Assessing the ability of the Cancer and Aging Research Group tool to predict chemotherapy toxicity in older Japanese patients: A prospective observational study.

INTRODUCTION: The Cancer and Aging Research Group (CARG) prediction tool was designed in the United States to predict grade ≥ 3 chemotherapy-related adverse events (CRAE) in older patients. However, its usefulness among Japanese people, who have different sensitivities to anticancer drugs and life expectancy, remains unknown. We aimed to prospectively evaluate the utility of the CARG tool for predicting severe CRAE in older Japanese patients with cancer. MATERIAL AND METHODS: Patients with solid tumors aged 65 years and older who commenced anticancer drug regimens from April 2018 to October 2020 were divided into three groups (low, medium, and high-risk) based on their CARG risk scores. Toxicity was prospectively observed by a pharmacist. The primary objective was to evaluate the correlation between the incidence of grade ≥ 3 CRAE and the CARG risk score. The secondary objective was to evaluate hematological and non-hematological toxicities. CRAE incidence was compared among the three groups using a closed testing procedure: (1) Cochran-Armitage test for trend and (2) chi-square test for paired comparison. RESULTS: The patients (N = 165) had a median age of 71 years (range: 65-89 years). CRAE in patients divided into low-, medium-, and high-risk groups, based on CARG risk scores, were 39%, 55%, and 82%, respectively (low vs high; p < 0.001, medium vs high; p < 0.01). The incidence of severe hematologic toxicity was 37%, 35%, and 50% in the low-, medium-, and high-risk groups, respectively; the incidence of severe non-hematologic toxicity was 15%, 36%, and 65%, respectively (low vs medium; p < 0.01, low vs high; p < 0.001, and medium vs high; p < 0.01). DISCUSSION: To our knowledge, this is the first prospective observational study to validate the CARG prediction tool in older Japanese patients with cancer. The CARG risk score may be effective in predicting the development of non-hematologic toxicities. These results should be considered when administering chemotherapy to older Japanese patients with advanced solid tumors.

Mutation spectra of the BRCA1/2 genes in human breast and ovarian cancer and germline.

Annotating genomic sequence alterations is sometimes a difficult decision, particularly in missense variants with uncertain pathogenic significance and also in those presumed as germline pathogenic variants. We here suggest that mutation spectrum may also be useful for judging them. From the public databases, 982 BRCA1/1861 BRCA2 germline missense variants and 294 BRCA1/420 BRCA2 somatic missense variants were obtained. We then compared their mutation spectra, i.e., the frequencies of two transition- and four transversion-type mutations, in each category. Intriguingly, in BRCA1 variants, A:T to C:G transversion, which was relatively frequent in the germline, was extremely rare in somatic, particularly breast cancer, cells (p = .03). Conversely, A:T to T:A transversion was most infrequent in the germline, but not rare in somatic cells. Thus, BRCA1 variants with A:T to T:A transversion may be suspected as somatic, and those with A:T to C:G as being in the germline. These tendencies of mutation spectrum may also suggest the biological and chemical origins of the base alterations. On the other hand, unfortunately, variants of uncertain significance (VUS) were not distinguishable by mutation spectrum. Our findings warrant further and more detailed studies.

New predictors of microvascular invasion for small hepatocellular carcinoma ≤ 3 cm.

BACKGROUND: Microvascular invasion (MVI) is a risk factor for postoperative recurrence of hepatocellular carcinoma (HCC), even in early-stage HCC. In small HCC ≤ 3 cm, treatment options include anatomical resection or non-anatomical resection, and MVI has a major effect on treatment decisions. We aimed to identify the predictors of MVI in small HCC ≤ 3 cm. METHODS: We retrospectively studied 129 patients with very early or early-stage HCC ≤ 3 cm who had undergone 18F-fluorodeoxyglucose positron emission tomography/computed tomography and subsequent hepatic resection from January 2016 to August 2023. These patients were divided into the derivation cohort (n = 86) and validation cohort (n = 43). We examined the risk factors for MVI using logistic regression analysis, and established a predictive scoring system in the derivation cohort. We evaluated the accuracy of our scoring system in the validation cohort. RESULTS: In the derivation cohort, a Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3), prothrombin induced by vitamin K deficiency or antagonist-II (PIVKA-II), and metabolic tumor volume (MTV) were independent predictors of MVI. We established the scoring system using these three factors. In the validation test, there were no MVI-positive cases with a score of 0 and 1, and all cases were MVI-positive with a score of 4. Moreover, with a score ≥ 2, the sensitivity, specificity, and accuracy of our scoring system were 100%, 71.4%, and 81.4%, respectively. CONCLUSIONS: Our scoring system can accurately predict MVI in small HCC ≤ 3 cm, and could contribute to establishing an appropriate treatment strategy.

A multicenter retrospective observational NAPOLEON2 study of nanoliposomal irinotecan with fluorouracil and folinic acid in patients with unresectable pancreatic cancer.

Nanoliposomal irinotecan with fluorouracil and folinic acid (NFF) is a standard regimen after gemcitabine-based therapy for patients with unresectable or recurrent pancreatic cancer. However, there are limited clinical data on its efficacy and safety in the real-world. We therefore initiated a retrospective and prospective observational study (NAPOLEON-2). The results of the retrospective part were reported herein. In this retrospective study, we evaluated 161 consecutive patients who received NFF as second-or-later-line regimen. The main endpoint was overall survival (OS), and the other endpoints were response rate, disease control rate, progression-free survival (PFS), dose intensity, and adverse events (AEs). The median age was 67 years (range, 38-85 years). The median OS and PFS were 8.1 and 3.4 months, respectively. The objective response and disease control rates were 5% and 52%, respectively. The median relative dose intensity was 81.6% for nanoliposomal irinotecan and 82.9% for fluorouracil. Grade 3 or 4 hematological and nonhematological AEs occurred in 47 and 42 patients, respectively. Common grade 3 or 4 AEs included neutropenia (24%), anorexia (12%), and leukocytopenia (12%). Subanalysis of patients treated with second-line and third-or-later-line demonstrated no statistical significant difference in OS (7.6 months vs. 9.1 months, respectively; hazard ratio, 0.92; 95% confidence interval, 0.64-1.35; p = 0.68). In conclusion, NFF has acceptable efficacy and safety profile even in real-world clinical settings. The prospective study is in progress to validate these findings.

Maximum resistance pressure at the time of lung tissue rupture after porcine lung transection using automatic linear staplers with different reinforcement methods.

PURPOSES: Polyglycolic acid (PGA) sheets, fibrin glue, and staple line reinforcement are frequently used to prevent air leakage during lung resection. However, the optimal staple-line reinforcement method remains unclear. METHODS: Cranial lung lobes of pigs were used to evaluate different staple line reinforcement methods (n = 6). Ventilator-assisted manometry was used to measure the maximum resistance pressure at the time of rupture of the lung tissue after stapling. RESULTS: The mean maximum resistance pressures at the time of lung tissue rupture after using the stapler alone, stapler with PGA sheet and fibrin glue, and stapler with reinforcement were 38.0 cmH2O, 51.3 cmH2O, and 62.7 cmH2O, respectively. A significant increase in the maximum resistance pressure was observed with stapler reinforcement (P < 0.001), while the differences between the other groups were not statistically significant (P = 0.055, P = 0.111). A histological assessment revealed disruption of alveolar structures near the needle-stitching site in the stapler alone, and in the stapler with PGA sheet and fibrin glue groups. Pleural rupture near the staple line was observed in the stapler with reinforcement group. CONCLUSIONS: The maximum resistance pressure before air leakage was significantly higher when using a stapler with reinforcement than when using a stapler alone.

Phase 2 trial of crizotinib in Japanese patients with advanced NSCLC harboring a MET gene alteration: a Co-MET study.

BACKGROUND: MET exon 14 skipping mutations occur in 3-4% and MET high amplifications occur in < 1% of patients with non-small-cell lung cancer (NSCLC). Crizotinib, a selective ATP-competitive small-molecule inhibitor of c-Met, ALK, and ROS1 tyrosine kinases, has shown activity in cancer models with various types of MET activation. METHODS: The Co-MET study is a single-arm phase 2 trial to assess the safety and efficacy of crizotinib in MET inhibitor-naïve patients with advanced NSCLC harboring MET exon 14 skipping mutation (cohort 1) or high MET gene copy number of ≥ 7 (cohort 2). The primary endpoint was the objective response rate (ORR) per RECIST v1.1 by independent radiology review in cohort 1. The key secondary endpoints were the duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 28 patients (23 in cohort 1 and 5 in cohort 2) were enrolled between March 2018 and February 2020. The primary endpoint was met as the ORR (90% confidence interval: CI) in cohort 1 was 38.1% (20.6-58.3). Median DoR, PFS, and OS (95% CI) were 7.6 (1.9-NE), 5.7 (2.1-11.3), 9.1 (4.0-19.9) months, respectively, in cohort 1. ORR in cohort 2 was 40.0% (18.9-92.4). The safety signals were generally consistent with the known safety profile of crizotinib. CONCLUSIONS: Crizotinib showed a clinical activity similar to that of tepotinib and capmatinib in patients with NSCLC harboring MET exon 14 skipping mutations. CLINICAL TRIAL INFORMATION: UMIN000031623.

Switching from FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab based on early tumor shrinkage in RAS wild-type metastatic colorectal cancer: A phase II trial (HYBRID).

BACKGROUND: Long-term anti-EGFR antibody treatment increases the risk of severe dermatologic toxicities. This single-arm, phase II trial aimed to investigate the strategy of switching from cetuximab to bevacizumab in combination with FOLFIRI based on early tumor shrinkage (ETS) in patients with RAS wild-type metastatic colorectal cancer (mCRC). METHODS: Radiologic assessment was performed to evaluate ETS, defined as ≥20% reduction in the sum of the largest diameters of target lesions 8 weeks after the introduction of FOLFIRI plus cetuximab. ETS-negative patients switched to FOLFIRI plus bevacizumab, whereas ETS-positive patients continued FOLFIRI plus cetuximab for eight more weeks, with a switch to FOLFIRI plus bevacizumab thereafter. The primary endpoint was progression-free survival. RESULTS: This trial was prematurely terminated due to poor accrual after a total enrollment of 30 patients. In 29 eligible patients, 7 were ETS-negative and 22 were ETS-positive. Two ETS-negative patients and 17 ETS-positive patients switched to FOLFIRI plus bevacizumab 8 weeks and 16 weeks after initial FOLFIRI plus cetuximab, respectively. Median progression-free and overall survival durations were 13.4 and 34.7 months, respectively. Six (20%) patients experienced grade ≥3 paronychia, which improved to grade ≤2 by 18 weeks. Grade ≥3 acneiform rash, dry skin, and pruritus were not observed in any patients. CONCLUSIONS: Our novel treatment strategy delivered acceptable survival outcomes and reduced severe dermatologic toxicities.

Identification of MUC1-C as a Target for Suppressing Progression of Head and Neck Squamous Cell Carcinomas.

The MUC1-C protein is aberrantly expressed in adenocarcinomas of epithelial barrier tissues and contributes to their progression. Less is known about involvement of MUC1-C in the pathogenesis of squamous cell carcinomas (SCC). Here, we report that the MUC1 gene is upregulated in advanced head and neck SCCs (HNSCC). Studies of HNSCC cell lines demonstrate that the MUC1-C subunit regulates expression of (i) RIG-I and MDA5 pattern recognition receptors, (ii) STAT1 and IFN regulatory factors, and (iii) downstream IFN-stimulated genes. MUC1-C integrates chronic activation of the STAT1 inflammatory pathway with induction of the ∆Np63 and SOX2 genes that are aberrantly expressed in HNSCCs. In extending those dependencies, we demonstrate that MUC1-C is necessary for NOTCH3 expression, self-renewal capacity, and tumorigenicity. The findings that MUC1 associates with ∆Np63, SOX2 and NOTCH3 expression by single-cell RNA sequencing analysis further indicate that MUC1-C drives the HNSCC stem cell state and is a target for suppressing HNSCC progression. SIGNIFICANCE: This work reports a previously unrecognized role for MUC1-C in driving STAT1-mediated chronic inflammation with the progression of HNSCC and identifies MUC1-C as a druggable target for advanced HNSCC treatment.

Immune checkpoint status and oncogenic mutation profiling of rectal cancer after neoadjuvant chemotherapy (KSCC1301-A2).

Aim: Immune checkpoint inhibitors (ICIs) are less effective in mismatch repair (MMR)-proficient (pMMR) colorectal cancers (CRCs) than in MMR-deficient CRCs. Here, we investigated changes in the tumor microenvironment after neoadjuvant chemotherapy (NAC) without radiotherapy in locally advanced rectal cancer (LARC) and the potential of ICIs as therapeutic agents for pMMR CRCs. Methods: This was an ad hoc analysis of a KSCC1301 randomized phase II trial in which patients with untreated resectable LARC were randomly assigned to receive S-1 and oxaliplatin or folinic acid, 5-fluorouracil, and oxaliplatin as NAC. Forty-nine patients were studied in this ad hoc analysis. As a reference cohort, we assessed 25 rectal cancer patients who underwent surgery without NAC outside the randomized trial. Immune checkpoint molecules (ICMs; PD-1, PD-L1, CTLA-4, LAG3), tumor-infiltrating lymphocytes (TILs; CD8, FOXP3), and other related proteins were evaluated by immunohistochemistry. Next-generation sequencing (NGS) using Oncomine™ Comprehensive Assay version 3 was conducted in 23 patients. Results: The expression levels of PD-1, CTLA-4, and LAG3 in the NAC group were significantly higher than in reference patients (p < 0.001). Additionally, the infiltration of CD8+ and FOXP3+ T cells, and the CD8/FOXP3 ratio were significantly higher in the NAC group than in reference patients (p < 0.0001). NGS analysis revealed no specific gene alteration related to TILs or ICMs. Conclusion: We demonstrated changes in the tumor immune microenvironment after NAC in pMMR rectal cancer. NAC was associated with increased expression of ICMs and TILs. Rectal cancer could be susceptible to combined immunotherapy with chemotherapy.

Phase II Trial of Adjuvant Atezolizumab Therapy in Elderly Patients with Completely Resected Stage II/III Non-Small Cell Lung Cancer: RELIANCE Trial.

INTRODUCTION: Atezolizumab following platinum chemotherapy and complete pulmonary resection has become the new standard of adjuvant care for patients with stage II-III non-small cell lung cancer (NSCLC) expressing programmed death-ligand 1 (PD-L1). However, the efficacy and safety of postoperative adjuvant therapy and subsequent atezolizumab in patients aged 75 and older have not been established. METHODS: Patients with completely resected stage II-III NSCLC aged 75 and older will be prospectively registered in this single-arm phase II study. The enrolled patients will receive cisplatin plus vinorelbine (CDDP + VNR) followed by atezolizumab for up to 12 months. PD-L1 expression in at least 1% of cells will be confirmed by immunohistochemical staining. We plan to enroll 33 patients over 1 year at 25 institutions in Japan. The primary endpoint is the completion rate of adjuvant treatment (CDDP + VNR initiation to atezolizumab completion). CONCLUSION: The present study represents the first prospective trial of the tolerability of postoperative adjuvant therapy with immune checkpoint inhibitors in elderly individuals. The results of this trial might help promote postoperative adjuvant immunotherapy in the future for the elderly.

Impact of central nervous system metastasis after complete resection of lung adenocarcinomas harboring common EGFR mutation - A real-world database study in Japan: The CReGYT-01 EGFR study.

OBJECTIVES: To clarify the impact of central nervous system (CNS) metastasis on performance status (PS) at relapse, on subsequent treatment(s), and on survival of patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutation. METHODS: We conducted the multicenter real-world database study for patients with radical resections for lung adenocarcinomas between 2015 and 2018 at 21 centers in Japan. EGFR mutational status was examined at each center. RESULTS: Of 4181 patients enrolled, 1431 underwent complete anatomical resection for lung adenocarcinoma harboring common EGFR mutations. Three-hundred-and-twenty patients experienced disease relapse, and 78 (24%) had CNS metastasis. CNS metastasis was significantly more frequent in patients with conventional adjuvant chemotherapy than those without (30% vs. 20%, P = 0.036). Adjuvant chemotherapy did not significantly improve relapse-free survival at any pathological stage (adjusted hazard ratio for stage IA2-3, IB, and II-III was 1.363, 1.287, and 1.004, respectively). CNS metastasis did not affect PS at relapse. Subsequent treatment, mainly consisting of EGFR-tyrosine kinase inhibitors (TKIs), could be equally given in patients with or without CNS metastasis (96% vs. 94%). Overall survival after relapse was equivalent between patients with and without CNS metastasis. CONCLUSION: The efficacy of conventional adjuvant chemotherapy may be limited in patients with lung adenocarcinoma harboring EGFR mutations. CNS metastasis is likely to be found in practice before deterioration in PS, and may have little negative impact on compliance with subsequent EGFR-TKIs and survival after relapse. In this era of adjuvant TKI therapy, further prospective observational studies are desirable to elucidate the optimal management of CNS metastasis.

Treatment-related adverse events of combination chemoimmunotherapy versus chemotherapy alone in first-line treatment for non-small cell lung cancer: a systematic review and meta-analysis of randomized clinical trials.

Background: Numerous meta-analyses have examined immunotherapy-induced adverse events (AEs) in non-small cell lung cancer (NSCLC). However, there is limited research comparing AEs from combination chemoimmunotherapy versus chemotherapy alone in the first-line NSCLC treatment, particularly regarding specific toxic symptoms and hematological toxicities associated with the addition of immune checkpoint inhibitors (ICIs). Methods: We conducted a meta-analysis of randomized clinical trials (RCTs) comparing ICIs + non-ICIs versus non-ICIs alone as first-line therapy in NSCLC, sourced from PubMed and Scopus databases. Our objective was to assess treatment-related AEs in both regimens, focusing on identifying the more prevalent toxic symptoms and hematological toxicities with ICI treatment. We calculated the relative risks (RRs) and 95% confidence intervals (CIs), and estimated the pooled RRs and 95% CIs using common- or random-effects models. Results: Our analysis included 10 trials with 6,008 patients. Combination chemoimmunotherapy significantly increased the risk of grade 3 or higher treatment-related AEs, treatment discontinuation, and deaths due to treatment-related AEs. Moreover, patients receiving combination chemoimmunotherapy had a significantly higher risk of certain toxic symptoms (all-grade: vomiting, diarrhea, and constipation; high-grade: fatigue and diarrhea) and pneumonitis (both all-grade and high-grade). Conclusions: These findings offer crucial insights into the toxicity profile of combination chemoimmunotherapy, serving as a valuable resource for clinicians managing lung cancer care.

Validation of Japanese indication criteria for deceased donor liver transplantation for hepatocellular carcinoma: Analysis of US national registry data.

AIM: The Japanese indication criteria for liver transplantation (LT) for hepatocellular carcinoma (HCC) have been updated based on living donor LT data to include either the Milan criteria (MC) or the 5-5-500 rule, which requires a nodule size of ≤5 cm, ≤5 nodules, and an alpha-fetoprotein (AFP) level ≤500 ng/mL. We aimed to validate the 5-5-500 rule and the MC for deceased donor LT (DDLT). METHODS: Using national registry data from the United States from 2010 to 2014, we separated DDLT patients into four groups based on the MC and the 5-5-500 rule. The AFP values were stratified into categories: ≤100, 101-300, 301-500, and >500 ng/mL. RESULTS: The 5-year survival rate was significantly lower for patients in the groups within MC/beyond 5-5-500 (56.3%) or beyond MC/5-5-500 (60.7%) than for patients in the groups within MC/5-5-500 (76.2%) and beyond MC/within 5-5-500 (72.3%) (p < 0.01). Hepatocellular carcinoma recurrence at 5 years was highest for the within MC/beyond 5-5-500 (25.4%) group, followed by the beyond MC/within 5-5-500 (13.1%), beyond MC/5-5-500 (9.6%), and within MC/5-5-500 (7.4%) groups. The stratified 5-year survival rates after DDLT were 76.5%, 72.4%, 58.4%, and 55.6% in the AFP ≤100, 101-300, 301-500, and >500 categories, respectively (p < 0.01). CONCLUSION: The 5-5-500 rule guides the appropriate selection of patients with HCC for DDLT. Patients with AFP levels from 300 to 500 ng/mL had inferior outcomes even when they met the 5-5-500 rule, so further investigation is needed to guide their treatment.

Prospective observational study to explore genes and proteins predicting efficacy and safety of brigatinib for ALK-gene rearranged non-small-cell lung cancer: study protocol for ABRAID study (WJOG11919L).

Background: ALK-tyrosine kinase inhibitors (ALK-TKIs) are effective for treating non-small-cell lung cancer with ALK gene rearrangement; however, resistance is inevitable. Brigatinib is a unique ALK-TKI that is effective against many resistance mutations. However, data on factors associated with its efficacy and resistance mechanisms are limited. Objectives: This study will evaluate the efficacy and safety of brigatinib in the real world and explore factors related to its efficacy, safety, and resistance mechanisms. Design: Prospective observational study. Ethics: This study is approved by the Ethics Committee of Wakayama Medical University. Written informed consent will be obtained from all patients before study-related procedures. Methods and analysis: This study comprises three cohorts. Cohorts A, B, and 0 will enroll patients receiving alectinib as the first ALK-TKI, receiving alectinib as the first ALK-TKI and subsequently cytotoxic agents and/or lorlatinib after alectinib, and without a history of ALK-TKI, respectively. Overall, 100, 30, and 50 patients will be enrolled in Cohorts A, B, and 0, respectively. Circulating tumor DNA before starting brigatinib and at disease progression will be analyzed in all cohorts using a hypersensitive next-generation sequencing (NGS) PGDx Elio plasma resolve panel. Serum protein levels will be analyzed using the Milliplex xMAP assay system with a Luminex 200 (Luminex, Austin, USA). The enrollment period is 31 months and the patients will be observed for 2 years after enrollment. Archived tissues will be collected for NGS analysis, gene expression analysis, and immunohistochemistry staining 1 year after completion of registration. Quality of life and safety evaluation using electronic patient-reported outcomes will be investigated. Discussion: This study will elucidate predictors of ALK-TKI efficacy and resistance mechanisms and evaluate the efficacy and safety of brigatinib in a real-world setting. The results will provide crucial information for establishing treatment strategies, discovering novel biomarkers, and developing new therapeutic agents. Trial registration: UMIN000042439.

MUC1-C Is a Common Driver of Acquired Osimertinib Resistance in NSCLC.

INTRODUCTION: Osimertinib is an irreversible EGFR tyrosine kinase inhibitor approved for the first-line treatment of patients with metastatic NSCLC harboring EGFR exon 19 deletions or L858R mutations. Patients treated with osimertinib invariably develop acquired resistance by mechanisms involving additional EGFR mutations, MET amplification, and other pathways. There is no known involvement of the oncogenic MUC1-C protein in acquired osimertinib resistance. METHODS: H1975/EGFR (L858R/T790M) and patient-derived NSCLC cells with acquired osimertinib resistance were investigated for MUC1-C dependence in studies of EGFR pathway activation, clonogenicity, and self-renewal capacity. RESULTS: We reveal that MUC1-C is up-regulated in H1975 osimertinib drug-tolerant persister cells and is necessary for activation of the EGFR pathway. H1975 cells selected for stable osimertinib resistance (H1975-OR) and MGH700-2D cells isolated from a patient with acquired osimertinib resistance are found to be dependent on MUC1-C for induction of (1) phospho (p)-EGFR, p-ERK, and p-AKT, (2) EMT, and (3) the resistant phenotype. We report that MUC1-C is also required for p-EGFR, p-ERK, and p-AKT activation and self-renewal capacity in acquired osimertinib-resistant (1) MET-amplified MGH170-1D #2 cells and (2) MGH121 Res#2/EGFR (T790M/C797S) cells. Importantly, targeting MUC1-C in these diverse models reverses osimertinib resistance. In support of these results, high MUC1 mRNA and MUC1-C protein expression is associated with a poor prognosis for patients with EGFR-mutant NSCLCs. CONCLUSIONS: Our findings reveal that MUC1-C is a common effector of osimertinib resistance and is a potential target for the treatment of osimertinib-resistant NSCLCs.

First-Line Osimertinib for Previously Untreated Patients With NSCLC and Uncommon EGFR Mutations: The UNICORN Phase 2 Nonrandomized Clinical Trial.

Importance: Non-small cell lung cancer (NSCLC) with uncommon EGFR mutations is a rare subgroup, composing 14% of all EGFR mutations. Objective: To determine the usefulness of osimertinib in previously untreated patients with metastatic NSCLC harboring uncommon EGFR mutations, excluding exon 20 insertion mutations. Design, Setting, and Participants: This multicenter, open-label, single-group, phase 2 nonrandomized clinical trial enrolled patients from April 10, 2020, to May 31, 2022, with a follow-up of 6 months from the date the last patient was enrolled. The study enrolled 42 patients with uncommon EGFR mutations, of whom 40 were eligible. Intervention: Osimertinib, 80 mg once daily, was administered orally to patients. Main Outcomes and Measures: The primary end point was the overall response rate (ORR). The secondary end points were disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), duration of response (DoR), and safety of osimertinib. Patients were included in the study on an intention-to-treat basis. Results: Of the 40 eligible patients, 22 were men (55.0%) and the median age was 72 years (range, 39.0-88.0 years). The most common mutations were G719X (20 [50.0%]), S768I (10 [25.0%]), and L861Q (8 [20.0%]). The ORR was 55.0% (90% CI, 40.9%-68.5%) and the DCR was 90.0% (95% CI, 76.3%-97.2%). The median PFS was 9.4 months (95% CI, 3.7-15.2 months) after a median follow-up of 12.7 months (range, 2.7-30.7 months). The median TTF was 9.5 months (95% CI, 5.6-30.3 months), median OS was not reached (NR; 95% CI, 19.3 months to NR), and median DoR was 22.7 months (95% CI, 9.5 months to NR). The ORR for patients with solitary or compound uncommon EGFR mutations was 45.5% (90% CI, 26.9%-65.3%) and 66.7% (90% CI, 43.7%-83.7%), respectively. Median PFS for patients with solitary or compound uncommon EGFR mutations was 5.4 months (95% CI, 3.6-22.7 months) and 9.8 months (95% CI, 5.1 months to NR), respectively. Median OS for patients with solitary or compound uncommon EGFR mutations was 23.0 months (95% CI, 12.3 months to NR) and NR, respectively. Median DoR for patients with solitary or compound uncommon EGFR mutations was 22.7 months (95% CI, 3.6-22.7 months) or NR (95% CI, 5.7 months to NR), respectively. Grade 3 or 4 adverse events were reported by 11 patients (27.5%), and 5 patients (12.5%) developed interstitial lung disease. All adverse events were manageable, and there were no treatment-related deaths. Conclusions and Relevance: Osimertinib showed clinical activity with manageable toxic effects among previously untreated patients with metastatic NSCLC harboring uncommon EGFR mutations other than exon 20 insertion mutations. The results support the use of osimertinib as a treatment option for this patient population. Trial Registration: Japan Registry of Clinical Trials Identifier: jRCTs071200002.

Biomarker Testing in Patients With Unresectable Advanced or Recurrent Non-Small Cell Lung Cancer.

Importance: Biomarker testing for driver mutations is essential for selecting appropriate non-small cell lung cancer (NSCLC) treatment but is insufficient. Objective: To investigate the status of biomarker testing and drug therapy for NSCLC in Japan for identifying problems in treatment. Design, Setting, and Participants: The REVEAL cohort study included retrospective data collection and prospective follow-up from 29 institutions across Japan. Of 1500 patients diagnosed with advanced or recurrent NSCLC between January 1 and March 18, 2021, 1479 were eligible. Cases recognized at the wrong clinical stage (n = 12), diagnosed outside the study period (n = 6), not treated according to eligibility criteria before recurrence (n = 2), and with deficient consent acquisition procedure (n = 1) were excluded. Main Outcomes and Measures: The primary end point was the biomarker testing status. Treatment-related factors were examined. Results: Among the 1479 patients included in the analysis, the median age was 72 (range, 30-95) years; 1013 (68.5%) were men; 1161 (78.5%) had an Eastern Cooperative Oncology Group performance status 0 or 1; 1097 (74.2%) were current or past smokers; and 947 (64.0%) had adenocarcinoma. Biomarker status was confirmed in 1273 patients (86.1%). Multigene testing was performed in 705 cases (47.7%); single-gene testing, in 847 (57.3%); and both, in 279 (18.9%). Biomarker testing was performed for EGFR in 1245 cases (84.2%); ALK, in 1165 (78.8%); ROS1, in 1077 (72.8%); BRAF, in 803 (54.3%); and MET, in 805 (54.4%). Positivity rates among 898 adenocarcinoma cases included 305 (34.0%) for EGFR, 29 (3.2%) for ALK, 19 (2.1%) for ROS1, 11 (1.2%) for BRAF, and 14 (1.6%) for MET. Positivity rates among 375 nonadenocarcinoma cases were 14 (3.7%) for EGFR, 6 (1.6%) for ALK, 1 (0.3%) for ROS1, 3 (0.8%) for BRAF, and 8 (2.1%) for MET. Poor physical status, squamous cell carcinoma, and other comorbidities were associated with hampered multigene testing. Targeted therapy was received as first-line treatment by 263 of 278 cases (94.6%) positive for EGFR, 25 of 32 (78.1%) positive for ALK, 15 of 24 (62.5%) positive for ROS1, 9 of 12 (75.0%) positive for BRAF, and 12 of 19 (63.2%) positive for MET. Median overall survival of patients with positive findings for driver gene alteration and who received targeted therapy was 24.3 (95% CI, not reported) months; with positive findings for driver gene alteration and who did not receive targeted therapy, 15.2 (95% CI, 7.7 to not reported) months; and with negative findings for driver gene alteration, 11.0 (95% CI, 10.0-12.5) months. Multigene testing for nonadenocarcinomas and adenocarcinomas accounted for 705 (47.7%) of all NSCLC cases. Conclusions and Relevance: These findings suggest that multigene testing has not been sufficiently implemented in Japan and should be considered prospectively, even in nonadenocarcinomas, to avoid missing rare driver gene alterations.

Efficacy of second-line chemotherapy after treatment with gemcitabine plus nab-paclitaxel or FOLFIRINOX in patients with metastatic pancreatic cancer.

First-line chemotherapy for patients with metastatic pancreatic cancer (MPC) includes gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX (FFX). However, the efficacy of second-line chemotherapy and the role of combination chemotherapy in clinical practice is still unknown. Data was gathered from 14 hospitals in the Kyushu area of Japan from December 2013 to March 2017. The median overall survival (mOS) from second-line treatment was contrasted between patients who received second-line chemotherapy (CT group) and those who received the best supportive care (BSC group). Furthermore, the mOS of combination chemotherapy was compared to mono chemotherapy in the CT group. To control possible bias in the selection of treatment, we performed a propensity score-adjusted analysis. A total of 255 patients received GnP or FFX as first-line chemotherapy. There were 156 in the CT group and 77 in the BSC group of these. The CT group had a significantly longer mOS than the BSC group (5.2 vs. 2.6 months; adjusted hazard ratio (HR) 0.38; 95% CI 0.27-0.54). In the CT group, 89 patients received combination chemotherapy while 67 received mono chemotherapy. The mOS did not differ significantly between the combination and mono chemotherapy groups (5.5 vs. 4.8 months; adjusted HR 0.88; 95% CI 0.58-1.33). Among patients with MPC receiving second-line treatment, the CT group had a significantly longer mOS than the BSC group, but combination chemotherapy conferred no improvement in survival compared to mono chemotherapy.

Efficacy of 3-day versus 5-day aprepitant regimens for long-delayed chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based chemotherapy.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) is an ongoing problem. While effectiveness of triplet antiemetic regimens in the delayed CINV phase (24-120 hours after administration of chemotherapy) has been studied, their effectiveness in the long-delayed phase (120-168 hours post-administration) is unknown. We compared the efficacy of 3- and 5-day courses of a triplet antiemetic prophylaxis containing aprepitant (APR) in controlling long-delayed CINV after cisplatin (CDDP)-based chemotherapy. RESEARCH DESIGN AND METHODS: We obtained patient-level data from a nationwide, multicenter, prospective observational study in Japan. The incidence and timing of CINV after 3- and 5-day APR-containing regimens were compared using inverse probability treatment weighting. RESULTS: The analysis included 380 patients. The incidence rates of long-delayed nausea and vomiting were significantly reduced for the 5-day compared with the 3-day regimen (29.1% vs. 22.2%, p = 0.0042; 6.7% vs. 0%, p < 0.0001, respectively). Among those without CINV, vomiting was not reported after day 2 in the 5-day APR group but increased after day 4 in the 3-day APR group. CONCLUSION: A 5-day regimen triplet antiemetic prophylaxis with APR decreased long-delayed vomiting compared with a 3-day regimen in patients receiving CDDP-based chemotherapy. However, the 5-day regimen showed no advantage over the 3-day regimen against long-delayed nausea.