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Primary tumor location is considered a predictor of overall survival (OS) in RAS wild-type (WT) metastatic colorectal cancer (mCRC) treated with bevacizumab (BEV) or an anti-epidermal growth factor antibody (cetuximab or panitumumab [CET/PAN]) as first-line molecularly targeted therapy. BEV is recommended for right-sided mCRC and CET/PAN for left-sided mCRC based on post-hoc analyses of clinical trial data, but real-world evidence is lacking.We retrospectively collected data of patients who started BEV or CET/PAN plus 5-fluorouracil-based doublet chemotherapy between January 2013 and December 2016 as first-line treatment for RAS WT mCRC at any of 24 Japanese institutions. OS was compared between the BEV and CET/PAN groups according to primary tumor location by Cox multivariate regression analysis in the full cohort and in a propensity score-matched cohort.In total, 935 patients were enrolled. Median OS was 24.6 months with BEV and 20.9 months with CET/PAN in right-sided mCRC (n = 213; adjusted hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.50-1.06) and 35.7 months and 30.0 months, respectively, in left-sided mCRC (n = 722; adjusted HR 0.92, 95% CI 0.74-1.13). In the propensity score-matched cohort, OS was significantly better in the BEV group than in the CET/PAN group in right-sided mCRC (HR 0.52, 95% CI 0.28-0.96) but was not significantly different in left-sided mCRC (HR 0.78, 95% CI 0.53-1.07).Real-world data showed that OS was better with BEV than with CET/PAN in right-sided mCRC. However, there was no significant difference in OS in left-sided mCRC.

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

Patients' characteristics of JACCRO CC-05/06 and 05/06AR trials

Molecular differences in tumor locations may contribute to the sidedness-specific response to cetuximab in metastatic colorectal cancer (mCRC). We investigated genes associated with the response to cetuximab treatment depending on tumor sidedness. Our study included 77 patients with mCRC (13/63, right/left) with KRAS exon 2 wild-type tumors from phase II trials of first-line therapy with cetuximab. Expression levels of 2,551 genes were measured in tissue samples by HTG EdgeSeq Oncology Biomarker Panel. Univariate Cox regression analysis using log2 values of counts per million (CPM) was conducted in each sidedness to assess associations with clinical outcomes, and to define the optimal cut-off point for clinically significant genes. In addition, a gene set enrichment analysis (GSEA) was performed to identify significant gene pathways in each sidedness. Sixty-nine patients were assessable for gene expression data. Overexpression of BECN1 [log2(CPM) ≥ 6.8] was associated with favorable survival, regardless of tumor sidedness. High expression of NOTCH1 [log2(CPM) ≥ 7.5] predicted significantly longer progression-free survival (PFS; median 14.7 vs. 11.1 months, HR 0.43, P = 0.01) and overall survival (OS; median 42.8 vs. 26.5 months, HR 0.35, P = 0.01) in left side but not in right side. The GSEA showed that regulation of DNA replication gene set correlated with favorable survival in the left, whereas the subcellular component and leukocyte migration gene sets were associated with good survival in the right. In conclusion, genes contributing to the efficacy of cetuximab treatment may differ according to the sidedness in mCRC. NOTCH1 may potentially discriminate favorable responders to cetuximab in patients with left-sided tumors.

Consort flow diagram of the study

Supplementary figureS1 - Representative cases of pancreatic NEN-G3

Supplementary Table S1. Breakdown of chemotherapy response regimens for PanNEN-G3 (55 cases)

Purpose: Patients with pancreatic neuroendocrine neoplasm grade-3 (PanNEN-G3) show variable responses to platinum-based chemotherapy. Recent studies indicated that PanNEN-G3 includes well-differentiated neuroendocrine tumor with G3 (NET-G3). Here, we examined the clinicopathologic and molecular features of PanNEN-G3 and assessed the responsiveness to chemotherapy and survival.Experimental Design: A total of 100 patients with PanNEN-G3 were collected from 31 institutions, and after central review characteristics of each histologic subtype [NET-G3 vs. pancreatic neuroendocrine carcinoma (NEC-G3)] were analyzed, including clinical, radiological, and molecular features. Factors that correlate with response to chemotherapy and survival were assessed.Results: Seventy patients analyzed included 21 NETs-G3 (30%) and 49 NECs-G3 (70%). NET-G3 showed lower Ki67-labeling index (LI; median 28.5%), no abnormal Rb expression (0%), and no mutated KRAS (0%), whereas NEC-G3 showed higher Ki67-LI (median 80.0%), Rb loss (54.5%), and KRAS mutations (48.7%). Chemotherapy response rate (RR), platinum-based chemotherapy RR, and prognosis differed significantly between NET-G3 and NEC-G3. Chemotherapeutic outcomes were worse in NET-G3 (P < 0.001). When we stratified PanNEN-G3 with Rb and KRAS, PanNENs-G3 with Rb loss and those with mutated KRAS showed significantly higher RRs to platinum-based chemotherapy than those without (Rb loss, 80% vs. normal Rb, 24%, P = 0.006; mutated KRAS, 77% versus wild type, 23%, P = 0.023). Rb was a predictive marker of response to platinum-based chemotherapy even in NEC-G3 (P = 0.035).Conclusions: NET-G3 and NEC-G3 showed distinct clinicopathologic characteristics. Notably, NET-G3 does not respond to platinum-based chemotherapy. Rb and KRAS are promising predictors of response to platinum-based chemotherapy for PanNEN-G3, and Rb for NEC-G3. Clin Cancer Res; 23(16); 4625–32. ©2017 AACR.

Supplementary Figure Legend

PURPOSE Genomic profiling programs have been implemented to apply next-generation sequencing (NGS) for facilitating trial enrollment. SCRUM-Japan GI-SCREEN is a large-scale genomic profiling program in advanced gastrointestinal cancers using a validated genomic assay with the goal of facilitating enrollment in targeted clinical trials, generating real-world data, and performing clinicogenomic analysis for biomarker discovery. PATIENTS AND METHODS Genotyping of tumor tissue samples from 5,743 patients with advanced gastrointestinal cancers enrolled in GI-SCREEN was centrally performed with NGS. Patients were enrolled in matched trials of targeted agents affiliated with GI-SCREEN on the basis of genotyping results. RESULTS A total of 11 gastrointestinal cancers were included, with colorectal cancer being the most common. The median age ranged from 59 to 70.5 years across cancer types. Patients enrolled after initiation of first-line treatment had significantly longer overall survival (OS) than that before treatment initiation with a median survival time difference of 8.9 months and a hazard ratio (HR) ranging from 0.25 to 0.73 across cancer types, demonstrating an immortal time bias. One hundred and forty-nine patients received matched therapies in clinical trials on the basis of their identified alterations. Among patients with colorectal cancer harboring actionable alterations, the median OS was significantly longer in patients who received matched therapies in trials than in those who did not (HR, 0.52; 95% CI, 0.26 to 1.01; P = .049). Cancer-specific pathway alterations were significantly associated with shorter survival and related to primary resistance to matched trial therapies. CONCLUSION Our genomic profiling program led to patient enrollment in targeted clinical trials and improved survival of patients with colorectal cancer who received matched therapies in clinical trials. To avoid immortal time bias, precautions are needed when using data from patients who have undergone NGS testing after initiation of the evaluated treatment line.

The usefulness of angiogenesis inhibitors as second-line treatment after the progression of anti-epidermal growth factor receptor antibody drug-containing regimens for RAS wild-type metastatic colorectal cancer (mCRC) has not been fully investigated. Therefore, we conducted a phase II study to verify the efficacy and safety of the combination of S-1 and irinotecan plus bevacizumab (SIRB regimen) as second-line treatment for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC.Patients with mCRC who had previously received oxaliplatin and cetuximab-containing regimen were eligible for this study. Patients were infused with bevacizumab 7.5 mg/kg and irinotecan 150 mg/mIn total, 17 patients were enrolled in this study. The 6-month PFS rate was 64.7% [95% confidence interval (CI)=41.99-87.43], median PFS was 10.1 months (95%CI=4.11-17.28), and median overall survival was 21.8 months (95%CI=9.79-37.91). The response rate was 23.5% (95%CI=6.81-49.90%). Grade ≥3 adverse events were observed in 10% of patients, and included leukopenia [3 (17.6%)], neutropenia [5 (29.4%)], anorexia [2 (11.8%)], diarrhea [2 (11.8%)], and hypertension [3 (17.6%)]. No treatment-related deaths or febrile neutropenia were observed.The SIRB regimen might be a promising second-line treatment option for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC in terms of efficacy and safety.

Objective Many clinical trials for older patients with metastatic colorectal cancer have been conducted, and fluoropyrimidine and bevacizumab are standard treatments. However, the relationship between age and the efficacy and safety of this treatment is unclear in older metastatic colorectal cancer patients. Methods Individual data from two phase II studies on older (≥75 years), non-frail patients with metastatic colorectal cancer treated with uracil-tegafur/leucovorin or S-1 combined with bevacizumab were collected. Patient characteristics were evaluated with multiple regression analyses for survival outcomes, using the Cox proportional hazard model and linear regression analyses for the worst grade of adverse events. Results We enrolled 102 patients with a median age of 80 years (range, 75–88 years). Of the 70 patients who died, seven (10%) died of causes unrelated to disease or treatment. The study treatment was discontinued due to adverse events in 19 patients (18.6%), with 63% aged ≥85 years. The adverse event that most commonly resulted in treatment discontinuation was grade 2 fatigue (21%). Chronological age was not associated with progression-free survival (Hazard ratio, 1.03; P = 0.40) or overall survival (Hazard ratio, 1.02; P = 0.65). Age was weakly associated with non-hematologic adverse events (regression coefficient [R], 0.27; P = 0.007), especially fatigue (R, 0.23; P = 0.02) and nausea (R, 0.19; P = 0.06), but not with hematologic (R, 0.05; P = 0.43) or bevacizumab-related (R, −0.06; P = 0.56) adverse events. Conclusions The efficacy of fluoropyrimidine plus bevacizumab was age-independent in patients with metastatic colorectal cancer aged ≥75 years, and attention should be paid to non-hematologic adverse events as age increases.

Indications of preoperative treatment for resectable (R-) or borderline resectable (BR-) pancreatic ductal adenocarcinoma (PDAC) are unclear, and the protocol remains to be standardized.Included 65 patients with R- and BR-PDAC with venous involvement (V-) received neoadjuvant chemoradiotherapy with S-1 and 50 Gy of radiation as the 5-week regimen. The outcomes of this group were compared with those of 52 patients who underwent S-1 and 30 Gy of radiation as the 2-week regimen, previously collected as our prospective phase II study.Compared with the 2-week regimen, there were no significant differences in the rate of protocol completion, adverse events, mortality and morbidity, or R0 resection in the 5-week regimen. In subgroup analyses of R-PDAC, there were no significant differences in overall survival and recurrence-free survival between the groups. In contrast, the 5-week regimen had significantly better overall survival and recurrence-free survival than the 2-week regimen for BRV-PDAC. Similar results were observed after propensity score matching analysis.The 5-week regimen of neoadjuvant chemoradiotherapy has good clinical efficacy and safety for R- and BRV-PDAC. The 5-week regimen could achieve better outcomes than the 2-week regimen for BRV-PDAC. In contrast, both regimens achieved similar outcomes for R-PDAC.

The number of patients who survive for a long time after cancer diagnosis is rapidly increasing; however, such patients experience major problems such as returning to work and changes in their income. This study aimed to determine the extent of income changes of cancer patients during the first year after cancer diagnosis and identify the influencing factors. From November 2019 through January 2020, we conducted a multicenter, self-administered anonymous survey of cancer patients in Kagawa Prefecture, Japan. The number of questionnaires collected was 483 (recovery rate 60.4%), and the number of participants who met the inclusion criteria was 72. Mean year-on-year income level one year since cancer diagnosis was 66% (SD: 32%; median: 70%). Cancer stage (p = 0.016), employment status at diagnosis (p = 0.006), and continued employment at the same workplace (p = 0.001) were associated with income change. Findings from this study showed that cancer patients lost one-thirds of their income one year after their diagnosis. It was related to the stage of their illness, employment status, and continued employment at their workplace just before the diagnosis. Employers should provide cancer patients with the support they need to keep them employed.

Regorafenib and trifluridine/tipiracil are standard third-line chemotherapies for colorectal cancer patients, but their efficacy is limited. Anti-epidermal growth factor receptor antibody rechallenge has been reported to be promising for patients who have obtained clinical benefit from first-line cetuximab-based chemotherapy. Moreover, panitumumab showed non-inferior efficacy to cetuximab. This study assessed the efficacy and safety of third-line panitumumab rechallenge in patients with metastatic KRAS exon 2 wild-type metastatic colorectal cancer who obtained clinical benefit from first-line panitumumab-based chemotherapy. This was a prospective, multicenter, phase II trial conducted from October 2013 to August 2017. Major eligibility criteria included KRAS exon 2 wild-type and achievement of complete response, partial response, or continued stable disease for at least 6 months in first-line panitumumab-based therapy. Irinotecan plus panitumumab treatment was continued until disease progression or unacceptable toxicity was observed. The primary endpoint was the 3-month progression-free survival (PFS) rate. Twenty-five patients were enrolled in this study. Their median age was 66.5 years, and the 3-month PFS rate was 50.0% (95% confidence interval 30.0–70.0). The median PFS and overall survival were 3.1 months and 8.9 months, respectively. The response rate and disease control rate were 8.3% and 50.0%, respectively. Common grade 3/4 adverse events were acneiform rash (17%), hypomagnesemia (13%), and dry skin (13%). No treatment-related deaths occurred. Irinotecan plus panitumumab rechallenge is a promising third-line treatment regimen in patients with metastatic wild-type KRAS colorectal cancer. UMIN000015916.

An infusion-related reaction (IRR) is a well-known adverse event related to monoclonal antibodies, and antihistamine premedication is recommended to prevent IRRs. Ramucirumab plus FOLFIRI therapy is the standard second-line treatment for metastatic colorectal cancer (CRC). Ramucirumab is a fully human antibody, suggesting that the incidence of IRRs is lower, however, the current recommendation for the proper use of ramucirumab is antihistamine premedication, but the incidence and severity of ramucirumab-induced IRR without antihistamine premedication have not been elucidated. A retrospective study to evaluate the incidence of ramucirumab-induced IRRs in unresectable CRC patients treated by ramucirumab plus FOLFIRI therapy. If the incidence of IRR without antihistamine premedication was not higher than that of cetuximab in a previous report (5.7%), planning a prospective study was considered. A total of 147 patients with unresectable CRC who had been treated by ramucirumab plus FOLFIRI therapy were identified. Of them, 106 (72%) patients received intravenous antihistamine premedication. An IRR occurred in 2 patients (1.4%), 1 grade 2 and 1 grade 3. They received antihistamine and steroid premedication. On the other hand, IRRs were not observed in 41 patients without antihistamine premedication, and the incidence of IRRs was significantly lower compared with the previous report of cetuximab (p

Purpose: FGFR2 amplification is associated with poor prognosis in advanced gastric cancer and its subclonal heterogeneity has been revealed. Here, we examined whether circulating tumor DNA (ctDNA) was useful for detecting FGFR2 amplification and co-occurring resistance mechanisms in advanced gastric cancer. Experimental Design: We assessed genomic characteristics of FGFR2-amplified advanced gastric cancer in a nationwide ctDNA screening study. We also analyzed FGFR2 amplification status in paired tissue and plasma samples with advanced gastric cancer. In addition, we examined patients with FGFR2-amplified advanced gastric cancer identified by ctDNA sequencing who received FGFR inhibitors. Results: FGFR2 amplification was more frequently detected by ctDNA sequencing in 28 (7.7%) of 365 patients with advanced gastric cancer than by tissue analysis alone (2.6%–4.4%). FGFR2 amplification profiling of paired tissue and plasma revealed that FGFR2 amplification was detectable only by ctDNA sequencing in 6 of 44 patients, which was associated with a worse prognosis. Two patients in whom FGFR2 amplification was detected by ctDNA sequencing after tumor progression following previous standard chemotherapies but not by pretreatment tissue analysis had tumor responses to FGFR inhibitors. A third patient with FGFR2 and MET co-amplification in ctDNA showed a limitation of benefit from FGFR inhibition, accompanied by a marked increase in the MET copy number. Conclusions: ctDNA sequencing identifies FGFR2 amplification missed by tissue testing in patients with advanced gastric cancer, and these patients may respond to FGFR inhibition. The utility of ctDNA sequencing warrants further evaluation to develop effective therapeutic strategies for patients with FGFR2-amplified advanced gastric cancer.

SummaryBackground FOLFOXIRI plus bevacizumab is the first-line treatment for metastatic colorectal cancer (mCRC) but demonstrates high neutropenia incidence among Asian patients. Hence, we conducted the randomized phase II QUATTRO-II study (ClinicalTrials.gov identifier: NCT04097444; Japan Registry of Clinical Trials identifier: jRTCs041190072) to evaluate the safety and efficacy of capecitabine, oxaliplatin, and irinotecan (CAPOXIRI) combination plus bevacizumab versus FOLFOXIRI plus bevacizumab, expecting a lower incidence of neutropenia without compromising the efficacy. Methods We investigated the recommended doses (RD) of oxaliplatin and irinotecan as a safety lead-in portion of Step 1 before initiating the randomized portion as Step 2. Four dose levels of CAPOXIRI (fixed dose of capecitabine, 1600 mg/m2; escalated/de-escalated doses of oxaliplatin and irinotecan) plus bevacizumab (7.5 mg/kg) were investigated in a 3 + 3 manner. A dose level of ≤ 2/6 of dose-limiting toxicity (DLT) cases was expected as the RD. Results In Step 1, we included nine patients (three and six in levels 0 and + 1, respectively). Level 0 (irinotecan, 200 mg/m2; oxaliplatin, 100 mg/m2) did not demonstrate DLTs. In level + 1 (irinotecan, 200 mg/m2; oxaliplatin, 130 mg/m2), although one patient experienced grade 4 febrile neutropenia, no further safety concerns were observed. As a preliminary efficacy result, the objective response rate in all nine patients was 89 % (100 and 83 % in levels 0 and + 1, respectively). Conclusions The RD of CAPOXIRI plus bevacizumab was 200, 130, and 1600 mg/m2 for irinotecan, oxaliplatin, and capecitabine, respectively, and 7.5 mg/kg for bevacizumab. The randomized portion is still ongoing.

Lessons Learned Background The role of neoadjuvant and adjuvant chemotherapy in the management of initially resectable colorectal cancer liver metastases (CLM) is still unclear. We evaluated the feasibility of 3-month adjuvant treatment with capecitabine plus oxaliplatin in combination (CAPOX) for postcurative resection of CLM. Methods Patients received one cycle of capecitabine followed by four cycles of CAPOX as adjuvant chemotherapy after curative resection of CLM. Oral capecitabine was given as 1,000 mg/m2 twice daily for 2 weeks in a 3-week cycle, and CAPOX consisted of oral capecitabine plus oxaliplatin 130 mg/m2 on day 1 in a 3-week cycle. Primary endpoint was the completion rate of adjuvant chemotherapy. Secondary endpoints included recurrence-free survival (RFS), overall survival (OS), dose intensity, and safety. Results Twenty-eight patients were enrolled. Median age was 69.5 years, 54% of patients had synchronous metastases, and 29% were bilobar. Mean number of lesions resected was two, and mean size of the largest lesion was 31 mm. Among patients, 20 (71.4%; 95% confidence interval, 53.6%–89.3%) completed the protocol treatment and met its primary endpoint. The most common grade 3 or higher toxicity was neutropenia (29%). Five-year recurrence-free survival and overall survival were 65.2% and 87.2%, respectively. Conclusion Three-month adjuvant treatment with CAPOX is tolerable and might be a promising strategy for postcurative resection of CLM.

PURPOSE Circulating tumor DNA (ctDNA) genotyping may guide targeted therapy for patients with advanced GI cancers. However, no studies have validated ctDNA genotyping for microsatellite instability (MSI) assessment in comparison with a tissue-based standard. PATIENTS AND METHODS The performance of plasma-based MSI assessment using Guardant360, a next-generation sequencing–based ctDNA assay, was compared with that of tissue-based MSI assessment using a validated polymerase chain reaction–based method in patients with advanced GI cancers enrolled in GOZILA study, a nationwide ctDNA profiling study. The primary end points were overall percent agreement, positive percent agreement (PPA), and negative percent agreement. The efficacy of immune checkpoint inhibitor therapy was also evaluated. RESULTS In 658 patients with advanced GI cancers who underwent both plasma and tissue testing for MSI, the overall percent agreement, PPA, and negative percent agreement were 98.2% (95% CI, 96.8 to 99.1), 71.4% (95% CI, 47.8 to 88.7), and 99.1% (95% CI, 98.0 to 99.7), respectively. In patients whose plasma samples had a ctDNA fraction ≥ 1.0%, the PPA was 100.0% (15/15; 95% CI, 78.2 to 100.0). Three patients with MSI-high (MSI-H) tumors detected only by ctDNA genotyping achieved clinical benefits after receiving anti–programmed cell death 1 therapy with the progression-free survival ranging from 4.3 to 16.7 months. One patient with an aggressive cancer of an unknown primary site benefited from pembrolizumab after rapid detection of MSI-H by ctDNA genotyping. CONCLUSION ctDNA genotyping was able to detect MSI with high concordance to validated tissue-based MSI testing, especially in patients with tumors that have sufficient ctDNA shedding. Furthermore, ctDNA genotyping enabled identification of patients with MSI-H tumors who benefited from immune checkpoint inhibitor treatment.

Purpose Effective second‐line chemotherapy options are limited in treating advanced biliary tract cancers (BTCs). Resminostat is an oral histone deacetylase inhibitor. Such inhibitors increase sensitivity to fluorouracil, the active form of S‐1. In the phase I study, addition of resminostat to S‐1 was suggested to have promising efficacy for pre‐treated BTCs. This study investigated the efficacy and safety of resminostat plus S‐1 in second‐line therapy for BTCs. Methods Patients were randomly assigned to receive resminostat or placebo (200 mg orally per day; days 1–5 and 8–12) and S‐1 group (80–120 mg orally per day by body surface area; days 1–14) over a 21‐day cycle. The primary endpoint was progression‐free survival (PFS). Secondary endpoints comprised overall survival (OS), response rate (RR), disease control rate (DCR), and safety. Results Among 101 patients enrolled, 50 received resminostat+S‐1 and 51 received placebo+S‐1. Median PFS was 2.9 months for resminostat+S‐1 vs. 3.0 months for placebo+S‐1 (HR: 1.154, 95% CI: 0.759–1.757, p = 0.502); median OS was 7.8 months vs. 7.5 months, respectively (HR: 1.049, 95% CI: 0.653–1.684, p = 0.834); the RR and DCR were 6.0% vs. 9.8% and 70.0% vs. 78.4%, respectively. Treatment‐related adverse events (TrAEs) of grade ≥ 3 occurring more frequently (≥10% difference) in the resminostat+S‐1 than in the placebo+S‐1 comprised platelet count decreased (18.0% vs. 2.0%) and decreased appetite (16.0% vs. 2.0%). Conclusions Resminostat plus S‐1 therapy improved neither PFS nor OS for patients with pre‐treated BTCs. Addition of resminostat to S‐1 was associated with higher incidence of TrAEs, but these were manageable (JapicCTI‐183883)., This randomized, placebo‐controlled, double‐blind study investigated the efficacy and safety of resminostat plus S‐1 as a second‐line therapy in patients with BTCs. This was the first randomized study to use S‐1, which is widely used in second‐line treatment for BTC patients in Japan, as an active comparator. The results showed that resminostat plus S‐1 prolonged neither PFS nor OS in comparison with placebo plus S‐1.

177 Background: Angiogenesis-factors (AFs) have been reported as prognostic biomarkers for metastatic colorectal cancer (mCRC). RAS status in circulating-tumor DNA (ctDNA) is considered to be associated with resistance and potential efficacy of re-challenge treatment of anti-EGFR antibody in mCRC with RAS wild-type tumors. However, there were few evidence to prospectively evaluate the dynamic change of AFs and association of RAS status in ctDNA with clinical outcomes in anti-angiogenic therapies after anti-EGFR therapy for mCRC. Methods: Plasma samples were collected at pre-, day 15 after, and post-treatments in the pre-planned biomarker study of the JACCRO CC-16 trial which evaluated 2nd-line FOLFIRI plus RAM after anti-EGFR therapy in mCRC patients with RAS wild-type tumors (UMIN000034885). In 42 enrolled patients (median age, 68-y; ECOG PS 0/1, 31/11; all pts with left-sided tumors; median PFS, 6.8 months; median OS, 21.4 months; ORR, 10.3 %), some AFs (VEGF-A, VEGF-D, PlGF, HGF, IL-8, and angiopoietin-2) and RAS status in plasma were measured using the multiplex assay with Luminex technology and OncoBEAM RAS CRC Kit, respectively. The associations between clinical outcomes and AFs/ RAS status were investigated at timepoint of pre-treatment, using t-test and log-rank test. The median value was used as the cut-off value of AFs for high or low. The associations between AFs and RAS status were investigated using Brunner-Munzel test. Results: AFs and RAS status were evaluable in 38 and 41 patients, respectively. The OS was significantly longer in patients with IL-8 low compared to patients with IL-8 high (32.2 vs. 14.5 months, HR 0.36, p= 0.024). However, there was no difference in PFS between patients with IL-8 high and low. On the contrary, RAS mutations were detected at pre-treatment in 18 (44%) patients: KRAS codon12 83%, codon13 17%, codon61 67%, codon117 6%, codon146 11%, NRAS codon12 39%, codon61 78% in RAS mutations. Median PFS was 6.4 months in patients with RAS mutations in ctDNA, while it was 7.4 months in patients without RAS mutations (p = 0.10). Median OS was significantly longer in patients without RAS mutations compared to patients with RAS mutations (25.4 vs. 14.5 months, HR 0.39, p = 0.024). The ORR was 14.3% and 5.6% in patients without RAS mutations and with RAS mutations, respectively. In an exploratory analysis regarding the relationship between AFs and RAS status, IL-8 level was significantly higher in patients with RAS mutations than those without in ctDNA. Conclusions: This biomarker study demonstrated the associations between clinical outcomes and IL-8/ RAS status in blood before treatment in RAS wild-type mCRC treated with 2nd-line FOLFIRI plus RAM after anti-EGFR antibody therapy. Clinical trial information: UMIN000034885 .

120 Background: Triplet regimen, FOLFOXIRI, plus bevacizumab is considered as one of standard first-line treatments in metastatic colorectal cancer (mCRC). On the contrary, FOLFOXIRI plus anti-EGFR antibody has been shown to be a promising regimen with greater depth of response (DpR) in patients with RAS wild-type mCRC from the VOLFI and MACBETH trials (J Clin Oncol 2019, JAMA Oncol 2018). We therefore performed a randomized phase II study, DEEPER trial (JACCRO CC-13) [NCT02515734], to investigate the efficacy and safety of cetuximab (cet) vs. bevacizumab (bev) in combination with modified (m)-FOLFOXIRI in previously untreated mCRC patients with RAS wild-type tumors. We have reported a significantly better DpR of m-FOLFOXIRI plus cet compared to bev as the primary endpoint (Tsuji A, et al. ASCO 2021). Methods: This trial was a randomized phase II trial to evaluate modified (m)-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2400 mg/m2) plus cet vs. bev as initial treatment in terms of DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC. The aim of the trial was to show that median DpR of cet arm was more than 12.5% higher than bev arm, with a power of 85% at a significance level of 0.05, in per protocol set (PPS) consisted of patients evaluable for the DpR. Secondary endpoints included progression-free survival, overall survival, overall response rate, early tumor shrinkage rate, secondary resection rate, and toxicity. A total of 359 patients were enrolled between July 2015 and June 2019. For the PPS (median age 65y, 64% male, PS0/1: 91%/9%, left/right primary: 84%/16%), 159 and 162 patients were randomly assigned to the cet and bev arms, respectively. Clinical outcomes will be analyzed according to primary tumor sidedness which is included in the stratification factor. Additionally, we will collect data of BRAF status, and analyze the clinical outcomes in mCRC patients with RAS/ BRAF wild-type tumors and/or left-sided tumors. Pre-planned survival analysis will be performed to compare the two treatment arms at the time of 3 years after last patients’ enrollment using a log-rank test. All statistical tests are two-sided, and P values ≤ 0.05 are deemed significant. Statistical analyses will be performed using SAS version 9.4. Clinical trial information: NCT02515734 .

The status and prognostic value of the disagreement between physician and patient assessments of symptomatic adverse events (AEs) remain unclear for patients with metastatic colorectal cancer treated with first‐line cetuximab plus chemotherapy. Paired data on patient‐reported outcomes using the EORTC QLQ‐C30 and physician‐reported outcomes using the NCI‐CTCAE for eight symptomatic AEs (fatigue, pain, insomnia, dyspnea, constipation, appetite loss, nausea/vomiting, and diarrhea) were collected from a prospective trial assessing the relationships between treatment efficacy, AEs, and quality of life. The overall agreement rates between patient and physician reporting at 4 weeks ranged from 40.2% to 76.5% for 129 patients. The level of agreement based on Cohen's κ statistics was slight to poor for dyspnea, pain, fatigue, and insomnia, while it was moderate to fair for the remaining AEs. No clinicopathological characteristics of disagreement were found. The underreporting by physicians ranged from 12.5% (nausea/vomiting) to 56.7% (fatigue). The 2‐year overall survival (OS) rate was more favorable for patients with high agreement than for those with low agreement (71.2% vs. 46.5%, p = .016), and the agreement status was an independent factor of OS (HR, 2.31; 95% CI, 1.13–4.71; p = .022). For patients who were reported as asymptomatic by the physician, the presence of patient‐reported symptoms resulted in a trend toward poor prognostic outcomes for appetite loss, dyspnea, diarrhea, and constipation. These findings provide the clinical importance of the monitoring of patient‐reported symptoms that can be complementary to physician‐reported data to ensure more accurate clinical outcomes., The routine use of PROs could be complementary to physician‐reported outcomes to ensure the accurate assessment of symptomatic AEs and facilitate patient‐centered healthcare in clinical practice.

FMS‐like tyrosine kinase 3 (FLT3) plays a key role in hematopoiesis. However, the oncogenic role of FLT3 amplification in patients with metastatic colorectal cancer (mCRC) remains unclear. Here, we aimed to evaluate the characteristics, prognosis, and treatment efficacy of an FLT3 inhibitor (regorafenib) in patients with mCRC with FLT3 amplifications. Tumor tissue samples from 2329 patients were sequenced using NGS in the Nationwide Cancer Genome Screening Project in Japan. The effects of clinicopathological features, co‐altered genes, prognosis, and efficacy of regorafenib were investigated. Between April 2015 and June 2018, 85 patients with mCRC with FLT3 amplification were observed. There were no differences in baseline characteristics between patients with or without FLT3 amplification. The frequency of RAS or other gene co‐alterations was inversely correlated with the copy number status. Median survival time in patients with FLT3 amplification was significantly shorter compared with those with non‐FLT3 amplification. Further investigations of FLT3 amplification as a potential treatment target in mCRC are warranted., High FLT3 amplification may function not only as a prognostic factor but a promising treatment target in metastatic colorectal cancer.

PURPOSE Several trials have evaluated the efficacy of rechallenge treatment with anti–epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) in patients with metastatic colorectal cancer (mCRC). A recent trial indicated that RAS status in circulating tumor DNA (ctDNA) may potentially predict patients with RAS wild-type mCRC resistant to anti-EGFR mAb who would benefit from rechallenge treatment, and the findings should be further investigated. MATERIAL AND METHODS We enrolled patients whose plasma samples were collected in prospective phase II trials, the JACCRO CC-08 (n = 36) and CC-09 (n = 25), which evaluated rechallenge chemotherapy with anti-EGFR mAb for KRAS wild-type mCRC. RAS in ctDNA was analyzed at the time points of baseline, 8 weeks, and progression using OncoBEAM RAS CRC kit. RESULTS Sixteen patients were enrolled in this study, with a response rate of 0% and a disease control rate (DCR) of 62.5%. RAS mutations were found at baseline in six patients. The DCR was 33% in patients with RAS mutations in ctDNA, whereas it was 80% in patients without RAS mutation at baseline. Patients with RAS mutation at baseline had significantly shorter progression-free survival (PFS) and overall survival (OS) than those without RAS mutation (median PFS, 2.3 v 4.7 months; hazard ratio [HR], 6.2; P = .013; median OS, 3.8 v 16.0 months; HR, 12.4; P = .0028). Six of 10 patients without RAS mutation at baseline acquired RAS mutations at progression. Postprogression survival after rechallenge treatment was numerically shorter in patients with RAS mutation at progression. CONCLUSION RAS status in ctDNA was significantly associated with clinical outcomes in patients with mCRC receiving rechallenge treatment with anti-EGFR mAb. These findings could support the clinical utility of OncoBEAM RAS CRC kits for anti-EGFR mAb rechallenge in RAS wild-type mCRC.

Background/objectives Pancreatic neuroendocrine carcinoma (PanNEC)-G3 often presents along with genetic abnormalities such as KRAS, RB1, and TP53 mutations. However, the association between these genetic findings and response to chemotherapy and prognosis has not been clarified. This study aimed to clarify the clinicopathological features of PanNEC-G3. Methods We performed a subgroup analysis of the Japanese PanNEN-G3 study (multicenter, retrospective study), which revealed that Rb loss and KRAS mutation were predictors of the response to platinum-based regimen in PanNEN-G3. We re-classified WHO grades of PanNENs using the 2017 WHO classification and then analyzed the clinicopathological features and prognostic factors in 49 patients with PanNEC-G3. Results The rates of Rb loss and KRAS mutation in PanNEC-G3 were 54.5% and 48.7%, respectively. Patients with Rb loss and/or KRAS mutation showed a higher response rate to first-line platinum-based regimen than those without Rb loss or KRAS mutation (object response rate 70.0% vs 33.3%, odds ratio 9.22; 95% CI 1.26–67.3, P = 0.029), but tended to have shorter overall survival rates than those without Rb loss or KRAS mutation (median 239 vs 473 days, hazard ratio 2.11; 95% CI 0.92–4.86, P = 0.077). Conclusions Patients with PanNEC-G3 have varied clinical outcomes for platinum-based regimen. When grouped based on Rb loss and KRAS mutation, there seemed to be two groups with distinct prognoses and responses to the platinum-based regimen. PanNEC-G3 could, therefore, be classified into two distinct groups based on immunohistochemical and genetic findings.

Background Regorafenib or trifluridine/tipiracil as third-line treatment have limited efficacy in metastatic colorectal cancer (mCRC). Methods This Phase 2 trial evaluated the efficacy and safety of irinotecan plus cetuximab rechallenge as third-line treatment in KRAS wild-type mCRC patients who achieved clinical benefit with first-line cetuximab-containing therapy. The primary endpoint was 3-month progression-free survival (PFS) rate. A sample size was calculated; 30 patients with a 3-month PFS rate of 45% deemed promising and 15% unacceptable. Patients with greater and less than the cut-off value of cetuximab-free intervals (CFIs) were classified into the long and short CFI groups, respectively, in subgroup analyses. Results Among 34 eligible patients who received treatment at least once, 3-month PFS rate was 44.1% (95% confidence interval, 27.4–60.8%). The median PFS and overall survival (OS) were 2.4 and 8.2 months, respectively. The response and disease control rates were 2.9 and 55.9%, respectively. PFS and OS were significantly longer in the long- than in the short CFI group. Conclusions Irinotecan plus cetuximab rechallenge as third-line treatment for KRAS wild-type mCRC was safe and had promising activity, especially in those with a long CFI, warranting further investigation in a Phase 3 randomised trial. Clinical trial registration UMIN000010638

Chemotherapy in relapsed colorectal cancer patients treated with oxaliplatin as adjuvant chemotherapy is under debate. REACT study aimed to investigate the efficacy of reintroducing modified FOLFOX6 (mFOLFOX6) or CAPOX with or without bevacizumab in recurrent colorectal cancer patients after oxaliplatin adjuvant chemotherapy. Patients that participated in this trial had a medical history of adjuvant chemotherapy, including oxaliplatin with a cumulative dose greater than 400 mg/m2, and recurrence that was diagnosed more six months post adjuvant chemotherapy. Primary endpoints were response rate (RR) and disease control rate (DCR), while key secondary endpoints were time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS), and safety. A total of 31 patients were enrolled between October 2012 and October 2016. Of the 29 eligible patients, 7 received mFOLFOX6 and 22 received CAPOX. The RR was 62.1% (95% confidence interval 42.3–79.3) and the DCR was 82.8% (95% confidence interval 64.2–94.2). The RR for oxaliplatin-free interval was 100.0% in months 6–12 and 56.0% after 12 months. Median TTF, PFS, and OS were 6.3, 10.8, and 28.7 months, respectively. Grade 3 or worse peripheral sensory neuropathy developed in 6.5%. Allergic reactions occurred in 12.9% of the patients, with one (3.2%) grade 3 episode. There were no other severe treatment-related adverse events. Reintroduction of oxaliplatin was feasible and achieved high RR or DCR in patients after more than 6 months post oxaliplatin adjuvant chemotherapy.

Background It remains unclear whether patients’ self‐perceptions of symptoms at baseline clinically impact the prognostic relevance, treatment efficacy, or toxicity profiles in metastatic colorectal cancer (mCRC) patients treated with the first‐line cetuximab and standard chemotherapy. Methods The data were collected from a prospective trial that assessed the relationships between quality of life (QOL), treatment efficacy, and adverse events (AEs). Results The analysis of 137 mCRC patients revealed a significant association between the presence of baseline tumor‐related symptoms and a lower overall survival (OS) compared to the absence of symptoms (HR, 2.49; 95% CI, 1.37‐4.62; P = .003). The asymptomatic responders had favorable outcomes compared to the symptomatic nonresponders (2‐year OS rates: 83.6% and 35.9%, respectively), while the symptomatic responders had similar outcomes to the asymptomatic nonresponders. The median postprogression survival differed significantly: 10.2 months for the symptomatic patients and 15.9 months for the asymptomatic patients (HR, 2.29; 95% CI, 1.25‐4.29, P = .008). The objective response rates and patient toxicity profiles were similar irrespective of the severity of baseline symptoms. Conclusion Baseline symptoms were associated with worse OS but not with impaired treatment efficacy or more frequent AEs in mCRC patients treated with cetuximab in addition to chemotherapy., This study provides that the baseline patient‐reported symptoms are associated with worse OS, but not with impaired treatment efficacy or deteriorated AEs, for patients treated with cetuximab plus chemotherapy.

Regorafenib is a multiple tyrosine kinase inhibitor, and the use of this drug is approved for the treatment of cancers that are resistant to chemotherapy, which include advanced colorectal cancer, gastrointestinal stromal tumor, and hepatocellular carcinoma. However, the drug causes adverse events, including skin toxicities that require dose modification in approximately 75% of cases. At present, the blood concentration of regorafenib is not assessed in clinical settings; thus, we recently developed a method that can assess the blood concentration of the drug using high-performance liquid chromatography. We measured the trough blood concentrations (Ctrough) of regorafenib and its metabolites (M2 and M5) in 14 and 4 patients with advanced colorectal cancer and gastrointestinal stromal tumor, respectively, using high-performance liquid chromatography. Then, the correlation between the Ctrough and therapeutic outcomes of regorafenib was analyzed. In patients who were receiving regorafenib 40–160 mg/day, the Ctrough values of regorafenib, M2, and M5 were 318–9467, 34–3594, and 38–3796 ng/mL, respectively. The difference in the values was significant. Although the specific factors influencing this difference were not elucidated, the Ctrough of regorafenib was extremely lower in some patients, even though the drug was administered at a standard dose, which may explain the lower response rate. Moreover, the Ctrough value of M5 was significantly correlated to the incidence of skin toxicities, which is the most frequent cause of dose modification. The use of regorafenib may not be suitable in patients with a low Ctrough value. To prevent skin toxicities, the Ctrough value of M5 should be monitored.

Background The phase 3 KEYNOTE-590 (NCT03189719) study showed first-line pembrolizumab plus chemotherapy significantly prolonged overall survival and progression-free survival versus placebo plus chemotherapy in patients with advanced unresectable or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or advanced/metastatic Siewert type I adenocarcinoma of the esophagogastric junction. We describe a subgroup analysis of Japanese patients from KEYNOTE-590. Methods Eligible patients were randomly assigned 1:1 to pembrolizumab 200 mg intravenously every 3 weeks or placebo plus chemotherapy (cisplatin 80 mg/m2 and 5-fluorouracil 800 mg/m2/day). Efficacy was evaluated in all Japanese patients and those with esophageal squamous cell carcinoma and programmed death ligand 1 combined positive score ≥ 10. Dual primary endpoints were overall survival and progression-free survival per RECIST v1.1 by investigator. Secondary endpoints included objective response rate per RECIST v1.1 by investigator and safety and tolerability. Results At data cutoff (July 2, 2020), 141 Japanese patients were randomly assigned (pembrolizumab plus chemotherapy, 74; placebo plus chemotherapy, 67). In all Japanese patients, median overall survival was 17.6 months with pembrolizumab plus chemotherapy versus 11.7 months with chemotherapy (hazard ratio, 0.71; 95% confidence interval, 0.47–1.09), median progression-free survival was 6.3 versus 6.0 months (hazard ratio, 0.58; 95% confidence interval, 0.40–0.84), and objective response rate was 56.8% versus 38.8%. Grade 3–5 treatment-related adverse events were 74.3% and 61.2%. Conclusion First-line pembrolizumab plus chemotherapy demonstrated improvement in overall survival and progression-free survival compared with placebo plus chemotherapy in Japanese patients with advanced/metastatic esophageal cancer; safety was comparable between treatment groups. Clinical trial registry ClinicalTrials.gov, NCT03189719.

Purpose Although early tumor shrinkage (ETS) is a predictor of improved overall survival (OS), the association between ETS and health-related quality of life (HRQOL) remains unclear for patients with metastatic colorectal cancer (mCRC) treated with first-line cetuximab plus chemotherapy. Methods The data were collected from a prospective trial that assessed HRQOL using the EORTC QLQ-C30. The impact of ETS on HRQOL was estimated using a linear mixed-effects model for repeated measures. Results ETS was achieved in 82 (64.1%) of 128 mCRC patients treated with first-line cetuximab plus chemotherapy, and these patients had a significantly longer OS than those without ETS (HR, 0.38; 95% CI, 0.20–0.72; P = .002). Asymptomatic patients with ETS had a favorable OS, while symptomatic patients without ETS had a worse OS (2-year OS rates, 77.8% vs. 42.5%). Symptomatic patients with ETS had similar outcomes as asymptomatic patients without ETS (2-year OS rates, 64.1% vs. 67.0%). For symptomatic patients, ETS was associated with improved HRQOL scores between baseline and 8 weeks: the mean changes for patients with and without ETS were 5.86 and -4.94 for global health status (GHS)/QOL, 26.73 and 3.79 for physical functioning, and 13.58 and -3.10 for social functioning, respectively. The improved HRQOL was comparable to that of asymptomatic patients without ETS. For asymptomatic patients, ETS showed a decreased deterioration in HRQOL. Conclusion Our findings highlight the importance of ETS for HRQOL and prognostic estimates, and assessing ETS may provide clinically useful information for physicians and patients to make more informed decisions.

Previous studies have shown sex‐related differences in the incidence of adverse events following treatment with fluoropyrimidines, however the mechanism of this difference is unknown. We examined sex‐related differences in the safety of S‐1 plus oxaliplatin (SOX) and S‐1 plus cisplatin (CS) in 663 metastatic gastric cancer patients taking part in a phase III study. The incidences of leukopenia (odds ratio [OR] 1.9; P = .015), neutropenia (OR 2.2; P = .002), nausea (OR 2.0; P = .009), and vomiting (OR 2.8; P

Summary Background VEGF and VEGF receptor 2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether the addition of ramucirumab, a VEGFR-2 antagonist monoclonal antibody, to first-line chemotherapy improves outcomes in patients with metastatic gastric or gastro-oesophageal junction adenocarcinoma. Methods For this double-blind, randomised, placebo-controlled, phase 3 trial done at 126 centres in 20 countries, we recruited patients aged 18 years or older with metastatic, HER2-negative gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. Eligible patients were randomly assigned (1:1) with an interactive web response system to receive cisplatin (80 mg/m2, on the first day) plus capecitabine (1000 mg/m2, twice daily for 14 days), every 21 days, and either ramucirumab (8 mg/kg) or placebo on days 1 and 8, every 21 days. 5-Fluorouracil (800 mg/m2 intravenous infusion on days 1–5) was permitted in patients unable to take capecitabine. The primary endpoint was investigator-assessed progression-free survival, analysed by intention to treat in the first 508 patients. We did a sensitivity analysis of the primary endpoint, including a central review of CT scans. Overall survival was a key secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT02314117. Findings Between Jan 28, 2015, and Sept 16, 2016, 645 patients were randomly assigned to receive ramucirumab plus fluoropyrimidine and cisplatin (n=326) or placebo plus fluoropyrimidine and cisplatin (n=319). Investigator-assessed progression-free survival was significantly longer in the ramucirumab group than the placebo group (hazard ratio [HR] 0·753, 95% CI 0·607–0·935, p=0·0106; median progression-free survival 5·7 months [5·5–6·5] vs 5·4 months [4·5–5·7]). A sensitivity analysis based on central independent review of the radiological images did not corroborate the investigator-assessed difference in progression-free survival (HR 0·961, 95% CI 0·768–1·203, p=0·74). There was no difference in overall survival between groups (0·962, 0·801–1·156, p=0·6757; median overall survival 11·2 months [9·9–11·9] in the ramucirumab group vs 10·7 months [9·5–11·9] in the placebo group). The most common grade 3–4 adverse events were neutropenia (85 [26%] of 323 patients in the ramucirumab group vs 85 [27%] of 315 in the placebo group), anaemia (39 [12%] vs 44 [14%]), and hypertension (32 [10%] vs 5 [2%]). The incidence of any-grade serious adverse events was 160 (50%) of 323 patients in the ramucirumab group and 149 (47%) of 315 patients in the placebo group. The most common serious adverse events were vomiting (14 [4%] in the ramucirumab group vs 21 [7%] in the placebo group) and diarrhoea (11 [3%] vs 19 [6%]). There were seven deaths in each group, either during study treatment or within 30 days of discontinuing study treatment, which were the result of treatment-related adverse events. In the ramucirumab group, these adverse events were acute kidney injury, cardiac arrest, gastric haemorrhage, peritonitis, pneumothorax, septic shock, and sudden death (n=1 of each). In the placebo group, these adverse events were cerebrovascular accident (n=1), multiple organ dysfunction syndrome (n=2), pulmonary embolism (n=2), sepsis (n=1), and small intestine perforation (n=1). Interpretation Although the primary analysis for progression-free survival was statistically significant, this outcome was not confirmed in a sensitivity analysis of progression-free survival by central independent review, and did not improve overall survival. Therefore, the addition of ramucirumab to cisplatin plus fluoropyrimidine chemotherapy is not recommended as first-line treatment for this patient population. Funding Eli Lilly and Company.