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Pembrolizumab; Non-small-cell lung cancer Pembrolizumab; Cáncer de pulmón de células no pequeñas Pembrolizumab; Càncer de pulmó de cèl·lules no petites Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present 5-year outcomes from the phase 3 KEYNOTE-189 study (ClinicalTrials.gov identifier: NCT02578680). Eligible patients with previously untreated metastatic nonsquamous non-small-cell lung cancer without EGFR/ALK alterations were randomly assigned 2:1 to pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles with pemetrexed and investigator's choice of carboplatin/cisplatin for four cycles, followed by maintenance pemetrexed until disease progression or unacceptable toxicity. Primary end points were overall survival (OS) and progression-free survival (PFS). Among 616 randomly assigned patients (n = 410, pembrolizumab plus pemetrexed-platinum; n = 206, placebo plus pemetrexed-platinum), median time from random assignment to data cutoff (March 8, 2022) was 64.6 (range, 60.1-72.4) months. Hazard ratio (95% CI) for OS was 0.60 (0.50 to 0.72) and PFS was 0.50 (0.42 to 0.60) for pembrolizumab plus platinum-pemetrexed versus placebo plus platinum-pemetrexed. 5-year OS rates were 19.4% versus 11.3%. Toxicity was manageable. Among 57 patients who completed 35 cycles of pembrolizumab, objective response rate was 86.0% and 3-year OS rate after completing 35 cycles (approximately 5 years after random assignment) was 71.9%. Pembrolizumab plus pemetrexed-platinum maintained OS and PFS benefits versus placebo plus pemetrexed-platinum, regardless of programmed cell death ligand-1 expression. These data continue to support pembrolizumab plus pemetrexed-platinum as a standard of care in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations.

Although nanoliposomal irinotecan combined with 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV) has been used to treat first-line resistant unresectable pancreatic cancer, the efficacy and safety data among the elderly remain limited. We retrospectively analyzed clinical outcomes among elderly patients. Patients treated with nal-IRI+5-FU/LV were assigned to the elderly (≥75 years) and non-elderly (

PURPOSE The phase III PACIFIC trial compared durvalumab with placebo in patients with unresectable, stage III non–small-cell lung cancer and no disease progression after concurrent chemoradiotherapy. Consolidation durvalumab was associated with significant improvements in the primary end points of overall survival (OS; stratified hazard ratio [HR], 0.68; 95% CI, 0.53 to 0.87; P = .00251) and progression-free survival (PFS [blinded independent central review; RECIST v1.1]; stratified HR, 0.52; 95% CI, 0.42 to 0.65; P < .0001), with manageable safety. We report updated, exploratory analyses of survival, approximately 5 years after the last patient was randomly assigned. METHODS Patients with WHO performance status 0 or 1 (any tumor programmed cell death-ligand 1 status) were randomly assigned (2:1) to durvalumab (10 mg/kg intravenously; administered once every 2 weeks for 12 months) or placebo, stratified by age, sex, and smoking history. Time-to-event end point analyses were performed using stratified log-rank tests. Medians and landmark survival rates were estimated using the Kaplan-Meier method. RESULTS Seven hundred and nine of 713 randomly assigned patients received durvalumab (473 of 476) or placebo (236 of 237). As of January 11, 2021 (median follow-up, 34.2 months [all patients]; 61.6 months [censored patients]), updated OS (stratified HR, 0.72; 95% CI, 0.59 to 0.89; median, 47.5 v 29.1 months) and PFS (stratified HR, 0.55; 95% CI, 0.45 to 0.68; median, 16.9 v 5.6 months) remained consistent with the primary analyses. Estimated 5-year rates (95% CI) for durvalumab and placebo were 42.9% (38.2 to 47.4) versus 33.4% (27.3 to 39.6) for OS and 33.1% (28.0 to 38.2) versus 19.0% (13.6 to 25.2) for PFS. CONCLUSION These updated analyses demonstrate robust and sustained OS and durable PFS benefit with durvalumab after chemoradiotherapy. An estimated 42.9% of patients randomly assigned to durvalumab remain alive at 5 years and 33.1% of patients randomly assigned to durvalumab remain alive and free of disease progression, establishing a new benchmark for standard of care in this setting.

Background Immune checkpoint inhibitors prolong the survival of non-small cell lung cancer (NSCLC) patients. Although it has been acknowledged that there is some correlation between the efficacy of anti-programmed cell death-1 (PD-1) antibody therapy and immunohistochemical analysis, this technique is not yet considered foolproof for predicting a favorable outcome of PD-1 antibody therapy. We aimed to predict the efficacy of nivolumab based on a comprehensive analysis of RNA expression at the gene level in advanced NSCLC. Methods This was a retrospective study on patients with NSCLC who were administered nivolumab at the Kansai Medical University Hospital. To identify genes associated with response to anti-PD-1 antibodies, we grouped patients into responders (complete and partial response) and non-responders (stable and progressive disease) to nivolumab therapy. Significant genes were then identified for these groups using Welch’s t-test. Results Among 42 analyzed cases (20 adenocarcinomas and 22 squamous cell carcinomas), enhanced expression of MAGE-A4, BBC3, and OTOA genes was observed in responders with adenocarcinoma, and enhanced expression of DAB2, HLA-DPB,1 and CDH2 genes was observed in responders with squamous cell carcinoma. Conclusions This study predicted the efficacy of nivolumab based on a comprehensive analysis of mRNA expression at the gene level in advanced NSCLC. We also revealed different gene expression patterns as predictors of the effectiveness of anti PD-1 antibody therapy in adenocarcinoma and squamous cell carcinoma.

This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE‐024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a programmed death ligand 1 (PD‐L1) tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum‐based chemotherapy (four to six cycles). The primary end‐point was progression‐free survival; secondary end‐points included overall survival and safety. Of 305 patients randomized in KEYNOTE‐024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). Median progression‐free survival was 41.4 (95% confidence interval [CI], 4.2‐42.5) months with pembrolizumab and 4.1 (95% CI, 2.8‐8.3) months with chemotherapy (hazard ratio [HR], 0.27 [95% CI, 0.11‐0.65]; one‐sided, nominal P = .001). Median overall survival was not reached (NR) (95% CI, 22.9‒NR) and 21.5 (95% CI, 5.2‐35.0) months, respectively (HR, 0.39 [95% CI, 0.17‐0.91]; one‐sided, nominal P = .012). Treatment‐related adverse events occurred in 21/21 (100%) pembrolizumab‐treated and 18/19 (95%) chemotherapy‐treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3‐5 events. Immune‐mediated adverse events and infusion reactions occurred in 11 pembrolizumab‐treated patients (52%) and four chemotherapy‐treated patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3‐5 events. Consistent with results from KEYNOTE‐024 overall, first‐line pembrolizumab improved progression‐free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a PD‐L1 tumor proportion score of 50% or higher. The trial is registered with Clinicaltrials.gov: NCT02142738., This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE‐024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a PD‐L1 tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Consistent with results from KEYNOTE‐024 overall, first‐line pembrolizumab improved progression‐free survival and overall survival vs chemotherapy with manageable safety among 40 Japanese patients in the study.

Recently, the addition of antiprogrammed cell death-ligand 1 (PD-L1) monoclonal antibodies, including durvalumab and atezolizumab to platinum-based chemotherapy, has demonstrated clinical benefits in patients with untreated advanced small cell lung cancer (SCLC). However, these clinical trials comprised small populations of elderly patients with SCLC. Therefore, the safety of anti-PD-L1 immunotherapy plus platinum and etoposide in elderly patients remains unclear.This prospective, multicenter, single-arm study was designed to evaluate the safety and efficacy of durvalumab plus carboplatin and etoposide in untreated elderly patients (aged 75) with extensive stage (ES) SCLC. A total of 40 patients were recruited. Patients received up to four cycles of durvalumab 1500 mg and carboplatin at a dose equivalent to an area under the curve of 5 on day 1, and etoposide 80 mg/mThe present study was designed to evaluate the safety of durvalumab plus carboplatin and etoposide in elderly patients with ES-SCLC.

Few clinical studies have been designed for elderly patients with locally advanced non-small cell lung cancer (NSCLC). We conducted a phase I study to evaluate the tolerability of carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy in elderly patients with locally advanced NSCLC. The eligibility criteria were: unresectable stage III NSCLC, performance status 0 or 1, and age ≥ 75 years. Eligible patients received 6 weeks of weekly carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy with a total dose of 64 Gy in 32 fractions. Carboplatin was fixed to an area under the plasma concentration time curve (AUC) of 2 mg/mL/min, and the recommended dose of nab-paclitaxel was evaluated using a dose-escalation study (30 or 40 mg/m2). Tolerability at the recommended dose was evaluated in an expansion study. Nineteen patients were enrolled at four institutions, all of whom were eligible and assessable. The recommended nab-paclitaxel dose was set at 30 mg/m2 because two patients experienced dose-limiting toxicity at 40 mg/m2. The treatment completion rate of the 17 patients analyzed at the recommended dose was 100% (80% confidence interval (CI), 83.8–100%). The overall response rate was 76.5%, and the median progression free survival was 13.4 months (95% CI, 4.2–21.4 months). Common grade 3 and 4 toxicities included leukopenia (23.5%), neutropenia (17.6%), anemia (5.9%), and infection (5.9%). One treatment-related death due to pneumonitis was observed six months after the end of the study. In conclusion, carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy show good tolerability and exhibit promising efficacy in elderly patients with locally advanced NSCLC. This trial was registered with the Japan Registry of Clinical Trials on March 11, 2019 (trial no. jRCTs042180077).

Background In the phase III KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed–platinum) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) versus placebo plus pemetrexed–platinum. We report updated efficacy outcomes from the protocol-specified final analysis, including outcomes in patients who crossed over to pembrolizumab from pemetrexed–platinum and in patients who completed 35 cycles (∼2 years) of pembrolizumab. Patients and methods Eligible patients were randomized 2 : 1 to receive pembrolizumab 200 mg (n = 410) or placebo (n = 206) every 3 weeks (for up to 35 cycles, ∼2 years) plus four cycles of pemetrexed (500 mg/m2) and investigators’ choice of cisplatin (75 mg/m2) or carboplatin (area under the curve 5 mg·min/ml) every 3 weeks, followed by pemetrexed until progression. Patients assigned to placebo plus pemetrexed–platinum could cross over to pembrolizumab upon progression if eligibility criteria were met. The primary endpoints were OS and PFS. Results After a median follow-up of 31.0 months, pembrolizumab plus pemetrexed–platinum continued to improve OS [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.46-0.69] and PFS (HR, 0.49; 95% CI, 0.41-0.59) over placebo plus pemetrexed–platinum regardless of programmed death-ligand 1 expression. Objective response rate (ORR) (48.3% versus 19.9%) and time to second/subsequent tumor progression on next-line treatment (PFS2; HR, 0.50; 95% CI, 0.41-0.61) were improved in patients who received pembrolizumab plus pemetrexed–platinum. Eighty-four patients (40.8%) from the placebo plus pemetrexed–platinum group crossed over to pembrolizumab on-study. Grade 3-5 adverse events occurred in 72.1% of patients receiving pembrolizumab plus pemetrexed–platinum and 66.8% of patients receiving placebo plus pemetrexed–platinum. Fifty-six patients completed 35 cycles (∼2 years) of pembrolizumab; ORR was 85.7% and 53 (94.6%) were alive at data cut-off. Conclusions Pembrolizumab plus pemetrexed–platinum continued to show improved efficacy outcomes compared with placebo plus pemetrexed–platinum, with manageable toxicity. These findings support first-line pembrolizumab plus pemetrexed–platinum in patients with previously untreated metastatic nonsquamous NSCLC.

Background Preliminary data suggest that combining savolitinib, a potent and highly selective MET-tyrosine kinase inhibitor (TKI), with osimertinib, a third-generation, irreversible, oral epidermal growth factor receptor-TKI (EGFR-TKI), may overcome MET-based resistance to EGFR-TKIs. Objective To investigate the safety and tolerability of savolitinib in Japanese patients with advanced solid malignancies. Patients and Methods In Part C of the phase Ib, multi-arm, open-label, multicenter TATTON study, two cohorts of Japanese adult patients were evaluated across six study centers in Japan. Patients with advanced solid malignancies received oral savolitinib monotherapy 400 mg once daily (qd), escalating to 600 mg; patients with advanced EGFR mutation-positive (EGFRm) non-small-cell lung carcinoma (NSCLC) who progressed on prior EGFR-TKI received oral osimertinib 80 mg+savolitinib 300/400/600 mg qd combination therapy. Primary endpoints: safety/tolerability of savolitinib±osimertinib, and maximum tolerated dose(s) (MTD) definition. Results Seventeen patients received monotherapy; 12 received combination. Dose-limiting toxicities (DLTs): with monotherapy, 400 mg, none reported; 600 mg, n = 3/9 evaluable patients (33%) reported DLTs (grade 3 and 4 alanine aminotransferase and aspartate transaminase increased, and grade 4 drug-induced liver injury). With combination: 400 mg, 1/6 (17%) reported DLTs (grade 2 fatigue, nausea, and myalgia); 300 mg, none reported; 600 mg, 3/4 (75%) reported DLTs (grade 2 pyrexia, grade 3 skin reaction, and anaphylactic shock). Grade ≥3 adverse events were reported in 41% of patients receiving monotherapy and 33% receiving combination. TATTON is no longer recruiting patients. Conclusions The MTD of savolitinib was 400 mg qd in both cohorts. Data demonstrate an acceptable safety profile for savolitinib alone, or with osimertinib. Trial registration: Clinicaltrials.gov; NCT02143466; 21 May 2014. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-021-00806-5., Plain Language Summary For patients with epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC), EGFR tyrosine kinase inhibitors, like osimertinib, are the standard treatment. However, for most patients, these treatments eventually stop working, as tumors develop resistance to them. Early studies suggest that combining osimertinib with savolitinib can overcome this resistance. We report Part C of the four-part TATTON study, in which two groups of Japanese adult patients received treatment. One group received savolitinib 400 mg once daily, then 600 mg. The other group received osimertinib 80 mg with savolitinib 300/400/600 mg once daily. The main objective of the study was to determine the maximum dose of savolitinib that patients could receive (maximum tolerated dose) and to monitor the safety of the combination. Overall, 17 patients received savolitinib alone and 12 received the combination. The maximum tolerated dose of savolitinib was found to be 400 mg once daily in both groups of patients. The data demonstrated that savolitinib had acceptable safety outcomes either alone, or in combination with osimertinib. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-021-00806-5.

Background: Pembrolizumab (Pemb) is a key drug for the treatment of advanced or recurrent non-small cell lung cancer (NSCLC). However, there are limited data on Pemb use in older adults aged >75 years with NSCLC, especially in terms of pharmacokinetics (PK). Methods: This open-label multicenter observational study aimed to evaluate real-world data on the safety, efficacy, and blood concentrations of Pemb (both monotherapy and combination therapies) in older adults with NSCLC. Blood samples for PK analysis were collected immediately before Pemb administration. Quantitative Pemb concentrations were measured by liquid chromatography-mass spectrometry. Results: We enrolled 100 patients from July 2019 to September 2020; one patient was excluded due to stage migration. Patient characteristics were as follows: median age, 78 (75-87) years; male/female ratio, 70/29; performance status (PS) 0-1/2-3, 85/14; adenocarcinoma/squamous cell carcinoma/others, 62/25/12; stage I-III/IV/postoperative recurrence (TNM 7th edition), 9/60/30; PD-L1 TPS Conclusion: In older adults aged >75 years with NSCLC and low albumin levels and PS and a high number of metastatic organs, C1 trough of Pemb is reduced and not expected to prolong PFS and OS. Citation Format: Yoshiro Nakahara, Kageaki Watanabe, Yukio Hosomi, Yuta Yamanaka, Takayasu Kurata, Hidehito Horinouchi, Yuichiro Ohe, Tetsuhiko Asao, Sho Saeki, Yukari Tsubata, Yu Fujita, Jun Sakakibara Konishi, Hidenori Mizugaki, Mayu Ohuchi, Shigehiro Yagishita, Akinobu Hamada. Multicenter pharmacokinetic study of pembrolizumab for non-small cell lung cancer in older adults aged over 75 years [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2797.

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.

PURPOSE In KEYNOTE-189, first-line pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus pemetrexed-platinum in patients with metastatic nonsquamous non‒small-cell lung cancer (NSCLC), irrespective of tumor programmed death-ligand 1 (PD-L1) expression. We report an updated analysis from KEYNOTE-189 (ClinicalTrials.gov: NCT02578680 ). METHODS Patients were randomly assigned (2:1) to receive pemetrexed and platinum plus pembrolizumab (n = 410) or placebo (n = 206) every 3 weeks for 4 cycles, then pemetrexed maintenance plus pembrolizumab or placebo for up to a total of 35 cycles. Eligible patients with disease progression in the placebo-combination group could cross over to pembrolizumab monotherapy. Response was assessed per RECIST (version 1.1) by central review. No alpha was assigned to this updated analysis. RESULTS As of September 21, 2018 (median follow-up, 23.1 months), the updated median (95% CI) OS was 22.0 (19.5 to 25.2) months in the pembrolizumab-combination group versus 10.7 (8.7 to 13.6) months in the placebo-combination group (hazard ratio [HR], 0.56; 95% CI, 0.45 to 0.70]). Median (95% CI) PFS was 9.0 (8.1 to 9.9) months and 4.9 (4.7 to 5.5) months, respectively (HR, 0.48; 95% CI, 0.40 to 0.58). Median (95% CI) time from randomization to objective tumor progression on next-line treatment or death from any cause, whichever occurred first (progression-free-survival-2; PFS-2) was 17.0 (15.1 to 19.4) months and 9.0 (7.6 to 10.4) months, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). OS and PFS benefits with pembrolizumab were observed regardless of PD-L1 expression or presence of liver/brain metastases. Incidence of grade 3-5 adverse events was similar in the pembrolizumab-combination (71.9%) and placebo-combination (66.8%) groups. CONCLUSION First-line pembrolizumab plus pemetrexed-platinum continued to demonstrate substantially improved OS and PFS in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.

Objectives SPECTRA is a multicenter, randomized phase II study of chemotherapy with cisplatin (CDDP) plus S-1 versus CDDP plus pemetrexed (PEM) in combination with thoracic radiotherapy (TRT) for locally advanced non-squamous non-small cell lung cancer, in order to determine which of these two regimens might be preferable for comparison with standard therapies in a future phase III study. Materials and methods Patients were randomly assigned to receive CDDP + S-1 (CDDP 60 mg/m2 on day 1 and S-1 80 mg/m2 on days 1–14, every 4 weeks, up to 4 cycles) or CDDP + PEM (CDDP 75 mg/m2 + PEM 500 mg/m2 on day 1, every 3 weeks, up to 4 cycles) combined with TRT (60 Gy in 30 fractions). The primary endpoint was the 2-year progression-free survival (PFS) rate. The sample size had been set at 100 patients. Results A total of 102 patients were randomized to receive CDDP + S-1 or CDDP + PEM (CDDP + S-1, n = 52; CDDP + PEM, n = 50) between January 2013 and October 2016. The results in the CDDP + S1 group and CDDP + PEM group were as follows: completion rates of TRT (60 Gy)/chemotherapy (4 cycles) was 92 %/73 % and 98 %/86 %, respectively; the response rates were 60 % and 64 %, respectively; median PFS after a median follow-up of 32.1 months, 12.7/13.8 months (hazard ratio [HR] = 1.16; 95 % confidence interval [CI], 0.73–1.84); 2-year PFS rate, 36.5 % (95 % CI, 23.5–49.6)/32.1 % (95 %CI, 18.9–45.4); median OS, 48.3/59.1 months (HR = 1.05; 95 %CI, 0.58–1.90); 2-year OS rate, 69.2 % (95 %CI, 56.7–81.8)/66.4 % (95 %CI, 53.0–79.9); Grade 3 toxicities: febrile neutropenia (12 %/2 %), anorexia (8 %/16 %), diarrhea (8 %/0 %), esophagitis (6 %/8 %), and neutropenia (35 %/50 %); Grade 2 or worse radiation pneumonitis, 15 % (8 patients)/4 % (2 patients). Conclusion The 2-year PFS rate in the CDDP + S-1 arm was higher than that in the CDDP + PEM arm. Both treatments were safe, with manageable toxicities.

Chemoimmunotherapy improved overall survival (OS) and progression-free survival (PFS) in patients with extensive-stage small cell lung cancer (ES-SCLC) in two phase III trials. They set the age-stratified subgroup analyses at 65 years; however, over half of the patients with lung cancer were newly diagnosed at ≥75 years in Japan. Therefore, treatment efficacy and safety in elderly patients ≥ 75 years with ES-SCLC should be evaluated through real-world Japanese evidence. Consecutive Japanese patients with untreated ES-SCLC or limited-stage SCLC unfit for chemoradiotherapy between 5 August 2019 and 28 February 2022 were evaluated. Patients treated with chemoimmunotherapy were divided into the non-elderly (

Motoko Tachihara,1 Kayoko Tsujino,2 Takeaki Ishihara,3 Hidetoshi Hayashi,4 Yuki Sato,5 Takayasu Kurata,6 Shunichi Sugawara,7 Isamu Okamoto,8 Shunsuke Teraoka,9 Koichi Azuma,10 Haruko Daga,11 Masafumi Yamaguchi,12 Takeshi Kodaira,13 Miyako Satouchi,14 Mototsugu Shimokawa,15 Nobuyuki Yamamoto,9 Kazuhiko Nakagawa4 On behalf of members of the West Japan Oncology Group (WJOG)1Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe City, Japan; 2Department of Radiation Oncology, Hyogo Cancer Center, Akashi City, Japan; 3Division of Radiation Oncology, Kobe University Graduate School of Medicine, Kobe City, Japan; 4Department of Medical Oncology, Kindai University, Osakasayama City, Japan; 5Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe City, Japan; 6Department of Thoracic Oncology, Kansai Medical University Hospital, Hirakata City, Japan; 7Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai City, Japan; 8Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka City, Japan; 9Internal Medicine III, Wakayama Medical University, Wakayama, Japan; 10Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Fukuoka City, Japan; 11Department of Medical Oncology, Osaka City General Hospital, Osaka, Japan; 12Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka City, Japan; 13Departments of Radiation Oncology, Aichi Cancer Center Hospital, Nagoya City, Aichi, Japan; 14Department of Thoracic Oncology, Hyogo Cancer Center, Akashi City, Japan; 15Department of Biostatistics, Yamaguchi University Graduate School of Medicine Yamaguchi, Ube City, JapanCorrespondence: Motoko TachiharaDivision of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe City, 650-0017, JapanTel +81-78-382-5660Fax +81-78-382-5661Email mt0318@med.kobe-u.ac.jpAbstract: Durvalumab (anti-programmed cell death ligand-1) administration after concurrent chemoradiotherapy (cCRT) has improved the survival of patients with unresectable, locally advanced (LA) stage III non-small cell lung cancer (NSCLC). Some patients are unable to complete cCRT and cannot receive immunotherapy due to poor performance status based on adverse events after cCRT. Immunotherapy plays an important role in anti-programmed cell death ligand-1 (PD-L1)-positive advanced NSCLC and is replacing chemotherapy. In addition, radiotherapy and immunotherapy have been reported to have a synergistic effect. This Phase II, multicenter study (DOLPHIN, WJOG11619L, JapicCTI-194840) is designed to assess the efficacy and safety of durvalumab plus concurrent curative radiation therapy for PD-L1-positive unresectable LA-NSCLC without chemotherapy. Unresectable LA stage III NSCLC patients aged 20 years or older with a World Health Organization/Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and PD-L1 positivity are enrolled. The patients will receive curative radiation therapy (60 Gy) plus durvalumab 10 mg/kg every 2 weeks (q2w) for up to 12 months until there is evidence of disease progression (PD) or unacceptable toxicity. The primary endpoint is the 12-month progression-free survival rate as assessed by an independent central review. The secondary endpoints are progression-free survival, overall survival, objective response rate, treatment completion rate, and safety. Recruitment began in September 2019.Keywords: clinical study, locally advanced non-small cell lung cancer, immunotherapy, programmed cell death ligand-1, durvalumab, radiation

Introduction Pembrolizumab plus chemotherapy significantly improved outcomes over chemotherapy alone as first-line treatment in patients with advanced non–small-cell lung cancer (NSCLC) in phase 3 international trials. In the phase 1 KEYNOTE-011 study (parts B and C), we evaluated the safety/activity of pembrolizumab plus chemotherapy as first-line treatment in Japanese patients with advanced NSCLC. Methods Eligible patients received 4 cycles (every 3 weeks) of pembrolizumab 200 mg plus chemotherapy (cisplatin 75 mg/m2/carboplatin area under the curve [AUC] 5 mg/mL/min and pemetrexed 500 mg/m2 in part B [nonsquamous]; carboplatin AUC 6 mg/mL/min and paclitaxel 200 mg/m2/nab-paclitaxel 100 mg/m2 (weekly) in part C [squamous]), followed by maintenance pembrolizumab (and pemetrexed, part B). The primary endpoint was incidence of dose-limiting toxicities (DLTs) during the first 3 weeks of treatment. Overall response rate (ORR; RECIST v1.1 by central review) was exploratory. Results In part B (median follow-up, 16.0 months; n = 12) 1 DLT occurred (grade 4 hyponatremia). Grade ≥3 treatment-related adverse events (AEs) occurred in 9 patients (75%). Two patients had grade 5 treatment-related AEs (pneumonitis and interstitial lung disease). In part C (median follow-up, 9.9 months; n = 14), 2 DLTs occurred (both grade 3 febrile neutropenia). Grade ≥3 treatment-related AEs occurred in 11 patients (79%); none were fatal. ORR was 73% in part B and 50% in part C, irrespective of PD-L1 status. Conclusion Safety results show first-line pembrolizumab plus chemotherapy is feasible in Japanese patients with advanced NSCLC. Antitumor activity was observed irrespective of PD-L1 status and was comparable to that in international studies. Trial register ClinicalTrials.gov, NCT01840579

Hypercalcemia is a common electrolyte abnormality in malignancy and is largely caused by activation of parathyroid hormone (PTH) pathways. We report the case of a 76-year-old man with hypercalcemia primarily owing to 1,25-dihydroxyvitamin D3 overproduction from a high-grade fetal lung adenocarcinoma. Histologically, the tumor itself and tumor-adjacent macrophages were positive for the CYP27B1 protein, a key enzyme that generates 1,25-dihydroxyvitamin D3. Suppression was observed in serum PTH and PTH-related hormone levels, suggesting hypercalcemia is independent of the PTH pathway. Serum calcium level returned to normal after surgical resection of the lung cancer, supporting extrarenal overproduction of 1,25-dihydroxyvitamin D3 elicited by the tumors is the cause of hypercalcemia in this patient.

Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC.This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomisation was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up.Between Jan 28, 2016, and Feb 1, 2018, 449 eligible patients were enrolled and randomly assigned to treatment with ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7 months (IQR 15·8-27·2). At the time of primary analysis, progression-free survival was significantly longer in the ramucirumab plus erlotinib group (19·4 months [95% CI 15·4-21·6]) than in the placebo plus erlotinib group (12·4 months [11·0-13·5]), with a stratified hazard ratio of 0·59 (95% CI 0·46-0·76; p0·0001). Grade 3-4 treatment-emergent adverse events were reported in 159 (72%) of 221 patients in the ramucirumab plus erlotinib group versus 121 (54%) of 225 in the placebo plus erlotinib group. The most common grade 3-4 treatment-emergent adverse events in the ramucirumab plus erlotinib group were hypertension (52 [24%]; grade 3 only) and dermatitis acneiform (33 [15%]), and in the placebo plus erlotinib group were dermatitis acneiform (20 [9%]) and increased alanine aminotransferase (17 [8%]). Treatment-emergent serious adverse events were reported in 65 (29%) of 221 patients in the ramucirumab plus erlotinib group and 47 (21%) of 225 in the placebo plus erlotinib group. The most common serious adverse events of any grade in the ramucirumab plus erlotinib group were pneumonia (seven [3%]) and cellulitis and pneumothorax (four [2%], each); the most common in the placebo plus erlotinib group were pyrexia (four [2%]) and pneumothorax (three [1%]). One on-study treatment-related death due to an adverse event occurred (haemothorax after a thoracic drainage procedure for a pleural empyema) in the ramucirumab plus erlotinib group.Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of the individual compounds in advanced lung cancer. The RELAY regimen is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC.Eli Lilly.

Background First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater. Methods This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (≥18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (≥50% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0·0122, p=0·0120, and p=0·0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894. Findings From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12·8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (≥50% hazard ratio 0·69, 95% CI 0·56-0·85, p=0·0003; ≥20% 0·77, 0·64-0·92, p=0·0020, and ≥1% 0·81, 0·71-0·93, p=0·0018). The median surival values by TPS population were 20·0 months (95% CI 15·4-24·9) for pembrolizumab versus 12·2 months (10·4-14·2) for chemotherapy, 17·7 months (15·3-22·1) versus 13·0 months (11·6-15·3), and 16·7 months (13·9-19·7) versus 12·1 months (11·3-13·3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively. Interpretation The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS. Funding Merck Sharp & Dohme.

Small cell lung cancer (SCLC) is the most aggressive neuroendocrine phenotype of the deadliest human lung cancers. However the therapeutic landscape for SCLC has not changed in over 30 years. Effective treatment and prognosis are needed to combat this aggressive cancer. Herein we report that Ser/Arg repetitive matrix 4 (SRRM4), a splicing activator, is abnormally expressed at high levels in SCLC and thus is a potential therapeutic target. We screened an effective gapmer antisense oligonucleotide (gASO) targeting SRRM4 in vitro which led to cell death of SCLC. Our gASO, which is stabilized by containing artificial nucleotides, effectively represses SRRM4 mRNA. We found that our gASO repressed SRRM4 synthesis leading to a dramatic tumor reduction in a lung cancer mouse model. We also analyzed miRNA microarray and found that the miR-4516 is abnormally increased in exosomes in the blood of SCLC patients. Treating with gASO suppressed tumors in the SCLC model mouse concurrently reduced plasma miR-4516. In conclusion this study reports that administration of an SRRM4-targeted gASO coupled with a novel miRNA diagnostic methodology represents a potential breakthrough in the therapeutic treatment of high mortality SCLC.

Few clinical studies have been designed for elderly patients with locally advanced non-small cell lung cancer (NSCLC). We conducted a phase I study to evaluate the tolerability of carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy in elderly patients with locally advanced NSCLC. The eligibility criteria were: unresectable stage III NSCLC, performance status 0 or 1, and age ≥75 years. Eligible patients received 6 weeks of weekly carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy with a total dose of 64 Gy in 32 fractions. Carboplatin was fixed to an area under the plasma concentration time curve (AUC) of 2 mg/mL/min, and the recommended dose of nab-paclitaxel was evaluated using a dose-escalation study (30 or 40 mg/m2). Tolerability at the recommended dose was evaluated in an expansion study. Nineteen patients were enrolled at four institutions, all of whom were eligible and assessable. The recommended nab-paclitaxel dose was set at 30 mg/m2 because two patients experienced dose-limiting toxicity at 40 mg/m2. The treatment completion rate of the 17 patients analyzed at the recommended dose was 100% (80% confidence interval (CI), 83.8–100%). The overall response rate was 76.5%, and the median progression free survival was 13.4 months (95% CI, 4.2–21.4 months). Common grade 3 and 4 toxicities included leukopenia (23.5%), neutropenia (17.6%), anemia (5.9%), and infection (5.9%). One treatment-related death due to pneumonitis was observed six months after the end of the study. In conclusion, carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy show good tolerability and exhibit promising efficacy in elderly patients with locally advanced NSCLC. This trial was registered with the Japan Registry of Clinical Trials on March 11, 2019 (trial no. jRCTs042180077).

Pembrolizumab plus pemetrexed‐platinum significantly improved overall survival (OS) and progression‐free survival (PFS) with manageable safety compared with placebo plus pemetrexed‐platinum in patients with previously untreated metastatic nonsquamous non–small‐cell lung cancer (NSCLC) without EGFR/ALK alterations in the global, randomized, double‐blind, phase 3 KEYNOTE‐189 study. We present results of Japanese patients enrolled in the KEYNOTE‐189 global and Japan extension studies. Patients were randomized 2:1 to intravenous pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for up to 35 cycles. All patients received pemetrexed 500 mg/m2 plus the investigator’s choice of cisplatin or carboplatin Q3W for four cycles, followed by maintenance pemetrexed 500 mg/m2 Q3W (all intravenous). Co–primary endpoints were OS and PFS. Forty Japanese patients enrolled (pembrolizumab, n = 25; placebo, n = 15). At data cutoff (20 May 2019; median time from randomization to data cutoff, 18.5 [range, 14.7‒38.2] months), the median OS was not reached in the pembrolizumab plus pemetrexed‐platinum arm; the median OS was 25.9 (95% confidence interval [CI], 11.9‒29.0) months in the placebo plus pemetrexed‐platinum arm (hazard ratio [HR] .29; 95% CI, .07‒1.15). The median (95% CI) PFS was 16.5 (8.8‒21.1) compared with 7.1 (4.7‒21.4) months (HR, .62; 95% CI, .27‒1.42), respectively. There were no grade 5 adverse events (AE). Grade 3/4 AE occurred in 72% vs 60% of patients in the pembrolizumab vs placebo arms; 40% vs 20% had immune‐mediated AE, and 4% vs 0% had infusion reactions. Efficacy and safety outcomes were similar to those from the global study and support first‐line therapy with pembrolizumab plus pemetrexed‐platinum in Japanese patients with nonsquamous NSCLC without EGFR/ALK alterations., In conclusion, consistent with the global KEYNOTE‐189 study, pembrolizumab in combination with pemetrexed and platinum improved OS, PFS, ORR, and PFS2 compared with placebo plus pemetrexed‐platinum and demonstrated a manageable safety profile in Japanese patients with previously untreated metastatic nonsquamous NSCLC. The results from this study confirm the role of pembrolizumab plus pemetrexed‐platinum as a first‐line standard‐of‐care therapy for Japanese patients with metastatic nonsquamous NSCLC.

Introduction This exploratory analysis retrospectively evaluated outcomes in patients with advanced NSCLC to determine whether baseline brain metastases influenced the efficacy of first-line pembrolizumab plus chemotherapy versus chemotherapy alone. Methods We pooled data for patients with advanced NSCLC in KEYNOTE-021 cohort G (nonsquamous), KEYNOTE-189 (nonsquamous), and KEYNOTE-407 (squamous). Patients were assigned to platinum-doublet chemotherapy with or without the addition of 35 cycles of pembrolizumab 200 mg every 3 weeks. All studies permitted enrollment of patients with previously treated or untreated (KEYNOTE-189 and KEYNOTE-407 only) stable brain metastases. Patients with previously treated brain metastases were clinically stable for 2 or more weeks (≥4 wk in KEYNOTE-021 cohort G), had no evidence of new or enlarging brain metastases, and had no steroid use at least 3 days before dosing. Patients with known untreated asymptomatic brain metastases required regular imaging of the brain. Results A total of 1298 patients were included, 171 with and 1127 without baseline brain metastases. Median (range) durations of follow-up at data cutoff were 10.9 (0.1‒35.1) and 11.0 (0.1‒34.9) months, respectively. Hazard ratios (pembrolizumab + chemotherapy/chemotherapy) were similar for patients with and without brain metastases for overall survival (0.48 [95% confidence interval (CI): 0.32‒0.70] and 0.63 [95% CI: 0.53‒0.75], respectively) and progression-free survival (0.44 [95% CI: 0.31‒0.62] and 0.55 [95% CI: 0.48‒0.63], respectively). In patients with brain metastases, median overall survival was 18.8 months with pembrolizumab plus chemotherapy and 7.6 months with chemotherapy, and median progression-free survival was 6.9 months and 4.1 months, respectively. Objective response rates were higher and duration of response longer with pembrolizumab plus chemotherapy versus chemotherapy regardless of brain metastasis status. Incidences of treatment-related adverse events with pembrolizumab plus chemotherapy versus chemotherapy were 88.2% versus 82.8% among patients with brain metastases and 94.5% versus 90.6% in those without. Conclusions With or without brain metastasis, pembrolizumab plus platinum-based histology-specific chemotherapy improved clinical outcomes versus chemotherapy alone across all programmed death ligand 1 subgroups, including patients with programmed death ligand 1 tumor proportion score less than 1% and had a manageable safety profile in patients with advanced NSCLC. This regimen is a standard-of-care treatment option for treatment-naive patients with advanced NSCLC, including patients with stable brain metastases.

Background: In Japan, docetaxel, a cytotoxic monotherapy, is the standard drug administered to elderly patients with advanced non-small cell lung cancer (NSCLC). Carboplatin plus nab-paclitaxel (nab-PC) demonstrated a high objective response rate (ORR) in patients with squamous histology and was suggested to improve overall survival (OS) for these patients. The CAPITAL trial aimed to assess the safety and efficacy of nab-PC versus docetaxel as first-line therapy for elderly patients with advanced squamous NSCLC. Methods: This multicenter, open-label, phase III, randomized trial was performed at 92 institutions in Japan. Inclusion criteria: 1) advanced squamous NSCLC with no prior systemic chemotherapy, 2) age ≥70 years, and 3) Eastern Cooperative Oncology Group performance status 0 or 1. Patients were randomized 1:1 to nab-PC arm (carboplatin AUC, 6 mg/mL/min plus nab-paclitaxel 100 mg/m2 weekly) or D arm (docetaxel 60 mg/m2) for each 21-day cycle. Findings: The nab-PC arm showed higher OS (hazard ratio [HR]: 0·52; 90%CI: 0·38–0·70; median: 16·9 versus 10·9 months; p = 0·0003), progression-free survival (median: 5·8 versus 4·0 months; HR: 0·42; 95%CI: 0·30–0·58; p < 0·0001), and ORR (66·3 versus 28·0%; p < 0·0001) than the D arm. The most common grade 3 or 4 adverse events were leukopenia (46·3%), neutropenia (63·2%), and anemia (38·9%) in the nab-PC arm, and leukopenia (56·7%), neutropenia (77·3%), and febrile neutropenia (17·5%) in the D arm; ≥ grade 2 sensory peripheral neuropathy was observed in 15 (15·8%) and 1 (1·0%) patient(s) in the nab-PC and D arms, respectively. Serious treatment-related adverse events and deaths occurred in 13 (13·7%) and 11 (11·3%) patients and in 2 and 1 patient(s) in the nab-PC and D arms, respectively. Interpretation: Nab-PC improved OS more than docetaxel and can be used as standard first-line treatment for elderly patients with advanced squamous NSCLC. Clinical Trial Registration Details: This trial was registered with the UMIN Clinical Trials Registry (UMIN000019843) and the Japan Registry of Clinical Trials (jRCTs041180110) and its protocol has been published previously. Funding Information: This study was conducted by the National Hospital Organization Nagoya Medical Center under a funding contract with Taiho Pharmaceutical Co. Ltd., Tokyo, Japan. Declaration of Interests: Y.K. reports grants from Taiho Pharmaceutical, during the conduct of the study; grants and personal fees from MSD, personal fees from AstraZeneca, Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Ono pharmaceutical, outside the submitted work. S.I. reports grants and personal fees from ONO PHARMACEUTICAL CO., LTD., personal fees from Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., MSD K.K, Bristol-Myers Squibb K.K., Taiho Pharmaceutical Co., Ltd., DAIICHI SANKYO COMPANY, LIMITED., outside the submitted work. H.S. reports grants from Taiho Pharmaceutical, during the conduct of the study; grants and personal fees from AstraZeneca, MSD K.K, Ono Pharmaceutical, personal fees from Boehringer Ingelheim, Chugai Pharma, from Kyorin, outside the submitted work. A.K. reports grants from Taiho Pharmaceutical Co., Ltd., during the conduct of the study; personal fees from Bayer Yakuhin, Ltd., outside the submitted work. S.A. reports grants from The National Cancer Center Research and Development Fund (26-A-22, 29-A-15, 2020-A-13), Taiho Pharmaceutical Co Ltd, during the conduct of the study; grants and personal fees from AstraZeneca, Ono, Taiho, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, MSD, Eli Lilly, Chugai, Merck, grants and non-financial support from F. Hoffmann-La Roche, personal fees from Hisamitsu, Kyowa Hakko Kirin, Novartis Pharma, Thermo Fisher Scientific, outside the submitted work.YT reports grants and personal fees from Taiho pharmaceutical Co, during the conduct of the study; grants and personal fees from Eli Lilly, Ono pharmaceutical Co, Chugai pharmaceutical Co, MSD, Takeda, grants from Daiichi Sankyo, Kyowa-Hakko Kirin, personal fees from Novartis, Boehringer Ingelheim, AstraZeneca, outside the submitted work. A.I. reports personal fees from AstraZeneca, Eli Lilly, Boehringer Ingelheim, Pfizer, Chugai Pharmaceutical, MSD, Daiichi Sankyo, outside the submitted work. T.K. reports personal fees from AstraZeneca, MSD, Eli Lilly, Chugai, Ono, Bristol Myers, Boehringer Ingelheim, grants from AstraZeneca, MSD, Ono, Eli Lilly, Takeda, outside the submitted work. I.O. reports grants from Boehringer Ingelheim, during the conduct of the study; grants and personal fees from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, MSD Oncology, Lilly, Bristol-Myers Squibb, Chugai Pharma, grants from Astellas Pharma, Novartis, AbbVie, personal fees from Pfizer, outside the submitted work. M.Y. reports grants and personal fees from Chugai Pharmaceutical, grants from Daiichi Sankyo, MSD, Pfizer Japan, outside the submitted work. M.S. reports grants and personal fees from Taiho Pharmaceutical Co., LTD, Chugai Pharmaceutical Co., LTD, MSD K.K, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly Japan K.K., personal fees from AstraZeneca Co., Ltd, outside the submitted work. T.Y. reports grants and personal fees from Takeda, Chugai, Taiho, Ono, Bayer, personal fees from Boehringer Ingelheim, Pfizer, Sysmex, Gilead Sciences, AstraZeneca, MSD, Sanofi, Otsuka, Kyowa Kirin, grants from Daiichi-Sankyo, Astellas, outside the submitted work. M.A. reports grants from Kyowa Kirin, Co. Ltd., outside the submitted work. K.K. reports grants and personal fees from Ono, Boehringer Ingelheim, personal fees from Chugai, MSD, AstraZeneca, Eli Lilly, Daiichi Sankyo, Bristol Myers Squibb, Kyowa Hakko KIRIN, Taiho, outside the submitted work. M.T. reports grants and personal fees from AstraZeneca, Chugai Pharmaceutical, Covidien Japan, Eli Lilly Japan, Kyowa Hakko Kirin, MSD, Nippon Boehringer Ingelheim, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical, personal fees from Bristol-Myers Squibb, Johnson & Johnson, Nippon Kayaku, and grants from KM Biologics, outside the submitted work. TS reports grants and personal fees from Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, MSD, Novartis Pharma, Pfizer Japan, Takeda Pharmaceutical, grants from AbbVie, Kissei Pharmaceutical, LOXO Oncology, Merck Biopharma, personal fees from AstraZeneca, Bristol-Myers Squibb, Covidien Japan, Kyowa Hakko Kirin, Mochida Pharmaceutical, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Taiho Pharmaceutical, Thermo Fisher Scientific, Precision Medicine Asia, outside the submitted work. N.Y. reports grants and personal fees from MSD K.K., Chugai Pharmaceutical CO., LTD., ONO PHARMACEUTICAL CO., LTD., DAIICHI SANKYO CO., LTD., TAIHO PHARMACEUTICAL CO., LTD., Takeda Pharmaceutical CO., LTD., Eli Lilly Japan K.K., Boehringer-Ingelheim, Novartis, Pfizer Inc., AstraZeneca, personal fees from Thermo Fisher Scientific, Bristol-Myers Squibb, Life Technologies Japan Ltd., NIPPON KAYAKU, Merk Biopharma, grants from Astellas Pharma Inc., TSUMURA & CO., SHIONOGI Co., Ltd., AbbVie GK., Amgen Inc., KYORIN Pharmaceutical Co., Ltd., Eisai Co., Ltd., TERUMO CORPORATION, Toppan Printing Co., Ltd., TOSOH, outside the submitted work. A.G. reports personal fees from Taiho, Nihon Kayaku, AstraZeneca, Chugai, Ono, Behringer-Ingelheim, outside the submitted work. All other authors declare no competing interests. Ethics Approval Statement: The study was approved by the Clinical Research Ethics Committee of each participating institution and written informed consent was obtained from each patient prior to participation in the study. It was conducted in accordance with the principles of the Declaration of Helsinki, 2013.

Background: To overcome resistance to EGFR TKI osimertinib in EGFR-mutated lung cancer is critically needed. We performed a biomarker study utilizing serially collected plasma samples in a phase I study to investigate the safety and efficacy of the combination of osimertinib and afatinib in patients who failed osimertinib (jRCTs051180008), in which a total of 13 patients were enrolled and the overall response rate and the median progression-free survival were 7.7% and 2.4 months, respectively, to access the trajectory of the mutational landscape and its association with the efficacy. Methods: Peripheral blood samples were collected from the patients in K2 EDTA vacutainers (Becton Dickinson) before and four weeks after administration of the combination therapy and upon disease progression. Plasma was isolated immediately after the blood draw and stored at -80℃ until use. Cell-free DNA (cfDNA) was extracted from the plasma and used for next-generation sequencing library construction using AVENIO ctDNA Surveillance Kit (Roche Diagnostics) to assess genetic alterations in 197 cancer-related genes. Sequencing was performed on Nextseq500 system (Illumina) followed by mutation analyses using an Avenio Oncology Analysis Server (Roche Diagnostics). Results: Mutations in EGFR gene were detected in 10 out of 13 cfDNA samples (77%) including T790M/cis-C797S mutations before treatment and among those harboring T790M/cis-C797S mutations, 2 patients had progressive disease (PD) and 1 had stable disease (SD), indicating little benefit from the combination therapy in this genotype. Although other mutations in genes such as TP53 and/or KRAS were detected before treatment, no relevant associations were observed between tumor response or progression-free survival. One patient who had SD harbored CNTN5 mutation at PD, suggesting the potential involvement with the acquired resistance. Early emergence of EGFR G796S mutation observed in one patient after the initiation of the treatment along with basal L858R/T790M mutations may confer early resistance to the treatment. We also observed the emergence of MET amplification in 2 patients and ERBB2 amplification in 1 patient at PD, strongly suggesting the potential mechanisms responsible for resistance. Conclusions: This signal seeking biomarker study using cfDNA to better understand the association of mutational status and the treatment efficacy of the combined treatment was feasible and informative despite the small-scale study, supporting the advantage of further implementation. Citation Format: Yasuhiro Koh, Satoru Miura, Jun Oyanagi, Hiroshige Yoshioka, Koichi Azuma, Hidenobu Ishii, Kayoko Kibata, Kenichi Koyama, Shunsuke Teraoka, Yuichi Ozawa, Takaaki Tokito, Toshio Shimokawa, Takayasu Kurata, Nobuyuki Yamamoto, Hiroshi Tanaka. Longitudinal cell-free DNA analysis in phase I study evaluating afatinib in combination with osimertinib in patients who failed prior osimertinib treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5153.

102 Background: Sotorasib, a specific, irreversible KRASG12C inhibitor, has been approved in multiple countries for adults with KRAS p.G12C-mutated locally advanced or metastatic NSCLC who received prior systemic therapy based on the global phase 1/2 CodeBreaK100 trial. Here we describe putative mechanisms of acquired resistance to sotorasib from the largest single dataset evaluated to-date. Methods: Patients with advanced KRAS p.G12C-mutated NSCLC or CRC from the CodeBreaK100 Ph1/2 trial who received sotorasib monotherapy at 960 mg once daily were analyzed for efficacy. Primary endpoint was objective response rate (ORR) assessed by central review. To investigate biomarkers of resistance to sotorasib, an exploratory endpoint was defined to examine acquired genomic alterations at disease progression. Plasma samples collected at baseline and progression were analyzed for genomic alterations with the 23-gene Resolution Bioscience ctDx Lung test for NSCLC and the 74-gene Guardant 360 ctDNA test for CRC. Acquired genomic alterations were defined by their absence at baseline and presence at progression. Results: In 174 pts with NSCLC and 91 pts with CRC-treated with sotorasib, the ORR were 41% and 12% respectively. Median progression-free survival and median overall survival were 6.3 months (mos) and 12.5 mos for NSCLC pts and 4.2 mos and 13.4 mos for CRC pts (median follow-up: 22.5 mos NSCLC; 12.5 mos CRC). A total of 67 NSCLC pts and 45 CRC pts had a plasma sample sequenced both at baseline and at progression. At least one new acquired genomic alteration at progression was detected in 19 (28%) NSCLC pts and in 33 (73%) CRC pts (Table). The acquired genomic alterations were heterogeneous in both NSCLC and CRC, with variants detected across multiple genes and pathways. The most prevalent putative pathway of resistance in both NSCLC and CRC was the receptor tyrosine kinase (RTK) pathway. Secondary RAS alterations occurred more frequently in CRC versus NSCLC pts (16% vs. 3%). Conclusions: Based on the largest descriptive dataset to-date, diverse mechanisms of acquired resistance occur in KRAS p.G12C-mutated NSCLC and CRC pts treated with sotorasib. New RTK pathway alterations frequently emerged at progression, highlighting the potential role for combining sotorasib with upstream inhibitors of RTK, such as SHP2 or EGFR inhibitors. Serial plasma DNA analysis revealed acquired resistance patterns that support the development of KRASG12C inhibitor combination therapies. Clinical trial information: NCT03600883. [Table: see text]

Introduction: In the Phase 3, placebo-controlled PACIFIC trial of patients with unresectable, stage III NSCLC without disease progression after concurrent chemoradiotherapy, consolidative durvalumab was associated with significant improvements in the primary end points of overall survival (OS) (hazard ratio [HR] = 0.68; 95% confidence interval [CI]: 0.53-0.87; p = 0.00251; data cutoff, March 22, 2018) and progression-free survival (PFS) (blinded independent central review; Response Evaluation Criteria in Solid Tumors version 1.1) (HR = 0.52; 95% CI: 0.42-65; p < 0.0001; February 13, 2017) with manageable safety. Here, we report updated analyses of OS and PFS, approximately 4 years after the last patient was randomized. Methods: Patients with WHO performance status of 0 or 1 (and any tumor programmed death-ligand 1 status) were randomized (2:1) to intravenous durvalumab (10 mg/kg) or placebo, administered every 2 weeks (

Background Pembrolizumab plus platinum‐based chemotherapy has demonstrated improved clinical outcomes over chemotherapy alone in patients with previously untreated advanced/metastatic non–small cell lung cancer (NSCLC), regardless of tumor programmed death ligand 1 (PD‐L1) expression. This study pooled data from 3 randomized controlled trials to evaluate outcomes with pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced/metastatic NSCLC negative for PD‐L1 (ie, a tumor proportion score < 1%). Methods Individual patient data were pooled from KEYNOTE‐021 cohort G (nonsquamous; NCT02039674), KEYNOTE‐189 (nonsquamous; NCT02578680 and NCT03950674), and KEYNOTE‐407 (squamous; NCT02775435). Treatment comprised pembrolizumab plus chemotherapy (pemetrexed and platinum for nonsquamous histology and carboplatin and paclitaxel/nab‐paclitaxel for squamous histology) or chemotherapy alone. Responses were assessed according to Response Evaluation Criteria in Solid Tumors version 1.1 by blinded, independent, central review. No α was assigned to this descriptive, exploratory analysis. Results Four hundred forty‐four of the 1328 patients (33.4%) who were enrolled across the 3 trials had PD‐L1‒negative tumors (256 on pembrolizumab plus chemotherapy [nonsquamous, n = 155; squamous, n = 94; other, n = 7] and 188 on chemotherapy alone [nonsquamous, n = 83; squamous, n = 99; other, n = 6]). The median time from randomization to the data cutoff was 28.0 months (range, 14.7‐55.4 months). Pembrolizumab plus chemotherapy improved overall survival (OS; hazard ratio [HR], 0.63; 95% CI, 0.50‐0.79) and progression‐free survival (HR, 0.68; 95% CI, 0.56‐0.83) over chemotherapy. Sixteen patients in the pembrolizumab plus chemotherapy arm completed 2 years of treatment; the objective response rate was 87.5% (95% CI, 61.7%‐98.4%), and the 3‐year OS rate was 100%. Adverse events (AEs) were experienced by 99.2% of the patients who received pembrolizumab plus chemotherapy and by 98.9% of the patients who received chemotherapy alone, with grade 3 or higher AEs occurring in 71.4% and 72.0%, respectively; immune‐mediated AEs and infusion reactions were experienced by 29.0% and 12.4%, respectively. Conclusions Pembrolizumab plus chemotherapy demonstrated response and survival improvements with manageable safety in comparison with chemotherapy alone in PD‐L1‒negative advanced/metastatic NSCLC, and it is a standard‐of‐care first‐line therapy for patients with advanced NSCLC, regardless of PD‐L1 expression. Lay Summary Some tumors produce a protein called programmed death ligand 1 (PD‐L1), which interacts with the body's immune system and prevents an immune response against cancer.Antibody therapies such as pembrolizumab block interactions between tumor PD‐L1 and the immune system and enable an immune response. Used alone, pembrolizumab provides benefit for patients with non–small cell lung cancer (NSCLC) tumors that produce PD‐L1. However, when it is combined with chemotherapy, which can stimulate anticancer immune responses, pembrolizumab provides a benefit, regardless of tumor PD‐L1 production.This article shows that among patients with NSCLC whose tumors produce no PD‐L1, outcomes are better with pembrolizumab plus chemotherapy in comparison with chemotherapy alone., This pooled analysis of individual patient data from 3 randomized controlled trials showed a clinically meaningful benefit and a manageable safety profile with pembrolizumab plus platinum‐based chemotherapy versus chemotherapy alone in previously untreated advanced/metastatic non–small cell lung cancer (NSCLC) negative for programmed death ligand 1 (PD‐L1). Pembrolizumab plus platinum‐based chemotherapy is a standard‐of‐care first‐line therapy for patients with advanced squamous or nonsquamous NSCLC, including patients with PD‐L1–negative tumors.

The pathological T descriptor of lung invasive mucinous adenocarcinoma (IMA) is currently defined according to mucin spread, whereas that of lung non-mucinous adenocarcinoma is defined according to invasive lesion. This study aimed to evaluate and compare the prognostic impact of mucin spread, tumor cell spread, and invasive lesion in patients with lung IMA.Twenty-seven patients with completely resected pT1-4N0M0 IMA were evaluated. The radiological size (RS), mucin spread size (MS), tumor cell spread size (TS), and invasive size (IS) of the primary tumors were determined. Cox proportional hazards models were used to estimate recurrence-free survival (RFS). Because the MS, TS, and IS may be mutually confounding factors, they were evaluated using separate multivariate models including potential prognostic factors identified as significant on univariate analyses.The median postoperative follow-up time was 4.9 years. TS and IS were significantly smaller than RS by a median of 0.3 cm (p = 0.027) and 1.4 cm (p 0.0001), whereas MS and RS were not significantly different (p 0.999). Univariate analyses identified T descriptors defined by MS, TS, and IS as potentially negative prognostic factors, in addition to age75 years and carcinoembryonic antigen5 ng/mL. Multivariate analyses revealed that T factors defined by MS, TS, and IS were significant predictors of RFS (p 0.0001, p = 0.0002, and p = 0.0067, respectively).MS is a reasonable determinant of the pathological T descriptor of lung IMA. TS and IS are potential candidates, although they remain discordant with RS. If the TS or IS is to be considered a candidate for the pathological T descriptor of lung IMA, the discordance with RS should first be resolved. If IS is used to define pathological T factor, clear criteria for mucinous AIS/MIA with IMA features should be developed.