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Background: Although escalated doses of radiation therapy (RT) for intrahepatic cholangiocarcinoma (iCCA) are associated with durable local control (LC) and prolonged survival, uncertainties persist regarding personalized RT based on biological factors. Compounding this knowledge gap, the assessment of RT response using traditional size-based criteria via computed tomography (CT) imaging correlates poorly with outcomes. We hypothesized that quantitative measures of enhancement would more accurately predict clinical outcomes than size-based assessment alone and developed a model to optimize RT., Methods: Pre-RT and post-RT CT scans of 154 patients with iCCA were analyzed retrospectively for measurements of tumor dimensions (for RECIST) and viable tumor volume using quantitative European Association for Study of Liver (qEASL) measurements. Binary classification and survival analyses were performed to evaluate the ability of qEASL to predict treatment outcomes, and mathematical modeling was performed to identify the mechanistic determinants of treatment outcomes and to predict optimal RT protocols., Results: Multivariable analysis accounting for traditional prognostic covariates revealed that percentage change in viable volume following RT was significantly associated with OS, outperforming stratification by RECIST. Binary classification identified ≥33% decrease in viable volume to optimally correspond to response to RT. The model-derived, patient-specific tumor enhancement growth rate emerged as the dominant mechanistic determinant of treatment outcome and yielded high accuracy of patient stratification (80.5%), strongly correlating with the qEASL-based classifier., Conclusion: Following RT for iCCA, changes in viable volume outperformed radiographic size-based assessment using RECIST for OS prediction. CT-derived tumor-specific mathematical parameters may help optimize RT for resistant tumors., Competing Interests: Conflicts of interest: BD reports honoraria from Sermo, Inc and funding from the Radiological Society of North America. EBH reports grants from Merck Serono. CMT reports a consulting/advisory role with Accuray. ACK reports ownership of shares in Aravive, Inc. PD reports honoraria from ASTRO, ASCO, Imedex, and Bayer. EJK reports grants from National Institutes of Health, Stand Up 2 Cancer, MD Anderson Cancer Center, Philips Healthcare, Elekta, and GE Healthcare; personal fees from RenovoRx and Taylor and Francis; and a consulting/advisory role with Augmenix. All reported conflicts are outside the current work.

Importance: Disparity in overall survival (OS) and differences in the frequency of driver gene variants by race and ethnicity have been separately observed in patients with colorectal cancer; however, how these differences contribute to survival disparity is unknown., Objective: To quantify the association of molecular, socioeconomic, and clinical covariates with racial and ethnic disparities in overall survival among patients with colorectal cancer., Design, Setting, and Participants: This single-center cohort study was conducted at a tertiary-level cancer center using relevant data on all patients diagnosed with colorectal cancer from January 1, 1973, to March 1, 2023. The relative contribution of variables to the disparity was determined using mediation analysis with sequential multivariate Cox regression models., Main Outcome: OS, from diagnosis date and from start of first-line chemotherapy., Results: The study population of 47 178 patients (median [IQR] age, 57.0 [49-66] years; 20 465 [43.4%] females and 26 713 [56.6%] males; 3.0% Asian, 8.7% Black, 8.8% Hispanic, and 79.4% White individuals) had a median (IQR) follow-up from initial diagnosis of 124 (174) months and OS of 55 (145) months. Compared with White patients, Black patients had worse OS (hazard ratio [HR], 1.16; 95% CI, 1.09-1.24; P <.001), whereas Asian and Hispanic patients had better OS (HR, 0.66; 95% CI, 0.59-0.74; P <.001; and 0.86; 95% CI, 0.81-0.92; P <.001, respectively). When restricted to patients with metastatic disease, the greatest disparity was between Black patients compared with White patients (HR, 1.2; 95% CI, 1.06-1.37; P <.001). Evaluating changes in OS disparity over 20 years showed disparity decreasing among Asian, Hispanic, and White patients, but increasing between Black patients and White patients (HRs, 1.18; 95% CI, 1.07-1.31 for 2008-2012; 1.24, 95% CI, 1.08-1.42 for 2013-2017; and 1.50; 95% CI, 1.20-1.87 for 2018-2023). Survival outcomes for first-line chemotherapy were worse for Black patients compared with White patients (median OS, 18 vs 26 months; HR, 1.30; 95% CI, 1.01-1.70). Among 7628 patients who had clinical molecular testing, APC, KRAS, and PIK3CA showed higher variant frequency in Black patients (false discovery rate [FDR], 0.01; < 0.001; and 0.01, respectively), whereas BRAF and KIT were higher among White patients (FDR, 0.001 and 0.01). Mediation analysis identified neighborhood socioeconomic status as the greatest contributor to OS disparity (29%), followed by molecular characteristics (microsatellite instability status, KRAS variation and BRAF variation, 10%), and tumor sidedness (9%)., Conclusions: This single-center cohort study identified substantial OS disparity and differing frequencies of driver gene variations by race and ethnicity. Socioeconomic status had the largest contribution but accounted for less than one-third of the disparity, with substantial contribution from tumor molecular features. Further study of the associations of genetic ancestry and the molecular pathogenesis of colorectal cancer with chemotherapy response is needed.

Background: Trastuzumab deruxtecan has shown encouraging activity in patients with treatment-refractory HER2-positive, RAS wild-type and BRAF wild-type metastatic colorectal cancer. Dose optimisation and further antitumour assessments in patients with RAS mutations and those with previous anti-HER2 therapy are warranted. We aimed to evaluate two doses of trastuzumab deruxtecan (5·4 mg/kg and 6·4 mg/kg) to establish the recommended dose in patients with pretreated HER2-positive, RAS wild-type or mutant metastatic colorectal cancer., Methods: DESTINY-CRC02 was a multicentre, randomised, two-stage, two-arm, phase 2 study done in 53 research hospitals and medical centres in Australia, Belgium, France, Italy, Japan, South Korea, Spain, Taiwan, the UK, and the USA. Eligible patients were aged 18 years and older or 20 years and older (depending on region) with pretreated pathologically documented, unresectable, recurrent, or metastatic HER2-positive, and RAS wild-type or mutant colorectal cancer. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and have received previous chemotherapy, and anti-EGFR, anti-VEGF, or anti-PD-L1 therapy, if clinically indicated. In stage 1, patients were randomly assigned (1:1), via a secure interactive response technology system, to receive 5·4 mg/kg or 6·4 mg/kg trastuzumab deruxtecan administered intravenously every 21 days. Stratification factors were ECOG performance status, HER2 status, and RAS status. In stage 2, patients were assigned into the 5·4 mg/kg treatment group only. The primary endpoint was confirmed objective response rate by blinded independent central review, assessed in all patients for whom treatment was assigned (full analysis set). Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04744831, and is ongoing (not recruiting)., Findings: Between March 5, 2021, and March 29, 2022, 135 patients were centrally screened, 122 of whom were enrolled. In stage 1, 40 patients each were randomly assigned to receive trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg. In stage 2, an additional 42 patients were enrolled in the 5·4 mg/kg group. 64 (52%) participants were male and 58 (48%) were female. The median duration of follow-up was 8·9 months (IQR 6·7-10·5) in the 5·4 mg/kg group and 10·3 months (5·9-12·7) in the 6·4 mg/kg group. The confirmed objective response rate by blinded independent central review was 37·8% (31/82 [95% CI 27·3-49·2]) in the 5·4 mg/kg group and 27·5% (11/40 [14·6-43·9]) in the 6·4 mg/kg group. 34 (41%) of 83 patients in the 5·4 mg/kg group and 19 (49%) of 39 in the 6·4 mg/kg group had grade 3 or worse drug-related treatment-emergent adverse events. The most common grade 3 or worse drug-related treatment-emergent adverse events were neutrophil count decreased (13 [16%] of 83 patients), anaemia (six [7%]), nausea (six [7%]), and white blood cell count decreased (five [6%]) in the 5·4 mg/kg group; and were neutrophil count decreased (10 [26%] of 39 patients), anaemia (eight [21%]), platelet count decreased (four [10%]), and white blood cell count decreased (four [10%]) in the 6·4 mg/kg group. Drug-related serious adverse events occurred in 11 (13%) of 83 patients in the 5·4 mg/kg group and six (15%) of 39 patients in the 6·4 mg/kg group; the most common in the 5·4 mg/kg group was nausea (three [4%] patients) and the most common in the 6·4 mg/kg group were fatigue (two [5%] patients), neutropenia (two [5%]), and thrombocytopenia (two [5%]). A drug-related treatment-emergent adverse event related to death occurred in one (1%) patient in the 5·4 mg/kg group (due to hepatic failure). Adjudicated drug-related interstitial lung disease or pneumonitis events were observed in seven (8%) patients in the 5·4 mg/kg group (all grade 1 or 2) and in five (13%) patients in the 6·4 mg/kg group (four grade 1 or 2; one grade 5)., Interpretation: The promising antitumour activity and favourable safety profile support trastuzumab deruxtecan 5·4 mg/kg as the optimal single-agent dose for patients with pretreated HER2-positive metastatic colorectal cancer, including those with RAS mutations, previous anti-HER2 therapy, or both., Funding: Daiichi Sankyo and AstraZeneca., Competing Interests: Declaration of interests KR has received research grants from Bayer, UCB BioSciences, Hibercell, Eisai, Merck, Janssen Pharmaceuticals, AbbVie, Daiichi Sankyo, Guardant Health, Innovent Biologics, and Xencor; has received payment or honoraria from Bayer, Daiichi Sankyo, and Seagen; and has participated on a data safety monitoring board or advisory board for Bayer, Eisai/Merck, SAGA Diagnostics, Daiichi Sankyo, Seagen, Pfizer, and AstraZeneca. SS has participated on a data safety monitoring board or advisory board for Agenus, AstraZeneca, Bayer, Bristol Myers Squibb, CheckmAb, Daiichi Sankyo, GlaxoSmithKline, MSD, Merck, Novartis, Pierre Fabre, Seagen, and T-One Therapeutics. AT has received research grants from Daiichi Sankyo, Ono Pharmaceutical, Bristol Myers Squibb, Pfizer, Merck Sharp & Dome, Isofol Medical, Incyte Corporation, and Hutchison Medipharma; and has received payment or honoraria from Eli Lilly, Taiho Pharmaceutical, Ono Pharmaceutical, Chugai Pharma, Merck Serono, and Takeda. TKat has received payment or honoraria from Chugai Pharmaceutical, Ono Pharmaceutical, Takeda Pharmaceutical, and Eli Lilly. FP has received payment or honoraria from Amgen, Merck-Serono, MSD, BMS, Astellas, Johnson & Johnson, Takeda, Bayer, Servier, Pierre Fabre, Ipsen, GSK, and Rottapharm. YK has received royalties or licenses from Ono Pharmaceutical, Chugai Pharmaceutical, Taiho Pharmaceutical, Shionogi, Nippon Zoki Pharmaceuticals, Asahi Kasei Pharma Corporation, Nippon, Kayaku, Daiichi Sankyo, IQVIA Services Japan, MSD, Astellas Pharma, Incyte Corporation, Eisai, National Cancer Center Japan, Syneos Health Clinical, ShiftZero, Parexel International, Japan Clinical Cancer Research Organization, EPS Holdings, Sysmex Corporation, Public Health Research Foundation, Aichi Cancer Center, and Kyushu Study group of Clinical Cancer; and has received payment or honoraria from Ono Pharmaceutical, TAIHO Pharmaceutical, Astellas Pharma, EA Pharma, Daiichi Sankyo, Nippon, Kayaku, Pfizer, Nippon Zoki Pharmaceuticals, Sanofi, NIPRO, MOROO, Alfresa Pharma Corporation, Boehringer Ingelheim, Hakodate National Hospital, Asahi Kasei Pharma Corporation, Chugai Pharmaceutical, MSD, Zeria Pharmaceutical, Bayer Yakuhin, Eli Lilly, Yakult Honsha, Sumitomo Dainippon Pharma, Incyte Corporation, Merck Biopharma, The Japanese Gastroenterological Association, Sapporo Minami Tokushukai Hospital, and Pancan Japan. HK has received consulting or advisory fees from Astellas Pharma, Daiichi-Sankyo, and AbbVie; honoraria from Bristol Myers Squibb, Bayer Yakuhin, Ono Pharmaceutical, Eli Lilly Japan, MSD, Chugai Pharmaceutical, Daiichi-Sankyo, Merck Biopharma, Teijin Pharma, Takeda Pharmaceutical, Yakult Pharmaceutical Industry, Taiho Pharmaceutical, Amgen, Otsuka Pharmaceutical, GlaxoSmithKline, and Nippon Kayaku; and research funding from Bristol Myers Squibb, Kobayashi Pharmaceutical, and Eisai. MP has received research grants from Amgen, Bayer, Bristol Myers Squibb, Ipsen, Novartis, and Roche; has received payment or honoraria from Amgen, Bayer, Bristol Myers Squibb, Merck, MSD, Roche, Sanofi, Servier, and Sirtex; has received consulting fees from Amgen, Bayer, Ipsen, Merck, MSD, Qurin, Remedus, Sanofi, Sirtex, and Terumo; and has participated on a data safety monitoring board or advisory board for Basilea. TA has received payment or honoraria from AstraZeneca, Bristol Myers Squibb, Gritstone Oncology, GlaxoSmithKline, Merck, Pierre Fabre, Seagen, and Servier Transgéne; has received support for attending meetings or travel from Bristol Myers Squibb and Merck; has received consulting fees from Aptitude Health, Astellas, Bristol Myers Squibb, Gritstone Oncology, GamaMabs Pharma, GlaxoSmithKline, Kaleido Oncology, Merck, Pierre Fabre, Seagen, Servier, and Transgène; and is president of the ARCAD Foundation. SL has received research grants from Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Hutchinson, Incyte, Merck Serono, Mirati, MSD, Pfizer, Roche, and Servier; has received payment or honoraria from Amgen, Bristol Myers Squibb, Incyte, GlaxoSmithKline, Eli Lilly, Merck Serono, MSD, Pierre Fabre, Roche, and Servier; and has received consulting fees from Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, GSK, Incyte, Eli Lilly, Merck Serono, MSD, Pierre Fabre, Roche, Takeda, and Servier. KY has received research grants from Taiho Pharm; and has received honoraria from Daiichi Sankyo, Chugai Pharmaceutical, Bristol Myers Squibb, Eli Lilly Japan, Taiho Pharmaceutical, Ono Pharmaceutical, Takeda Pharmaceutical, and Merck. JT has received honoraria from Servier and Pierre Fabre; has received consulting fees from Haystack Oncology; has participated on a data safety monitoring board or advisory board for Gilead, MSD, Bristol Myers Squibb, Pierre Fabre, Novartis, and Daiichi Sankyo; and has participated with leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for Australasian Gastro-Intestinal Trials Group and European Society for Medical Oncology. CGC has received honoraria from Amgen, Merck, Servier, Pierre Fabre, and Incyte; has received support for attending meetings or travel from Merck, Servier, and Pierre Fabre; and is the Secretary of the Spanish Group for Treatment of Gastrointestinal Tumours (TTD). JHS has received research grants from AbbVie, Amgen, AStar D3, Bayer, Curegenix, Daiichi Sankyo, Eli Lilly, Erasca, Gossamer Bio, Leap Therapeutics, Nektar, Roche/Genentech, Sanofi, Seagen, and Silverback Therapeutics; has received payment or honoraria from Seagen, Bayer, and Natera; has received consulting fees from AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Natera, Pfizer, Roche/Genentech, Seagen, Silverback Therapeutics, Takeda, and Viatris; has participated on a data safety monitoring board or advisory board for AbbVie, Pionyr Immunotherapeutics, and Beigene; and has received support for attending meetings or travel from Seagen. YC has received consulting fees from IMBdx, Ono Pharmaceutical, Boryung Pharmaceutical, Interpark Bioconvergence, and GC Genome Corporation; and has received honoraria from Roche and MSD Korea. DB is an employee of Daiichi Sankyo. QY has received employee benefits (stocks or other financial or non-financial interests) from Daiichi Sankyo. TKam has received employee benefits (financial or non-financial interests) from Daiichi Sankyo. KK is an employee of Daiichi Sankyo. AB has received employee benefits (stocks or other financial or non-financial interests) from Daiichi Sankyo; and has received support for attending meetings or travel from Daiichi Sankyo. MK is an employee of Daiichi Sankyo. JDA has received employee benefits (stocks or other financial or non-financial interests) from Daiichi Sankyo. TY has received research grants from Amgen, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, FALCO Biosystems, Genomedia, Molecular Health, MSD, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Pfizer Japan, Roche Diagnostics, Sanofi, Sysmex, and Taiho Pharmaceutical; has received honoraria from Chugai Pharmaceutical, Takeda Pharmaceutical, Merck Biopharma, Bayer Yakuhin, Ono Pharmaceutical, and MSD; and has received consulting fees from Sumitomo Corporation. MVdE, H-CH, and T-YK declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Cancer cells with BRCA1/2 deficiencies are sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. We evaluated the efficacy of talazoparib in DNA-Damage Repair (DDR)-altered patients. In this phase II trial, patients were enrolled onto one of four cohorts based on molecular alterations: (1) somatic BRCA1/2, (2) other homologous recombination repair pathway, (3) PTEN and (4) germline BRCA1/2. The primary endpoint was a clinical benefit rate (CBR): complete response, partial response or stable disease ≥24 weeks. 79 patients with a median of 4 lines of therapy were enrolled. CBR for cohorts 1-4 were: 32.5%, 19.7%, 9.4% and 30.6%, respectively. PTEN mutations correlated with reduced survival and a trend towards shorter time to progression.Talazoparib demonstrated clinical benefit in selected DDR-altered patients. PTEN mutations/loss patients derived limited clinical benefit. Further study is needed to determine whether PTEN is prognostic or predictive of response to PARP inhibitors., (© 2024. The Author(s).)

Purpose: Appendiceal adenocarcinoma (AA) remains an orphan disease with limited treatment options for patients unable to undergo surgical resection. Evidence supporting the efficacy of combined VEGF and PD-1 inhibition in other tumor types provided a compelling rationale for investigating this combination in AA, where immune checkpoint inhibitors have not been explored previously., Experimental Design: We conducted a prospective, single-arm phase II study evaluating efficacy and safety of atezolizumab in conjunction with bevacizumab (Atezo+Bev) in advanced, unresectable AA., Results: Patients treated with the Atezo+Bev combination had 100% disease control rate (1 partial response, 15 stable disease) with progression-free survival (PFS) of 18.3 months and overall survival not-yet-reached with median duration of follow-up of 40 months. These survival intervals were significantly longer relative to a clinically and molecularly matched synthetic control cohort treated with cytotoxic chemotherapy designed for colorectal cancer (PFS of 4.4 months, P = 0.041)., Conclusions: In light of recent data demonstrating a lack of efficacy of 5-fluorouracil-based chemotherapy, Atezo+Bev is a promising treatment option for patients with low-grade unresectable AA; further study is warranted., Significance: AA remains an orphan disease with limited systemic therapy options for patients who are not candidates for surgical resection. These data suggest activity from combined VEGF and PD-L1 inhibition that warrants further study., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: This first-in-human phase I dose-escalation study evaluated the safety, pharmacokinetics, and efficacy of tinengotinib (TT-00420), a multi-kinase inhibitor targeting fibroblast growth factor receptors 1-3 (FGFRs 1-3), Janus kinase 1/2, vascular endothelial growth factor receptors, and Aurora A/B, in patients with advanced solid tumors., Patients and Methods: Patients received tinengotinib orally daily in 28-day cycles. Dose escalation was guided by Bayesian modeling using escalation with overdose control. The primary objective was to assess dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and dose recommended for dose expansion (DRDE). Secondary objectives included pharmacokinetics and efficacy., Results: Forty-eight patients were enrolled (dose escalation, n = 40; dose expansion, n = 8). MTD was not reached; DRDE was 12 mg daily. DLTs were palmar-plantar erythrodysesthesia syndrome (8 mg, n = 1) and hypertension (15 mg, n = 2). The most common treatment-related adverse event was hypertension (50.0%). In 43 response-evaluable patients, 13 (30.2%) achieved partial response (PR; n = 7) or stable disease (SD) ≥ 24 weeks (n = 6), including 4/11 (36.4%) with FGFR2 mutations/fusions and cholangiocarcinoma (PR n = 3; SD ≥ 24 weeks n = 1), 3/3 (100.0%) with hormone receptor (HR)-positive/HER2-negative breast cancer (PR n = 2; SD ≥ 24 weeks n = 1), 2/5 (40.0%) with triple-negative breast cancer (TNBC; PR n = 1; SD ≥ 24 weeks n = 1), and 1/1 (100.0%) with castrate-resistant prostate cancer (CRPC; PR). Four of 12 patients (33.3%; HR-positive/HER2-negative breast cancer, TNBC, prostate cancer, and cholangiocarcinoma) treated at DRDE had PRs. Tinengotinib's half-life was 28-34 hours., Conclusions: Tinengotinib was well tolerated with favorable pharmacokinetic characteristics. Preliminary findings indicated potential clinical benefit in FGFR inhibitor-refractory cholangiocarcinoma, HER2-negative breast cancer (including TNBC), and CRPC. Continued evaluation of tinengotinib is warranted in phase II trials., (© The Author(s) 2024. Published by Oxford University Press.)

Although V600E accounts for the majority of the BRAF mutations in metastatic colorectal cancer (mCRC), non-V600 BRAF variants have been shown in recent years to represent a distinct molecular subtype. This study provides a comprehensive profile of BRAF variants in mCRC using a large genomic database of circulating tumor DNA (ctDNA) and analyzing clinical outcomes in a cohort of patients with atypical (non-V600) BRAF variants ( aBRAF ; class II, class III, unclassified). Overall, 1733 out of 14,742 mCRC patients in the ctDNA cohort had at least one BRAF variant. Patients with atypical BRAF variants tended to be younger and male. In contrast to BRAF V600E , BRAF class II and III variants and their co-occurrence with KRAS / NRAS mutations were increased at baseline and especially with those patients predicted to have prior anti-EGFR exposure. Our clinical cohort included 38 patients with atypical BRAF mCRC treated at a large academic referral center. While there were no survival differences between atypical BRAF classes, concurrent RAS mutations or liver involvement was associated with poorer prognosis. Notably, patients younger than 50 years of age had extremely poor survival. In these patients, the high-frequency KRAS / NRAS co-mutation and its correlation with poorer prognosis underlines the urgent need for novel therapeutic strategies. This study represents one of the most comprehensive characterizations to date of atypical BRAF variants, utilizing both ctDNA and clinical cohorts.

Importance: Serum tumor markers carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and cancer antigen 125 (CA125) have been useful in the management of gastrointestinal and gynecological cancers; however, there is limited information regarding their utility in patients with appendiceal adenocarcinoma., Objective: To assess the association of serum tumor markers (CEA, CA19-9, and CA125) with clinical outcomes and pathologic and molecular features in patients with appendiceal adenocarcinoma., Design, Setting, and Participants: This is a retrospective cohort study at a single tertiary care comprehensive cancer center. The median (IQR) follow-up time was 52 (21-101) months. Software was used to query the MD Anderson internal patient database to identify patients with a diagnosis of appendiceal adenocarcinoma and at least 1 tumor marker measured at MD Anderson between March 2016 and May 2023. Data were analyzed from January to December 2023., Main Outcomes and Measures: Association of serum tumor markers with survival in patients with appendiceal adenocarcinoma. Cox proportional hazards regression analyses were also performed to assess associations between clinical factors (serum tumor marker levels, demographics, and patient and disease characteristics) and patient outcomes (overall survival)., Results: A total of 1338 patients with appendiceal adenocarcinoma were included, with a median (range) age at diagnosis of 56.5 (22.3-89.6) years. The majority of the patients had metastatic disease (1080 patients [80.7%]). CEA was elevated in 742 of the patients tested (56%), while CA19-9 and CA125 were elevated in 381 patients (34%) and 312 patients (27%), respectively. Individually, elevation of CEA, CA19-9, or CA125 were associated with worse 5-year survival; elevated vs normal was 81% vs 95% for CEA (hazard ratio [HR], 4.0; 95% CI, 2.9-5.6), 84% vs 92% for CA19-9 (HR, 2.2; 95% CI, 1.4-3.4), and 69% vs 93% for CA125 (HR, 4.6; 95% CI, 2.7-7.8) (P < .001 for all). Quantitative evaluation of tumor markers was associated with outcomes. Patients with highly elevated (top 10th percentile) CEA, CA19-9, or CA125 had markedly worse survival, with 5-year survival rates of 59% for CEA (HR, 9.8; 95% CI, 5.3-18.0), 64% for CA19-9 (HR, 6.0; 95% CI, 3.0-11.7), and 57% for CA125 (HR, 7.6; 95% CI, 3.5-16.5) (P < .001 for all). Although metastatic tumors had higher levels of all tumor markers, when restricting survival analysis to 1080 patients with metastatic disease, elevated CEA, CA19-9, or CA125 were all still associated worse survival (HR for CEA, 3.4; 95% CI, 2.5-4.8; P < .001; HR for CA19-9, 1.8; 95% CI, 1.2-2.7; P = .002; and HR for CA125, 3.9; 95% CI, 2.4-6.4; P < .001). Interestingly, tumor grade was not associated with CEA or CA19-9 level, while CA-125 was slightly higher in high-grade tumors relative to low-grade tumors (mean value, 18.3 vs 15.0; difference, 3.3; 95% CI, 0.9-3.7; P < .001). Multivariable analysis identified an incremental increase in the risk of death with an increase in the number of elevated tumor markers, with an 11-fold increased risk of death in patients with all 3 tumor markers elevated relative to those with none elevated. Somatic mutations in KRAS and GNAS were associated with significantly higher levels of CEA and CA19-9., Conclusions and Relevance: In this retrospective study of serum tumor markers in patients with appendiceal adenocarcinoma, CEA, CA19-9, and CA125 were associated with overall survival in appendiceal adenocarcinoma. Given their value, all 3 biomarkers should be included in the initial workup of patients with a diagnosis of appendiceal adenocarcinoma.

Although dual HER2 inhibition has shown promising clinical activity in patients with RAS wild-type HER2-positive metastatic colorectal cancer, predictive biomarkers of response/resistance are less well characterized. Activating HER2/RTK/MAPK genomic alterations appears to blunt the clinical benefit of dual anti-HER2 therapy and may hold a potential albeit partial role in patient selection. See related article by Randon et al., p. 436., (©2023 American Association for Cancer Research.)

Introduction: Many patients with mucinous appendiceal adenocarcinoma experience peritoneal recurrence despite complete cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Prior work has demonstrated that repeat CRS/HIPEC can prolong survival in select patients. We sought to validate these findings using outcomes from a high-volume center., Patients and Methods: Patients with mucinous appendiceal adenocarcinoma who underwent CRS/HIPEC at MD Anderson Cancer Center between 2004 and 2021 were stratified by whether they underwent CRS/HIPEC for recurrent disease or as part of initial treatment. Only patients who underwent complete CRS/HIPEC were included. Initial and recurrent groups were compared., Results: Of 437 CRS/HIPECs performed for mucinous appendiceal adenocarcinoma, 50 (11.4%) were for recurrent disease. Patients who underwent CRS/HIPEC for recurrent disease were more often treated with an oxaliplatin or cisplatin perfusion (35%/44% recurrent vs. 4%/1% initial, p < 0.001), had a longer operative time (median 629 min recurrent vs. 511 min initial, p = 0.002), and had a lower median length of stay (10 days repeat vs. 13 days initial, p < 0.001). Thirty-day complication and 90-day mortality rates did not differ between groups. Both cohorts enjoyed comparable recurrence free survival (p = 0.82). Compared with patients with recurrence treated with systemic chemotherapy alone, this select cohort of patients undergoing repeat CRS/HIPEC enjoyed better overall survival (p < 0.001)., Conclusions: In appropriately selected patients with recurrent appendiceal mucinous adenocarcinoma, CRS/HIPEC can provide survival benefit equivalent to primary CRS/HIPEC and that may be superior to that conferred by systemic therapy alone in select patients. These patients should receive care at a high-volume center in the context of a multidisciplinary team., (© 2023. The Author(s).)

Immune checkpoint inhibitors improve survival in patients with mismatch repair deficiency/microsatellite instability-high (MSI-H) colorectal cancer. The recurrence outcomes following discontinuation of immunotherapy after prolonged disease control have not been definitively reported in large series. Records from patients with advanced MSI-H colorectal cancer from The University of Texas - MD Anderson Cancer Center who received immunotherapy between 2014 and 2022 and stopped after prolonged clinical benefit were reviewed. Median progression-free and overall survival were estimated. Associations between the event of recurrence and coexisting mutations (KRAS/NRAS, BRAFV600E), metastatic organ involvement (lung, liver, lymph node, or peritoneum), metastatic timing (synchronous vs. metachronous), prior immunotherapy [anti-PD-(L)1 alone or in combination with anti-CTLA antibodies], etiology of MSI status (sporadic vs. hereditary non-polyposis colorectal cancer), and duration of immunotherapy were assessed. Sixty-four patients with MSI-H colorectal cancer without progression on immunotherapy were reviewed. Of these 48 and 16 received anti-PD(L)1 antibody alone or in combination with anti-CTLA-4 antibody, respectively. Median exposure to immunotherapy was 17.6 months (range, 1.3-51.9). After a median follow-up of 22.6 months (range, 0.3-71.7) after stopping immunotherapy, 56 of 64 patients (88%) remained without disease progression. Lung metastases were associated with recurrence/progression (OR, 6.1; P = 0.04), but coexisting mutation, primary tumor sidedness, and immunotherapy were not. These data provide a retrospective, single-institution analysis that showed that most patients with advanced MSI-H colorectal cancer do not recur after treatment cessation, regardless of the reason for stopping treatment or a variety of patient and disease features, supporting an optimistic prognosis of sustained disease control., Significance: Outcomes for patients with MSI-H colorectal cancer stopping immunotherapy after disease control remain unknown. Sixty-four patients with MSI-H colorectal cancer from our institution stopping treatment for sustained benefit or toxicity were retrospectively assessed. After median follow up of 22 months and median immunotherapy exposure of 18 months, 88% patients remained without progression. All patients who recurred or progressed and were rechallenged with immunotherapy have continued to experience disease control., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Purpose: Cancer of unknown primary (CUP) accounts for 2-5% of all cancer diagnoses, wherein standard investigations fail to reveal the original tumor site. Basket trials allocate targeted therapeutics based on actionable somatic mutations, independent of tumor entity. These trials, however, mostly rely on variants identified in tissue biopsies. Since liquid biopsies (LB) represent the overall tumor genomic landscape, they may provide an ideal diagnostic source in CUP patients. To identify the most informative liquid biopsy compartment, we compared the utility of genomic variant analysis for therapy stratification in two LB compartments (circulating cell-free (cf) and extracellular vesicle (ev) DNA)., Methods: CfDNA and evDNA from 23 CUP patients were analyzed using a targeted gene panel covering 151 genes. Identified genetic variants were interpreted regarding diagnostic and therapeutic relevance using the MetaKB knowledgebase., Results: LB revealed a total of 22 somatic mutations in evDNA and/or cfDNA in 11/23 patients. Out of the 22 identified somatic variants, 14 are classified as Tier I druggable somatic variants. Comparison of variants identified in evDNA and cfDNA revealed an overlap of 58% of somatic variants in both LB compartments, whereas over 40% of variants were only found in one or the other compartment., Conclusion: We observed substantial overlap between somatic variants identified in evDNA and cfDNA of CUP patients. Nonetheless, interrogation of both LB compartments can potentially increase the rate of druggable alterations, stressing the significance of liquid biopsies for possible primary-independent basket and umbrella trial inclusion., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Neoadjuvant immune checkpoint blockade (IO) is emerging as a therapeutic option for patients with deficient mismatch repair (dMMR) colorectal cancer (CRC) given high pathological response rates. The aim of the study was to characterise imaging and endoscopic response to IO., Methods: A retrospective analysis of patients with localised dMMR CRC that received at least one cycle of neoadjuvant anti-PD-1 therapy was conducted. Endoscopy, imaging, and pathological outcomes were reviewed to determine response to treatment according to standardised criteria., Results: Thirty-eight patients had received IO for the treatment of localised CRC (median eight cycles). Among evaluable cases (n = 31 for endoscopy and n = 34 for imaging), the best endoscopic response was complete response (CR) in 45% of cases, and the best radiographic response was CR in 23% of cases. Imaging CR rate after ≤4 cycles of IO (n = 1) was 6% compared to 44% after >4 IO cycles (n = 7). Among 28 patients with imaging and endoscopy available, a discrepancy in best response was noted in 15 (54%) cases. At a median follow-up of 28.2 months from IO start, 18 patients underwent surgical resection of which 11 (61%) had pathological CR (pCR). Despite pCR or no evidence of progression ≥6 months after completion of IO among non-operatively managed patients, 72% and 42% of patients had non-CR on imaging and endoscopy, respectively., Conclusions: Discrepancies between imaging and endoscopy are prevalent, and irregularities identified on these modalities can be identified despite pathological remission. Improved clinical response criteria are warranted., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Tsuyoshi Konishi: travel, accommodations, expenses – advent health; Michener Institute of Education at UHN. Kanwal Pratap Singh Raghav: Honoraria - Bayer; Daiichi Sankyo/Astra Zeneca; Eisai; Merck; Seagen. Consulting or advisory role – Bayer; Daiichi Sankyo/Astra Zeneca; Eisai; Merck; Seagen. Research funding – Abbvie (Inst); Abbvie (Inst); Bayer (Inst); Daiichi Sankyo/Astra Zeneca (Inst); Eisai (Inst); Guardant Health (Inst); HiberCell (Inst); Innovent Biologics (Inst); Janssen (Inst); Merck Serono (Inst); Roche/Genentech (Inst); UCB (Inst); Xencor (Inst). Phillip S. Ge: consulting or advisory role – Alira Health; Boston Scientific; Neptune Medical; Ovesco Endoscopy. Benny Johnson: consulting or advisory role – Gritstone Bio; Incyte; Insmed; Pfizer; Taiho Oncology. Research funding – Bristol-Myers Squibb (Inst); Gateway Foundation (Inst); Syntrix Biosystems (Inst). Van K. Morris: consulting or advisory role – Axiom Healthcare Strategies; Bicara Therapeutics; BioMedical Insights; Boehringer Ingelheim; Incyte. Research funding – Bicara Therapeutics (Inst); BioNTech (Inst); Bristol-Myers Squibb (Inst); EMD Serono (Inst); Immatics; Pfizer (Inst). Scott Kopetz: stock and other ownership interests – Frontier Medicines; Iylon; Lutris; Navire; Xilis. Consulting or advisory role – Abbvie; Accademia Nazionale Di Medicina; Amal Therapeutics; Amgen; Astra Zeneca/MedImmune; Bayer Health; Bicara Therapeutics; Black Diamond Therapeutics; Boehringer Ingelheim; Bristol-Myers Squibb/Medarex; Cardiff Oncology; Carina Biotech; CureTeq; EMD Serono; Endeavor BioMedicines; Flame Biosciences; Foundation Medicine; Frontier Medicines; Genentech; Genomic Health; Gilead Sciences; GlaxoSmithKline; HalioDx; Harbinger Oncology, Inc; Holy Stone Healthcare; Inivata; Ipsen; Iylon; Jacobio; Jazz Pharmaceuticals; Johnson & Johnson/Janssen; Lilly; Lutris; Merck; Mirati Therapeutics; NeoGenomics Laboratories; Novartis; Numab; Ono Pharmaceutical; Pfizer; Redx Pharma; Repare Therapeutics; Replimune; Servier; Taiho Pharmaceutical; Takeda; Tempus; Xilis; Zentalis. Research funding – Amgen; Array BioPharma; Biocartis; Daiichi Sankyo; EMD Serono; Genentech/Roche; Guardant Health; Lilly; MedImmune; Novartis; Sanofi. George J. Chang: consulting or advisory role – Medicaroid. Kaysia Ludford: research funding – Merck (Inst). Michael J. Overman: consulting or advisory role – 3D Medicines; Array BioPharma; Bristol-Myers Squibb; Eisai; Gritstone Bio; Janssen; Janssen; MedImmune; Merck; Novartis; Pfizer; Pfizer; Promega; Roche/Genentech; Spectrum Pharmaceuticals. Research funding – Bristol-Myers Squibb; MedImmune; Merck; Roche. The remining authors do not have any disclosures., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The development of acquired resistance to anti-EGFR therapies remains poorly understood, with most research to date exploring, and trying to overcome, various genomic mechanisms of resistance. However, recent work supports a model of resistance whereby transcriptomic mechanisms of resistance predominate in the presence of active cytotoxic chemotherapy combined with anti-EGFR therapy in the first-line setting, with a greater predominance of acquired MAPK mutations after single-agent anti-EGFR therapy in the later-line setting. The proposed model has implications for prospective studies evaluating anti-EGFR rechallenge strategies guided by acquired MAPK mutations and highlights the need to address transcriptional mechanisms of resistance., Competing Interests: Author K.R. was employed by AstraZeneca, Bayer, Eisai, Daiichi Sankyo, Seattle Genetics for Consulting or Advisory Roles; Bayer (Inst), Roche/Genentech (Inst), Guardant Health (Inst), Daiichi Sankyo/Astra Zeneca (Inst), HiberCell (Inst), Merck Serono (Inst) for research funding. Author S.K. was employed by Genentech, EMD Serono, Merck, Holy Stone’ for Consulting or Advisory Roles; MolecularMatch, Lutris, Iylon, Frontier Medicines for Stock or Other Ownership Interests. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Parseghian, Eluri, Kopetz and Raghav.)

Purpose: In metastatic colorectal cancer, the detection of RAS mutations by circulating tumor DNA (ctDNA) has emerged as a valid and noninvasive alternative approach to determining RAS status. However, some RAS mutations may be missed, that is, false negatives can occur, possibly compromising important treatment decisions. We propose a statistical model to assess the probability of false negatives when performing ctDNA testing for RAS., Methods: Cohorts of 172 subjects with tissue and multipanel ctDNA testing from MD Anderson Cancer Center and 146 subjects from Massachusetts General Hospital were collected. We developed a Bayesian model that uses observed frequencies of reference mutations (the maximum of APC and TP53 ) to provide information about the probability of KRAS false negatives. The model was alternatively trained on one cohort and tested on the other. All data were collected on Guardant assays., Results: The model suggests that negative KRAS findings are believable when the maximum of APC and TP53 frequencies is at least 8% (corresponding posterior probability of false negative <5%). Validation studies demonstrated the ability of our tool to discriminate between false-negative and true-negative subjects. Simulations further confirmed the utility of the proposed approach., Conclusion: We suggest clinicians use the tool to more precisely quantify KRAS false-negative ctDNA results when at least one of the reference mutations ( APC , TP53 ) is observed; usage may be especially important for subjects with a maximum reference frequency of <8%. Extension of the methodology to predict false negatives of other genes is possible. Additional reference genes can also be considered. Use of personal training data sets is supported. An open-source R Shiny application is available for public use.

Real-world evidence regarding the value of integrating genomic profiling (GP) in managing cancer of unknown primary (CUP) is limited. We assessed this clinical utility using a prospective trial of 158 patients with CUP (October 2016-September 2019) who underwent GP using next-generation sequencing designed to identify genomic alterations (GAs). Only 61 (38.6%) patients had sufficient tissue for successful profiling. GAs were seen in 55 (90.2%) patients of which GAs with US Food and Drug Administration-approved genomically matched therapy were seen in 25 (40.9%) patients. A change in therapy was recommended and implemented (primary endpoint of the study) in 16 (10.1%) and 4 (2.5%) patients of the entire study cohort, respectively. The most common reason for inability to implement the profiling-guided therapy was worsening of performance status (56.3%). Integrating GP in management of CUP is feasible but challenging because of paucity of tissue and aggressive natural history of the disease and requires innovative precision strategies., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The oncogene ERBB2 encoding the receptor tyrosine-protein kinase erbB-2 (HER2) is frequently overexpressed or amplified and occasionally mutated in a variety of human cancers. The early discovery of this oncogene, its established oncogenic relevance in diverse cancers, its substantial expression on the surface of cancer cells, and its druggable catalytic activity have made it one of the most pursued targets in the history of cancer drug development. Initiatives targeting HER2 provided the early stimulus for several transformational pharmaceutical technologies, including mAbs, tyrosine kinase inhibitors, antibody-drug conjugates, and others. The seismic impact of these efforts has been felt in treatment of many cancers, including breast, gastroesophageal, lung, colorectal, and others. This impact continues to broaden with increasing indications on the horizon and a plethora of novel agents in development. However, implementation of these therapeutic strategies has been complex. The clinical translation of every one of these classes of agents has been notable for underperformance or overperformance characteristics that have informed new lines of research providing deeper insights into the mechanistic complexities and unrealized opportunities provided by this molecular target. Despite all the successes to date, the preponderance of scientific evidence indicates that the full potential of HER2 as a target for cancer therapeutics is far greater than currently realized, and numerous lines of investigation are ongoing to deepen and broaden the scope of impact of HER2 as a signaling, homing, or immunologic target. In this review, we explore the existing data and evolving paradigms surrounding this remarkable target for cancer therapy., (©2022 American Association for Cancer Research.)

DESTINY-CRC01 (NCT03384940) was a multicenter, open-label, phase 2 trial assessing the efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients with HER2-expressing metastatic colorectal cancer (mCRC) that progressed after ≥2 prior regimens; results of the primary analysis are published. Patients received T-DXd 6.4 mg/kg every 3 weeks and were assigned to either: cohort A (HER2-positive, immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+), cohort B (IHC 2+/ISH-), or cohort C (IHC 1+). Primary endpoint was objective response rate (ORR) by independent central review in cohort A. Secondary endpoints included ORR (cohorts B and C), duration of response, disease control rate, progression-free survival, overall survival, pharmacokinetics, and safety of T-DXd. 86 patients were enrolled (53 in cohort A, 15 in cohort B, and 18 in cohort C). Results of the primary analysis are published, reporting an ORR of 45.3% in cohort A. Here, we report the final results. No responses occurred in cohorts B or C. Median progression-free survival, overall survival, and duration of response were 6.9, 15.5, and 7.0 months, respectively. Overall serum exposure (cycle 1) of T-DXd, total anti-HER2 antibody, and DXd were similar regardless of HER2 status. Most common grade ≥3 treatment-emergent adverse events were decreased neutrophil count and anemia. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8 patients (9.3%). These findings support the continued exploration of T-DXd in HER2-positive mCRC., (© 2023. The Author(s).)

Importance: Appendiceal adenocarcinoma is a rare tumor, and given the inherent difficulties in performing prospective trials in such a rare disease, there are currently minimal high-quality data to guide treatment decisions, highlighting the need for more preclinical and clinical investigation for this disease., Objective: To prospectively evaluate the effectiveness of fluoropyrimidine-based systemic chemotherapy in patients with inoperable low-grade mucinous appendiceal adenocarcinoma., Design, Setting, and Participants: This open-label randomized crossover trial recruited patients at a single tertiary care comprehensive cancer center from September 2013 to January 2021. The data collection cutoff was May 2022. Enrollment of up to 30 patients was planned. Eligible patients had histological evidence of a metastatic low-grade mucinous appendiceal adenocarcinoma, with radiographic imaging demonstrating the presence of mucinous peritoneal carcinomatosis and were not considered candidates for complete cytoreductive surgery. Key exclusion criteria were concurrent or recent investigational therapy, evidence of bowel obstruction, and use of total parenteral nutrition. Data were analyzed from November 2021 to May 2022., Interventions: Patients were randomized to either 6 months observation followed by 6 months of chemotherapy, or initial chemotherapy followed by observation., Main Outcomes and Measures: The primary end point was the percentage difference in tumor growth in treatment and observation groups. Key secondary end points included patient-reported outcomes in the chemotherapy and observation periods, objective response rate, rate of bowel complications, and differences in overall survival (OS)., Results: A total of 24 patients were enrolled, with median (range) age of 63 (38 to 82) years, and equal proportion of men and women (eg, 12 men [50%]); all patients had ECOG performance status of 0 or 1. A total of 11 patients were randomized to receive chemotherapy first, and 13 patients were randomized to receive observation first. Most patients (15 patients [63%]) were treated with either fluorouracil or capecitabine as single agent; 3 patients (13%) received doublet chemotherapy (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin or folinic acid, fluorouracil, and irinotecan hydrochloride), and bevacizumab was added to cytotoxic chemotherapy for 5 patients (21%). Fifteen patients were available to evaluate the primary end point of difference in tumor growth during treatment and observation periods. Tumor growth while receiving chemotherapy increased 8.4% (95% CI, 1.5% to 15.3%) from baseline but was not significantly different than tumor growth during observation (4.0%; 95% CI, -0.1% to 8.0%; P = .26). Of 18 patients who received any chemotherapy, none had an objective response (14 patients [77.8%] had stable disease; 4 patients [22.2%] had progressive disease). Median (range) OS was 53.2 (8.1 to 95.5) months, and there was no significant difference in OS between the observation-first group (76.0 [8.6 to 95.5] months) and the treatment-first group (53.2 [8.1 to 64.1] months; hazard ratio, 0.64; 95% CI, 0.16-2.55; P = .48). Patient-reported quality-of-life metrics identified that during treatment, patients experienced significantly worse fatigue (mean [SD] score, 18.5 [18.6] vs 28.9 [21.3]; P = .02), peripheral neuropathy (mean [SD] score, 6.67 [12.28] vs 38.89 [34.88]; P = .01), and financial difficulty (mean [SD] score, 8.9 [15.2] vs 28.9 [33.0]; P = .001) compared with during observation., Conclusions and Relevance: In this prospective randomized crossover trial of systemic chemotherapy in patients with low-grade mucinous appendiceal adenocarcinoma, patients did not derive clinical benefit from fluorouracil-based chemotherapy, given there were no objective responses, no difference in OS when treatment was delayed 6 months, and no difference in the rate of tumor growth while receiving chemotherapy., Trial Registration: ClinicalTrials.gov Identifier: NCT01946854.

Objective: To evaluate the association of perioperative ctDNA dynamics on outcomes after hepatectomy for CLM., Summary Background Data: Prognostication is imprecise for patients undergoing hepatectomy for CLM, and ctDNA is a promising biomarker. However, clinical implications of perioperative ctDNA dynamics are not well established., Methods: Patients underwent curative-intent hepatectomy after preoperative chemotherapy for CLM (2013-2017) with paired prehepatectomy/postoperative ctDNA analyses via plasma-only assay. Positivity was determined using a proprietary variant classifier. Primary endpoint was recurrence-free survival (RFS). Median follow-up was 55 months., Results: Forty-eight patients were included. ctDNA was detected before and after surgery (ctDNA+/+) in 14 (29%), before but not after surgery (ctDNA+/-) in 19 (40%), and not at all (ctDNA-/-) in 11 (23%). Adverse tissue somatic mutations were detected in TP53 (n = 26; 54%), RAS (n = 23; 48%), SMAD4 (n = 5; 10%), FBXW7 (n = 3; 6%), and BRAF (n = 2; 4%). ctDNA+/+ was associated with worse RFS (median: ctDNA+/+, 6.0 months; ctDNA+/-, not reached; ctDNA-/-, 33.0 months; P = 0.001). Compared to ctDNA+/+, ctDNA+/- was associated with improved RFS [hazard ratio (HR) 0.24 (95% confidence interval (CI) 0.1-0.58)] and overall survival [HR 0.24 (95% CI 0.08-0.74)]. Adverse somatic mutations were not associated with survival. After adjustment for prehepatectomy chemotherapy, synchronous disease, and ≥2 CLM, ctDNA+/- and ctDNA-/- were independently associated with improved RFS compared to ctDNA+/+ (ctDNA+/-: HR 0.21, 95% CI 0.08-0.53; ctDNA-/-: HR 0.21, 95% CI 0.08-0.56)., Conclusions: Perioperative ctDNA dynamics are associated with survival, identify patients with high recurrence risk, and may be used to guide treatment decisions and surveillance after hepatectomy for patients with CLM., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Primary end point (PEP) changes to an active clinical trial raise questions regarding trial quality and the risk of outcome reporting bias. It is unknown how the frequency and transparency of the reported changes depend on reporting method and whether the PEP changes are associated with trial positivity (ie, the trial met the prespecified statistical threshold for PEP positivity)., Objectives: To assess the frequency of reported PEP changes in oncology randomized clinical trials (RCTs) and whether these changes are associated with trial positivity., Design, Setting, and Participants: This cross-sectional study used publicly available data for complete oncology phase 3 RCTs registered in ClinicalTrials.gov from inception through February 2020., Main Outcomes and Measures: The main outcome was change between the initial PEP and the final reported PEP, assessed using 3 methods: (1) history of tracked changes on ClinicalTrials.gov, (2) self-reported changes noted in the article, and (3) changes reported within the protocol, including all available protocol documents. Logistic regression analyses were performed to evaluate whether PEP changes were associated with US Food and Drug Administration approval or trial positivity., Results: Of 755 included trials, 145 (19.2%) had PEP changes found by at least 1 of the 3 detection methods. Of the 145 trials with PEP changes, 102 (70.3%) did not have PEP changes disclosed within the manuscript. There was significant variability in rates of PEP detection by each method (χ2 = 72.1; P < .001). Across all methods, PEP changes were detected at higher rates when multiple versions of the protocol (47 of 148 [31.8%]) were available compared with 1 version (22 of 134 [16.4%]) or no protocol (76 of 473 [16.1%]) (χ2 = 18.7; P < .001). Multivariable analysis demonstrated that PEP changes were associated with trial positivity (odds ratio, 1.86; 95% CI, 1.25-2.82; P = .003)., Conclusions and Relevance: This cross-sectional study revealed substantial rates of PEP changes among active RCTs; PEP changes were markedly underreported in published articles and mostly occurred after reported study completion dates. Significant discrepancies in the rate of detected PEP changes call into question the role of increased protocol transparency and completeness in identifying key changes occurring in active trials.

Purpose: Pembrolizumab significantly improves clinical outcomes in advanced/metastatic microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) solid tumors but is not well studied in the neoadjuvant space., Methods: This is a phase II open-label, single-center trial of localized unresectable or high-risk resectable MSI-H/dMMR tumors. Treatment is pembrolizumab 200 mg once every 3 weeks for 6 months followed by surgical resection with an option to continue therapy for 1 year followed by observation. To continue on study, patients are required to have radiographic or clinical benefit. The coprimary end points are safety and pathologic complete response. Key secondary end points are response rate and organ-sparing at one year for patients who declined surgery. Exploratory analyses include interrogation of the tumor immune microenvironment using imaging mass cytometry., Results: A total of 35 patients were enrolled, including 27 patients with colorectal cancer and eight patients with noncolorectal cancer. Among 33 evaluable patients, best overall response rate was 82%. Among 17 (49%) patients who underwent surgery, the pathologic complete response rate was 65%. Ten patients elected to receive one year of pembrolizumab followed by surveillance without surgical resection (median follow-up of 23 weeks [range, 0-54 weeks]). An additional eight did not undergo surgical resection and received less than 1 year of pembrolizumab. During the study course of the trial and subsequent follow-up, progression events were seen in six patients (four of whom underwent salvage surgery). There were no new safety signals. Spatial immune profiling with imaging mass cytometry noted a significantly closer proximity between granulocytic cells and cytotoxic T cells in patients with progressive events compared with those without progression., Conclusion: Neoadjuvant pembrolizumab in dMMR/MSI-H cancers is safe and resulted in high rates of pathologic, radiographic, and endoscopic response, which has implications for organ-sparing strategies.

Background: Anti-programmed cell death protein 1 antibodies plus multikinase inhibitors have shown encouraging activity in several tumour types, including colorectal cancer. This study assessed regorafenib plus nivolumab in patients with microsatellite stable/mismatch repair-proficient metastatic colorectal cancer., Methods: This single-arm, open-label, multicentre phase 2 study enrolled adults from 13 sites in the USA with previously treated advanced microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Eligible patients had known extended RAS and BRAF status, progression or intolerance to no more than two (for extended RAS mutant) or three (for extended RAS wild type) lines of systemic chemotherapy and an Eastern Cooperative Oncology Group performance status of 0 or 1. Regorafenib 80 mg/day was administered orally for 3 weeks on/1 week off (increased to 120 mg/day if 80 mg/day was well tolerated) with intravenous nivolumab 480 mg every 4 weeks. Primary endpoint was objective response rate. Secondary endpoints included safety, overall survival, and progression-free survival. Exploratory endpoints included biomarkers associated with antitumour activity. Patients who received at least one dose of study intervention were included in the efficacy and safety analyses. Tumour assessments were carried out every 8 weeks for the first year, and every 12 weeks thereafter until progressive disease/end of the study, and objective response rate was analysed after all patients had met the criteria for primary completion of five post-baseline scans and either 10-months' follow-up or drop out. This trial is registered with ClinicalTrials.gov, number NCT04126733., Findings: Between 14 October 2019 and 14 January 2020, 94 patients were enrolled, 70 received treatment. Five patients had a partial response, yielding an objective response rate of 7% (95% CI 2.4-15.9; p = 0.27). All responders had no liver metastases at baseline. Median overall survival (data immature) and progression-free survival were 11.9 months (95% CI 7.0-not evaluable) and 1.8 months (95% CI 1.8-2.4), respectively. Most patients (97%, 68/70) experienced a treatment-related adverse event; 51% were grade 1 or 2, 40% were grade 3, 3% were grade 4, and 3% were grade 5. The most common (≥20%) events were fatigue (26/70), palmar-plantar erythrodysesthesia syndrome (19/70), maculopapular rash (17/70), increased blood bilirubin (14/70), and decreased appetite (14/70). Higher baseline expression of tumour biomarkers of immune sensitivity correlated with antitumour activity., Interpretation: Further studies are warranted to identify subgroups of patients with clinical characteristics or biomarkers that would benefit most from treatment with regorafenib plus nivolumab., Funding: Bayer/Bristol Myers Squibb., Competing Interests: YAW, AW, and HS report employment with Bayer. BP and BB report employment and stock ownership with Bayer. CO and SC report previous employment with Bayer. HZG report previous employment and stock or stock options with Bayer. DDA reports employment and stock ownership from Bristol Myers Squibb. MF reports research funding (to institution) from Amgen, Bristol Myers Squibb, Genentech, Verastem, and Novartis, consulting fees from AstraZeneca, Bristol Myers Squibb, Incyte, PsiOxus, Zhuhai Yufan Biotech, and Taiho Pharmaceutical, honoraria from Guardant360, and advisory roles from Amgen, Bayer, Array Biopharma, Eisai, GSK, Merck, Mirati, Nouscom, Roche/Genentech, and Xenthera. NS reports employment, support for attending meetings and stock ownership with Bayer. ASP reports research funding (to institution) from Ipsen, Bristol Myers Squibb, Exelixis, Hutchison MediPharma, Taiho Pharmaceutical, Lilly, AstraZeneca, Incyte, Deciphera, G1 Therapeutics, Zentalis, Tempus, Camurus, Relay Therapeutics, Nucana, Merck, Bayer, Seattle Genetics, Sotio, Innovative Cellular Therapeutics, Camurus, Regenxbio, Gilead Sciences, Gritstone Bio, BioNTech S, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Cardinal Health and Ideo Oncology, leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from Amgen, Bristol Myers Squibb, Eisai, Ipsen, Advanced Accelerator Applications, Incyte, Exelixis, Pfizer, QED Therapeutics, Lilly, Mirati Therapeutics, Hutchison MediPharma, Astellas Pharma, AADi, Stromatis Pharma, EMD Serono, AstraZeneca, and Servier, and stock or stock options from Actinium Pharmaceuticals, Aptose Biosciences, Alexion Pharmaceuticals, Lynx Health, and Stromatis Pharma. KPSR reports research funding to institution from Bayer, Daiichi Sankyo, Merck, Hibercell, UCB Biosciences, Janssen, Eisai, AbbVie, Guardant, Innovent, and Xencor, payment or honoraria for educational events from Bayer, Daiichi Sankyo, and Seagen, and participation on advisory board of Daiichi Sankyo, Eisai, Merck, SAGA Diagnostics, Bayer, Seagen, Pfizer, and AstraZeneca. RT reports employment and stock ownership with Bristol Myers Squibb. UM reports consulting fees from Bayer as a statistician for ClinStat. AC, DZC, DC, TH, TL, and JF have nothing to disclose., (© 2023 The Authors.)

Introduction: Tumor-related liver failure (TRLF) is the most common cause of death in patients with intrahepatic cholangiocarcinoma (ICC). Though we previously showed that liver radiotherapy (L-RT) for locally advanced ICC is associated with less frequent TRLF and longer overall survival (OS), the role of L-RT for patients with extrahepatic metastatic disease (M1) remains undefined. We sought to compare outcomes for M1 ICC patients treated with and without L-RT., Methods: We reviewed ICC patients that found to have M1 disease at initial diagnosis at a single institution between 2010 and 2021 who received L-RT, matching them with an institutional cohort by propensity score and a National Cancer Database (NCDB) cohort by frequency technique. The median biologically effective dose was 97.5 Gy (interquartile range 80.5-97.9 Gy) for L-RT. Patients treated with other local therapies or supportive care alone were excluded. We analyzed survival with Cox proportional hazard modeling., Results: We identified 61 patients who received L-RT and 220 who received chemotherapy alone. At median follow-up of 11 months after diagnosis, median OS was 9 months (95% confidence interval [CI] 8-11) and 21 months (CI: 17-26) for patients receiving chemotherapy alone and L-RT, respectively. TRLF was the cause of death more often in the patients who received chemotherapy alone compared to those who received L-RT (82% vs. 47%; p = 0.001). On multivariable propensity score-matched analysis, associations with lower risk of death included duration of upfront chemotherapy (hazard ratio [HR] 0.82; p = 0.005) and receipt of L-RT (HR: 0.40; p = 0.002). The median OS from diagnosis for NCDB chemotherapy alone cohort was shorter than that of the institutional L-RT cohort (9 vs. 22 months; p < 0.001)., Conclusion: For M1 ICC, L-RT associated with a lower rate of death due to TRLF and longer OS versus those treated with chemotherapy alone. Prospective studies of L-RT in this setting are warranted., Competing Interests: BD reports consulting honoraria from Sermo Inc. EBH reports research funding from Merck Serono. CT reports a consulting/advisory role with Accuray. EJK reports grants from National Institutes of Health, Stand Up 2 Cancer, MD Anderson Cancer Center, Philips Healthcare, Elekta, and GE Healthcare; personal fees from RenovoRx and Taylor and Francis; and a consulting/advisory role with Augmenix. ACK reports ownership of shares in Aravive, Inc. PD reports consulting/advisory relationships with the American Society for Radiation Oncology and the National Cancer Institute. All reported conflicts are outside of the submitted work., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Appendiceal neoplasms have a propensity for peritoneal dissemination. The standard of care for select individuals is CRS/HIPEC. In the current 8 th AJCC Staging system, a finding of only intraperitoneal acellular mucin (M1a) is classified as Stage IVa. There is concern that the current AJCC system may over-stage patients., Methods: This was a single-institution retrospective review of 164 cases of mucinous appendiceal neoplasm. Patients undergoing CRS/HIPEC with M1a disease were compared to patients with peritoneal deposits containing tumor cells (well-differentiated adenocarcinoma; low-grade mucinous carcinoma peritonei-M1b,G1). Overall and recurrence-free survival were assessed., Results: Median age was 51 years, 70% were female, and 75% White. Sixty-four patients had M1a disease and 100 M1b,G1 disease. M1a disease had a lower median PCI score (11 vs. 20, p = .0001) and a higher rate of complete CRS (62% vs. 50%, p = .021). Median follow-up was 7.6 years (IQR 5.6-10.5 years). For M1a disease, there were no recurrences and only one patient died during the study interval. In comparison, for M1b disease, 66/100 (66%) recurred with a 5-year RFS of 40.5% (HR 8.0, 95% CI 4.9-15.1, p < .0001), and 31/100 (31%) died with a 5-year OS of 84.8% (HR 4.5, 95% CI 2.2-9.2, p < .0001)., Conclusions: Acellular mucin (M1a disease) after CRS/HIPEC for appendiceal neoplasm is associated with longer OS and RFS compared to M1b, G1 disease. Current AJCC staging does not accurately reflect the differing outcomes of these two patient populations. The presence of acellular mucin in the peritoneal cavity should not be perceived as a metastatic equivalent., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Over the past two decades of successive clinical trials in metastatic colorectal cancer (CRC), the median overall survival of both control and experimental arms has steadily improved. However, the incremental change in survival for metastatic CRC patients not treated on trial has not yet been quantified. We performed a retrospective review of 1420 patients with de novo metastatic CRC who received their primary treatment at the University of Texas M.D. Anderson Cancer Center (UTMDACC) from 2004 through 2019. Median OS was roughly stable for patients diagnosed between 2004 and 2012 (22.6 months) but since has steadily improved for those diagnosed in 2013 to 2015 (28.8 months), and 2016 to 2019 (32.4 months). Likewise, 5-year survival rate has increased from 15.7% for patients diagnosed from 2004 to 2006 to 26% for those diagnosed from 2013 to 2015. Notably, survival improved for patients with BRAF V600E mutant as well as microsatellite unstable (MSI-H) tumors. Multivariate regression analysis identified surgical resection of liver metastasis (HR = 0.26, 95% CI, 0.19-0.37), use of immunotherapy (HR = 0.44, 95% CI, 0.29-0.67) and use of third line chemotherapy (regorafenib or trifluridine/tipiracil, HR = 0.74, 95% CI, 0.58-0.95), but not year of diagnosis (HR = 0.99, 95% CI, 0.98-1), as associated with better survival, suggesting that increased use of these therapies are the drivers of the observed improvement in survival., (© 2023. The Author(s).)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Acquired genomic alterations (Acq-GAs), specifically RAS , BRAF , and EGFR -ectodomain mutations and ERBB2 and MET amplifications, are recognized as major mechanisms of resistance to later-line anti-EGFR-antibody therapy in metastatic colorectal cancer (mCRC). However, data regarding emergence of these Acq-GAs under the selective pressure of first-line anti-EGFR-chemotherapy are lacking. We performed next-generation sequencing (Guardant360) on circulating tumor DNA obtained from paired plasma samples (pretreatment and postprogression) from the CALGB/SWOG-80405 trial, which randomly assigned patients with mCRC between first-line chemotherapy with cetuximab (anti-EGFR-chemotherapy) or bevacizumab (anti-VEGF-chemotherapy). The primary objective was to determine the prevalence of Acq-GAs on anti-EGFR-chemotherapy and compare this to the prevalence with anti-VEGF-chemotherapy on trial and pooled estimates (N = 292) seen with later-line anti-EGFR-antibody therapy as reported in the literature. Among the 61 patients on anti-EGFR-chemotherapy, only four (6.6%) developed ≥ 1 Acq-GAs of interest compared with 10.1% (7) on anti-VEGF-chemotherapy (odds ratio, 0.62; 95% CI, 0.20 to 2.11) and 62.0% on anti-EGFR-antibody therapy in later lines (odds ratio, 0.09; 95% CI, 0.03 to 0.23). Acq-GAs, classically associated with anti-EGFR-antibody resistance in later lines ( RAS , BRAF , and EGFR -ectodomain mutations; ERBB2 and MET amplifications), were rare with up-front use of anti-EGFR-chemotherapy indicating divergent resistance mechanisms. These findings have critical translational relevance to timing and value of circulating tumor DNA-guided anti-EGFR rechallenge in patients with mCRC, especially those treated with anti-EGFR therapy upfront.

Purpose: Acquired resistance to anti-epidermal growth factor receptor (EGFR) inhibitor (EGFRi) therapy in colorectal cancer (CRC) has previously been explained by the model of acquiring new mutations in KRAS/NRAS/EGFR , among other MAPK-pathway members. However, this was primarily on the basis of single-agent EGFRi trials and little is known about the resistance mechanisms of EGFRi combined with effective cytotoxic chemotherapy in previously untreated patients., Methods: We analyzed paired plasma samples from patients with RAS/BRAF/EGFR wild-type metastatic CRC enrolled in three large randomized trials evaluating EGFRi in the first line in combination with chemotherapy and as a single agent in third line. The mutational signature of the alterations acquired with therapy was evaluated. CRC cell lines with resistance to cetuximab, infusional fluorouracil, leucovorin, and oxaliplatin, and SN38 were developed, and transcriptional changes profiled., Results: Patients whose tumors were treated with and responded to EGFRi alone were more likely to develop acquired mutations (46%) compared with those treated in combination with cytotoxic chemotherapy (9%). Furthermore, contrary to the generally accepted hypothesis of the clonal evolution of acquired resistance, we demonstrate that baseline resistant subclonal mutations rarely expanded to become clonal at progression, and most remained subclonal or disappeared. Consistent with this clinical finding, preclinical models with acquired resistance to either cetuximab or chemotherapy were cross-resistant to the alternate agents, with transcriptomic profiles consistent with epithelial-to-mesenchymal transition. By contrast, commonly acquired resistance alterations in the MAPK pathway do not affect sensitivity to cytotoxic chemotherapy., Conclusion: These findings support a model of resistance whereby transcriptomic mechanisms of resistance predominate in the presence of active cytotoxic chemotherapy combined with EGFRi, with a greater predominance of acquired MAPK mutations after single-agent EGFRi. The proposed model has implications for prospective studies evaluating EGFRi rechallenge strategies guided by acquired MAPK mutations, and highlights the need to address transcriptional mechanisms of resistance.

Background: HER2-targeted therapies have substantially improved outcomes for patients with HER2-positive breast and gastric or gastro-oesophageal junction cancers. Several other cancers exhibit HER2 expression or amplification, suggesting that HER2-targeted agents can have broader therapeutic impact. Zanidatamab is a humanised, bispecific monoclonal antibody directed against two non-overlapping domains of HER2. The aim of this study was to evaluate the safety and anti-tumour activity of zanidatamab across a range of solid tumours with HER2 expression or amplification., Methods: This first-in-human, multicentre, phase 1, dose-escalation and expansion trial included patients aged 18 years and older, with a life expectancy of at least 3 months, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and locally advanced or metastatic, HER2-expressing or HER2-amplified solid tumours of any kind who had received all available approved therapies. The primary objectives of part 1 were to identify the maximum tolerated dose, optimal biological dose, or recommended dose of zanidatamab; all patients were included in the primary analyses. Part 1 followed a 3 + 3 dose-escalation design, including different intravenous doses (from 5 mg/kg to 30 mg/kg) and intervals (every 1, 2, or 3 weeks). The primary objective of part 2 was to evaluate the safety and tolerability of zanidatamab monotherapy in solid tumours. This trial is registered with ClinicalTrials.gov (NCT02892123), and parts 1 and 2 of the trial are complete. Part 3 of the study evaluates the use of zanidatamab in combination with chemotherapy and is ongoing., Findings: Recruitment took place between Sept 1, 2016, and March 13, 2021. In Part 1 (n=46), no dose-limiting toxicities were detected and the maximum tolerated dose was not reached. The recommended dose for part 2 (n=22 for biliary tract cancer; n=28 for colorectal cancer; and n=36 for other HER2-expressing or HER2-amplified cancers excluding breast or gastro-oesophageal cancers; total n=86) was 20 mg/kg every 2 weeks. The most frequent treatment-related adverse events in part 1 of the study were diarrhoea (24 [52%] of 46 patients; all grade 1-2) and infusion reactions (20 [43%] of 46 patients; all grade 1-2). The most frequent treatment-related adverse events in part 2 of the study were diarrhoea (37 [43%] of 86 patients; all grade 1-2 except for one patient) and infusion reactions (29 [34%] of 86 patients; all grade 1-2). A total of six grade 3 treatment-related adverse events were reported in four (3%) of 132 patients. In part 2, 31 (37%; 95% CI 27·0-48·7) of 83 evaluable patients had a confirmed objective response. There were no treatment-related deaths., Interpretation: These results support that HER2 is an actionable target in various cancer histologies, including biliary tract cancer and colorectal cancer. Evaluation of zanidatamab continues in ongoing studies., Funding: Zymeworks., Competing Interests: Declaration of interests FM-B reports consulting or personal fees from AbbVie, Aduro BioTech, Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F Hoffman-La Roche, Genentech, IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, Lengo Therapeutics, OrigiMed, PACT Pharma, Parexel International, Pfizer, Samsung Bioepis, Seagen, Tallac Therapeutics, Tyra Biosciences, Xencor, Zymeworks, and Chugai; advisory board participation for Black Diamond, Biovica, Eisai, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology, Seagen, Silverback Therapeutics, Spectrum Pharmaceuticals, and Zentalis; and research support, unrelated to this work and paid to institution, from Aileron Therapeutics, AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences, Curis, CytomX Therapeutics, Daiichi Sankyo, Debiopharm International, eFFECTOR Therapeutics, Genentech, Guardant Health, Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology, and Taiho Pharmaceutical. EH reports consulting fees or research grants outside of the scope of this work and paid to the institution from AbbVie, Acerta Pharma, ADC Therapeutics, AKESOBIO Australia, Amgen, Aravive, Arcus, ArQule, Arvinas, AstraZeneca, AtlasMedx, Black Diamond, Boehringer Ingelheim, Clovis, Compugen, Curis, CytomX, Daiichi Sankyo, the Dana-Farber Cancer Institute, Dantari, Deciphera, eFFECTOR Therapeutics, Eisai, Ellipses Pharma, EMD Serono, Fochon, FujiFilm, G1 Therapeutics, Greenwich LifeSciences, H3 Biomedicine, Harpoon, Hutchinson MediPharma, Immunogen, Immunomedics, Incyte, InvestisBio, iTeos, Jacobio, Janssen, Karyopharm, Leap Therapeutics, Lilly, Loxo, Lycera, Mabspace Biosciences, Macrogenics, MedImmune, Merck, Mersana, Merus, Millennium, Molecular Templates, Myraid Genetic Laboratories, Novartis, Nucana, Olema, OncoMed, Onconova Therapeutics, ORIC Pharmaceuticals, Orinove, Orum Therapeutics, Pfizer, PharmaMar, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Plexxikon, Puma Biotechnology, Radius Health, Regeneron, Relay Therapeutics, Repertoire Immune Medicine, Rgenix, Roche/Genentech, Seagen, Sermonix Pharmaceuticals, Shattuck Labs, Silverback Therapeutics, StemCentRx, Sutro, Syndax, Syros, Taiho, TapImmune, Tesaro, Treadwell Therapeutics, Verastem, Vincerx Pharma, Zenith Epigenetics, and Zymeworks. D-YO reports consulting fees or Advisory Board participation for AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, Bristol Myers Squibb/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, and research support outside the scope of this work from AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok. Y-KK reports consulting fees from ALX Oncology, Zymeworks, Amgen, Novartis, Macrogenics, Daehwa, Blueprint, Surface Oncology, Bristol Myers Squibb, MSD, and Roche. EE reports consulting fees from Bristol Myers Squibb, Zymeworks, Adaptimmune, BeiGene; research support outside the scope of this work from Bristol Myers Squibb, Zymeworks, and AstraZeneca; and a family member employedby Merck. RG reports consulting fees or advisory board participation for Pfizer, Apobiologix, Ipsen, Novartis, Eisai, Incyte, Bristol Myers Squibb, AstraZeneca, Merck, Roche, and Advanced Accelerator Applications; and education grants from Pfizer, Apobiologix, and Ipsen. SP reports consulting fees or advisory board participation for Xencor, 4D Pharma, Zymeworks, Ipsen, Novartis, and Janssen; research support outside the scope of this work and paid to institution from Mirati Therapeutics, Pfizer, Lilly, Xencor, Novartis, Bristol Myers Squibb, Ipsen, Astellas Pharma, Purple Biotech, 4D Pharma, Boehringer Ingelheim, NGM Biopharmaceuticals, Janssen, Arcus Biosciences, Elicio Therapeutics, Zymeworks, and BioNtech. KR reports personal fees from AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, and Seattle Genetics; and research support from Bayer, Daiichi-Sankyo, Genentech/Roche, Guardant Health, Janssen, Lilly, and Medimmune outside the submitted work. JWK reports consulting fees from AstraZeneca, BeiGene, Beyond Bio, Bristol Myers Squibb/Celgene, Eisai, GC Cell, MSD, ONO, Sanofi-Aventis, Servier, and TCUBEit. AP reports consulting or advisory fees from Genentech/Roche, Merck, Bristol Myers Squibb, Bayer, Novartis, Seagen, Gilead Sciences, Silverback Therapeutics, Daiichi, and HalioDx. TG, RD, and MAO report employment by Zymeworks at the time of the study and ownership of Zymeworks stock. JW reports employment by Zymeworks at the time of the study and ownership of Seagen stock. K-WL reports consulting fees from ISU ABXIS, Bayer, Daiichi Sankyo, Merck Sharp and Dohme, Bristol Myers Squibb, Vifor Pharma, Ono Pharmaceutical, and Boryung; and research grants outside of the scope of this work from AstraZeneca, Ono Pharmaceutical, Merck Sharp and Dohme, Merck KGaA, Pfizer, BeiGene, Astellas Pharma, ALX Oncology, Macrogenetics, Five Prime Therapeutics, Seagen, Bolt Therapeutics, Trishula Therapeutics, Oncologie, Pharmacyclics, LSK BioPharma, MedPacto, Green Cross Corp, ABLBIO, Y-BIOLOGICS, Genexine, Daiichi Sankyo, Taiho Pharmaceutical, InventisBio, and Leap Therapeutics. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Immune checkpoint blockade (ICB) has improved outcomes for patients with microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) tumors. However, not all MSI-H/dMMR patients will exhibit the same ICB efficacy. Previous studies suggest that concomitant antibiotic use while receiving ICB may result in poorer outcomes. We aimed to evaluate this association in patients with MSI-H/dMMR metastatic colorectal cancer (mCRC)., Materials and Methods: A single-site, retrospective review of 57 patients with MSI-H/dMMR mCRC that received ICB was completed. Data collected included patient demographics, ICB information, and antibiotic use. Antibiotic exposure was considered from 90 days prior to ICB through 6 weeks after initiation. Primary endpoint was overall response rate (ORR)., Results: The majority of patients received pembrolizumab (27 [47%]) or nivolumab (17 [30%]) monotherapy as their ICB agent. Of the 57 patients, 19 (33.3%) had antibiotic exposure from 90 days prior to ICB initiation through 6 weeks after initiation with most (13 [68%]) having antibiotic use in the 30 days preceding ICB initiation. Similar ORRs were seen in both groups (P-value > .99). No difference was observed in OS (P-value .29) or PFS (P-value .36) between groups., Conclusion: Our data show no association of lower response rates or survival in those MSI-H/dMMR patients with mCRC who receive antibiotics around the initiation of ICB. This information needs to be confirmed in a larger prospective cohort., (© The Author(s) 2022. Published by Oxford University Press.)

Importance: The potential relationship between obesity and colorectal cancer (CRC) outcome is poorly understood in patients with late-stage disease. Increased body mass index may negate aspirin use for cancer prevention, but its role as a factor on the effectiveness of postdiagnosis aspirin use is unclear., Objective: To evaluate how prediagnosis obesity and postdiagnosis aspirin use may be associated with overall survival in patients with late-stage colorectal cancer., Design, Setting, and Participants: This cross-sectional study used self-reported data from patients with metastatic or treatment-refractory disease who consented to a clinical protocol at MD Anderson Cancer Center, a large US cancer treatment center. Patients were enrolled between 2010 and 2018 and followed up for mortality through July 2020. Analyses were conducted through March 2022., Exposures: Body mass index in the decade prior to initial diagnosis and regular aspirin use at survey completion., Main Outcomes and Measures: Overall survival was measured from stage IV diagnosis until death or last follow-up. Cox proportional hazards models were constructed to estimate associations of prediagnosis obesity and postdiagnosis aspirin use with overall survival., Results: Of 656 patients included in this analysis, 280 (42.7%) were women, 135 (20.6%) were diagnosed with CRC before age 45 years, 414 (63.1%) were diagnosed between ages 45 and 65 years, and 107 (16.3%) were diagnosed at 65 years or older; 105 patients (16.0%) were Black or Hispanic, and 501 (76.4%) were non-Hispanic White. Controlling for age, sex, race, stage at initial diagnosis, and weight change between prediagnosis and survey date, patients with obesity in the decade prior to CRC diagnosis had significantly higher likelihood of death (hazard ratio, 1.45; 95% CI, 1.11-1.91) compared with those with normal prediagnosis body mass index. Furthermore, only patients with normal prediagnosis body mass index experienced significant survival benefit with postdiagnosis aspirin use (hazard ratio, 0.59; 95% CI, 0.39-0.90)., Conclusions and Relevance: In this cross-sectional study, our findings suggest potentially differential tumor development in the long-term physiologic host environment of obesity. Confirmation and further evaluation are needed to determine whether prediagnosis body mass index may be used to estimate the benefit from postdiagnosis aspirin use.

Localized malignant peritoneal mesothelioma is a rare tumor with limited information in the literature. In this study, we present our experience with 18 cases seen in our hospital over a period of 43 years (1978 to 2021). Patients' median age was 55 years (y) (range: 33 to 79 y) and most of them were Caucasians. Patients presented with abdominal pain (11), ascites and right leg swelling (1), abdominal mass (1), and as incidental finding (1). Thirty percent of patients reported asbestos exposure, and all patients with available information had family history of tumors; a third had personal history of tumors. Seventy-seven percent had some form of abdominopelvic surgery and/or inflammatory process. Most cases had microscopic features typically seen in malignant mesothelioma; however, some cases had confounding features such as signet-ring cells, spindle cells, clear cell changes, and adenomatoid tumor-like appearance. BAP-1 by immunohistochemistry was lost in 1/3 cases. Only 1 patient underwent genetic testing and had an MSH2 germline mutation. Homozygous deletion of CDKN2A by FISH was not found in 1 tested case, although next-generation sequencing identified a CDKN2A pathogenic mutation. 16/18 (88%) had surgical treatment, and some also received adjuvant chemotherapy. The mean overall survival (OS) of our patients was 80.4 months (95% confidence interval: 54.3-106.52); the 3-year OS was 79%, while the 5-year OS was 52.6%. Fifty-three percent of patients had recurrences and 20% had tumor progression. Although the limited sample precludes definitive conclusions, small tumor size, low-grade cytology, and low mitotic index appeared to be associated with an indolent behavior., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Identification of circulating tumor DNA (ctDNA) following curative intent therapies is a surrogate for microscopic residual disease for patients with metastatic colorectal cancer (mCRC). Preclinically, in micrometastatic microsatellite stable (MSS) CRC, increased TGF-β signaling results in exclusion of anti-tumor cytotoxic T cells from the tumor microenvironment. Bintrafusp alfa (BA) is a bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor ("TGF-β trap") and anti-PD-L1 antibody., Methods: Patients with liver-limited, MSS mCRC and with detected ctDNA after complete resection of all known tumors and standard-of-care therapy were treated with 1200 mg of BA intravenously every 14 days for six doses. The primary endpoint was ctDNA clearance. Radiographic characteristics at recurrence were compared using independent t-tests to historical data from a similar cohort of patients with liver-limited mCRC who underwent observation., Results: Only 4 of 15 planned patients received BA before the study was stopped early for loss of equipoise. There was no grade ≥3 AE. None of the patients cleared ctDNA. All patients developed radiographic recurrence by the first planned restaging. Although not detectable at prior to treatment, TGFβ3 was found in circulation in all patients at cycle 2 day 1. Compared to a historical cohort, patients administered BA developed more metastases (15 versus 2, p=0.005) and greater tumor volumes (9 cm vs 2 cm, p=0.05)., Conclusions: Treatment with BA in patients with ctDNA-detected, liver-limited mCRC did not clear ctDNA and was associated with large-volume recurrence, highlighting the potential context-specific complexity of dual TGF-β and PD-L1 inhibition.

Background: Monotherapy with immune checkpoint blockade is ineffective for patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC). This study investigates whether the combination of trametinib (T) with durvalumab (D) can alter the immune tumor microenvironment (TME) by successfully priming and activating T-cells., Methods: Open-label, single-center, phase II trial with primary endpoint of immune-related response rate for combination of T+D in refractory MSS mCRC pts (NCT03428126). T is 2 mg/day orally starting 1 week prior to D, which is given 1500 mg intravenously every 4 weeks. Simon 2-stage design used to enroll 29 pts into first stage, requiring a response in two or more pts to proceed to stage 2. Tumor biopsies were collected at baseline (BL) and early on-treatment (OT) at week 4., Results: Twenty nine treated pts include 48% females, median age 48 years (range 28-75), and median prior therapies 2 (range 1-5). No grade (G) 4 or 5 treatment-related adverse events (TRAE). The most common TRAE of any grade was acneiform rash, 17% being G3. One of 29 pts had confirmed partial response (PR) lasting 9.3 months (mo) for an overall response rate of 3.4%. Seven pts had stable disease (SD) and five pts (1 PR, 4 SD) demonstrated decrease in total carcinoembryonic antigen ng/mL (best percentage reduction: 94%, 95%, 42%, 34%, and 22%, respectively). Median progression-free survival was 3.2 mo (range 1.1-9.3 months). Three pts with both liver and lung metastases demonstrated discrepant responses in which clinical benefit was present in the lung metastases but not liver metastases. Comparison of BL and 4-week OT tumor tissue flow cytometry demonstrated no changes in T-cell infiltration but upregulation expression of PD-1 and Tim3 on CD8 T cells. However, expression of PD-1 and Tim3 as single markers and as coexpressed markers was observed to increase OT relative to BL (p=0.03, p=0.06 and p=0.06, respectively)., Conclusions: T+D demonstrated acceptable tolerability in pts with refractory MSS mCRC. The response rate in the first stage of the study did not meet efficacy criteria to proceed to the second stage. Specific site of metastatic disease may impact outcomes in novel immunotherapy combination trials., Trial Registration Number: NCT03428126., Competing Interests: Competing interests: BJ has a consulting or advisory role with Gritstone bio, Incyte, Taiho Oncology and Insmed Oncology. He has received research support from Bristol Myers Squibb, Syntrix and Gateway for Cancer Research. CLH reports speaker’s fees from the Society for Immunotherapy of Cancer, serves as an advisory board member for Briacell and the Mesothelioma Applied Research Foundation, has received personal fees from Nanobiotix and receives funding to the MD Anderson Cancer Center from Iovance, Sanofi, Dragonfly Therapeutics, and BTG outside the submitted work. EV has a consulting or advisory role with Janssen Research and Development and Recursion Pharma. He has received research support from Janssen Research and Development. CE has a consulting or advisory role with Bayer, Boston Scientific, GSK, Halio Dx, J&J, Merck, and Natera. MJO has a consulting or advisory role with Phanes therapeutics, Pfizer, Merck, Glaxosmithkline, 3D Medicine, Nouscom, Gritstone bio, Tempus, Roche. He has received research support from Roche, Merck, BMS and Astrazeneca., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Single-institution studies have shown the oncologic benefit of ablative liver radiotherapy (A-RT) for patients with unresectable intrahepatic cholangiocarcinoma (ICC). However, adoption of A-RT across the United States and its associated outcomes are unknown., Methods: We queried the National Cancer Data Base for nonsurgically managed patients with ICC diagnosed between 2004 and 2018. Patients were labeled A-RT for receipt of biologically effective doses (BED 10 ) ≥ 80.5 Gy and conventional RT (Conv-RT) for lower doses. Associations with A-RT use and overall survival were identified using logistic and Cox regressions, respectively., Results: Of 27,571 patients, the most common treatments were chemotherapy without liver RT (45%), no chemotherapy or liver RT (42%), and liver RT ± chemotherapy (13%). Use of liver RT remained constant over time. Of 1112 patients receiving liver RT with known doses, RT was 73% Conv-RT (median BED 10 , 53 Gy; median, 20 fractions) and 27% A-RT (median BED 10 , 100 Gy; median, 5 fractions). Use of A-RT increased from 5% in 2004 to 48% in 2018 (P trend < .001). With a median follow-up of 52.3 months, median survival estimates for Conv-RT and A-RT were 12.8 and 23.7 months (P < .001), respectively. On multivariable analysis, stage III and IV disease correlated with a higher risk of death, whereas chemotherapy and A-RT correlated with a lower risk., Conclusions: Although A-RT has been increasingly used, use of liver RT as a whole in the United States remained constant despite growing evidence supporting its use, suggesting continued unmet need. A-RT is associated with longer survival versus Conv-RT., Lay Summary: Bile duct cancer is a rare, deadly disease that often presents at advanced stages. Single-institution retrospective studies have demonstrated that use of high-dose radiotherapy may be associated with longer survival, but larger studies have not been conducted. We used a large, national cancer registry of patients diagnosed between 2004 and 2018 to show that liver radiotherapy use remains low in the United States, despite growing evidence that patients who receive it live longer. Furthermore, we showed that patients who received high-dose radiotherapy lived longer than those who received lower doses. Greater awareness of the benefits of liver radiotherapy is needed to improve patient outcomes., (© 2022 American Cancer Society.)

Purpose: VEGF receptor-2 (VEGFR-2)-mediated angiogenesis contributes to pathogenesis of biliary tract cancers (BTC). We investigated ramucirumab, a mAb targeting VEGFR-2 for treatment of advanced, chemorefractory BTC., Patients and Methods: This is a phase II, single-arm trial for advanced, unresectable, pre-treated patients with BTC with ECOG 0/1, adequate liver, renal, and marrow functions. Ramucirumab was administered at 8 mg/kg, 2 weekly with restaging performed 8 weekly. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. Exploratory endpoints included correlation of tumor mutational status with PFS and OS., Results: 61 patients were enrolled: the median age was 58.5 years; 59 with stage IV disease; 62%, intrahepatic cholangiocarcinoma; 22%, gallbladder cancer; and 16%, extrahepatic cholangiocarcinoma. All received prior chemotherapy: 52% had 1 prior, and rest ≥2 prior lines. Median treatment duration was 10.1 weeks (range, 2.1-86). Median PFS was 3.2 months [95% confidence interval (CI), 2.1-4.8]; median OS, 9.5 months (95% CI, 5.8-13.6). One (1.7%) patient achieved partial response; 26 (43.3%), stable disease; and 25 (41.7%), disease progression; DCR, 45%. Median 6-month PFS and OS rates were 32% (95% CI, 0.22-0.46) and 58% (95% CI, 0.47-0.72). The majority of toxicities were grade 1 or 2; grade 3 proteinuria (1, 2%), hypertension (13, 22%), and pulmonary embolism (1, 2%), and grade 4 gastrointestinal bleeding (1, 2%) occurred., Conclusions: Ramucirumab was well tolerated and resulted in PFS similar to that achieved with other chemotherapy regimens used historically for chemorefractory BTC., (©2022 American Association for Cancer Research.)

Background: Cancer of unknown primary (CUP) is an aggressive rare malignancy with limited treatment options. Data regarding clinical activity of immune checkpoint inhibitors in CUP is lacking. Therefore, we evaluated the efficacy of pembrolizumab, a programmed cell death-1 inhibitor, in patients with CUP., Methods: The study was designed as a phase 2 basket trial for independent rare tumor cohorts including CUP. Adult patients with CUP who had progressed on previous systemic therapy, performance status 0/1 and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST V.1.1) were eligible. Patients received pembrolizumab (200 mg) intravenously every 21 days. Twenty-nine patients were enrolled and treated between August 2016 and June 2020. The primary endpoint was non-progression rate (NPR) at 27 weeks (NPR-27) per immune-related RECIST. Key prespecified secondary endpoints were confirmed objective response rate (ORR), safety, duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Pretreatment biopsies were examined for biomarkers of response (programmed cell death ligand-1 (PD-L1) expression and tumor infiltrating lymphocytes (TILs))., Results: Among 25 (of 29 enrolled) eligible and evaluable patients, 14 (56%) had poorly differentiated carcinoma. Patients received a median of two lines of therapy prior to enrollment. Median follow-up was 27.3 months. NPR-27 was observed in seven patients (28.0% (95% CI: 12.1 to 49.4)). ORR was 20.0% (95% CI: 6.8 to 40.7) with five patients achieving immune-related partial response with median DoR of 14.7 months (95% CI: 9.8 to 19.6). Median PFS and OS were 4.1 (95% CI: 3.1 to 5.1) and 11.3 (95% CI: 5.5 to 17.1) months, respectively. Treatment-related adverse events of any and grade ≥3 were seen in 19 (76%) and 4 (16%) patients, respectively. One (4%) patient had grade 3 immune-related acute kidney injury requiring treatment discontinuation. Neither PD-L1 nor TILs were associated with NPR-27. Both positive PD-L1 staining (44.4% vs 6.3%; p=0.040) and intense TIL infiltration (44.4% vs 6.3%; p=0.040) were associated with response., Conclusion: Pembrolizumab showed encouraging efficacy in patients with CUP with acceptable safety profile., Trial Registration Number: NCT02721732., Competing Interests: Competing interests: KPR reports research support from Bayer, AstraZeneca, and Daiichi outside the submitted work; SAP-P reports research support from AbbVie, ABM Therapeutics, Acepodia, Alkermes, Aminex Therapeutics, Amphivena Therapeutics, BioMarin Pharmaceutical, Boehringer Ingelheim, Bristol Myers Squibb, Cerulean Pharma, Chugai Pharmaceutical Co., Curis, Daiichi Sankyo, Eli Lilly, ENB Therapeutics, Five Prime Therapeutics, Gene Quantum, Genmab A/S, GlaxoSmithKline, Helix BioPharma Corp., Incyte Corp., Jacobio Pharmaceuticals Co., Medimmune, LLC., Medivation, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals, Pieris Pharmaceuticals, Pfizer; Principia Biopharma, Puma Biotechnology, Rapt Therapeutics, Seattle Genetics, Silverback Therapeutics, Taiho Oncology, Tesaro, TransThera Bio, NCI/NIH, P30CA016672 – Core Grant (CCSG Shared Resources) outside the submitted work; DSH reports research support from AbbVie, Adaptimmune, Adlai Nortye, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daichi-Sankyo, Eisai, Eli Lilly, EMD Sereno, Erasca, Fate Therapeutics, Genentech, Genmab, GlaxoSmithKline, Ignyta, Infinity, Kite, Kyowa, LOXO, Merck, MedImmune, Millenium, Mirati, miRNA, Molecular TeMpLaTeS, Mologen, NaVier, nci-cep, Novartis, Numab, Pfizer, Seattle Genetics, Takeda, Turning Point, Vernstam, VM Oncology, and other support from Adaptimmune, Amgen, AstraZeneca, Bayer, Genentech, GlaxoSmithKline, Infinity, Numab, Pfizer, Seattle Genetics, Alpha Insights, Acuta, Axiom, Baxter, Boxer Capital, COG, Ecor1, GLG, Group H, Guidepoint, HCW Precision, Janssen, Merrimack, Medscape, Prime Oncology, STCube, Tavistock, Trieza Therapeutics, Molecular Match, Oncoresponse, Presagia, AACR, ASCO, Celgene, Eli Lilly, SITC, and Phillips, outside of the submitted work; MO reports research support from Merck Sharp & Dohme Corp, AbbVie, Agilvax, Takeda Pharmaceuticals (Japan), Acrotech Biopharma, Janssen Research & Development LLC, Pfizer outside the submitted work; FM-B reports research support from Aileron Therapeutics, AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences, Curis, CytomX Therapeutics, Daiichi Sankyo Co., Debiopharm International, eFFECTOR Therapeutics, Genentech, Guardant Health, Klus Pharma, Millennium Pharmaceuticals, Novartis, Puma Biotechnology, Taiho Pharmaceutical Co.; consulting fees from Aduro BioTech, Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche, Genentech, IBM Watson, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer, Samsung Bioepis, Seattle Genetics, Tyra Biosciences, Xencor, Zymeworks; has served on advisory committees for Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology, Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis; receives honoraria from Chugai Biopharmaceuticals, Mayo Clinic, Rutgers Cancer Institute of New Jersey; and support for travel and accommodation from Beth Israel Deaconess Medical Center outside the submitted work; AN reports research support from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor/Millendo, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera BioSciences, TopAlliance BioSciences, Eli Lilly, Kymab, PsiOxus, Arcus Biosciences, NeoImmuneTech, ImmuneOncia, and Surface Oncology, non-financial support for travel and accommodation from ARMO BioSciences, has served as an advisory board member for Novartis, CytomX Therapeutics, Genome and Company, STCube Pharmaceuticals, OncoSec KEYNOTE-695, and Kymab, reports research funding for his spouse from Immune Deficiency Foundation, Jeffery Modell Foundation and chao physician-scientist, and Baxalta, and his spouse has served as an advisory board member for Takeda, CSL, Behring, Horizon, and Pharming outside the submitted work. BSt, DDK, DJ, DOCO, AA, AFW, BSm, RWH, GRV declare no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: BRAF V600E mutations occur in fewer than 10% of all patients with metastatic colorectal cancer (CRC) and arise from sessile serrated adenomas. Despite efficacy with targeted therapies against MAPK signaling and with immunotherapies in this population, survival outcomes for patients with BRAF V600E mutated metastatic CRC in general are poor. Characteristics distinguishing patients with BRAF V600E mutated metastatic CRC with favorable versus unfavorable outcomes have not been well annotated., Methods: Records of 187 patients with BRAF V600E mutated metastatic CRC evaluated at MD Anderson Cancer Center between 2005-2020 were reviewed. Patients with the shortest and longest metastatic survival (N=25 for each group) were compared. Associations between prognostic group and clinical/pathologic features were measured by odds ratio and for median survival by log-rank testing., Results: Median metastatic survival differed between the 2 BRAF V600E mutated metastatic CRC populations (8.6 vs. 83.9 months, hazard ratio 32; P<0.0001). Patients with poor survival more commonly had hepatic involvement [75% vs. 28%, odds ratio (OR) 8.1, 95% confidence interval (CI): 2.3-29; P=0.001]. Patients with favorable survival were more likely to develop metachronous metastases (52% vs. 16%, OR 5.7, 95% CI: 1.5-21; P=0.01) and undergo definitive locoregional therapy to metastatic disease (40% vs. 0%, OR 34.5, 95% CI: 1.9-630; P=0.01). Microsatellite instability (36% vs. 4%, OR 19.8, 95% CI: 2.2-180; P=0.008) and prior tobacco exposure (44% vs. 16%, OR 4.1, 95% CI: 1.1-15.6, P=0.04) were associated with a favorable prognosis. Durable responses to MAPK-targeted therapies and immunotherapy were noted in the favorable group., Conclusions: A small fraction of patients with BRAF V600E mutated metastatic CRC can achieve excellent long-term survival which belies conventional context and is driven by either surgical metastectomy or by systemic treatment options. While poor overall prognosis remains the recognized outcome for most patients with BRAF V600E mutated metastatic CRC, it is possible that few may achieve exceptionally favorable survival., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-21-471/coif). The authors have no conflicts of interest to declare., (2022 Journal of Gastrointestinal Oncology. All rights reserved.)

Background: Hepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma., Methods: In this single-centre, randomised, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma were randomly assigned (1:1) to receive 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery at 6 weeks) followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for 2 years, or 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery) plus one dose of 1 mg/kg of ipilimumab intravenously concurrently with the first preoperative dose of nivolumab, followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for up to 2 years plus 1 mg/kg of ipilimumab intravenously every 6 weeks for up to four cycles. Patients were randomly assigned to the treatment groups by use of block randomisation with a random block size. The primary endpoint was the safety and tolerability of nivolumab with or without ipilimumab. Secondary endpoints were the proportion of patients with an overall response, time to progression, and progression-free survival. This trial is registered with ClinicalTrials.gov (NCT03222076) and is completed., Findings: Between Oct 30, 2017, and Dec 3, 2019, 30 patients were enrolled and 27 were randomly assigned: 13 to nivolumab and 14 to nivolumab plus ipilimumab. Grade 3-4 adverse events were higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumab alone (three [23%] of 13). The most common treatment-related adverse events of any grade were increased alanine aminotransferase (three [23%] of 13 patients on nivolumab vs seven [50%] of 14 patients on nivolumab plus ipilimumab) and increased aspartate aminotransferase (three [23%] vs seven [50%]). No patients in either group had their surgery delayed due to grade 3 or worse adverse events. Seven of 27 patients had surgical cancellations, but none was due to treatment-related adverse events. Estimated median progression-free survival was 9·4 months (95% CI 1·47-not estimable [NE]) with nivolumab and 19·53 months (2·33-NE) with nivolumab plus ipilimumab (hazard ratio [HR] 0·99, 95% CI 0·31-2·54); median time to progression was 9·4 months (95% CI 1·47-NE) in the nivolumab group and 19·53 months (2·33-NE) in the nivolumab plus ipilimumab group (HR 0·89, 95% CI 0·31-2·54). In an exploratory analysis, three (23%) of 13 patients had an overall response with nivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) of nine patients had a major pathological response (ie, ≥70% necrosis in the resected tumour area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumab plus ipilimumab., Interpretation: Perioperative nivolumab alone and nivolumab plus ipilimumab appears to be safe and feasible in patients with resectable hepatocellular carcinoma. Our findings support further studies of immunotherapy in the perioperative setting in hepatocellular carcinoma., Funding: Bristol Myers Squibb and the US National Institutes of Health., Competing Interests: Declaration of interests AOK reports consulting, advisory roles or stock ownership, or both, for Gilead Sciences, Bayer Health, Bristol-Myers Squibb, Exelixis, and Merck; reports research funding to the MD Anderson Cancer Center from Adaptimmune, Bayer/Onyx, Bristol Myers Squibb, Genentech, Hengrui Pharmaceutical, Hengrui Pharmaceutical, and Merck; honoraria from Bayer Health, Bristol Myers Squibb, Exelixis, and Merck; and other expenses from Bayer/Onyx, Bristol Myers Squibb, Exelixis, and Merck. EH reports research funding to the MD Anderson Cancer Center from Conquer Cancer Foundation, Kidney Cancer Association, and International Kidney Cancer Coalation. KPSR reports research funding to the MD Anderson Cancer Center from Bayer, Daiichi, AstraZeneca, Genentech, Guardant, and Merck; and consulting fees from Bayer, Daiichi, AstraZeneca; and honoraria from Bayer, and Daiichi. RS reports consulting fees from Boehringer Ingelheim. CWDT reports consulting fees donated to the MD Anderson Cancer Center from PanTher Therapeutics. RAW reports royalties or licenses from McGraw Hill for the MD Anderson Manual of Medical Oncology, 3rd edition; and travel support from Modern Medicine Emirates Oncology Society. JCY reports consulting fees from Hutchinson Medi Pharma, Ipsen Biopharmaceuticals, Amgen, Chiasma Pharma, Crinetics Pharmaceuticals, Advanced Accelerator Applications International, and Novartis Pharmaceuticals; and leadership roles at the North American Neuroendocrine Tumor Society. PS reports consulting fees from Achelois, Adaptive Biotechnologies, Affini-T, Apricity, BioAtla, BioNTech, Candel Therapeutics, Catalio, Codiak, Constellation, Dragonfly, Earli, Enable Medicine, Glympse, Hummingbird, ImaginAb, Infinity Pharma, Jounce, JSL Health, Lava Therapeutics, Lytix, Marker, Oncolytics, PBM Capital, Phenomic AI, Polaris Pharma, Sporos, Time Bioventures, Trained Therapeutix, Two Bear Capital, and Venn Biosciences; and ownership of stocks for Achelois, Adaptive Biotechnologies, Affini-T, Apricity, BioAtla, BioNTech, Candel Therapeutics, Catalio, Codiak, Constellation, Dragonfly, Earli, Enable Medicine, Glympse, Hummingbird, ImaginAb, Infinity Pharma, Jounce, JSL Health, Lava Therapeutics, Lytix, Marker, Oncolytics, PBM Capital, Phenomic AI, Polaris Pharma, Sporos, Time Bioventures, Trained Therapeutix, Two Bear Capital, and Venn Biosciences. JPA reports consulting fees from Achelois, Adaptive Biotechnologies, Apricity, BioAtla, BioNTech, Candel Therapeutics, Codiak, Dragonfly, Earli, Enable Medicine, Hummingbird, ImaginAb, Jounce, Lava Therapeutics, Lytix, Marker, PBM Capital, Phenomic AI, Polaris Pharma, Time Bioventures, Trained Therapeutix, Two Bear Capital, and Venn Biosciences; ownership of stocks for Achelois, Adaptive Biotechnologies, Apricity, BioAtla, BioNTech, Candel Therapeutics, Codiak, Dragonfly, Earli, Enable Medicine, Hummingbird, ImaginAb, Jounce, Lava Therapeutics, Lytix, Marker, PBM Capital, Phenomic AI, Polaris Pharma, Time Bioventures, Trained Therapeutix, Two Bear Capital, and Venn Biosciences. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: There has been an increase in the incidence of rectal cancer diagnosed in young adults (age < 50 years). We evaluated outcomes among young adults treated with pre-operative long course chemoradiation (CRT) and total mesorectal excision (TME)., Methods: The medical records of 219 patients, age 18-49, with non-metastatic, cT3-4, or cN1-2 rectal adenocarcinoma treated from 2000 to 2017 were reviewed for demographic and treatment characteristics, as well as pathologic and oncologic outcomes. The Kaplan-Meier test, log-rank test, and Cox regression analysis were used to evaluate survival outcomes., Results: The median age at diagnosis was 44 years. CRT followed by TME and post-operative chemotherapy was the most frequent treatment sequence (n = 196), with FOLFOX (n = 115) as the predominant adjuvant chemotherapy. There was no difference in sex, stage, MSS/pMMR, or pCR by age (< 45 years [n = 111] vs. ≥ 45 years [n = 108]). The 5-year rates of DFS were 77.2% for all patients, 69.8% for age < 45 years and 84.7% for age ≥ 45 years (P = .01). The 5-year rates of OS were 89.6% for all patients, 85.1% for patients with age < 45 years and 94.3% for patients with age ≥ 45 years (P = .03). Age ≥ 45 years was associated with a lower risk of disease recurrence or death on multivariable Cox regression analysis (HR = 0.55, 95% CI 0.31-0.97, P = .04)., Conclusion: Among young adults, patients with age < 45 years had lower rates of DFS and OS, compared to those with age ≥ 45 years. These outcomes could serve as a benchmark by which to evaluate newer treatment approaches., (Copyright © 2021. Published by Elsevier Inc.)

Only a few cases of malignant peritoneal mesothelioma (MPeM) associated with endometriosis have been published; with chronic inflammation of the peritoneum associated with the latter being postulated as an inducing factor in the pathogenesis of this tumor. We assessed the clinicopathologic characteristics of MPeM associated with endometriosis to determine if there were other factors besides inflammation that may contribute to the pathogenesis in this patient population. Fifteen MPeM associated with endometriosis were retrieved from our files. Most presented with abdominal/pelvic pain, mass or distention; median age was 45 yr. Only 16% of patients had a history of asbestos exposure. In contrast, a third of the patients had a personal history of other neoplasms, and >80% had a family history of malignancies. Although most tumors had gross and microscopic features typical of MPeM, some had confounding features including "adhesion-like" appearance or gelatinous cysts/nodules, and signet ring cells. Tumors were epithelioid (9) and biphasic (6). MPeM was misdiagnosed as Müllerian carcinoma in 40% of cases. All patients (n=15) had cytoreductive surgery in addition to other therapies. Only 2/12 patients died of disease (17%). The 3- and 5-yr overall survival was 90%. MPeM associated with endometriosis tends to occur in patients with personal/familial history of malignancies, which may be a predisposing factor. In light of this finding, the role of endometriosis in the pathogenesis of MPeM is likely less relevant. The favorable outcome seen in these patients may be related to germline mutations or the hormonal milieu and needs further investigation., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 by the International Society of Gynecological Pathologists.)

We have previously shown that ablative radiotherapy (A-RT) with a biologically effective dose (BED 10 ) ≥ 80.5 Gy for patients with unresectable intrahepatic cholangiocarcinoma (ICC) is associated with longer survival. Despite recent large-scale sequencing efforts in ICC, outcomes following RT based on genetic alterations have not been described. We reviewed records of 156 consecutive patients treated with A-RT for unresectable ICC from 2008 to 2020. For 114 patients (73%), next-generation sequencing provided molecular profiles. The overall survival (OS), local control (LC), and distant metastasis-free survival (DMFS) were estimated using the Kaplan-Meier method. Univariate and multivariable Cox analyses were used to determine the associations with the outcomes. The median tumor size was 7.3 (range: 2.2-18.2) cm. The portal vein thrombus (PVT) was present in 10%. The RT median BED 10 was 98 Gy (range: 81-144 Gy). The median (95% confidence interval) follow-up was 58 (42-104) months from diagnosis and 39 (33-74) months from RT. The median OS was 32 (29-35) months after diagnosis and 20 (16-24) months after RT. The one-year OS, LC, and intrahepatic DMFS were 73% (65-80%), 81% (73-87%), and 34% (26-42%). The most common mutations were in IDH1 (25%), TP53 (22%), ARID1A (19%), and FGFR2 (13%). Upon multivariable analysis, the factors associated with death included worse performance status, larger tumor, metastatic disease, higher CA 19-9, PVT, satellitosis, and IDH1 and PIK3CA mutations. TP53 mutation was associated with local failure. Further investigation into the prognostic value of individual mutations and combinations thereof is warranted.

Malignant peritoneal mesothelioma (MPeM) is a rare but aggressive malignancy with limited treatment options. VEGF inhibition enhances efficacy of immune-checkpoint inhibitors by reworking the immunosuppressive tumor milieu. Efficacy and safety of combined PD-L1 (atezolizumab) and VEGF (bevacizumab) blockade (AtezoBev) was assessed in 20 patients with advanced and unresectable MPeM with progression or intolerance to prior platinum-pemetrexed chemotherapy. The primary endpoint of confirmed objective response rate per RECISTv1.1 by independent radiology review was 40% [8/20; 95% confidence interval (CI), 19.1-64.0] with median response duration of 12.8 months. Six (75%) responses lasted for >10 months. Progression-free and overall survival at one year were 61% (95% CI, 35-80) and 85% (95% CI, 60-95), respectively. Responses occurred notwithstanding low tumor mutation burden and PD-L1 expression status. Baseline epithelial-mesenchymal transition gene expression correlated with therapeutic resistance/response ( r = 0.80; P = 0.0010). AtezoBev showed promising and durable efficacy in patients with advanced MPeM with an acceptable safety profile, and these results address a grave unmet need for this orphan disease. SIGNIFICANCE: Efficacy of atezolizumab and bevacizumab vis-à-vis response rates and survival in advanced peritoneal mesothelioma previously treated with chemotherapy surpassed outcomes expected with conventional therapies. Biomarker analyses uncovered epithelial-mesenchymal transition phenotype as an important resistance mechanism and showcase the value and feasibility of performing translationally driven clinical trials in rare tumors. See related commentary by Aldea et al., p. 2674 . This article is highlighted in the In This Issue feature, p. 2659 ., (©2021 The Authors; Published by the American Association for Cancer Research.)

Background: Objective responses to first-line systemic chemotherapy in metastatic pancreatic cancer patients are seen in less than one third of cases. Unfortunately, a significant amount will have disease progression (PD) on their first restaging imaging. With patients' short life expectancy, it is crucial for clinicians to be prudent when deciding whom and when to treat. Our study aimed to evaluate outcomes of patients that progressed on their first restaging imaging on 1 st line therapy., Methods: We retrospectively analyzed patients diagnosed between 2010-2017 whose first restaging imaging demonstrated PD. The primary outcome was overall survival (OS) from metastatic diagnosis date to death. Patients who were lost to follow-up were excluded., Results: Out of 262 total patients reviewed, 98 patients (37%) were included. Sixty-five (66%) received 2 nd line therapy, and 33 (34%) did not. Reasons patients did not pursue 2 nd line therapy were performance status (PS) decline, organ dysfunction, or patient choice for alternative therapy. Median ages for patients who did and did not receive 2 nd line therapy were 61 and 67, respectively (P<0.001). More patients had a poor PS at the time of initial diagnosis in the non-2 nd line therapy group (7.5% vs. 31.0%, P=0.021). Median OS for those receiving 2 nd line therapy was 9 months (95% CI: 7-11 months) compared to 4 months (95% CI: 3-5 months) for those not receiving 2nd-line therapy (P<0.001)., Conclusions: Although likely biased due to better performance status and younger age, our patients who progressed rapidly on 1 st line therapy showed an OS benefit if they received 2 nd line therapy. These results suggest that patients maintaining a good PS after immediate progression on 1 st line therapy should be offered 2 nd line therapy., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jgo-20-569). MMJ currently serves as unpaid editorial board member of the Journal of Gastrointestinal Oncology from Jan 2021–Dec 2022. The other authors have no conflicts of interest to declare., (2021 Journal of Gastrointestinal Oncology. All rights reserved.)