Comparison of platinum combination chemotherapy plus pembrolizumab versus platinum combination chemotherapy plus nivolumab-ipilimumab for treatment-naive advanced non-small-cell lung cancer in Japan (JCOG2007): an open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: The combination of platinum-based chemotherapy and an antibody to PD-1 or to its ligand PD-L1, with or without an antibody to CTLA-4, has improved the survival of individuals with metastatic non-small-cell lung cancer (NSCLC). However, no randomised controlled trial has evaluated the survival benefit of adding a CTLA-4 inhibitor to platinum-based chemotherapy plus a PD-1 or PD-L1 inhibitor. METHODS: This open-label, randomised, phase 3 trial was conducted at 48 hospitals in Japan. Eligible patients were aged 20 years or older with previously untreated advanced NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with known driver oncogenes were excluded. Participants were randomly assigned (1:1) to receive platinum-based chemotherapy (four cycles) plus pembrolizumab (pembrolizumab group) or platinum-based chemotherapy (two cycles) plus nivolumab-ipilimumab (nivolumab-ipilimumab group). The primary endpoint was overall survival and assessed in all randomly assigned patients on an intention-to-treat basis. The trial is registered in the Japan Registry for Clinical Trials, jRCTs031210013, and is now closed to new enrolment and is ongoing. FINDINGS: Between patient accrual initiation on April 6, 2021, and discontinuation of the trial on March 30, 2023, 11 (7%) of 148 patients in the nivolumab-ipilimumab group had a treatment-related death. Because of the high number of treatment-related deaths, patient accrual was terminated early, resulting in 295 patients (236 [80%] male and 59 [20%] female) enrolled; the primary analysis was done on the basis of 117 deaths (fewer than the required 329 deaths). By May 25, 2023 (data cutoff), overall survival did not differ significantly between the nivolumab-ipilimumab group and the pembrolizumab group (median 23·7 months [95% CI 17·6-not estimable] vs 20·5 months [17·6-not estimable], respectively; hazard ratio 0·98 [90% CI 0·72-1·34]; p=0·46). Non-haematological adverse events of grade 3 or worse occurred in 87 (60%) of 146 patients in the nivolumab-ipilimumab group and 59 (41%) of 144 patients in the pembrolizumab group. The pembrolizumab group tended to have a better quality of life compared with the nivolumab-ipilimumab group. INTERPRETATION: The safety and efficacy data suggest an unfavourable benefit-risk profile for nivolumab-ipilimumab combined with platinum-based chemotherapy relative to pembrolizumab combined with platinum-based chemotherapy as a first-line treatment for patients with advanced NSCLC, although a definitive conclusion awaits an updated analysis of overall survival. FUNDING: The National Cancer Center Research and Development Fund and Japan Agency for Medical Research and Development.

Trastuzumab Deruxtecan in Advanced Solid Tumors With Human Epidermal Growth Factor Receptor 2 Amplification Identified by Plasma Cell-Free DNA Testing: A Multicenter, Single-Arm, Phase II Basket Trial.

PURPOSE: HERALD/EPOC1806 was conducted as a multicenter phase II trial assessing trastuzumab deruxtecan (T-DXd) therapy for patients with human epidermal growth factor receptor 2 (HER2)-amplified progressive stage solid tumors detected by cell-free DNA (cfDNA) testing. PATIENTS AND METHODS: Patients exhibited advanced solid tumors with HER2 amplification that was identified via next-generation sequencing of cfDNA testing, without the requirement for immunohistochemical HER2 testing. The studied group was administered T-DXd at 5.4 mg/kg once every 3 weeks until onset of disease progression or intolerable toxicity. RESULTS: Overall, 4,734 patients underwent cfDNA testing from December 2019 to January 2022, and 252 demonstrated HER2 amplification. Finally, the study included 62 patients with 16 cancer types with a median baseline plasma HER2 copy number (CN) of 8.55 (range, 2.4-73.9). Confirmed overall response rate (ORR) by investigator assessment was 56.5% (95% CI, 43.3 to 69.0), thus showing a value beyond the 5% threshold. Responses were evaluated for 13 cancer types, including KRAS-mutant colorectal (1/3), PIK3CA-mutant endometrial (5/6), and tissue HER2-negative gastric (1/2) cancers. Plasma HER2 CN above versus below the baseline median value did not differ for impact response; however, clearance of HER2 amplification in cfDNA on cycle 2 day 1 had higher response values compared with persistence. Median progression-free survival and response duration were 7.0 (95% CI, 4.9 to 9.7) and 8.8 (95% CI, 5.8 to 11.2) months, respectively, with the majority of complications being mild to moderate. Interstitial lung diseases were identified in 16 (26%) patients, including 14 patients with grade 1 disease, one patient with grade 2 disease, and one patient with grade 3 disease. CONCLUSION: T-DXd treatment demonstrated high ORR with durable response in patients with advanced HER2-amplified solid tumors determined with cfDNA testing.

Comparison between asymptotic and re-randomisation tests under non-proportional hazards in a randomised controlled trial using the minimisation method.

BACKGROUND: Pocock-Simon's minimisation method has been widely used to balance treatment assignments across prognostic factors in randomised controlled trials (RCTs). Previous studies focusing on the survival outcomes have demonstrated that the conservativeness of asymptotic tests without adjusting for stratification factors, as well as the inflated type I error rate of adjusted asymptotic tests conducted in a small sample of patients, can be relaxed using re-randomisation tests. Although several RCTs using minimisation have suggested the presence of non-proportional hazards (non-PH) effects, the application of re-randomisation tests has been limited to the log-rank test and Cox PH models, which may result in diminished statistical power when confronted with non-PH scenarios. To address this issue, we proposed two re-randomisation tests based on a maximum combination of weighted log-rank tests (MaxCombo test) and the difference in restricted mean survival time (dRMST) up to a fixed time point τ , both of which can be extended to adjust for randomisation stratification factors. METHODS: We compared the performance of asymptotic and re-randomisation tests using the MaxCombo test, dRMST, log-rank test, and Cox PH models, assuming various non-PH situations for RCTs using minimisation, with total sample sizes of 50, 100, and 500 at a 1:1 allocation ratio. We mainly considered null, and alternative scenarios featuring delayed, crossing, and diminishing treatment effects. RESULTS: Across all examined null scenarios, re-randomisation tests maintained the type I error rates at the nominal level. Conversely, unadjusted asymptotic tests indicated excessive conservatism, while adjusted asymptotic tests in both the Cox PH models and dRMST indicated inflated type I error rates for total sample sizes of 50. The stratified MaxCombo-based re-randomisation test consistently exhibited robust power across all examined scenarios. CONCLUSIONS: The re-randomisation test is a useful alternative in non-PH situations for RCTs with minimisation using the stratified MaxCombo test, suggesting its robust power in various scenarios.

Efficacy and safety of chemoimmunotherapy in advanced non-small cell lung cancer patients with antibiotics-induced dysbiosis: a propensity-matched real-world analysis.

PURPOSE: The gut microbiota is hypothesized as a prognostic biomarker for cancer immunotherapy. Antibiotic-induced dysbiosis negatively affects the clinical outcomes of immunotherapy. However, the effect of dysbiosis on the efficacy and safety of Chemoimmunotherapy (chemo-IOs), the frontline standard of care, in advanced non-small cell lung cancer (NSCLC) remains unknown. We aimed to compare the efficacy and safety of chemo-IOs in patients exposed to antibiotics before treatment with those of patients who were not exposed. METHODS: We retrospectively reviewed patients with advanced NSCLC treated with first-line chemo-IOs between 2018 and 2020 at the National Cancer Center Hospital. The patients were divided into two groups: those exposed to antibiotics within 30 days before induction therapy (ABx group) and those did not antibiotics (Non-ABx group). Propensity score matching was used to control for potential confounding factors. Clinical outcomes including progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) were compared. RESULTS: Of 201 eligible patients, 21 were in the ABx group, and 42 were in the non-ABx group after propensity score matching. No differences in PFS or OS emerged between the two groups (ABx group vs. Non-ABx group) (PFS:7.0 months vs. 6.4 months, hazard ratio [HR] 0.89; 95% confidence interval [CI], 0.49-1.63, OS:20.4 months vs. 20.1 months, HR 0.87; 95% CI 0.44-1.71). The frequency of irAEs before propensity score matching was similar across any-grade irAEs (39.4% vs. 42.9%) or grade 3 or higher irAEs (9.1% vs. 11.3%). CONCLUSION: Antibiotic-induced dysbiosis may not affect the efficacy of chemo-IOs in patients with advanced NSCLC.

Artemis: A Multicenter, Open-Label, Single-Arm, Phase II Study to Evaluate the Efficacy and Safety of First-Line Carboplatin/Paclitaxel/Lenvatinib/Pembrolizumab Combination for Previously Untreated Advanced or Recurrent Thymic Carcinomas.

BACKGROUND: Thymic carcinoma is a rare cancer with an aggressive clinical presentation and no organotypic symptoms. Despite using platinum-based chemotherapy as first-line treatment, the prognosis remains poor, necessitating a novel therapeutic strategy. METHODS: The artemis trial is a Phase II, single-arm, multicenter study designed to evaluate the efficacy and safety of carboplatin, paclitaxel, lenvatinib, and pembrolizumab as first-line chemotherapy for patients with advanced or recurrent thymic carcinoma. A total of 35 patients will be enrolled in this study and will receive induction therapy every 3 weeks for up to 4 cycles, followed by pembrolizumab every 3 weeks, and daily lenvatinib as maintenance therapy for up to 31 cycles (for 2 years). Lenvatinib will be continued until disease progression or unacceptable toxicity based on the discretion of the attending physician. CONCLUSION: The primary endpoint of the study is the objective response rate, with secondary endpoints including progression-free survival, overall survival, duration of response, disease control rate, and safety profile. TRIAL REGISTRATION: ClinicalTrials.gov NCT05832827 Registered on April 27, 2023, https://classic. CLINICALTRIALS: gov/ct2/show/NCT05832827. Japan Registry of Clinical Trials (jRCT), jRCT2031230114. Registered on May 22, 2023, https://jrct.niph.go.jp/latest-detail/jRCT2031230114.

Plasma Angiogenic Factors as Predictors of the Efficacy of Second-line Chemotherapy Combined with Angiogenesis Inhibitors in Metastatic Colorectal Cancer: Results From the GI-SCREEN CRC-Ukit Study.

BACKGROUND: The significance of angiogenic factors as predictors of second-line (2L) chemotherapy efficacy when combined with angiogenesis inhibitors for metastatic colorectal cancer (mCRC) remains unestablished. PATIENTS AND METHODS: In this multicenter prospective observational study, 17 angiogenic factors were analyzed in plasma samples collected at pretreatment and progression stages using a Luminex multiplex assay. Patients who received chemotherapy plus bevacizumab (BEV group), FOLFIRI plus ramucirumab (RAM group), or FOLFIRI plus aflibercept (AFL group) as the 2L treatment were included. Interactions between pretreatment and treatment groups for progression-free survival (PFS), overall survival (OS), and response rate (RR) were assessed using the propensity-score weighted Cox proportional hazards model. RESULTS: From February 2018 to September 2020, 283 patients were analyzed in the 2L cohort. A strong interaction was observed for PFS between BEV and RAM with HGF, sNeuropilin-1, sVEGFR-1, and sVEGFR-3. Interactions for RR between the BEV and RAM groups were observed for sNeuropilin-1 and sVEGFR-1. Contrarily, OS, PlGF, sVEGFR-1, and sVEGFR-3 differentiated the treatment effect between BEV and AFL. Plasma samples were evaluable for dynamic analysis in 203 patients. At progression, VEGF-A levels significantly decreased in the BEV group and increased in the RAM and AFL groups. CONCLUSION: The pretreatment plasma sVEGFR-1 and sVEGFR-3 levels could be predictive biomarkers for distinguishing BEV and RAM when combined with chemotherapy in 2L mCRC treatment. Based on the VEGF-A dynamics at progression, selecting RAM or AFL for patients with significantly elevated VEGF-A levels may be a 2L treatment strategy, with BEV considered for the third-line treatment. CLINICAL TRIAL NUMBER: UMIN000028616.

Reconsidering the Cutoff Value for Sensitive and Refractory Relapses in Extensive-Stage SCLC in the Era of Immunotherapy.

INTRODUCTION: Traditionally, relapsed SCLC has been classified as "sensitive" or "refractory" on the basis of cutoff values (60 or 90 d) for the duration between the last chemotherapy and disease progression. Nevertheless, these cutoff values are not derived from rigorous analytical methods, and their applicability to contemporary treatments remains uncertain. METHODS: We conducted a retrospective multicenter study on patients with extensive-stage SCLC who underwent second-line therapy after platinum-doublet chemotherapy with or without immune checkpoint inhibitor (ICI) resistance before (pre-ICI cohort) and after (post-ICI cohort) approval of combination immunotherapy. We selected the optimal platinum-free interval cutoff value with the lowest two-sided p value in the multivariable Cox regression model for second-line overall survival. The internal validity of the chosen cutoff value was assessed using twofold cross-validation. RESULTS: There were 235 and 98 patients in the pre-ICI and post-ICI cohorts, respectively. In the pre-ICI cohort, the optimal cutoff was 59 days (p = 0.0001); the hazard ratio calculated using twofold cross-validation was 1.31 (95% confidence interval: 0.95-1.82]). In the post-ICI cohort, although the 60- and 90-day cutoff values could predict prognosis (60 d; p = 0.002, 90 d; p = 0.005), the optimal cutoff value was 75 days (p = 0.0002), which resulted in a median second-line overall survival of 15.9 and 5.0 months for patients with sensitive and refractory relapse, respectively (hazard ratio = 2.77, 95% confidence interval: 1.56-4.93). CONCLUSIONS: We clarified the previously ambiguous cutoff values for classifying relapsed SCLC and revealed that the 75-day cutoff most accurately predicts subsequent prognosis than the traditional cutoffs in the post-ICI era.

Development of a nomogram to predict survival in advanced biliary tract cancer.

The prognosis of advanced biliary tract cancer (BTC) patients remains poor due to limited efficacy of chemotherapy and difficulties in management. Thus, prediction of survival is crucial for the clinical management of advanced BTC. The aim was to develop and validate a nomogram to predict 6-month and 12-month survival in advanced BTC patients treated with chemotherapy. A multivariable Cox regression model was used to construct a nomogram in a training set (JCOG1113, a phase III trial comparing gemcitabine plus S-1 [GS] and gemcitabine plus cisplatin, n = 351). External validity of the nomogram was assessed using a test set (JCOG0805, a randomized, phase II trial comparing GS and S-1 alone, n = 100). Predictive performance was assessed in terms of discrimination and calibration. The constructed nomogram included lymph node metastasis, liver metastasis, carbohydrate antigen 19-9, carcinoembryonic antigen, albumin, and C-reactive protein. Uno's concordance index was 0.661 (95% confidence interval [CI] 0.629-0.696) in the training set and 0.640 (95% CI 0.566-0.715) in the test set. The calibration plots for 6-month and 12-month survival showed good agreement in the two analysis sets. The present nomogram can facilitate prediction of the prognosis of advanced BTC patients treated with chemotherapy and help clinicians' prognosis-based decision-making.

Role of plasma angiogenesis factors in the efficacy of first-line chemotherapy combined with biologics in RAS wild-type metastatic colorectal cancer: Results from the GI-SCREEN CRC-Ukit study.

BACKGROUND: Several biomarkers have been established for metastatic colorectal cancer (mCRC). We investigated whether plasma angiogenesis factors could predict the efficacy of biologics combined with chemotherapy in first-line (1L) treatment in patients with RAS wild-type mCRC and the dynamics of plasma angiogenesis factors at progression during 1L treatment. METHODS: In this multicenter prospective observational study, serial plasma samples were prospectively collected at pretreatment and progression stages; 17 plasma angiogenesis factors were analyzed using the multiplex assay with Luminex® technology. Interactions between the pretreatment measurements and treatment groups on progression-free survival (PFS) and overall survival (OS) in patients with RAS wild-type were assessed using the propensity-score weighted Cox proportional hazards model. RESULTS: From February 2018 to September 2020, 202 patients were enrolled in the 1L cohort; 133 patients had RAS wild-type (chemotherapy plus bevacizumab [BEV group, n = 33] and plus anti-epidermal growth factor receptor monoclonal antibodies [aEGFR group, n = 100]). A trend of strong interaction on PFS was observed for interleukin-8 (IL-8) (p = 0.0752) and soluble vascular cell adhesion molecule-1 (sVCAM-1) (p = 0.0156). Regarding OS, IL-8 (p = 0.0283), soluble vascular endothelial growth factor-receptor-1 (sVEGFR-1) (p = 0.0777) and sVCAM-1 (p = 0.0011) tended to differentiate the treatment effect. In 112 patients, plasma samples were evaluable for dynamic analysis (57 and 55 from the BEV and aEGFR groups, respectively). In the BEV group, six factors significantly increased during progression, whereas two decreased. In the aEGFR group, three factors significantly increased, and six decreased. CONCLUSION: Pretreatment plasma IL-8 and sVCAM-1 levels could be predictive biomarkers to distinguish BEV and anti-EGFR mAbs when combined with chemotherapy in the 1L treatment of RAS wild-type mCRC. Several plasma angiogenesis factors showed significant change at progression in 1L chemotherapy plus biologics for RAS wild-type mCRC, which are potential biomarkers for selecting an optimal angiogenesis inhibitor in second-line treatment.

Continuation of osimertinib in EGFR-mutant non-small-cell lung cancer patients bearing CNS metastasis (EPONA study).

The patients harboring EGFR-mutated non-small-cell lung cancer, treated with EGFR tyrosine kinase inhibitor will lead to longer survival than those having non-small-cell lung cancer (NSCLC) patient who do not harbor EGFR mutations. This ongoing clinical trial is to investigate the secondary chemoprevention effect of osimertinib from CNS with platinum doublets chemotherapy in patients who had progressive disease outside of CNS lesions. The aim of this randomized, phase II trial is to evaluate platinum and pemetrexed chemotherapy followed by pemetrexed maintenance with or without continuation of osimertinib for secondary CNS prevention in patients with brain metastatic NSCLC with EGFR mutation, with other than CNS lesions, but no progressive disease in the CNS lesion after osimertinib. The primary end point is to assess progression-free survival by investigator assessment. The key secondary end points are overall survival, response rate, time to CNS controlling, time to whole-brain irradiation and safety. Clinical trial registration: Japan Registry of Clinical Trials (jRCT), Japan (jRCTs071200029).

The authors are conducting a clinical trial aimed at improving treatment for individuals diagnosed with non-small-cell lung cancer, a specific type of lung cancer. In some cases, this cancer can spread to the brain. This study focuses on patients whose cancer is stable in the brain but progressing in other parts of the body. The study is comparing two different treatment approaches. One involves a combination of two drugs, platinum and pemetrexed, while the other combines these drugs with a third one called osimertinib. The main objective is to determine if continuing osimertinib treatment benefits these patients. The authors are evaluating the time it takes for the cancer to start growing again, known as progression-free survival, to identify the most effective treatment. Progression-free survival represents the duration that patients live without their disease worsening. This study, the EPONA study, will provide valuable insights into optimizing the treatment of this type of cancer.

Regulation of MEK inhibitor selumetinib sensitivity by AKT phosphorylation in the novel BRAF L525R mutant.

BACKGROUND: Oncogenic mutations in BRAF genes are found in approximately 5-10% of colorectal cancers. The majority of BRAF mutations are located within exons 11-15 of the catalytic kinase domains, with BRAF V600E accounting for more than 80% of the observed BRAF mutations. Sensitivity to BRAF- and mitogen-activated protein kinase (MEK) inhibitors varies depending on BRAF mutations and tumor cell types. Previously, we newly identified, BRAF L525R-mutation, in the activation segment of the kinase in colorectal cancer patient. Here, we characterized the function of the BRAF L525R mutation. METHODS: HEK293 cells harboring a BRAF mutation (V600E or L525R) were first characterized and then treated with cetuximab, dabrafenib, and selumetinib. Cell viability was measured using WST-1 assay and the expression of proteins involved in the extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) signaling pathways was evaluated using western blot analysis. RESULTS: The MEK inhibitor selumetinib effectively inhibited cell proliferation and ERK phosphorylation in BRAF L525R cells but not in BRAF V600E cells. Further studies revealed that AKT phosphorylation was reduced by selumetinib in BRAF L525R cells but not in BRAF V600E cells or selumetinib-resistant BRAF L525R cells. Moreover, the AKT inhibitor overcame the selumetinib resistance. CONCLUSIONS: We established a model system harboring BRAF L525R using HEK293 cells. BRAF L525R constitutively activated ERK. AKT phosphorylation caused sensitivity and resistance to selumetinib. Our results suggest that a comprehensive network analysis may provide insights to identify effective therapies.

Adjuvant S-1 compared with observation in resected biliary tract cancer (JCOG1202, ASCOT): a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: S-1 has shown promising efficacy with a mild toxicity profile in patients with advanced biliary tract cancer. The aim of this study was to evaluate whether adjuvant S-1 improved overall survival compared with observation for resected biliary tract cancer. METHODS: This open-label, multicentre, randomised phase 3 trial was conducted in 38 Japanese hospitals. Patients aged 20-80 years who had histologically confirmed extrahepatic cholangiocarcinoma, gallbladder carcinoma, ampullary carcinoma, or intrahepatic cholangiocarcinoma in a resected specimen and had undergone no local residual tumour resection or microscopic residual tumour resection were randomly assigned (1:1) to undergo observation or to receive S-1 (ie, 40 mg, 50 mg, or 60 mg according to body surface area, orally administered twice daily for 4 weeks, followed by 2 weeks of rest for four cycles). Randomisation was performed by the minimisation method, using institution, primary tumour site, and lymph node metastasis as adjustment factors. The primary endpoint was overall survival and was assessed for all randomly assigned patients on an intention-to-treat basis. Safety was assessed in all eligible patients. For the S-1 group, all patients who began the protocol treatment were eligible for a safety assessment. This trial is registered with the University hospital Medical Information Network Clinical Trials Registry (UMIN000011688). FINDINGS: Between Sept 9, 2013, and June 22, 2018, 440 patients were enrolled (observation group n=222 and S-1 group n=218). The data cutoff date was June 23, 2021. Median duration of follow-up was 45·4 months. In the primary analysis, the 3-year overall survival was 67·6% (95% CI 61·0-73·3%) in the observation group compared with 77·1% (70·9-82·1%) in the S-1 group (adjusted hazard ratio [HR] 0·69, 95% CI 0·51-0·94; one-sided p=0·0080). The 3-year relapse-free survival was 50·9% (95% CI 44·1-57·2%) in the observation group compared with 62·4% (55·6-68·4%) in the S-1 group (HR 0·80, 95% CI 0·61-1·04; two-sided p=0·088). The main grade 3-4 adverse events in the S-1 group were decreased neutrophil count (29 [14%]) and biliary tract infection (15 [7%]). INTERPRETATION: Although long-term clinical benefit would be needed for a definitive conclusion, a significant improvement in survival suggested adjuvant S-1 could be considered a standard of care for resected biliary tract cancer in Asian patients. FUNDING: The National Cancer Center Research and the Ministry of Health, Labour, and Welfare of Japan.

Large-scale clinico-genomic profile of non-small cell lung cancer with KRAS G12C: Results from LC-SCRUM-Asia study.

INTRODUCTION: KRAS G12C is an oncogenic driver mutation, accounting for approximately 14% of Caucasian patients with non-small cell lung cancer (NSCLC). Recently, several KRAS G12C-targeted drugs have been developed; however, the clinico-genomic characteristics of NSCLC patients with KRAS G12C remain unclear. MATERIALS AND METHODS: Based on the large-scale prospective lung cancer genomic screening project (LC-SCRUM-Asia) database, the clinico-genomic characteristics and therapeutic outcomes of NSCLC patients with KRAS G12C were evaluated. RESULTS: From March 2015 to March 2021, 10,023 NSCLC patients were enrolled in LC-SCRUM-Asia. KRAS mutations were detected in 1258 patients (14 %), including G12C in 376 (4.0 %), G12D in 289 (3.1 %) and G12V in 251 (2.7 %). The proportions of males and smokers were higher in patients with KRAS G12C than in those with KRAS non-G12C mutations (males: 73 % vs 63 %, p < 0.001; smokers: 89 % vs 76 %, p < 0.001). KRAS G12C-positive tumors showed a higher tumor mutation burden (TMB) (mean, 8.1 mut/Mb, p < 0.001) and a higher percentage of tumors with programmed cell death ligand-1 (PD-L1) expression ≥50 % (52 %, p = 0.08). The overall survival in patients with KRAS G12C (median, 24.6 months) was not different between patients with other mutation subtypes (G12V: 18.2 months, p = 0.23; G12D: 20.6 months, p = 0.65; other KRAS mutations: 18.3 months, p = 0.20). Among KRAS-mutated patients who received immune checkpoint inhibitors (ICIs), the progression-free survival in G12C-positive patients (median, 3.4 months) was similar to that in G12V-positive patients (4.2 months, p = 0.90), but significantly longer than that in G12D- (2.0 months, p = 0.02) and other KRAS mutation-positive patients (2.5 months, p = 0.02). CONCLUSIONS: The frequencies of KRAS G12C were lower in Asian than in Caucasian NSCLC patients. Among the KRAS-mutated NSCLC patients, G12C-positive tumors showed increased immunogenicity, such as high TMB and high PD-L1 expression, and potential sensitivity to ICIs.

Germline variants in cancer-predisposing genes in pancreatic cancer patients with a family history of cancer.

BACKGROUND: Our phase II trial (FABRIC study) failed to verify the efficacy of gemcitabine plus oxaliplatin (GEMOX) in patients with pancreatic ductal adenocarcinoma (PDAC) with a familial or personal history of pancreatic, breast, ovarian or prostate cancer, which suggested that a family and personal history may be insufficient to determine response to platinum-based chemotherapy. METHODS: This ancillary analysis aimed to investigate the prevalence of germline variants of homologous recombination repair (HRR)-related genes and clarify the association of germline variants with the efficacy of GEMOX and patient outcome in PDAC patients. Of 45 patients enrolled in FABRIC study, 27 patients were registered in this ancillary analysis. RESULTS: Of the identified variants in HRR-related genes, one variant was considered pathogenic and eight variants in six patients (22%) were variants of unknown significance (VUS). Objective response to GEMOX was achieved by 43% of the seven patients and tended to be higher than that of patients without such variants (25%). Pathogenic/VUS variant in HRR-related genes was an independent favorable factor for progression-free survival (hazard ratio, 0.322; P = 0.047) and overall survival (hazard ratio, 0.195; P = 0.023) in multivariable analysis. CONCLUSIONS: The prevalence of germline variants in PDAC patients was very low even among patients with a familial/personal history of pancreatic, breast, ovarian or prostate cancer. Patients with one or more germline variants in HRR-related genes classified as pathogenic or VUS may have the potential to obtain better response to GEMOX and have better outcomes.

Effectiveness of Etoposide and Cisplatin vs Irinotecan and Cisplatin Therapy for Patients With Advanced Neuroendocrine Carcinoma of the Digestive System: The TOPIC-NEC Phase 3 Randomized Clinical Trial.

Importance: Etoposide plus cisplatin (EP) and irinotecan plus cisplatin (IP) are commonly used as community standard regimens for advanced neuroendocrine carcinoma (NEC). Objective: To identify whether EP or IP is a more effective regimen in terms of overall survival (OS) in patients with advanced NEC of the digestive system. Design, Setting, and Participants: This open-label phase 3 randomized clinical trial enrolled chemotherapy-naive patients aged 20 to 75 years who had recurrent or unresectable NEC (according to the 2010 World Health Organization classification system) arising from the gastrointestinal tract, hepatobiliary system, or pancreas. Participants were enrolled across 50 institutions in Japan between August 8, 2014, and March 6, 2020. Interventions: In the EP arm, etoposide (100 mg/m2/d on days 1, 2, and 3) and cisplatin (80 mg/m2/d on day 1) were administered every 3 weeks. In the IP arm, irinotecan (60 mg/m2/d on days 1, 8, and 15) and cisplatin (60 mg/m2/d on day 1) were administered every 4 weeks. Main Outcomes and Measures: The primary end point was OS. In total, data from 170 patients were analyzed to detect a hazard ratio (HR) of 0.67 (median OS of 8 and 12 months in inferior and superior arms, respectively) with a 2-sided α of 10% and power of 80%. The pathologic findings were centrally reviewed following treatment initiation. Results: Among the 170 patients included (median [range] age, 64 [29-75] years; 117 [68.8%] male), median OS was 12.5 months in the EP arm and 10.9 months in the IP arm (HR, 1.04; 90% CI, 0.79-1.37; P = .80). The median progression-free survival was 5.6 (95% CI, 4.1-6.9) months in the EP arm and 5.1 (95% CI, 3.3-5.7) months in the IP arm (HR, 1.06; 95% CI, 0.78-1.45). A subgroup analysis of OS demonstrated that EP produced more favorable OS in patients with poorly differentiated NEC of pancreatic origin (HR, 4.10; 95% CI, 1.26-13.31). The common grade 3 and 4 adverse events in the EP vs IP arms were neutropenia (75 of 82 [91.5%] patients vs 44 of 82 [53.7%] patients), leukocytopenia (50 of 82 [61.0%] patients vs 25 of 82 [30.5%] patients), and febrile neutropenia (FN) (22 of 82 [26.8%] patients vs 10 of 82 [12.2%] patients). While incidence of FN was initially high in the EP arm, primary prophylactic use of granulocyte colony-stimulating factor effectively reduced the incidence of FN. Conclusions and Relevance: Results of this randomized clinical trial demonstrate that both EP and IP remain the standard first-line chemotherapy options. Although AEs were generally manageable, grade 3 and 4 AEs were more common in the EP arm. Trial Registration: Japan Registry of Clinical Trials: jRCTs031180005; UMIN Clinical Trials Registry: UMIN000014795.

Phase II study of BKM120 in patients with advanced esophageal squamous cell carcinoma (EPOC1303).

BACKGROUND: PI3K/AKT/mTOR pathway is frequently overactive in esophageal squamous cell carcinoma (ESCC), making it an attractive treatment target. BKM120 is an oral pan-class I PI3K inhibitor with promising activity in several cancers. We prospectively investigated efficacy, safety, and biomarkers of BKM120 in advanced ESCC. We conducted a multicenter phase II study of BKM120 monotherapy in patients with pretreated advanced ESCC. METHODS: BKM120 (100 mg/day) was administered orally in a 28-day cycle. The primary end point was disease control rate (DCR). Tumor samples for all patients were collected for gene alteration analysis in a comprehensive genomic profiling assay. RESULTS: Of 42 patients enrolled, 20 had stable disease and two had confirmed partial response. One ineligible patient was excluded from the primary analysis, which met the primary end point (DCR 51.2%; 95% confidence interval [CI], 35.1-67.1). In the 42 patients, median progression-free survival and overall survival were 2.3 (95% CI 1.8-3.2) and 9.0 (95% CI 6.5-11.4) months, respectively. Common grade 3 or 4 adverse events were rash, anorexia, hyponatremia, and abnormal hepatic function; profiles of these events in this study were similar to those in previous studies of BKM120 monotherapy. No treatment-related deaths occurred. PI3K pathway activation was observed in patients with good clinical response. CONCLUSIONS: BKM120 monotherapy showed promising efficacy and a manageable toxicity profile even in patients with pretreated advanced ESCC. This study showed the potential target PI3K for ESCC, and further confirmatory trial will be necessary to confirm it. Unique ID issued by UMIN: UMIN 000011217.

Impact of Older Age and Medico-social Factors on the Decision to Offer Adjuvant Chemotherapy to Patients With Breast Cancer.

BACKGROUND/AIM: Although clinicians are expected to set a higher threshold for administering adjuvant chemotherapy to older than younger patients with breast cancer, the extent to which older patients are less likely to be offered adjuvant chemotherapy and the medico-social factors that influence decision-making are unclear. PATIENTS AND METHODS: We retrospectively evaluated the correlations of clinicopathological factors, including age (≥75 years vs. <75 years), for all candidates for adjuvant chemotherapy, and of additional medico-social factors, including the number of family members living together, for older patients, with the rate of referral from breast surgeons to medical oncologists. RESULTS: Among 872 candidates for adjuvant chemotherapy, age ≥75 years was significantly correlated with a lower referral rate (24 % vs. 44%, p<0.001). In the analysis by age group, we did not identify specific medicosocial factors that were differentially emphasized, but older patients who lived with ≥2 other family members tended not to be referred to a medical oncologist compared to those who lived alone or with one family member (1/23 vs. 15/47). Although 5 of 22 older patients (23%) who were referred to a medical oncologist actually received adjuvant chemotherapy (vs. 60% of younger patients), all needed treatment modifications. CONCLUSION: Breast surgeons regard age ≥75 years as a key factor for avoiding adjuvant chemotherapy but they also consider similar medico-social factors irrespective of the patient's age regarding the decision to refer patients to medical oncologists.

Clinical Validity of Plasma-Based Genotyping for Microsatellite Instability Assessment in Advanced GI Cancers: SCRUM-Japan GOZILA Substudy.

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.

A Multicenter, Randomized Phase III Study Comparing Platinum Combination Chemotherapy Plus Pembrolizumab With Platinum Combination Chemotherapy Plus Nivolumab and Ipilimumab for Treatment-Naive Advanced Non-Small Cell Lung Cancer Without Driver Gene Alterations: JCOG2007 (NIPPON Study).

BACKGROUND: First-line treatment of non-small cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination chemotherapy together with an immune checkpoint inhibitor, regardless of the expression level of the programmed cell death-1 (PD-1) ligand PD-L1 on tumor cells. Moreover, such chemotherapy plus nivolumab (antibody to PD-1) and ipilimumab (antibody to cytotoxic T lymphocyte-associated protein-4) prolonged survival in advanced NSCLC patients compared with chemotherapy alone. We have now designed a randomized, controlled phase III trial (NIPPON, JCOG2007) to confirm that platinum combination chemotherapy plus nivolumab and ipilimumab is superior to such chemotherapy plus pembrolizumab (antibody to PD-1) for treatment-naive patients with advanced NSCLC. PATIENTS AND METHODS: Chemotherapy-naïve patients aged 20 years or older with a performance status of 0 or 1 are randomly assigned in a 1:1 ratio to receive platinum combination chemotherapy and either pembrolizumab or nivolumab plus ipilimumab. Patients with known genetic driver alterations such as those affecting EGFR or ALK are excluded. Enrollment of 422 patients over 3 years at 55 oncology facilities throughout Japan is planned. The primary endpoint is overall survival. In addition, as ancillary research, metagenomic analysis of the gut microbiota will be performed with fecal samples collected before treatment onset, and the results will be examined for their association to therapeutic effect and adverse events. CONCLUSION: If the primary endpoint is met, platinum combination chemotherapy together with nivolumab plus ipilimumab will be established as a new, more effective standard treatment for advanced NSCLC.

Comparison of Treatment Completion Rate Between Conventional and Dose-dense Doxorubicin and Cyclophosphamide (AC) Followed by a Taxane in Patients With Breast Cancer: A Propensity Score-matched Analysis.

BACKGROUND/AIM: To maximize the effect of perioperative chemotherapy in breast cancer, it is critical to keep the relative dose intensity (RDI) high. While bi-weekly doxorubicin and cyclophosphamide, dose-dense AC (ddAC), instead of tri-weekly conventional AC (cAC) followed by a taxane has been adopted as standard perioperative chemotherapy, postponement or discontinuation are sometimes experienced during ddAC or subsequent taxane phase. This study aimed at evaluating whether ddAC, compared to cAC, was associated with reduced RDI. PATIENTS AND METHODS: We compared ddAC and cAC, both followed by a taxane, for perioperative breast cancer regarding the proportion of completion of planned treatment (%completion), defined as an RDI ≥85% for both AC and taxane phases. RESULTS: There was no remarkable difference between the groups in patient characteristics after propensity score matching (n=46 in ddAC, and n=86 in cAC). The %completion was similar between the groups (67.4% vs. 65.1%). Most other endpoints related to RDI were similar between groups. The incidence of pneumonia was higher in the ddAC group (13% vs. 3%) including one Pneumocystis jiroveci pneumonia. CONCLUSION: ddAC followed by a taxane can be considered with sufficient supportive measures and precautions for pneumonia.