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Purpose Transarterial chemoembolization (TACE) is the standard of care for patients with intermediate-stage hepatocellular carcinoma (HCC). Lenvatinib, a multikinase inhibitor, and pembrolizumab, a PD-1 inhibitor, have shown efficacy and tolerability in patients with HCC, and adding this combination to TACE may enhance clinical benefit. Protocol LEAP-012 is a prospective, double-blind randomized phase 3 study. Adults with confirmed HCC localized to the liver without portal vein thrombosis and not amenable to curative treatment, ≥ 1 measurable tumor per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1), Eastern Cooperative Oncology Group performance status 0 or 1, Child–Pugh class A and no previous systemic treatment for HCC are eligible. Patients will be randomly assigned to lenvatinib once daily plus pembrolizumab every 6 weeks plus TACE or placebos plus TACE. Dual primary endpoints are overall survival and progression-free survival per RECIST 1.1 by blinded independent central review (BICR). Secondary endpoints are progression-free survival, objective response rate, disease control rate, duration of response and time to progression per modified RECIST by BICR; objective response rate, disease control rate, duration of response and time to progression per RECIST 1.1 by BICR; and safety. Statistics The planned sample size, 950 patients, was calculated to permit accumulation of sufficient overall survival events in 5 years to achieve 90% power for the overall survival primary endpoint. Discussion LEAP-012 will evaluate the clinical benefit of adding lenvatinib plus pembrolizumab to TACE in patients with intermediate-stage HCC not amenable to curative treatment. ClinicalTrials.gov NCT04246177.

Background: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. Methods: KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. Findings: Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7–30·4). Median overall survival was 12·7 months (95% CI 11·5–13·6) in the pembrolizumab group versus 10·9 months (9·9–11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72–0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events. Interpretation: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Supplementary Data from Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial

Editorial from Serum Antioxidant Nutrients, Vitamin A, and Mortality in U.S. Adults

Supplementary Table from Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial

Background: Observational studies have suggested that antioxidant nutrients may reduce cancer and overall mortality risks. However, most randomized trials have failed to show survival benefits. Examining nonlinear associations between antioxidant levels and health outcomes may help to explain these discrepant findings.Methods: We evaluated all-cause, cancer, and cardiovascular mortality risks associated with quintiles (Q1–Q5) of serum antioxidant (vitamins C and E, β-carotene, and selenium) and vitamin A levels, in 16,008 adult participants of The Third National Health and Nutrition Examination Survey (NHANES III; 1988–1994).Results: Over a median follow-up period of 14.2 years, there were 4,225 deaths, including 891 from cancer and 1,891 from cardiovascular disease. We observed a dose–response decrease in cancer and overall mortality risks with higher vitamin C levels. In contrast, for vitamin A, risk of cancer death decreased from Q1–Q2, with no further decline in risk at higher levels. For vitamin E, having levels in Q4 was associated with the lowest cancer mortality risk. Both vitamin A and E had U-shaped associations with all-cause mortality. Cancer mortality risks decreased from Q1–Q2 for β-carotene and from Q1–Q4 for selenium. However, for β-carotene and selenium, overall mortality risks decreased from Q1–Q2 but then did not change significantly with higher levels.Conclusions: Antioxidant supplement use should be studied in the context of overall mortality and other competing mortality risks.Impact: These data suggest the need for novel intervention studies where doses of these agents are individualized based on their serum levels, and possibly, markers of oxidative stress and systemic inflammatory response. Cancer Epidemiol Biomarkers Prev; 22(12); 2202–11. ©2013 AACR.

PDF - 304 KB, Table S1. Hazard Ratios Additionally Adjusted for Serum C-reactive Protein Levels Table S2. Hazard Ratios Additionally Adjusted for Serum Levels of Other Micronutrients in the study Table S3. Hazard Ratios after Excluding NHANES III Participants who are Current Smokers Table S4. Hazard Ratios after Excluding NHANES III Participants with History of Heart Attack, Congestive Heart Failure, Stroke or Cancer Table S5. Hazard Ratios after excluding Deaths within the First Three Years of the Survey Table S6. Hazard Ratios for All-Cause Mortality for 5- and 10-years of Follow-up Table S7. Hazard Ratios for All-Cause Mortality Stratified by Age, Gender, Race-Ethnicity, BMI and Supplement Use Table S8. Hazard Ratios for Gastrointestinal and Respiratory Tract Cancer Mortality Table S9. Hazard Ratios for Ischemic Heart Disease and Stroke Mortality Figure S1. Restricted Cubic Splines for All-Cause Mortality Figure S2. Restricted Cubic Splines for Cancer Mortality Figure S3. Restricted Cubic Splines for Cardiovascular Mortality

Supplementary Figure from Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial

Purpose:KEYNOTE-224 cohort 1 demonstrated that pembrolizumab was efficacious and tolerable in patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib. We report results from KEYNOTE-224 (NCT02702414) cohort 2, which enrolled patients with advanced HCC and no prior systemic therapy.Patients and Methods:KEYNOTE-224 was an open-label, multicountry phase II trial. Eligible patients in cohort 2 had advanced HCC not amenable or refractory to locoregional therapy and not previously treated with systemic therapy. Patients received pembrolizumab 200 mg intravenously every 3 weeks for ≤2 years. Primary endpoint was objective response rate (ORR) by central imaging review per RECIST v1.1. Secondary endpoints included duration of response (DOR), disease control rate (DCR), time to progression (TTP), progression-free survival (PFS), overall survival (OS), and safety/tolerability.Results:Between September 4, 2018, and February 20, 2019, 51 patients were allocated in cohort 2. The median time from the first dose to data cutoff (January 19, 2021) was 27 months (range, 23–29). ORR was 16% [95% confidence interval (CI), 7–29] and was similar across key subgroups. Median DOR was 16 months (range, 3–24+), and DCR was 57%. The median PFS was 4 months (95% CI, 2–8), and median TTP was 4 months (95% CI, 3–9). Median OS was 17 months (95% CI, 8–23). Grade ≥3 treatment-related adverse events occurred in 16% of patients.Conclusions:In patients with advanced HCC with no prior systemic therapy, pembrolizumab provided durable antitumor activity, promising OS, and had a safety profile consistent with previous observations. These findings support further evaluation of pembrolizumab-based regimens for HCC.

PURPOSE We evaluated the efficacy and safety of pembrolizumab in patients from Asia with previously treated advanced hepatocellular carcinoma (HCC). METHODS In a double-blind, phase III trial, 453 patients with advanced HCC and progression during or after treatment with or intolerance to sorafenib or oxaliplatin-based chemotherapy were randomly assigned in a 2:1 ratio to receive pembrolizumab (200 mg) or placebo once every 3 weeks for ≤ 35 cycles plus best supportive care. The primary end point was overall survival (one-sided significance threshold, P = .0193 [final analysis]). Secondary end points included progression-free survival (PFS) and objective response rate (ORR; one-sided significance threshold, P = .0134 and .0091, respectively [second interim analysis]; RECIST version 1.1, by blinded independent central review). RESULTS Median overall survival was longer in the pembrolizumab group than in the placebo group (14.6 v 13.0 months; hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P = .0180). Median PFS was also longer in the pembrolizumab group than in the placebo group (2.6 v 2.3 months; hazard ratio for progression or death, 0.74; 95% CI, 0.60 to 0.92; P = .0032). ORR was greater in the pembrolizumab group (12.7% [95% CI, 9.1 to 17.0]) than in the placebo group (1.3% [95% CI, 0.2 to 4.6]; P < .0001). Treatment-related adverse events occurred in 66.9% of patients (grade 3, 12.0%; grade 4, 1.3%; grade 5, 1.0%) in the pembrolizumab group and 49.7% of patients (grade 3, 5.9%; grade 4, 0%; grade 5, 0%) in the placebo group. CONCLUSION In patients from Asia with previously treated advanced HCC, pembrolizumab significantly prolonged overall survival and PFS, and ORR was greater versus placebo.

In the U.S., Hepatocellular carcinoma (HCC) incidence rates have increased. We aimed to determine whether environmental exposure plays a role in the high incidence of HCC observed in New York City. We conducted a hospital-based case only study to examine the prevalence of aflatoxin B1 (AFB1)- and polycyclic aromatic hydrocarbon (PAH)-albumin adducts and the distribution of adducts by different characteristics of HCC patients. Blood samples were collected from 155 HCC patients for biomarker analyses. We observed that about 46% and 49% of cases had detectable AFB1- and PAH-albumin adducts, respectively. There were significant differences between AFB1-albumin adducts and selected factors such as HCV infection status (p = 0.04), diabetes (p = 0.03) and Barcelona Clinic Liver Cancer (BCLC) stage (p = 0.02). Cases with detectable PAH-albumin adducts had a smoking history compared with those with nondetectable levels (p = 0.04). The level of AFB1-albumin adducts was positively correlated with plasma bilirubin (rs=0.32, p s=0.28, p = 0.0005). The level of aflatoxin B1-albumin adducts was negatively associated with blood albumin concentration (rs=-0.28, p = 0.0009) and plasma DNA LINE-1 methylation (rs=-0.16, p = 0.04). Our study provides additional evidence that environmental exposures including to aflatoxin might partially explain the increase in the incidence of HCC in the US.

Introduction: KEYNOTE-240 investigated the efficacy and safety of pembrolizumab plus best supportive care (BSC) in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC). Results for the subgroup of patients from Asia are described. Methods: Adults with advanced HCC previously treated with sorafenib were randomized 2:1 to pembrolizumab or placebo plus BSC. Here, the Asian subgroup comprised patients enrolled in Hong Kong, Japan, Korea, the Philippines, Taiwan, and Thailand. Primary endpoints were progression-free survival (PFS) per blinded central imaging review and overall survival (OS). Secondary endpoints included objective response rate (ORR) per blinded central imaging review, duration of response (DOR), and safety. Results: The Asian subgroup included 157 patients. As of January 2, 2019, the median follow-up in this subgroup was 13.8 months for pembrolizumab and 8.3 months for placebo. The median PFS was 2.8 months for pembrolizumab (95% confidence interval [CI] 2.6–4.1) versus 1.4 months (95% CI 1.4–2.4) for placebo (hazard ratio [HR] 0.48; 95% CI 0.32–0.70). The median OS was 13.8 months (95% CI 10.1–16.9) for pembrolizumab versus 8.3 months (95% CI 6.3–11.8) for placebo (HR 0.55; 95% CI 0.37–0.80). ORR was 20.6% (95% CI 13.4–29.5) for pembrolizumab versus 2.0% (95% CI 0.1–10.6) for placebo (difference: 18.5%; 95% CI 8.3–27.6). The median DOR was 8.6 and 2.8 months for pembrolizumab and placebo, respectively. Any grade treatment-related adverse events (TRAEs) occurred in 63 patients (58.9%) receiving pembrolizumab and 24 patients (48.0%) receiving placebo; 14 (13.1%) and 2 (4.0%) patients experienced grade 3–5 TRAEs, respectively. No treatment-related deaths occurred. Conclusion: Pembrolizumab demonstrated antitumor activity and was well tolerated in the Asian subgroup of KEYNOTE-240. A trend toward greater benefit with pembrolizumab in the Asian subgroup was observed compared with the overall cohort, supporting further evaluation of pembrolizumab treatment in this population.

Purpose: KEYNOTE-224 cohort 1 demonstrated that pembrolizumab was efficacious and tolerable in patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib. We report results from KEYNOTE-224 (NCT02702414) cohort 2, which enrolled patients with advanced HCC and no prior systemic therapy. Patients and Methods: KEYNOTE-224 was an open-label, multicountry phase II trial. Eligible patients in cohort 2 had advanced HCC not amenable or refractory to locoregional therapy and not previously treated with systemic therapy. Patients received pembrolizumab 200 mg intravenously every 3 weeks for ≤2 years. Primary endpoint was objective response rate (ORR) by central imaging review per RECIST v1.1. Secondary endpoints included duration of response (DOR), disease control rate (DCR), time to progression (TTP), progression-free survival (PFS), overall survival (OS), and safety/tolerability. Results: Between September 4, 2018, and February 20, 2019, 51 patients were allocated in cohort 2. The median time from the first dose to data cutoff (January 19, 2021) was 27 months (range, 23–29). ORR was 16% [95% confidence interval (CI), 7–29] and was similar across key subgroups. Median DOR was 16 months (range, 3–24+), and DCR was 57%. The median PFS was 4 months (95% CI, 2–8), and median TTP was 4 months (95% CI, 3–9). Median OS was 17 months (95% CI, 8–23). Grade ≥3 treatment-related adverse events occurred in 16% of patients. Conclusions: In patients with advanced HCC with no prior systemic therapy, pembrolizumab provided durable antitumor activity, promising OS, and had a safety profile consistent with previous observations. These findings support further evaluation of pembrolizumab-based regimens for HCC.

Background Health-related quality of life (HRQoL) is an important outcome measure and prognostic indicator in hepatocellular carcinoma (HCC). KEYNOTE-240 (NCT02702401) assessed the efficacy and safety of pembrolizumab plus best supportive care (BSC) versus placebo plus BSC in patients with HCC who previously received sorafenib. This study presents the results of a prespecified exploratory analysis of patient-reported outcomes. Methods Patients completed the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) and its HCC supplement (EORTC QLQ-HCC18) electronically at baseline; at weeks 2, 3, 4, 6, 9, 12, and 18; and then every 9 weeks until 1 year or end of treatment, and at the 30-day safety follow-up visit. Results The HRQoL population included 271 and 127 patients randomly assigned to pembrolizumab and placebo, respectively. From baseline to week 12, changes in both scores were similar between pembrolizumab and placebo; global health status/QoL scores were stable. The proportions of patients who improved, remained stable, or deteriorated across all functional domain and symptom scores were generally similar between pembrolizumab and placebo. Time to deterioration was similar between the 2 arms based on the prespecified analysis of EORTC QLQ-HCC18 domains of abdominal swelling, fatigue, and pain. Conclusion Pembrolizumab preserved HRQoL during treatment for advanced HCC. Combined with efficacy and safety results from KEYNOTE-240, these findings support a positive benefit/risk profile for pembrolizumab in a second-line treatment setting for patients with HCC who previously received sorafenib.

Background The rationale for the evaluation of trametinib in advanced biliary cancer (BC) is based on the presence of mitogen-activated protein kinase alterations and on earlier promising results with MEK inhibitors in BC. Methods Patients with histologically proven BC who progressed on gemcitabine/platinum were randomised to trametinib daily (arm 1) versus fluoropyrimidine therapy (infusional 5-fluorouracil or oral capecitabine, arm 2). The primary end-point was overall survival (OS). Secondary end-points included progression free survival (PFS) and response rate. A planned interim futility analysis of objective response was performed on the first 14 patients registered to the trametinib arm. Results The study was stopped early based on the lack of measurable response in the trametinib arm. A total of 44 eligible patients were randomised (24 patients in arm 1 and 20 patients in arm 2). Median age was 62 years and the primary sites of tumour were cholangiocarcinoma (68%) and gallbladder (32%). The overall response rate was 8% (95% CI 0%–19%) in arm 1 versus 10% (95% CI 0%–23%) in arm 2 (p > .99) Median OS was 4.3 months for arm 1 and 6.6 months for arm 2. The median PFS was 1.4 months for arm 1 and 3.3 months for arm 2. Conclusions This is the first prospective randomised study of a targeted agent versus chemotherapy for the second-line treatment of BC. In this unselected population, the interim analysis result of unlikely benefit with trametinib resulted in early closure.

506 Background: In LEAP-002 (NCT03713593), len + pembro achieved a median OS of 21.2 mo vs 19.0 mo with len + pbo with manageable safety in both arms in 1L aHCC, although the significance thresholds for OS and PFS were not met. We present here the results of prespecified exploratory patient (pt)-reported outcomes (PROs). Methods: 794 pts were randomized. PROs were assessed by EORTC QLQ-C30, EuroQol-5D5L (EQ5D-5L), and EORTC QLQ-HCC18 questionnaires. Analysis population for HRQoL endpoints included pts who received ≥1 dose of study Tx and completed ≥1 HRQoL assessment. Least squares mean (LSM) score changes from baseline (BL) to wk 27 were compared using a constrained longitudinal data analysis model (covariates: Tx, time, Tx by time interaction, and stratification factors). Kaplan-Meier method was used to estimate time to deterioration (TTD, time to 1st onset of ≥10 [out of 100] deterioration from BL in a given scale or subscale/confirmed by a 2nd adjacent ≥10 deterioration from BL) for EORTC QLQ-C30 global health status (GHS)/QoL, physical functioning (PF), and EORTC QLQ-HCC18 abdominal swelling, pain and fatigue, as reported by pts. Stratified Cox proportional hazards model was used to assess the magnitude of the Tx difference (HR) between arms in TTD. Results: Compliance with PRO assessments was >91% from BL until wk 27 in both arms. From BL to wk 27, LSM changes in GHS/QoL, PF, role functioning (RF), QLQ-HCC18 functional/domain scores and EQ5D-5L VAS were generally similar between the two arms (Table). Treatment with len + pembro delayed deterioration of patient-reported quality of life vs len + pbo (median TTD, 11.5 vs 4.3 mo; HR, 0.80; 95% CI, 0.65-0.98). LSM score difference (95% CI) was 0.5 (-2.5, 3.4) for GHS/QoL, -1.7 (-4.5, 1.1) for PF, -1.0 (-4.9, 2.9) for RF, 1.0 (-2.2, 4.3) for abdominal swelling, 2.0 (-1.2, 5.2) for fatigue, 2.0 (-1.0, 5.0) for pain, and 0.6 (-2.0, 3.2) for EQ5D-5L VAS. Median TTD in QLQ-C30 PF (5.7 vs 9.1 mo; HR, 1.14; 95% CI, 0.93-1.41) and QLQ-HCC18 abdominal swelling (NR vs NR; HR, 1.19; 95% CI, 0.89-1.60) /fatigue (2.9 vs 2.8 mo; HR, 0.98; 95% CI, 0.81-1.19)/pain (9.6 vs 7.9 mo; HR, 0.93; 95% CI, 0.75-1.16) was similar between the arms. Conclusions: Len + pembro generally preserved HRQoL vs len + pbo in 1L for aHCC. Combined with efficacy and safety results from LEAP-002, these findings support continued development of len + pembro in HCC. Clinical trial information: NCT03713593 . [Table: see text]

Aims: This post hoc analysis evaluated albumin/bilirubin (ALBI) score, an objective measure of liver function, in patients receiving pembrolizumab plus best supportive care (BSC) compared with placebo plus BSC in the KEYNOTE-240 study. Methods: Patients with confirmed hepatocellular carcinoma (HCC) and progression after/intolerance to sorafenib, Child–Pugh class A liver function, and Eastern Cooperative Oncology Group performance status of 0–1 were randomly assigned 2:1 to pembrolizumab 200 mg or placebo intravenously every 3 weeks plus BSC for ⩽35 cycles or until confirmed progression/unacceptable toxicity. Outcomes were assessed by ALBI grade. Results: Of 413 patients, at baseline 116 had an ALBI grade 1 score (pembrolizumab, n = 74; placebo, n = 42) and 279 had an ALBI grade 2 score ( n = 193; n = 86). Change from baseline in ALBI score to the end of treatment was similar in both arms [difference in least squares mean, −0.039; 95% confidence interval (CI): −0.169 to 0.091]. Time to ALBI grade increase was similar in both arms [median for pembrolizumab versus placebo: 7.8 versus 6.9 months; hazard ratio (HR) = 0.863 (95% CI: 0.625–1.192)]. Regardless of baseline ALBI grade, a trend toward improved overall survival was observed with pembrolizumab [grade 1: HR = 0.725 (95% CI: 0.454–1.158); grade 2: HR = 0.827 (95% CI: 0.612–1.119)]. Conclusion: Pembrolizumab did not adversely impact liver function compared with placebo in patients with HCC, as measured by changes in ALBI scores. A trend toward improved overall survival was observed with pembrolizumab in both ALBI grade groups. ClinicalTrials.gov identifier: NCT02702401.

OBJECTIVE: Pembrolizumab, a PD-1 inhibitor, demonstrated anti-tumour activity and tolerability in patients treated with sorafenib and with advanced hepatocellular carcinoma in KEYNOTE-224. Longer-term efficacy and safety after ∼2.5 years of additional follow-up are reported. PATIENTS AND METHODS: Adults with confirmed hepatocellular carcinoma who experienced progression after or intolerance to sorafenib treatment received pembrolizumab 200 mg every 3 weeks for ≤35 cycles or until confirmed progression, unacceptable toxicity, withdrawal of consent or investigator decision. The primary end-point was objective response rate assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumours v1.1. The secondary end-points included duration of response, disease control rate, time to progression, progression-free survival, overall survival and adverse events. RESULTS: Efficacy and safety were assessed in 104 patients. The median time from first dose to data cutoff was 45.1 months (range, 41.3-49.3). Objective response rate was 18.3% (95% CI: 11.4-27.1), and median duration of response was 21.0 months (range, 3.1 to 39.5+). Disease control rate was 61.5%, and median time to progression was 4.8 months (95% CI: 3.9-7.0). Median progression-free survival was 4.9 months (95% CI: 3.5-6.7) and median overall survival was 13.2 months (95% CI: 9.7-15.3). Of 104 patients, 76 (73.1%) patients reported treatment-related adverse events; most were low grade in severity (grade 3-4, n = 26 [25.0%]; grade 5, n = 1 [1.0%]). Immune-mediated hepatitis occurred in 3 patients (all grade 3). No viral-induced hepatitis flares occurred. CONCLUSIONS: After ∼2.5 years of additional follow-up, pembrolizumab continued to provide durable anti-tumour activity and no new safety concerns were identified. GOV IDENTIFIER: NCT02702414. ispartof: EUROPEAN JOURNAL OF CANCER vol:167 pages:1-12 ispartof: location:England status: published

Background: In patients (pts) with previously treated aHCC, pembro demonstrated comparable efficacy and safety vs placebo (pbo) in the phase 3 KEYNOTE-240 (NCT02702401) and KEYNOTE-394 (NCT03062358) studies in global and Asian populations, respectively. The hazard ratio ([HR]; 95% confidence interval [CI]) for OS was 0.781 (0.611-0.998) in KEYNOTE-240 and 0.79 (0.63-0.99) in KEYNOTE-394; HR (95% CI) for PFS was 0.78 (0.61-0.99) and 0.74 (0.60-0.92), respectively. ORR differences with pembro vs pbo were similar in KEYNOTE-240 (13.8% [95% CI, 7.7-19.5]) and KEYNOTE-394 (11.4% [95% CI, 6.7-16.0]). We performed a prespecified meta-analysis of KEYNOTE-240 and KEYNOTE-394 to obtain a more precise estimate of the pembro treatment effect. Methods: In KEYNOTE-240 and KEYNOTE-394, pts with confirmed aHCC and progression or intolerance to sorafenib or oxaliplatin-based chemotherapy (KEYNOTE-394 only) were randomized 2:1 to pembro (200 mg IV Q3W) or pbo for ≤35 cycles, both with best supportive care. Inclusion/exclusion criteria were similar. Meta-analysis of pt data pooled from the ITT population of the pembro and pbo arms of each study was completed. OS, PFS (blinded independent central review [BICR] per RECIST 1.1), and ORR (BICR per RECIST 1.1) were assessed. Results: In total, 578 pts who received pembro and 288 who received pbo were included. The HR for OS and PFS and the difference in ORR for pembro vs pbo in all pts was 0.79 (95% CI, 0.67-0.93), 0.76 (0.64-0.89), and 12.5 (8.8-16.2), respectively (Table). Results were consistent across subgroups, including viral etiology, BCLC stage, and age. Conclusions: This meta-analysis of two studies with similar design, inclusion/exclusion criteria, and endpoints, showed improvement in OS, PFS, and ORR with pembro vs pbo across studies. These data also show consistent outcomes between the studies, providing further evidence for the benefit of second-line pembro for aHCC globally. All Patients Patients With Sorafenib-Treated aHCC Pembrolizumab(n = 578) Placebo(n = 288) Pembrolizumab(n = 550) Placebo (n = 274) OS, median (95% CI), mo 14.2 (12.8-16.2) 12.5 (10.2-13.6) 14.2 (12.8-16.0) 12.5 (10.4-13.6) HR (95% CI)a,b 0.79 (0.67-0.93) 0.78 (0.66-0.92) PFS, median (95% CI), mo 2.8 (2.7-2.9) 2.7 (1.6-2.8) 2.8 (2.7-2.9) 2.7 (1.6-2.8) HR (95% CI)a,b 0.76 (0.64-0.89) 0.76 (0.64-0.90) ORR, % (95% CI) 15.4 (12.6-18.6) 2.8 (1.2-5.4) 15.6 (12.7-18.9) 2.9 (1.3-5.7) Estimated treatment difference, (95% CI)b,c 12.5 (8.8-16.2) 12.6 (8.8-16.4) aHCC, advanced hepatocellular carcinoma; CI, confidence interval; HR, hazard ratio.aStratified Cox proportional hazard model with treatment as a single covariate and Efron’s method of tie handling was used to estimate the OS and PFS HR and its 95% CI.bStratification was performed per protocol and within each protocol, by strata used in the analysis of the respective protocol.cMiettinen & Nurminen method was used to estimate the difference in ORR and its 95% CI. Citation Format: Richard S. Finn, Kangsheng Gu, Xi Chen, Philippe Merle, Kyung-Hun Lee, Mohamed Bouattour, Peiguo Cao, Wei Wang, Ann-Lii Cheng, Liangjun Zhu, Ho Yeong Lim, Masatoshi Kudo, Yueyin Pan, Ting-Tsung Chang, Julien Edeline, Wei Li, Ping Yang, Chen Li, Jianfeng Li, Abby B. Siegel, Shukui Qin. Pembrolizumab (pembro) for previously treated advanced hepatocellular carcinoma (aHCC): Meta-analysis of the phase 3 KEYNOTE-240 and KEYNOTE-394 studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT222.

4090 Background: BTC is associated with poor prognosis and limited treatment choices. There is limited evidence on HCRU and costs among BTC patients receiving systemic treatments (ST). This study examined HCRU and total direct cost of care among BTC patients treated with ST to understand the disease burden in management of BTC. Methods: A retrospective cohort study of BTC patients who received first line (1L) ST was conducted, using US private payer Cancer Care Quality Program data and administrative claims from the HealthCore Integrated Research Database between 07/01/2014 - 03/31/2021. Patients with ampullary cancer, brain/ CNS metastases, other primary cancer before BTC diagnosis were excluded. Per patient per month (PPPM) costs in 2020 USD were calculated during 1L, 2L, and 3L treatments associated with HCRU from inpatient, emergency room, and outpatient visits as well as outpatient pharmacy dispensing. Results: Among 298 BTC patients (biliary tract, n=203; gallbladder, n=65; bile duct, n=30; stage IV, n=231; stage III, n=28; stage I/II, n=39) who received ST, mean (SD) age was 61.7 (9) years at 1L treatment initiation, and the majority were female (58%). Following 1L treatment, 44% received 2L treatment, and 16% received 3L treatment. Median follow-up was 7.6 months. Among 201 (67%) patients who had hospitalization in the follow-up period, mean (SD) number of hospitalizations was 2.5 (2), and the average length of stay was 7.0 (5) days. Total PPPM all-cause costs were the lowest during 1L treatment (mean [SD]: $19,589 [$22,603]), and increased as the treatment advanced (2L: $22,617[$19,302]; 3L: $33,534[$40,588]). Similar trend was observed in BTC-related total costs with $16,237 ($22,452) in 1L, $19,083 ($18,670) in 2L and $27,609 ($39,949) in 3L. The table summarizes BTC-related HCRU and PPPM cost during each line of therapy. Conclusions: Study findings suggest significant resource use burden and high total direct medical costs for BTC patients receiving ST. Hospitalizations and outpatient visits represent important HCRU and cost for BTC. These data indicate a need for future newer innovative therapies in the management of BTC.[Table: see text]

4109 Background: Pembrolizumab monotherapy showed durable antitumor activity and a manageable safety profile in patients with sorafenib-treated (cohort 1) and treatment-naive (cohort 2) aHCC in the open-label, phase 2 KEYNOTE-224 (NCT02702414) study. Longer term data from KEYNOTE-224 after ̃3 years of follow-up for patients with treatment-naive aHCC are reported. Methods: Eligible patients in cohort 2 had histologically, cytologically, or radiologically confirmed aHCC, Barcelona Clinic Liver Cancer stage C or B not amenable or refractory to locoregional therapy and not amenable to curative treatment, Child-Pugh A liver function, measurable disease per RECIST v1.1 by blinded independent central review (BICR), and ECOG PS 0 or 1. Patients received pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles (̃2 years). Primary end point was ORR assessed per RECIST v1.1 by BICR. Secondary end points included DOR, DCR, TTP, and PFS, all assessed per RECIST v1.1 by BICR, OS, and safety/tolerability. Results: All 51 patients enrolled in cohort 2 received ≥1 dose of pembrolizumab. Median follow-up, defined as the time from first dose to the data cutoff (October 1, 2021), was 35 months (range, 31-37). ORR was 16% (95% CI, 7-29). Median DOR was not reached (NR; range, 3 to 24+ months); 58% of responders were estimated to have a response duration ≥18 months. Best overall response was 8 (16%) PRs, 21 (41%) SDs, and 17 (33%) PDs; no CRs were observed and response was not evaluable for 2 patients (4%) and not assessed for 3 patients (6%). DCR was 57% (95% CI, 42-71). ORR was generally consistent among patients with a viral and nonviral etiology for HCC, although sample sizes were small. The median TTP was 4 months (95% CI, 3-9). Median PFS was 4 months (95% CI, 2-8). Estimated PFS rate at 24 months was 15%. Median OS was 17 months (95% CI, 8-23). Estimated OS rate at 24 months was 34%. No new or unexpected adverse events (AEs) occurred. Treatment-related AEs were reported in 28 patients (55%; grade 3-5, 8 [16%]). Conclusions: Updated results from cohort 2 of the KEYNOTE-224 study continued to demonstrate durable antitumor activity, promising OS, and manageable safety for pembrolizumab monotherapy in patients with aHCC and no prior systemic therapy. These data, together with recent positive results from KEYNOTE-394, underscore the broad applicability of pembrolizumab in patients with aHCC both as monotherapy and in combination with other therapies. Clinical trial information: NCT02702414.

383 Background: The anti–PD-1 antibody pembro showed efficacy and manageable safety in the global phase 2 KEYNOTE-224 and phase 3 KEYNOTE-240 studies of patients (pts) with previously treated advanced HCC, a population of high unmet need. KEYNOTE-394 is a randomized, double-blind, phase 3 study conducted in Asia to evaluate the efficacy and safety of pembro vs placebo, both given with BSC, as second-line therapy for previously treated advanced HCC (NCT03062358). Methods: Eligible pts in Asia with confirmed advanced HCC and progression on or intolerance to sorafenib or oxaliplatin-based chemotherapy were randomized 2:1 to pembro 200 mg or placebo Q3W for ≤35 cycles plus BSC per local guidelines. The primary endpoint was OS. Secondary endpoints were PFS, ORR, DOR, DCR, and TTP, all assessed per RECIST v1.1 by blinded independent central review, and safety. Treatment differences were assessed using the stratified log-rank test (OS and PFS) or the stratified Miettinen & Nurminen method (ORR). The P value boundary for OS superiority at final analysis (FA) was 0.019307. If OS was superior, PFS and ORR superiority at the second interim analysis (IA2; primary analysis timepoint for these endpoints) could be tested at boundaries of 0.013447 and 0.009139, respectively. Results: 453 pts were randomized to pembro (N = 300) or placebo (N = 153). Baseline characteristics were generally balanced between arms; 90.7% had received sorafenib as first-line therapy. As of the June 30, 2021 cutoff date for FA, median study follow-up was 33.8 mo (range 18.7-49.0). At FA, pembro significantly improved OS vs placebo (HR 0.79, 95% CI 0.63-0.99, P = 0.0180); median (95% CI) OS was 14.6 mo (12.6-18.0) for pembro vs 13.0 mo (10.5-15.1) for placebo and 24-mo OS rate was 34.3% vs 24.9%. At IA2, pembro significantly improved PFS (HR 0.74, 95% CI 0.60-0.92, P = 0.0032) and ORR (estimated difference 11.4%, 95% CI 6.7-16.0, P = 0.00004); median (95% CI) PFS was 2.6 mo (1.5-2.8) for pembro vs 2.3 mo (1.4-2.8) for placebo, 12-mo PFS rates were 15.9% vs 1.4%, and ORR was 12.7% vs 1.3%. At FA, ORR was 13.7% vs 1.3%, median DOR was 23.9 mo vs 5.6 mo, DCR was 52.7% vs 47.7%, and median TTP was 2.7 mo vs 1.7 mo (HR 0.72, 95% CI 0.58-0.90). At FA, treatment-related AEs occurred in 66.9% of pts in the pembro arm and 49.7% in the placebo arm, including 14.4% and 5.9% with grade 3-5 events. 3 pts (1.0%) in the pembro arm and 0 in the placebo arm died of treatment-related AEs. Conclusions: Pembro plus BSC significantly improved OS, PFS, and ORR compared with placebo plus BSC as second-line therapy for patients from Asia with advanced HCC. The pembro safety profile was as expected. Overall, results were consistent with those previously observed in KEYNOTE-224 and KEYNOTE-240 and thus add to the body of evidence supporting the use of pembro as second-line therapy for advanced HCC. Clinical trial information: NCT03062358.

TPS494 Background: Limited treatment options are available for patients with intermediate HCC. Lenvatinib, a potent multikinase inhibitor, and pembrolizumab, a PD-1 inhibitor, are approved first- and second-line therapies for advanced HCC, respectively. The LEAP-012 study (NCT04246177) is investigating lenvatinib plus pembrolizumab in combination with TACE versus placebo plus TACE in patients with intermediate-stage HCC. Methods: LEAP-012 is a randomized, double-blind, phase 3 study. Adults with confirmed HCC localized to the liver without portal vein thrombosis and not amenable to curative treatment, ≥1 measurable lesion per RECIST v1.1, Eastern Cooperative Oncology Group performance status of 0 or 1, and no previous systemic treatment for HCC are eligible. Patients will be randomly assigned to receive lenvatinib 8 mg (body weight < 60 kg) or 12 mg (body weight ≥60 kg) orally once daily plus pembrolizumab 400 mg intravenously (IV) every 6 weeks (Q6W) plus TACE or placebo orally once daily plus placebo IV Q6W plus TACE. Response will be assessed by imaging every 9 weeks; safety will be assessed throughout the study and up to 90 days after the end of treatment. Dual primary end points are overall survival and progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are PFS, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and time to progression (TTP) per modified RECIST by BICR; ORR, DCR, DOR, and TTP per RECIST v1.1 by BICR; and safety. Exploratory end points are PFS, ORR, DCR, DOR, TTP, and time from randomization to second/subsequent disease progression after initiation of new anticancer therapy or death from any cause, whichever occurs first, per RECIST v1.1 by investigator review, identification of molecular biomarkers, and health-related quality of life. Recruitment began in April 2020, and the planned sample size is 950 patients. The results of the LEAP-012 study will show the clinical benefit of adding lenvatinib plus pembrolizumab to the current standard of care TACE for patients with intermediate-stage HCC not amenable to curative treatment. Clinical trial information: NCT04246177.

Summary Background Immune checkpoint blockade therapy has shown promising results in patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy and safety of pembrolizumab in this patient population. Methods KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical centres and hospitals across ten countries. Eligible patients had pathologically confirmed hepatocellular carcinoma; had previously been treated with sorafenib and were either intolerant to this treatment or showed radiographic progression of their disease after treatment; an Eastern Cooperative Oncology Group performance status of 0–1; adequate organ function, and were Child-Pugh class A. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response in all patients who received at least one dose of pembrolizumab, which was radiologically confirmed by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central review. Safety was also assessed in all treated patients. This trial is ongoing but closed to enrolment and is registered with ClinicalTrials.gov number NCT02702414. Findings Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17%; 95% CI 11–26) of 104 patients. The best overall responses were one (1%) complete and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease, 34 (33%) had progressive disease, and six (6%) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares. Interpretation Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma. Funding Merck & Co, Inc.

The impact of folate deficiency on global DNA methylation is uncertain. It also is unclear whether global DNA methylation is associated with outcome in HCC. LINE-1 methylation levels, as a surrogate marker of global methylation, may be influenced by folate deficiency. However, the interaction between LINE-1 methylation and folate level on overall survival (OS) in hepatocellular carcinoma (HCC) patients is unknown. We evaluated whether LINE-1 hypomethylation and folate deficiency are associated with HCC prognosis. We prospectively recruited 172 HCC patients between 2008 and 2012. LINE-1 methylation levels in plasma and white blood cells (WBC) were measured by pyrosequencing, and plasma folate levels by a radioprotein-binding assay. Patients with plasma LINE-1 methylation

PURPOSE The immunomodulatory effect of lenvatinib (a multikinase inhibitor) on tumor microenvironments may contribute to antitumor activity when combined with programmed death receptor-1 (PD-1) signaling inhibitors in hepatocellular carcinoma (HCC). We report results from a phase Ib study of lenvatinib plus pembrolizumab (an anti–PD-1 antibody) in unresectable HCC (uHCC). PATIENTS AND METHODS In this open-label multicenter study, patients with uHCC received lenvatinib (bodyweight ≥ 60 kg, 12 mg; < 60 kg, 8 mg) orally daily and pembrolizumab 200 mg intravenously on day 1 of a 21-day cycle. The study included a dose-limiting toxicity (DLT) phase and an expansion phase (first-line patients). Primary objectives were safety/tolerability (DLT phase), and objective response rate (ORR) and duration of response (DOR) by modified RECIST (mRECIST) and RECIST version 1.1 (v1.1) per independent imaging review (IIR; expansion phase). RESULTS A total of 104 patients were enrolled. No DLTs were reported (n = 6) in the DLT phase; 100 patients (expansion phase; included n = 2 from DLT phase) had received no prior systemic therapy and had Barcelona Clinic Liver Cancer stage B (n = 29) or C disease (n = 71). At data cutoff, 37% of patients remained on treatment. Median duration of follow-up was 10.6 months (95% CI, 9.2 to 11.5 months). Confirmed ORRs by IIR were 46.0% (95% CI, 36.0% to 56.3%) per mRECIST and 36.0% (95% CI, 26.6% to 46.2%) per RECIST v1.1. Median DORs by IIR were 8.6 months (95% CI, 6.9 months to not estimable [NE]) per mRECIST and 12.6 months (95% CI, 6.9 months to NE) per RECIST v1.1. Median progression-free survival by IIR was 9.3 months per mRECIST and 8.6 months per RECIST v1.1. Median overall survival was 22 months. Grade ≥ 3 treatment-related adverse events occurred in 67% (grade 5, 3%) of patients. No new safety signals were identified. CONCLUSION Lenvatinib plus pembrolizumab has promising antitumor activity in uHCC. Toxicities were manageable, with no unexpected safety signals.

PURPOSE Pembrolizumab 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 METHODS This 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. RESULTS Between 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. CONCLUSION In 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.

4072 Background: KEYNOTE-240 (NCT02702401) examined the anti–PD-1 antibody pembro and showed improvement in OS and PFS vs pbo in pts with aHCC previously treated with sorafenib. The study did not meet prespecified statistical significance criteria for OS and PFS. Median OS (final analysis) was 13.9 mo for pembro vs 10.6 mo for pbo (HR 0.781; 95% CI 0.611-0.998). At the first interim analysis when testing for PFS and ORR was prespecified, median PFS was 3.0 mo for pembro vs 2.8 mo for pbo (HR 0.775; 95% CI 0.609-0.987) and ORR was 16.9% (CR, n = 3) for pembro and 2.2% (CR, n = 0) for pbo. AEs were consistent with the known safety profile of pembro. Longer term data from KEYNOTE-240 after ̃1.5 y of additional follow-up are reported. Methods: Adults with confirmed aHCC for whom sorafenib therapy failed (progression or intolerance) were randomly assigned 2:1 to receive pembro 200 mg IV Q3W + best supportive care (BSC) or pbo + BSC for ≤35 cycles or until confirmed progression/unacceptable toxicity, pt withdrawal of consent, or investigator decision to withdraw pt. Dual primary end points were OS and PFS, assessed by blinded independent central review (BICR) per RECIST v1.1. Secondary end points included ORR, DOR, DCR, TTP (all assessed by BICR per RECIST v1.1), and safety. Results: Of 413 pts, 278 were randomized to receive pembro; 135, to pbo.As of July 13, 2020, median time (range) from randomization to data cutoff was 39.6 mo (31.7-48.8) for pembro and 39.8 mo (31.7-47.8) for pbo. Median OS (95% CI) was 13.9 mo (11.6-16.0) for pembro and 10.6 mo (8.3-13.5) for pbo (HR 0.771; 95% CI 0.617-0.964). Estimated OS rates at 24 and 36 mo for pembro and pbo were 28.8% and 20.4% and 17.7% and 11.7%, respectively. Median PFS (95% CI) was 3.3 mo (2.8-4.1) for pembro and 2.8 mo (1.6-3.0) for pbo (HR 0.703; 95% CI 0.559-0.885). Estimated PFS rate at 24 mo was 11.8% for pembro and 4.8% for pbo. ORR (95% CI) was 18.3% (14.0-23.4) for pembro and 4.4% (1.6-9.4) for pbo. Median time to response (95% CI) was 2.7 mo (1.2-16.9) for pembro and 2.9 mo (1.1-6.9) for pbo. Median DOR (range) was 13.9 mo (1.5+ to 41.9+) for pembro and 15.2 mo (2.8-21.9) for pbo; 53.7% of responders in the pembro arm and 50.0% of responders in the pbo arm had DOR ≥12 mo. DCR was 61.9% for pembro and 53.3% for pbo. Best overall responses were 10 CR, 41 PR, 121 SD, and 85 PD for pembro and 0 CR, 6 PR, 66 SD, and 54 PD for pbo. Median TTP (95% CI) was 4.0 mo (2.8-5.3) for pembro and 2.8 mo (1.6-3.0) for pbo. No new or unexpected AEs occurred. The frequency of sponsor-assessed immune-mediated hepatitis events did not increase with additional follow-up. There continued to be no HBV or HCV viral flare events. Conclusions: In previously treated pts with aHCC, improvement in OS and PFS was maintained over time with pembro vs pbo, and the safety profile remained consistent. These data support the benefit:risk profile of pembro. Clinical trial information: NCT02702401.

e16122 Background: Studies have shown that OR is prognostic of OS in pts with HCC. KEYNOTE-224 (NCT02702414) evaluated pembrolizumab (pembro; anti–PD-1) in sorafenib (sora)-treated pts with aHCC and showed an ORR of 17% that was durable in responders receiving pembro, ultimately leading to FDA approval. In KEYNOTE-224, a landmark analysis showed that OR in pembro-treated pts was prognostic of longer OS. The KEYNOTE-240 (NCT02702401) study evaluated pembro + best supportive care (BSC) vs placebo (pbo) + BSC in sora-treated pts with aHCC. Although clinical benefit was observed in KEYNOTE-240 with pembro vs pbo, prespecified statistical significance criteria for OS and PFS were not met. This post hoc analysis of KEYNOTE-240 was performed to determine whether OR at landmark is prognostic of longer survival after landmark time. Methods: Eligible pts were aged ≥18 y, had confirmed aHCC, and experienced progression during or after sora treatment or intolerance to sora. Landmark analyses of OS according to OR at 6, 12, and 18 wk after randomization were performed on the pembro arm to evaluate the association between survival after the landmark with response achieved before the landmark. OR was assessed by blinded independent central review per RECIST v1.1. Responders at each landmark were defined as pts with any response assessment of CR or PR before the landmark date; all other pts were defined as nonresponders. HR and 95% CI for survival after the landmark were calculated from the Cox proportional hazards model using Efron method of tie handling, with responder status as a single covariate. Analysis was performed on the ITT population. Results: As of Jan 2, 2019, median time from randomization to data cutoff was 21.2 mo (range 13.4-30.4) for pembro. In the pembro arm, 51 pts (18.3%) had a best OR of CR or PR and 6 pts (4.4%) in the pbo arm had a best OR of PR (no CR) (excluded from landmark analyses). OS after landmark time was longer for responders than nonresponders at the wk 6, 12, and 18 time points (Table). The HR for OS after landmark time for responders vs nonresponders was 0.37 (95% CI 0.18-0.75), 0.39 (95% CI 0.23-0.66), and 0.37 (95% CI 0.21-0.63) at wk 6, 12, and 18, respectively. Conclusions: This post hoc analysis showed that pts with sora-treated aHCC who achieved OR by landmark time with pembro have longer OS after the landmark time, confirming the prognostic association between OR with pembro and OS observed in KEYNOTE-224. Clinical trial information: NCT02702401. [Table: see text]

Background: SWOG initiated a cancer care delivery research study of virus infection rates among newly diagnosed cancer patients. This study will inform viral screening guidelines in oncology clinics. Methods: In a first step ‘vanguard’ phase, we evaluated the feasibility of multiple study procedures. Site investigators were surveyed to obtain feedback on study implementation. Results: Much higher enrollment occurred at sites where all physicians participated and viral testing was performed as routine practice. These procedures will be required going forward. Additional protocol changes based on site investigator input were implemented. Conclusion: This multistep protocol design process illustrates how cancer care delivery research studies can adapt to real-world strategies and procedures that exist at community clinics where the predominance of cancer patients are treated.

297 Background: Results from cohort 1 of KEYNOTE-224, an open-label, single-arm, multi-country phase II trial, demonstrated that pembro monotherapy was efficacious and tolerable in patients (pts) with advanced HCC previously treated with sorafenib. Here, we report results from KEYNOTE-224 cohort 2, which enrolled pts with advanced HCC and no prior systemic therapy. Methods: Eligible pts in cohort 2 had radiologically, histologically, or cytologically confirmed, incurable HCC not amenable or refractory to locoregional therapy, Child Pugh A liver disease, measurable disease based on RECIST 1.1 by blinded independent central review (BICR), ECOG PS 0-1, and BCLC stage C or B. Pts received pembro 200 mg IV Q3W for ~2 years or until disease progression, unacceptable toxicity, consent withdrawal, or investigator decision. Primary endpoint was ORR (RECIST 1.1 by BICR). Secondary endpoints included DOR, DCR, TTP, PFS, OS, and safety/tolerability. Response was assessed every 9 weeks. Efficacy and safety were assessed in pts who received ≥1 dose of study treatment. DOR was assessed in responders. The estimate and 95% CI of the ORR and DCR were based on the Clopper-Pearson method. Kaplan-Meier method was used to estimate OS, PFS, and DOR. A sample size of ~50 pts was chosen to provide acceptable precision for the assessment of ORR. Results: Cohort 2 enrolled 51 pts. The median time from the first dose to data cutoff (July 31, 2020) was 21 (range, 17-23) mo. The median age of pts was 68 (range, 41-91) years, one pt was HBV+, 80% had alcohol use, 8% were HCV+, 18% had vascular invasion, 35% had extrahepatic disease, 33% had BCLC Stage B disease, and 67% had BCLC Stage C HCC. ORR was 16% (95% CI, 7-29) and was similar across most subgroups. Median DOR was not reached (range, 3-20+ mo); 70% were estimated to have response duration ≥12 mo. Best overall responses were 0 CR, 8 (16%) PRs, 21 (41%) SDs, and 17 (33%) PDs; response was not evaluable or not assessed for 5 (10%) pts. DCR was 57%. The median TTP was 4 (95% CI, 3-8) mo. The median PFS was 4 (95% CI, 2-6) mo, and median OS was 17 (95% CI, 8-NA) mo. PFS rate at 18 mo was 16%, and OS rate at 18 mo was 46%. Treatment-related AEs (TRAEs) occurred in 27 (53%) pts; the most common TRAEs were diarrhea, fatigue, hypothyroidism, and myalgia. Grade ≥3 TRAEs occurred in 7 (14%) pts. TRAEs led to treatment discontinuation in 6% of pts. Immune-mediated AEs and infusion reactions occurred in 11 (22%) pts. One treatment-related death occurred due to myocarditis, with associated immune-related hepatitis. Conclusions: In pts with advanced HCC and no prior systemic therapy, pembro monotherapy provided durable anti-tumor activity, promising overall survival, and demonstrated a safety profile consistent with that previously observed for pembro in advanced HCC. These findings support further evaluation of pembro-based regimens for the treatment of HCC in the frontline setting. Clinical trial information: NCT02702414.

268 Background: KEYNOTE-240 (NCT02702401) examined the anti-PD-1 antibody pembro and demonstrated improvement in OS and PFS vs pbo in pts with aHCC previously treated with sorafenib. However, the study did not meet prespecified statistical significance criteria for OS and PFS. Median OS (final analysis) was 13.9 mo for pembro vs 10.6 mo for pbo (HR 0.781; 95% CI 0.611-0.998). At the first interim analysis when PFS and ORR were prespecified to be tested, median PFS was 3.0 mo for pembro vs 2.8 mo for pbo (HR 0.775; 95% CI 0.609-0.987) and ORR was 16.9% (CR, n = 3) for pembro and 2.2% (CR, n = 0) for pbo. AEs were consistent with the known safety profile of pembro. Longer-term data from KEYNOTE-240 after ~1.5 years of additional follow-up are reported. Methods: Adults with confirmed aHCC who experienced failure (progression or intolerance) to sorafenib therapy were randomized 2:1 to pembro 200 mg IV Q3W + best supportive care (BSC) or pbo + BSC for ≤35 cycles or until confirmed progression/unacceptable toxicity, pt withdrawal of consent, or investigator decision. Dual primary end points were OS and PFS, assessed by blinded independent central review (BICR) per RECIST v1.1. Secondary end points included ORR, DOR, DCR, TTP (all assessed by BICR per RECIST v1.1), and safety. Results: Of 413 pts, 278 were randomized to pembro and 135 to pbo. As of July 13, 2020, median time from randomization to data cutoff was 39.6 mo (range 31.7-48.8) for pembro and 39.8 mo (31.7-47.8) for pbo. Median OS was 13.9 mo (95% CI 11.6-16.0) for pembro and 10.6 mo (8.3-13.5) for pbo (HR 0.771; 95% CI 0.617-0.964). Estimated OS rates at 24 and 36 mo for pembro and pbo were 28.8% and 20.4% and 17.7% and 11.7%, respectively. Median PFS was 3.3 mo (95% CI 2.8-4.1) for pembro and 2.8 mo (1.6-3.0) for pbo (HR 0.703; 95% CI 0.559-0.885). Estimated PFS rate at 24 mo was 11.8% for pembro and 4.8% for pbo. ORR was 18.3% (95% CI 14.0-23.4) for pembro and 4.4% (1.6-9.4) for pbo. Median time to response was 2.7 mo (95% CI 1.2-16.9) for pembro and 2.9 mo (1.1-6.9) for pbo. Median DOR was 13.9 mo (range 1.5+ to 41.9+) for pembro and 15.2 mo (2.8-21.9) for pbo; 45.1% of responders in pembro arm and 33.3% of responders in pbo arm had DOR ≥12 mo. DCR was 61.9% for pembro and 53.3% for pbo. Best overall responses were 10 CR, 41 PR, 121 SD, and 85 PD for pembro and 0 CR, 6 PR, 66 SD, and 54 PD for pbo. The median TTP was 4.0 mo (95% CI 2.8-5.3) for pembro and 2.8 mo (1.6-3.0) for pbo. No new or unexpected AEs occurred. The frequency of sponsor-assessed immune-mediated hepatitis events did not increase with additional follow-up. There continued to be no HBV or HCV viral flare events. Conclusions: In previously treated pts with aHCC, improvement in OS and PFS was maintained over time with pembro vs pbo, and the safety profile remained consistent over time. These data support the benefit:risk profile of pembro. Clinical trial information: NCT02702401.

318 Background: Studies have shown that OR is prognostic of OS in pts with HCC. KEYNOTE (KN)-224 (NCT02702414) evaluated pembrolizumab (pembro; anti-PD-1) in sorafenib (sora)-treated pts with aHCC and demonstrated an OR rate of 17% that was durable in responders receiving pembro, ultimately leading to its FDA approval. In KN-224, a landmark analysis showed that OR in pembro-treated pts was prognostic of longer OS. The KN-240 (NCT02702401) study evaluated pembro + best supportive care (BSC) vs placebo (pbo) + BSC in sora-treated pts with aHCC. Although clinical benefit was observed in KN-240 with pembro vs pbo, prespecified statistical significance criteria for OS and PFS were not met. This post hoc analysis of KN-240 was performed to determine whether OR at landmark is prognostic of longer survival after landmark time. Methods: Eligible pts were aged ≥18 y, had confirmed aHCC, and experienced progression during or after sora treatment or intolerance to sora. Landmark analyses of OS according to OR at 6, 12, and 18 wk after randomization were performed on the pembro arm to examine the association between survival after the landmark with response achieved prior to the landmark. OR was assessed by blinded independent central review per RECIST v1.1. Responders at each landmark were defined as pts with any response assessment of CR or PR before the landmark date; all other pts were defined as nonresponders. HRs and 95% CIs for survival after the landmark were calculated from the Cox proportional model with Efron’s method of tie handling with responder status as a single covariate. Analyses were performed in the ITT population. Results: As of Jan 2, 2019, the median time from randomization to data cutoff was 21.2 months (range 13.4-30.4) for pembro. There were 51 pts (18.3%) with a BOR of CR or PR in the pembro arm and 6 pts (4.4%) with a BOR of PR (no CR) in the pbo arm (excluded from landmark analyses). OS after landmark time was longer for responders compared with nonresponders at the wk 6, 12, and 18 time points (Table). The HR for OS after landmark time for responders versus nonresponders were 0.37 (95% CI 0.18-0.75), 0.39 (95% CI 0.23-0.66), and 0.37 (95% CI 0.21-0.63) at wk 6, 12, and 18, respectively. Conclusions: This post hoc analysis demonstrates that pts with sora-treated aHCC who achieve OR by landmark time with pembro have longer OS after the landmark time, confirming the prognostic association between OR with pembro and OS observed in KN-224. Clinical trial information: NCT02702401. [Table: see text]

Background: Biliary tract cancer (BTC), including intra- or extrahepatic cholangiocarcinoma (CCA) and gallbladder cancer, is an aggressive malignancy with limited treatment options. Most patients (pts) present with advanced or unresectable disease, for which the current first-line standard of care is gemcitabine with cisplatin. Prognosis for these pts is poor, with median survival of approximately 12 months. Pembrolizumab (pembro) has improved outcomes when combined with platinum-based chemotherapy in other tumor types (eg, gastric/GEJ, NSCLC). The randomized, placebo-controlled, double-blind, phase 3 KEYNOTE-966 trial (NCT04003636) will be conducted to evaluate pembro plus gemcitabine and cisplatin compared with placebo plus gemcitabine and cisplatin in pts with metastatic or unresectable locally advanced BTC. Methods: Pts will be randomly assigned 1:1 to receive pembro 200 mg or placebo IV every 3 weeks plus gemcitabine 1000 mg/m2 IV and cisplatin 25 mg/m2 IV on days 1 and 8 of every 3-week cycle. Cisplatin will be given for a maximum of 8 cycles. Treatment with pembro/placebo will continue for up to 35 administrations or until disease progression, unacceptable toxicity, or withdrawal from the study. Gemcitabine will be continued until disease progression, unacceptable toxicity, or withdrawal from the study. Pts will be stratified by region (Asia, non-Asia), stage (locally advanced, metastatic), and site of origin (gallbladder, intrahepatic CCA, or extrahepatic CCA). Key eligibility criteria are age ≥18 years; histologically confirmed metastatic or unresectable locally advanced BTC, measurable by RECIST v1.1; no prior systemic therapy for advanced BTC; Eastern Cooperative Oncology Group performance status of 0 or 1; and tumor sample adequate for biomarker analyses. Pts with past or ongoing hepatitis C or controlled hepatitis B virus infection are eligible per protocol-defined criteria. During the initial stage, response will be assessed by imaging every 6 weeks until week 54 and every 12 weeks thereafter. Safety, assessed by CTCAE v.5.0, will be monitored throughout the study and for 30 days after treatment end or 90 days for serious adverse events. The primary end points are progression-free survival (as assessed by blinded independent central review) and overall survival (OS). Secondary end points are objective response rate, duration of response, and safety. Additional analyses will include disease control rate, health-related quality of life (by EORTC QLQ-C30, EuroQol EQ-5D, and EORTC QLQ-BIL21), and molecular and genetic biomarkers. The study opened to recruitment on September 24, 2019. Recruitment is underway in 17 countries and will continue until approximately 788 pts are enrolled. Citation Format: Richard S. Finn, Robin K. Kelley, Junji Furuse, Julien Edeline, Zhenggang Ren, Shu-Chih Su, Usha Malhotra, Abby B. Siegel, Juan W. Valle. KEYNOTE-966: A randomized, double-blind, placebo-controlled, phase 3 study of pembrolizumab in combination with gemcitabine and cisplatin for the treatment of advanced biliary tract carcinoma [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 CT283.