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Background: Pleural mesothelioma usually presents at an advanced, incurable stage. Chemotherapy with platinum-pemetrexed is a standard treatment. We hypothesised that the addition of pembrolizumab to platinum-pemetrexed would improve overall survival in patients with pleural mesothelioma., Methods: We did this open-label, international, randomised phase 3 trial at 51 hospitals in Canada, Italy, and France. Eligible participants were aged 18 years or older, with previously untreated advanced pleural mesothelioma, with an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) to intravenous chemotherapy (cisplatin [75 mg/m 2 ] or carboplatin [area under the concentration-time curve 5-6 mg/mL per min] with pemetrexed 500 mg/m 2 , every 3 weeks for up to 6 cycles), with or without intravenous pembrolizumab 200 mg every 3 weeks (up to 2 years). The primary endpoint was overall survival in all randomly assigned patients; safety was assessed in all randomly assigned patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02784171, and is closed to accrual., Findings: Between Jan 31, 2017, and Sept 4, 2020, 440 patients were enrolled and randomly assigned to chemotherapy alone (n=218) or chemotherapy with pembrolizumab (n=222). 333 (76 %) of patients were male, 347 (79%) were White, and median age was 71 years (IQR 66-75). At final analysis (database lock Dec 15, 2022), with a median follow-up of 16·2 months (IQR 8·3-27·8), overall survival was significantly longer with pembrolizumab (median overall survival 17·3 months [95% CI 14·4-21·3] with pembrolizumab vs 16·1 months [13·1-18·2] with chemotherapy alone, hazard ratio for death 0·79; 95% CI 0·64-0·98, two-sided p=0·0324). 3-year overall survival rate was 25% (95% CI 20-33%) with pembrolizumab and 17% (13-24%) with chemotherapy alone. Adverse events related to study treatment of grade 3 or 4 occurred in 60 (27%) of 222 patients in the pembrolizumab group and 32 (15%) of 211 patients in the chemotherapy alone group. Hospital admissions for serious adverse events related to one or more study drugs were reported in 40 (18%) of 222 patients in the pembrolizumab group and 12 (6%) of 211 patients in the chemotherapy alone group. Grade 5 adverse events related to one or more drugs occurred in two patients on the pembrolizumab group and one patient in the chemotherapy alone group., Interpretation: In patients with advanced pleural mesothelioma, the addition of pembrolizumab to standard platinum-pemetrexed chemotherapy was tolerable and resulted in a significant improvement in overall survival. This regimen is a new treatment option for previously untreated advanced pleural mesothelioma., Funding: The Canadian Cancer Society and Merck & Co., Competing Interests: Declaration of interests MP has received grants for research to institution from AstraZeneca and Roche; payment for educational events from Astellas, Pfizer, and AstraZeneca; and received drugs for research from Roche and AstraZeneca. GLR received consulting fees from MSD, BMS, AstraZeneca, Roche, Novartis, Lilly, Amgen, Sanofi, Pfizer, Takeda, GSK, and Italfarmaco; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from MSD, BMS, AstraZeneca, Roche, Novartis, Lilly, Amgen, Sanofi, Pfizer, Takeda, GSK, and Italfarmaco; received support for attending meetings or travel from Roche, MSD, BMS, and Amgen; has participated on a Data Safety Monitoring Board or Advisory Board for MSD, BMS, AstraZeneca, Roche, Novartis, Lilly, Amgen, Sanofi, Pfizer, Takeda, GSK, and Italfarmaco; and has other financial or non-financial interests from MSD, BMS, AstraZeneca, Roche, Novartis, Amgen, Sanofi, Pfizer, Takeda, and GSK. YL holds stock or stock options from Merck. SL received consulting fees from Lilly, MSD, Sanofi, and AbbVie and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca. AS received grants or contracts (payments to institution) from MSD, BMS, AstraZeneca, Roche, and Amphera; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca, BMS, MSD, and Roche; received support for attending meetings or travel from AstraZeneca, BMS, MSD, and Roche; and participated on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, BMS, MSD, and Roche. MF received consulting fees from AstraZeneca, BMS, and Takeda and received honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca, BMS, and Takeda. SAL has participated on a Data Safety Monitoring Board or Advisory Board for Sanofi and Bayer. JRG received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca and BMS. PB received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Merck and participated on a Data Safety Monitoring Board or Advisory Board for Mirati and AbbVie. NL has received editorial support from EMD Serono; received grants to institute (unrelated) from Amgen, AstraZeneca, Bayer, BMS, Eli Lilly, EMD Serono, Guardant Health, Inivata, Janssen, Merck/MSD, Novartis, Pfizer, Roche, and Takeda; received honoraria or travel funding for CME lectures (unrelated) from AstraZeneca, Beigene, BMS, Janssen, Merck, Novartis, and Takeda; and participated on a Data Safety Monitoring Board or Advisory Board for Mirati, Helsinn, and Daichii Sankyo. LS has received grants or contracts to institution to support clinical trial from AstraZeneca, Merck, Bayer, Novartis, Repare, GSK, and Janssen and holds stock or stock options from AstraZeneca. DED has received research grants from CIHR, CancerCare Manitoba Foundation, and AstraZeneca; received research grants and salary awards from Manitoba Medical Services Foundation; received payment for educational events from Roche, Boehringer Ingelheim, and BMS; served on an advisory board for Merck, AstraZeneca, Pfizer, Jazz Pharmaceuticals, and Novartis; has acted in a leadership or fiduciary role in a board, society, committee or advocacy group, paid or unpaid for Lung Cancer Canada (Medical Advisory Committee), Canadian Association of Medical Oncologists (Chair, Fellowship Committee), and Canadian Cancer Trials Group (Chair, Small Cell Lung Cancer Working Group); and received equipment, materials, drugs, medical writing, gifts, or other services from AstraZeneca (Medical writing assistance on a small-cell lung cancer paper). QC has received grants to institution from Alkermes, Amgen, Apollomics, Astellas, AstraZeneca, Bicycle, BMS, Conjupro, Decipher, Eli Lilly, Esperas, Exactis, GSK, iTEOS, Kelun, Merck, Mirati, Nuvalent, Ocellaris, Pfizer, Rvolution Medicines, Roche, SeaGen, Spectrum, and Treadwell; received consulting fees from Amgen, AnHeart, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GSK, Jazz Pharmaceuticals, Janssen, Merck and Co, Novartis, Pfizer, Roche, and Takeda; received payment for speaking or presentations from AstraZeneca; acted on an advisory board for Amgen, AnHeart, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GSK, Jazz Pharmaceuticals, Janssen, Merck and Co, Novartis, Pfizer, Roche, and Takeda; acted on a Data Safety Monitoring Committee for Merck and KGaA; and occupied a leadership or fiduciary role in a board, society, committee, or advocacy group, paid or unpaid for Lung Cancer Canada and Canadian Mesothelioma Foundation. CWL has served as a member of the Board of Directors for Canadian Mesothelioma Foundation. LG received grants or contracts to institution from BMS, MSD, Takeda, Pfizer, Roche, Amgen, Sanofi, Janssen, Lilly, and Novartis; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, MSD, Takeda, Pfizer, Roche, Amgen, Sanofi, Janssen, Lilly, and Novartis; received support for attending meetings or travel from Pfizer, MSD, AstraZeneca, and Takeda; and participated on a Data Safety Monitoring Board or Advisory Board for Inhatarget Therapeutics. XQ received support for attending meetings or travel from Pfizer (ESMO 2022), Janssen (ASCO 2022), and Sanofi (ASCO 2023). VW received consulting fees from Amgen; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, Bristol Myers Squibb, MSD, Roche, and Sanofi; received support for attending meetings or travel from AstraZeneca, Bristol Myers Squibb, Janssen, MSD, Roche, and Sanofi; and participated on a Data Safety Monitoring Board or Advisory Board for Amgen, AstraZeneca, and Ipsen. GZ received honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Inventiva Pharma, Lilly, MSD Oncology, Pfizer, and Roche; acted in a consulting or advisory role for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Da Volterra, Inventiva Pharma, MSD Oncology, Pfizer, and Roche; received research funding from AstraZeneca, Bristol-Myers Squibb, Pfizer, Roche, and Takeda; and received travel, accommodations, and expenses from AbbVie, AstraZeneca, Bristol-Myers Squibb, Lilly, Pfizer, and Roche. MLS received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from BMS and support for attending meetings or travel from Pfizer (ESMO 2022). AM received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Roche, AstraZeneca, BMS, MSD, Pfizer, Takeda, Boehringer, Sanofi, Lilly, Novartis, and Italfarmaco and participated on a Data Safety Monitoring Board or Advisory Board for Roche, AstraZeneca, Pfizer, MSD, and Takeda. FG received consulting fees from Novocure, BMS, Novartis, PharmaMar, Pierre Fabre, and MSD; received payment for speaker bureau from Novocure; received support for attending meetings or travel from Novartis, MSD, BMS, PharmaMar, and Pierre Fabre. SD received payment for presentations from Novartis, Pierre-Fabre, and BMS and travel and accommodation support during meetings from Istituto Gentili, Novartis, Pierre-Fabre, and BMS. GLC received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Novocure and BMS and participated on a Data Safety Monitoring Board or Advisory Board for Novocure. PAZ received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Merck Sharp and Dohme, Astellas, Janssen, Sanofi, Ipsen, Pfizer, Novartis, Bristol Meyer Squibb, Amgen, AstraZeneca, Roche, and Bayer; received support for attending meetings or travel from Merck Sharp and Dohme, Astellas, Janssen, Sanofi, Ipsen, Pfizer, Novartis, Bristol Meyer Squibb, Amgen, AstraZeneca, Roche, and Bayer; and participated on a Data Safety Monitoring Board or Advisory Board for Merck Sharp and Dohme, Astellas, Janssen, Sanofi, Ipsen, Pfizer, Novartis, Bristol Meyer Squibb, Amgen, AstraZeneca, Roche, and Bayer. MM received support for attending meetings or travel from Roche, Pfizer, and Novartis. FLC received consulting fees from Takeda, Amgen, Novartis, AstraZeneca, and Roche; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Takeda, Amgen, Novartis, AstraZeneca, and Roche; and received support for attending meetings or travel from Takeda and Amgen. CG received consulting fees from Karyopharm, Menarini, and Roche; received payment or honoraria for lectures, presentations, speakers' bureaux, manuscript writing, or educational events from MSD, BMS, Novartis, Amgen, Sanofi, Eli Lilly, GSK, Roche, Takeda, Boehringer, AstraZeneca, and Pfizer; and participated on a Data Safety Monitoring Board or Advisory Board for MSD, BMS, Novartis, Amgen, Sanofi, Eli Lilly, GSK, Roche, Takeda, Boehringer Ingelheim, AstraZeneca, and Pfizer. FP received partial funding to institution and experimental study drug from Pfizer; received financial support to institution from Roche, Bayer, AstraZeneca, Pfizer, Incyte, Tesaro/GSK, and Merck; and received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bayer, Pierre Fabre, AstraZeneca, Incyte, Ipsen, Clovis, Astellas, Sanofi, Roche, and Pfizer. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Importance: Immune checkpoint inhibitors (ICIs) have limited activity in microsatellite-stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer. Recent findings suggest the efficacy of ICIs may be modulated by the presence of liver metastases (LM)., Objective: To investigate the association between the presence of LM and ICI activity in advanced MSS colorectal cancer., Design, Setting, and Participants: In this secondary analysis of the Canadian Cancer Trials Group CO26 (CCTG CO.26) randomized clinical trial, patients with treatment-refractory colorectal cancer were randomized in a 2:1 fashion to durvalumab plus tremelimumab or best supportive care alone between August 10, 2016, and June 15, 2017. The primary end point was overall survival (OS) with 80% power and 2-sided α = .10. The median follow-up was 15.2 (0.2-22.0) months. In this post hoc analysis performed from February 11 to 14, 2022, subgroups were defined based on the presence or absence of LM and study treatments., Intervention: Durvalumab plus tremelimumab or best supportive care., Main Outcomes and Measures: Hazard ratios (HRs) and 90% CIs were calculated based on a stratified Cox proportional hazards regression model. Plasma tumor mutation burden at study entry was determined using a circulating tumor DNA assay. The primary end point of the study was OS, defined as the time from randomization to death due to any cause; secondary end points included progression-free survival (PFS) and disease control rate (DCR)., Results: Of 180 patients enrolled (median age, 65 [IQR, 36-87] years; 121 [67.2%] men; 19 [10.6%] Asian, 151 [83.9%] White, and 10 [5.6%] other race or ethnicity), LM were present in 127 (70.6%). For patients with LM, there was a higher proportion of male patients (94 of 127 [74.0%] vs 27 of 53 [50.9%]; P = .005), and the time from initial cancer diagnosis to study entry was shorter (median, 40 [range, 8-153] vs 56 [range, 14-181] months; P = .001). Plasma tumor mutation burden was significantly higher in patients with LM. Patients without LM had significantly improved PFS with durvalumab plus tremelimumab (HR, 0.54 [90% CI, 0.35-0.96]; P = .08; P = .02 for interaction). Disease control rate was 49% (90% CI, 36%-62%) in patients without LM treated with durvalumab plus tremelimumab, compared with 14% (90% CI, 6%-38%) in those with LM (odds ratio, 5.70 [90% CI, 1.46-22.25]; P = .03). On multivariable analysis, patients without LM had significantly improved OS and PFS compared with patients with LM., Conclusions and Relevance: In this secondary analysis of the CCTG CO.26 study, the presence of LM was associated with worse outcomes for patients with advanced colorectal cancer. Patients without LM had improved PFS and higher DCR with durvalumab plus tremelimumab. Liver metastases may be associated with poor outcomes of ICI treatment in advanced colorectal cancer and should be considered in the design and interpretation of future clinical studies evaluating this therapy.

Background: The number of somatic mutations detectable in circulating tumor DNA (ctDNA) is highly heterogeneous in metastatic colorectal cancer (mCRC). The optimal number of mutations required to assess disease kinetics is relevant and remains poorly understood., Objectives: To determine whether increasing panel breadth (the number of tracked variants in a ctDNA assay) would alter the sensitivity in detecting ctDNA in patients with mCRC., Design: We used archival tissue sequencing to perform an in silico assessment of the optimal number of tracked mutations to detect and monitor disease kinetics in mCRC using sequencing data from the Canadian Cancer Trials Group CO.26 trial., Methods: For each patient, 1, 2, 4, 8, 12, or 16 of the most clonal (highest variant allele frequency) somatic variants were selected from archival tissue-based whole-exome sequencing and assessed for the proportion of variants detected in matched ctDNA at baseline, week 8, and progression timepoints., Results: Data from 110 patients were analyzed. Genes most frequently encountered among the top four highest VAF variants in archival tissue were TP53 (51.9% of patients), APC (43.3%), KRAS (42.3%), and SMAD4 (9.6%). While the frequency of detecting at least one tracked variant increased when expanding beyond variant pool sizes of 1 and 2 in baseline ( p  = 0.0030) and progression ( p  = 0.0030) ctDNA samples, we observed no significant benefit to increases in variant pool size past four variants in any of the ctDNA timepoints ( p  < 0.05)., Conclusion: While increasing panel breadth beyond two tracked variants improved variant re-detection in ctDNA samples from patients with treatment refractory mCRC, increases beyond four tracked variants yielded no significant improvement in variant re-detection., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

Immune checkpoint inhibitors have activity in mesothelioma. IND.227 was a phase 2 trial (120 patients planned) comparing progression-free survival of standard platinum and pemetrexed (CP) versus CP + pembrolizumab (pembro) versus pembro. Accrual to the pembro arm was discontinued on the basis of interim analysis (IA-16 wk disease control rate). CP + pembro was tolerable, with progression-free survival similar between arms and median survival and overall response rate higher than those of CP alone (19.8 mo [95% confidence interval or CI: 8.4-41.36] versus 8.9 mo [95% CI: 5.3-12.8] and 47% [95% CI: 24%-71%] versus 19% [95% CI: 5%-42%], respectively). The subsequent phase 3 trial has completed accrual; results are expected in 2023., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)