%) were male; the median age was 66 years (range, 26-over 90). Pembrolizumab was prescribed as first-line, second-line, and third-line/later for 39 (23%), 87 (52%), and 42 (25%) patients, respectively. In total, 41 patients (24%) had brain metastases. At pembrolizumab initiation, 21/129 (16%) had Eastern Cooperative Oncology Group performance status (ECOG PS) >1; 51/116 (44%) had elevated lactate dehydrogenase. Median follow-up was 10.5 months (range, 0-25.1); median OS was 19.4 months (95% confidence interval, 14.0-not reached); median PFS was 4.2 months (95% confidence interval, 2.9-5.3). Brain metastases, ECOG PS>1, elevated lactate dehydrogenase, and third-line/later (vs. first-line) pembrolizumab were significant predictors (P<0.01) of decreased survival. Treatment-related toxicity was a discontinuation reason for 25% (29/117) of patients, and for 10 of these 29 patients (6% of the full-study cohort) treatment-related toxicity was the only reported reason. The real-world effectiveness and safety of pembrolizumab for advanced melanoma are consistent with clinical trial findings.

Background: Predictive biomarkers of patients likely to benefit from anti-programmed death 1 inhibitor therapy have clinical relevance. We examined whether line of therapy or tumour programmed death ligand 1 (PD-L1) expression affects the efficacy and safety of pembrolizumab, compared with ipilimumab, in advanced melanoma. Methods: Of 834 patients enrolled in the randomised, open-label phase III KEYNOTE-006 study, 833 were included in this analysis. Patients were randomly assigned 1: 1: 1 to receive pembrolizumab 10 mg/kg every 2 or 3 weeks (for 24 months) or ipilimumab 3 mg/kg every 3 weeks (for four doses) until disease progression/intolerable toxicity. This analysis evaluated progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). Data cut-off: 03 November 2016. Results: Of the patients, 60.3% were male, 65.9% were treatment naive and 80.6% had PD-L1 epositive tumours (median follow-up was 33.9 months). Twenty-four-month survival rates were higher with pembrolizumab than with ipilimumab in treatment-naive (PFS 31.0% versus 14.6%; OS 58.0% versus 44.7%) and previously treated patients (PFS 25.7% versus 11.3%; OS 49.2% versus 37.9%). Twenty-four-month survival rates were higher with pembrolizumab than with ipilimumab in patients with PD-L1-positive tumours (PFS 33.2% versus 13.1%; OS 58.4% versus 45.0%) and similar in PD-L1-negative tumours (PFS 14.9% versus NR [no data at 24 months for a PFS estimate]; OS 43.6% versus 31.8%). Safety of pembrolizumab by subgroup was consistent with previous reports. Conclusions: Findings support pembrolizumab monotherapy as standard of care in patients with advanced melanoma, regardless of first-or second-line therapy or PD-L1 status. ClinicalTrials.gov identifier: NCT01866319. (C) 2018 Elsevier Ltd. All rights reserved.

4020 Background: Initial results from KEYNOTE-224 (NCT02702414), an open label, phase 2 trial showed that pembro, an anti-PD-1 antibody, was active and safe in pts with advanced HCC previously treated with sorafenib. Here we report updated clinical results and biomarker studies. Methods: Eligible pts were age ≥18 y with histologically confirmed HCC, radiographic progression on/intolerance to sorafenib and disease not amenable to curative treatment, Child Pugh A, ECOG PS 0-1 and BCLC stage C or B. Pts received pembro 200 mg IV Q3W for 2 y or until disease progression, unacceptable toxicity, withdrawal of consent or investigator decision. Response was assessed every 9 wk. Primary endpoint was ORR (RECIST v1.1, central review). Secondary endpoints were DOR, DCR, PFS, OS and safety. Exploratory endpoint was relationship of PD-L1 IHC combined positive and tumor proportion scores (CPS and TPS; n = 52), and T cell inflamed gene expression profile (GEP; n = 42) with response. Data cutoff date was Nov 24, 2017. Results: Of 104 treated pts, 18 remained on therapy. Median age was 68 y (range 43-87), 21.2% were HBV+, 26% were HCV+, 94.2% were Child Pugh A, 79.8% had PD on sorafenib and 64.4% had extrahepatic disease. ORR was 16.3% (95% CI, 9.8 to 24.9, n = 17) and similar across differing etiologies; 66% of responders had duration ≥12 mo (Kaplan Meier) and median response duration was not reached (3.1 - 12.5+ mo). Best response was CR in 1 pt (1.0%), PR in 16 (15.4%), SD in 47 (45.2%) and PD in 34 (32.7%); DCR was 61.5%. Median PFS (95% CI) was 4.9 mo (3.4 to 7.0) and OS was 12.9 mo (9.7 to NA). PFS and OS 12 mo rates were 25.4% and 53.6%, respectively. Safety was similar to that observed for pembrolizumab in other indications. Immune-mediated hepatitis occurred in 3 (2.9%) pts; no cases of HBV/HCV flare were seen. Higher PD-L1 CPS in tumor and immune cells was associated with higher ORR and longer PFS, while PD-L1 TPS in tumor cells alone and GEP showed less robust associations with outcomes. Conclusions: These results confirm that pembro may be a promising treatment option for pts with advanced HCC. PD-L1 CPS was associated with clinical response to pembro while results for PD-L1 TPS and GEP were less robust; further study is needed to better define these relationships. Clinical trial information: NCT02702414.

Purpose Pembrolizumab provides durable antitumor activity in metastatic melanoma, including complete response (CR) in about 15% of patients. Data are limited on potential predictors of CR and patient disposition after pembrolizumab discontinuation after CR. We describe baseline characteristics and long-term follow-up in patients who experienced CR with pembrolizumab in the KEYNOTE-001 study ( ClinicalTrials.gov identifier: NCT01295827). Patients and Methods Patients with ipilimumab-naive or -treated advanced/metastatic melanoma received one of three dose regimens of pembrolizumab. Eligible patients who received pembrolizumab for ≥ 6 months and at least two treatments beyond confirmed CR could discontinue therapy. Response was assessed every 12 weeks by central Response Evaluation Criteria in Solid Tumors version 1.1. For this analysis, CR was defined per investigator assessment, immune-related response criteria, and potential predictors of CR were evaluated using univariate and multivariate analyses. Results Of 655 treated patients, 105 (16.0%) achieved CR after median follow-up of 43 months. At data cutoff, 92 patients (87.6%) had CR, with median follow-up of 30 months from first CR. Fourteen (13.3%) patients continued to receive treatment for a median of ≥ 40 months. Pembrolizumab was discontinued by 91 patients (86.7%), including 67 (63.8%) who proceeded to observation without additional anticancer therapy. The 24-month disease-free survival rate from time of CR was 90.9% in all 105 patients with CR and 89.9% in the 67 patients who discontinued pembrolizumab after CR for observation. Tumor size and programmed death-ligand 1 status were among the baseline factors independently associated with CR by univariate analysis. Conclusion Patients with metastatic melanoma can have durable complete remission after discontinuation of pembrolizumab, and the low incidence of relapse after median follow-up of approximately 2 years from discontinuation provides hope for a cure for some patients. The mechanisms underlying durable CR require further investigation.