First‐line pembrolizumab vs chemotherapy in metastatic non‐small‐cell lung cancer: KEYNOTE‐024 Japan subset

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: {"type":"clinical-trial","attrs":{"text":"NCT02142738","term_id":"NCT02142738"}}NCT02142738.     

Vascular endothelial growth factor receptor 2 expression and immunotherapy efficacy in non–small cell lung cancer

It is unclear whether tumor vascular endothelial growth factor receptor 2 expression affects the therapeutic efficacy of immune‐checkpoint inhibitors and antiangiogenic agents. This retrospective, multicenter study included patients with advanced non–small cell lung cancer who were treated with immune‐checkpoint inhibitors. We constructed tissue microarrays and performed immunohistochemistry with an anti‐vascular endothelial growth factor receptor 2 antibody. We analyzed immune and tumor cell staining separately in order to determine their correlation with the objective response rate, progression‐free survival, and overall survival in patients receiving immune‐checkpoint inhibitors. Of 364 patients, 37 (10%) expressed vascular endothelial growth factor receptor 2 in immune cells and 165 (45%) in tumor cells. The objective response rate, progression‐free survival, and overall survival were significantly worse in patients treated with immune checkpoint inhibitor monotherapy who expressed vascular endothelial growth factor receptor 2 in immune cells than those who did not (10% vs 30%, p = 0.028; median = 2.2 vs 3.6 months, p = 0.012; median = 7.9 vs 17.0 months, p = 0.049, respectively), while there was no significant difference based on tumor cell expression (24% vs 30%, p = 0.33; median = 3.1 vs 3.5 months, p = 0.55; median = 13.6 vs 16.8 months, p = 0.31). There was no significant difference in overall survival between patients treated with and without antiangiogenic agents in any treatment period based on vascular endothelial growth factor receptor 2 expression. Immune checkpoint inhibitor efficacy was limited in patients expressing vascular endothelial growth factor receptor 2 in immune cells.     

A modified MethyLight assay predicts the clinical outcomes of anti‐epidermal growth factor receptor treatment in metastatic colorectal cancer

DNA methylation status correlates with clinical outcomes of anti‐epidermal growth factor receptor (EGFR) treatment. There is a strong need to develop a simple assay for measuring DNA methylation status for the clinical application of drug selection based on it. In this study, we collected data from 186 patients with metastatic colorectal cancer (mCRC) who had previously received anti‐EGFR treatment. We modified MethyLite to develop a novel assay to classify patients as having highly methylated colorectal cancer (HMCC) or low‐methylated colorectal cancer (LMCC) based on the methylation status of 16 CpG sites of tumor‐derived genomic DNA in the development cohort (n = 30). Clinical outcomes were then compared between the HMCC and LMCC groups in the validation cohort (n = 156). The results showed that HMCC had a significantly worse response rate (4.2% vs 33.3%; P = .004), progression‐free survival (median: 2.5 vs 6.6 mo, P < .001, hazard ratio [HR] = 0.22), and overall survival (median: 5.6 vs 15.5 mo, P < .001, HR = 0.23) than did LMCC in patients with RAS wild‐type mCRC who were refractory or intolerable to oxaliplatin‐ and irinotecan‐based chemotherapy (n = 101). The DNA methylation status was an independent predictive factor and a more accurate biomarker than was the primary site of anti‐EGFR treatment. In conclusion, our novel DNA methylation measurement assay based on MethyLight was simple and useful, suggesting its implementation as a complementary diagnostic tool in a clinical setting.     

SMARCA4 mutations in KRAS‐mutant lung adenocarcinoma: a multi‐cohort analysis

KRAS is a key oncogenic driver in lung adenocarcinoma (LUAD). Chromatin‐remodeling gene SMARCA4 is comutated with KRAS in LUAD; however, the impact of SMARCA4 mutations on clinical outcome has not been adequately established. This study sought to shed light on the clinical significance of SMARCA4 mutations in LUAD. The association of SMARCA4 mutations with survival outcomes was interrogated in four independent cohorts totaling 564 patients: KRAS‐mutant patients with LUAD who received nonimmunotherapy treatment from (a) The Cancer Genome Atlas (TCGA) and (b) the MSK‐IMPACT Clinical Sequencing (MSK‐CT) cohorts; and KRAS‐mutant patients with LUAD who received immune checkpoint inhibitor‐based immunotherapy treatment from (c) the MSK‐IMPACT (MSK‐IO) and (d) the Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) immunotherapy cohorts. Of the patients receiving nonimmunotherapy treatment, in the TCGA cohort (n = 155), KRAS‐mutant patients harboring SMARCA4 mutations (KS) showed poorer clinical outcome [P = 6e‐04 for disease‐free survival (DFS) and 0.031 for overall survival (OS), respectively], compared to KRAS‐TP53 comutant (KP) and KRAS‐only mutant (K) patients; in the MSK‐CT cohort (n = 314), KS patients also exhibited shorter OS than KP (P = 0.03) or K (P = 0.022) patients. Of patients receiving immunotherapy, KS patients consistently exhibited the shortest progression‐free survival (PFS; P = 0.0091) in the MSK‐IO (n = 77), and the shortest PFS (P = 0.0026) and OS (P = 0.0014) in the WFBCCC (n = 18) cohorts, respectively. Therefore, mutations of SMARCA4 represent a genetic factor leading to adverse clinical outcome in lung adenocarcinoma treated by either nonimmunotherapy or immunotherapy.

Abbreviations

DCB

durable clinical benefit

DFS

disease‐free survival

K

KRAS‐only mutant

KL

KRAS‐STK11 comutant

KP

KRAS‐TP53 comutant

KS

KRAS‐SMARCA4 comutant

LUAD

lung adenocarcinoma

LUSC

lung squamous carcinoma

MSK‐CT

the MSK‐IMPACT clinical sequencing cohort

MSK‐IO

MSK‐IMPACT cohort

NSCLC

non‐small‐cell lung cancer

OS

overall survival

PFS

progression‐free survival

TCGA

The Cancer Genome Atlas

WFBCCC

the Wake Forest Baptist Comprehensive Cancer Center

     

CD24, not CD47, negatively impacts upon response to PD‐1/L1 inhibitors in non–small‐cell lung cancer with PD‐L1 tumor proportion score < 50

CD24, a heavily glycosylated glycosylphosphatidylinositol–anchored surface protein, inhibits phagocytosis as potently as CD47. The relationship between such anti‐phagocytic factors and the immune response with immune–checkpoint inhibitors (ICI) remains unexplored. We evaluated CD24 and CD47 tumor proportion scores (TPS) in 68 of the 106 patients with advanced non–small‐cell lung cancer who participated in a prospective observational study of ICI treatment. We also explored the impact of CD24 TPS and CD47 TPS on ICI efficacy and serum cytokine changes. CD24 positivity (TPS ≥ 1) was negatively associated with progression–free survival (PFS) of ICI when PD‐L1 TPS was < 50 (median PFS; 37 vs 127 d, P = .033), but there was no association when PD‐L1 TPS was ≥ 50 (median PFS; 494 vs 144 d, P = .168). CD24 positivity was also related to significantly higher increase of CCL2 from baseline to 4‐6 wk later, and such increase was notably observed only when PD‐L1 TPS < 50 (P = .0004). CCL2 increase after ICI initiation was negatively predictive for survival after initiation of ICI (median survival time; not reached vs 233 d; P = .028). CD47 TPS high (≥60) significantly suppressed the increase in vascular endothelial growth factor (VEGF)‐A, D and PDGF‐AB/BB after ICI initiation. There was no association, however, between CD47 tumor expression and the efficacy of ICI. In conclusion, CD24, not CD47, is a candidate negative predictive marker of ICI in advanced, non–small‐cell lung cancer with PD‐L1 TPS < 50. Tumor expression of both CD24 and CD47 was associated with changes in factors related to monocytes and angiogenesis after ICI initiation (UMIN000024414).     

Low‐carbohydrate diet and risk of cancer incidence: The Japan Public Health Center‐based prospective study

Epidemiological evidence on the effects of a long‐term low‐carbohydrate diet (LCD) on cancer incidence remains sparse. We investigate the association between LCD and the risk of overall and specific cancer site incidence in a Japanese population‐based prospective cohort study among 90 171 participants aged 45‐74. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During a median 17.0 y of follow‐up, we identified 15 203 cancer cases. A higher overall LCD score was associated with increased overall cancer risk (HR = 1.08 [CI: 1.02‐1.14], P‐trend = .012), while it was associated with decreased gastric cancer (GC) risk (0.81 [0.71‐0.93], P‐trend = .006). A higher animal‐based LCD score was associated with higher risk of overall cancer (1.08 [1.02‐1.14], P‐trend = .003), colorectal cancer (CRC) (1.11 [0.98‐1.25], P‐trend = .018), rectal cancer (RC) (1.24 [1.00‐1.54], P‐trend = .025), lung cancer (LC) (1.16 [1.00‐1.34], P‐trend = .042), and lower risk of GC (0.90 [0.79‐1.01], P‐trend = .033). Furthermore, we found that plant‐based LCD score was related to lower GC incidence (0.87 [0.77‐0.99], P‐trend = .031). Additionally, adjusted for plant fat intake amplified the adverse associations (overall cancer: 1.08 [1.02‐1.14] vs. 1.11 [1.05‐1.18]; CRC: 1.08 [0.95‐1.22] vs. 1.13 [0.99‐1.30]; LC: 1.14 [0.98‐1.33] vs. 1.19 [1.01‐1.41]). We conclude that LCD enriching with animal products was associated with increased overall cancer, CRC, and LC incidence. These adverse associations could be attenuated by plant fat consumption. LCD reduces the risk of developing GC. Long‐term adherence to LCD without paying attention to the balance between animal and plant food source consumption might cause adverse overall cancer incidence consequences.     

Pertuzumab retreatment for HER2‐positive advanced breast cancer: A randomized,open‐label phase III study (PRECIOUS)

No standard options existed for human epidermal growth factor receptor 2 (HER2)‐positive advanced breast cancer that progresses after second‐line trastuzumab emtansine therapy before 2020. The purpose of this study was to examine the efficacy of pertuzumab retreatment after disease progression following pertuzumab‐containing therapy for HER2‐positive locally advanced or metastatic breast cancer for the first time. This randomized, open‐label, multicenter phase III trial was undertaken in 93 sites in Japan. Eligible patients with HER2‐positive breast cancer who had received pertuzumab, trastuzumab, and chemotherapy as first‐ and/or second‐line therapy were randomly assigned (1:1) to: (i) pertuzumab, trastuzumab, and physician''s choice chemotherapy (PTC), or (ii) trastuzumab and physician''s choice chemotherapy (TC). The primary end‐point was investigator‐assessed progression‐free survival (PFS). Between August 1, 2015 and December 31, 2018, 219 patients were randomized to PTC (n = 110) or TC (n = 109). Median follow‐up was 14.2 months (interquartile range, 9.0–22.2), and median PFS was 5.3 months (95% confidence interval [CI], 4.0–6.6) with PTC and 4.2 months (95% CI, 3.2–4.8) with TC (stratified hazard ratio 0.76 [95% CI upper limit 0.967]; p = 0.022). Progression‐free survival was improved by adding pertuzumab in all prespecified subgroups. The PTC arm showed a trend towards better overall survival and duration of response, but similar objective response and health‐related quality of life. The incidence of treatment‐related adverse events was similar between groups except for diarrhea. Pertuzumab retreatment contributes to disease control for HER2‐positive locally advanced or metastatic breast cancer previously treated with pertuzumab‐containing regimens.     

Role of aneuploid circulating tumor cells and CD31+ circulating tumor endothelial cells in predicting and monitoring anti‐angiogenic therapy efficacy in advanced NSCLC

Prognosticating the efficacy of anti‐angiogenic therapy through longitudinal monitoring and early detection of treatment resistance in cancer patients remain highly challenging. In this study, co‐detection and comprehensive phenotypic and karyotypic molecular characterization of aneuploid circulating tumor cells (CTCs) and circulating tumor endothelial cells (CTECs) were conducted on non‐small cell lung cancer (NSCLC) patients receiving bevacizumab plus chemotherapy. Prognostic values of the cell‐based significant univariate risk factors identified by Cox regression analyses were progressively investigated. Subjects showing an increase in total post‐therapeutic platelet endothelial cell adhesion molecule‐1 (CD31)^– CTCs and CD31⁺ CTECs exhibited a significantly reduced median progression‐free survival (mPFS) and overall survival. Further stratification analyses indicated that pretherapeutic patients bearing vimentin (Vim)⁺ CTECs (mesenchymal M‐type) at baseline revealed a significantly shortened mPFS compared with patients with Vim^– CTECs. Post‐therapeutic patients harboring epithelial cell adhesion molecule (EpCAM)⁺ CTCs and CTECs (epithelial E‐type), regardless of Vim expression or not, showed a significantly reduced mPFS. Post‐therapeutic patients possessing de novo EpCAM⁺/Vim⁺ (hybrid E/M‐type) CTECs displayed the shortest mPFS. Patients harboring either pre‐ or post‐therapeutic EpCAM^–/Vim^– null CTECs (N‐type) exhibited a better response to therapy compared to patients harboring EpCAM⁺ and/or Vim⁺ CTECs. The presented results support the notion that baseline Vim⁺ CTECs and post‐therapeutic EpCAM⁺ CTCs and CTECs are predictive biomarkers for longitudinal monitoring of response to anti‐angiogenesis combination regimens in NSCLC patients.     

Ramucirumab or placebo plus erlotinib in EGFR‐mutated,metastatic non‐small‐cell lung cancer: East Asian subset of RELAY

In the global phase III RELAY study, ramucirumab plus erlotinib (RAM + ERL) demonstrated superior progression‐free survival (PFS) to placebo plus erlotinib (PL + ERL) in untreated patients with epidermal growth factor receptor (EGFR) mutation‐positive metastatic non‐small‐cell lung cancer (NSCLC) (hazard ratio (HR) [95% CI]: 0.59 [0.46‐0.76]). This prespecified analysis assessed RAM + ERL efficacy and safety in the RELAY subset enrolled in East Asia (Japan, Taiwan, South Korea, Hong Kong). Randomized (1:1) patients received oral ERL (150 mg/d) plus intravenous RAM (10 mg/kg) or PL Q2W. Primary endpoint was PFS (investigator‐assessed). Key secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), overall survival (OS), and safety. Exploratory endpoints included biomarker analyses and time to second progression (PFS2). Median PFS was 19.4 vs 12.5 mo for RAM + ERL (n = 166) vs PL + ERL (n = 170) (HR: 0.636 [0.485‐0.833]; P = .0009). The 1‐y PFS rate was 72.4% vs 52.2%, respectively. PFS benefit was consistent in most subgroups, including by EGFR mutation (Ex19del, Ex21.L858R). ORR and DCR were similar in both arms, but median DoR was longer with RAM + ERL. OS and PFS2 were immature at data cut‐off (censoring rates, 81.2%‐84.3% and 64.1%‐70.5%, respectively). Grade ≥ 3 treatment‐emergent adverse events were more frequent with RAM + ERL (70.7%) than PL + ERL (49.4%). Adverse events leading to treatment discontinuation were similar in both arms (RAM + ERL, 13.3%; PL + ERL, 12.9%), as were post‐progression EGFR T790M mutation rates (43%; 50%). With superior PFS over PL + ERL and safety consistent with the overall RELAY population, RAM + ERL is a viable treatment option for EGFR‐mutated metastatic NSCLC in East Asia.     

Pembrolizumab plus pemetrexed‐platinum for metastatic nonsquamous non–small‐cell lung cancer: KEYNOTE‐189 Japan Study

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.     

Alpha‐actinin‐4 (ACTN4) gene amplification is a predictive biomarker for adjuvant chemotherapy with tegafur/uracil in stage I lung adenocarcinomas

Although adjuvant tegafur/uracil (UFT) is recommended for patients with completely resected stage I non‐small‐cell lung cancer (NSCLC) in Japan, only one‐third of cases has received adjuvant chemotherapy (ADJ) according to real‐world data. Therefore, robust predictive biomarkers for selecting ADJ or observation (OBS) without ADJ are needed. Patients who underwent complete resection of stage I lung adenocarcinoma with or without adjuvant UFT were enrolled. The status of ACTN4 gene amplification was analyzed by FISH. Statistical analyses to determine whether the status of ACTN4 gene amplification affected recurrence‐free survival (RFS) were carried out. Formalin‐fixed, paraffin‐embedded samples from 1136 lung adenocarcinomas were submitted for analysis of ACTN4 gene amplification. Ninety‐nine (8.9%) of 1114 cases were positive for ACTN4 gene amplification. In the subgroup analysis of patients aged 65 years or older, the ADJ group had better RFS than the OBS group in the ACTN4‐positive cohort (hazard ratio [HR], 0.084, 95% confidence interval [CI], 0.009‐0.806; P = .032). The difference in RFS between the ADJ group and the OBS group was not significant in ACTN4‐negative cases (all ages: HR, 1.214; 95% CI, 0.848‐1.738; P = .289). Analyses of ACTN4 gene amplification contributed to the decision regarding postoperative ADJ for stage I lung adenocarcinomas, preventing recurrence, improving the quality of medical care, preventing the unnecessary side‐effects of ADJ, and saving medical costs.     

Predictive value of EGFR mutation in non–small‐cell lung cancer patients treated with platinum doublet postoperative chemotherapy

The mutation status of tumor tissue DNA (n = 389) of resected stage II‐III non‐squamous non–small‐cell lung cancer (Ns‐NSCLC) was analyzed using targeted deep sequencing as an exploratory biomarker study (JIPANG‐TR) for the JIPANG study, a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) vs vinorelbine/cisplatin (Vnr/Cis). The TP53 mutation, common EGFR mutations (exon 19 deletion and L858R), and KRAS mutations were frequently detected. The frequency of the EGFR mutation was significant among female patients. Patients with an EGFR mutation‐positive status had a significantly shorter recurrence‐free survival (RFS) time (24 mo vs not reached) (HR, 1.64; 95% CI, 1.22‐2.21; P = .0011 for EGFR mutation status). Multivariable analysis identified both the pathological stage and EGFR mutation status as independent prognostic factors for RFS (HR, 1.78; 95% CI, 1.30‐2.44; P = .0003 for disease stage; and HR, 1.57; 95% CI, 1.15‐2.16; P = .0050 for EGFR mutation status). This study demonstrated that the EGFR mutation has either a poor prognostic or predictive impact on a poor response to postoperative chemotherapy with platinum doublet chemotherapy for stage II‐III Ns‐NSCLC patients. This result supports a role for mandatory molecular diagnosis of early‐stage Ns‐NSCLC for precision oncology and signifies the importance of adjuvant for the 3rd generation tyrosine kinase inhibitor rather than platinum‐based chemotherapy. This study is registered with the UMIN Clinical Trial Registry (UMIN 000012237).     

Efficacy and safety of standard of care with/without bevacizumab for platinum‐resistant ovarian/fallopian tube/peritoneal cancer previously treated with bevacizumab: The Japanese Gynecologic Oncology Group study JGOG3023

We investigated the efficacy and safety of further bevacizumab therapy in patients with platinum‐resistant ovarian cancer whose disease had progressed after bevacizumab plus chemotherapy. In this multicenter, open‐label, phase II trial (JGOG3023), patients were randomized 1:1 to a single‐agent chemotherapy alone (either pegylated liposomal doxorubicin [40 or 50 mg/m² administered intravenously], topotecan [1.25 mg/m² intravenously], paclitaxel [80 mg/m² intravenously], or gemcitabine [1000 mg/m² intravenously]) or single‐agent chemotherapy + bevacizumab (15 mg/m² intravenously). The primary endpoint was investigator‐assessed progression‐free survival (PFS) according to RECIST version 1.1. Secondary endpoints were overall survival (OS), objective response rate (ORR), and response rate according to Gynecological Cancer Intergroup cancer antigen 125 criteria. In total, 103 patients were allocated to chemotherapy (n = 51) or chemotherapy + bevacizumab (n = 52). Median investigator‐assessed PFS was 3.1 and 4.0 mo in each group, respectively (hazard ratio [HR] = 0.54, 95% confidence interval [CI]: 0.32‐0.90, P = .0082). Median OS was 11.3 and 15.3 mo in each group, respectively (HR = 0.67, 95% CI: 0.38‐1.17, P = .1556). Respective ORRs were 13.7% and 25.0% (P = .0599) and response rates were 16.7% and 21.4% (P = .8273). The incidence of grade ≥3 treatment‐related AEs was 42.0% in the chemotherapy group and 54.9% in the chemotherapy + bevacizumab group; AEs were well tolerated, with only 2 and 12 events leading to discontinuation of therapy, respectively. Bevacizumab was effective beyond progressive disease and AEs were manageable. The observed improvement in PFS requires further verification.     

Circulating tumor cells with FGFR2 expression might be useful to identify patients with existing FGFR2‐overexpressing tumor

Fibroblast growth factor receptor (FGFR) is associated with proliferation, migration, and angiogenesis of carcinomas, and FGFR signaling inhibitors are considered a key drug for the treatment of solid tumors with FGFR overexpression. Amplification of FGFR2 is reportedly identified in 3%‐10% of gastric cancers (GCs). The aim of this study is to clarify whether the identification of the circulating tumor cells (CTCs) with FGFR2 overexpression is useful to detect patients with FGFR2‐overexpressing GC. One hundred GC patients who underwent gastrectomy were enrolled. A total volume of 8 mL of peripheral blood was collected from each patient just before gastrectomy, and mononuclear cells were enriched by Ficol density gradient centrifugation. These cells were immunostained with PI/CD45/EpCAM/FGFR2. The number of CTCs with FGFR2 expression in each sample was enumerated by FACScan. The FGFR2 expression level of the resected primary tumor was assessed by immunohistochemistry. The number of FGFR2‐positive CTCs in the GC patients'' peripheral blood was significantly correlated with the FGFR2 expression level of the primary GC. The relapse‐free survival of the patients with FGFR2‐positive CTCs (≥5 cells/10 mL blood) was significantly poorer (P = .018, log‐rank) than that of the patients without FGFR2‐positive CTCs (<5 cell/10 mL blood). These findings suggested that the determination of FGFR2‐positive CTCs might help identify an existing tumor with FGFR2 overexpression.     

Current status of first‐line treatment with pembrolizumab for non–small‐cell lung cancer with high PD‐L1 expression

It is not clear whether pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum‐based chemotherapy (COMB) should be selected for patients with advanced non–small‐cell lung cancer (NSCLC) exhibiting high PD‐L1 expression (tumor proportion score ≥ 50%). We performed a retrospective, multicenter study of 300 patients with NSCLC exhibiting high PD‐L1 expression who received MONO or COMB as first‐line treatment between December 2018 and January 2020. We reviewed the medical records of all consecutive patients with no driver mutations, and assessed the patient characteristics, therapeutic regimens, treatment periods, and adverse events. In total, 166 (55%; median age: 74 years) and 134 (45%; median age: 68 years) patients received MONO and COMB, respectively. Patients were younger and had better performance status (0–1) in the COMB group (p < 0.01). With a median follow‐up time of 10.6 (range: 0.1–20.6) months, the median progression‐free survival was 7.1 months with MONO and 13.1 months with COMB. The objective response rate was 42.2% with MONO and 67.9% with COMB. With respect to treatment discontinuation, 36 out of 166 (21.7%) and 28 out of 134 (20.1%) patients discontinued MONO and COMB, respectively. In conclusion, COMB may be a promising option for first‐line treatment for NSCLC with high PD‐L1 expression and good performance status.     

Immune‐related adverse events in urothelial cancer patients: Adjustment for immortal time bias

To investigate the association between the onset, severity, and type of immune‐related adverse events (irAEs) and the efficacy of pembrolizumab in patients with platinum‐pretreated advanced urothelial carcinoma (UC), we retrospectively collected clinical datasets of 755 patients and conducted landmark analysis. Patients who survived for fewer than 3 months were excluded from the evaluation to reduce the immortal time bias. In total, 620 patients were evaluated, of whom 220 patients (35.5%) experienced grade ≥2 irAEs, including 134 patients with grade 2 irAEs and 86 with grade ≥3 irAEs. Propensity score matching extracted 198 patients with and without grade ≥2 irAEs. The onset of grade ≥2 irAEs was associated with longer median progression‐free survival (PFS) (8.3 months vs. 4.5 months, p = 0.003) and overall survival (OS) (20.4 months vs. 14.3 months, p = 0.031) and a higher objective response rate (ORR) (44.8% vs. 30.2%, p = 0.004). Patients with grade 2 irAEs had significantly better oncological outcomes (PFS, OS, and ORR) than grade ≤1 and ≥3 irAEs. Patients with grade ≥3 irAEs had worse outcomes than grade 2 irAEs. Endocrine and skin irAEs were related with better survival outcomes, and the rate of severities was lower in these categories. In conclusion, the occurrence of irAEs, particularly low‐grade irAEs, was predictive of pembrolizumab efficacy in patients with platinum‐pretreated advanced UC.     

Liquid biopsy reveals KLK3 mRNA as a prognostic marker for progression free survival in patients with metastatic castration‐resistant prostate cancer undergoing first‐line abiraterone acetate and prednisone treatment

Circulating RNAs extracted from liquid biopsies represent a promising source of cancer‐ and therapy‐related biomarkers. We screened whole blood from patients with metastatic castration‐resistant prostate cancer (mCRPC) following their first‐line treatment with abiraterone acetate and prednisone (AA‐P) to identify circulating RNAs that may correlate with progression‐free survival (PFS). In a prospective multicenter observational study, 53 patients with mCRPC were included after they started first‐line AA‐P treatment. Blood was drawn at baseline, 1, 3, and 6 months after treatment initiation. The levels of predefined circulating RNAs earlier identified as being upregulated in patients with mCRPC (e.g., microRNAs, long noncoding RNAs, and mRNAs), were analyzed. Uni‐ and multivariable Cox regression and Kaplan–Meier analyses were used to analyze the prognostic value of the various circulating RNAs for PFS along treatment. Detectable levels of kallikrein‐related peptidase 3 (KLK3) mRNA at baseline were demonstrated to be an independent prognostic marker for PFS (201 vs 501 days, P = 0.00054). Three months after AA‐P treatment initiation, KLK3 could not be detected in the blood of responding patients, but was still detectable in 56% of the patients with early progression. Our study confirmed that KLK3 mRNA detection in whole blood is an independent prognostic marker in mCRPC patients receiving AA‐P treatment. Furthermore, the levels of circulating KLK3 mRNA in patients receiving AA‐P treatment might reflect treatment response or early signs of progression.     

Circulating tumor DNA as a biomarker for monitoring early treatment responses of patients with advanced lung adenocarcinoma receiving immune checkpoint inhibitors

Immunotherapy for metastasized non‐small‐cell lung cancer (NSCLC) can show long‐lasting clinical responses. Selection of patients based on programmed death‐ligand 1 (PD‐L1) expression shows limited predictive value for durable clinical benefit (DCB). We investigated whether early treatment effects as measured by a change in circulating tumor DNA (ctDNA) level is a proxy of early tumor response to immunotherapy according to response evaluation criteria in solid tumors v1.1 criteria, progression‐free survival (PFS), DCB, and overall survival (OS). To this aim, blood tubes were collected from advanced‐stage lung adenocarcinoma patients (n = 100) receiving immune checkpoint inhibitors (ICI) at baseline (t₀) and prior to first treatment evaluation (4–6 weeks; t₁). Nontargetable (driver) mutations detected in the pretreatment tumor biopsy were used to quantify tumor‐specific ctDNA levels using droplet digital PCR. We found that changes in ctDNA levels were strongly associated with tumor response. A > 30% decrease in ctDNA at t₁ correlated with a longer PFS and OS. In total, 80% of patients with a DCB of ≥ 26 weeks displayed a > 30% decrease in ctDNA levels. For patients with a PD‐L1 tumor proportion score of ≥ 1%, decreasing ctDNA levels were associated with a higher frequency a DCB (80%) and a prolonged median PFS (85 weeks) and OS (101 weeks) compared with patients with no decrease in ctDNA (34%; 11 and 39 weeks, respectively). This study shows that monitoring of ctDNA dynamics is an easy‐to‐use and promising tool for assessing PFS, DCB, and OS for ICI‐treated NSCLC patients.     

Significance of TP53 mutations as predictive markers of adjuvant cisplatin‐based chemotherapy in completely resected non‐small‐cell lung cancer

Adjuvant cisplatin‐based chemotherapy only marginally improves survival in patients with completely resected non‐small‐cell lung cancer (NSCLC). We have evaluated the predictive value of mutations in TP53, encoding the tumour suppressor p53, in the International Adjuvant Lung Cancer Trial (IALT), a randomized trial of adjuvant cisplatin‐based chemotherapy against observation. TP53 (exons 4–8) was sequenced in 524 archived specimens of IALT patients with a median follow‐up of 7.5 years. Predictive analyses were based on Cox models adjusted for clinical and pathological variables. P‐values ≤0.01 were considered as significant. Mutations were detected in 221 patients (42%) and had no predictive value for the effect of chemotherapy (interaction between TP53 and treatment: p = 0.17 for Overall Survival (OS); p = 0.06 for Disease‐Free Interval, (DFS)). However, among patients with mutations, outcome appeared worse in treatment compared to observation arms (HR for OS = 1.36 (95% CI [0.97–1.31), p = 0.08; DFS = 1.40 (95% CI [1.01–1.95]), p = 0.04). When grouping mutations into classes according to predicted effects on protein structure, the tendency towards worse outcomes was restricted to “structure” mutations affecting residues of the hydrophobic core that are not located at the p53 protein‐DNA interface (HR for death in this class vs wild‐type T53 = 1.66; 95% CI [1.10–2.52], p = 0.02). Overall, TP53 mutations are not significant predictors of outcome in this trial of cisplatin‐based chemotherapy, although a specific class of structural mutations may be associated with a tendency towards worse outcomes upon treatment.     

Prognostic biomarker study in patients with clinical stage I esophageal squamous cell carcinoma: JCOG0502‐A1

We undertook genomic analyses of Japanese patients with stage I esophageal squamous cell carcinoma (ESCC) to investigate the frequency of genomic alterations and the association with survival outcomes. Biomarker analysis was carried out for patients with clinical stage T1bN0M0 ESCC enrolled in JCOG0502 (UMIN000000551). Whole‐exome sequencing (WES) was performed using DNA extracted from formalin‐fixed, paraffin‐embedded tissue of ESCC and normal tissue or blood sample. Single nucleotide variants (SNVs), insertions/deletions (indels), and copy number alterations (CNAs) were identified. We then evaluated the associations between each gene alteration with a frequency of 10% or more and progression‐free survival (PFS) using a Cox regression model. We controlled for family‐wise errors at 0.05 using the Bonferroni method. Among the 379 patients who were enrolled in JCOG0502, 127 patients were successfully analyzed using WES. The median patient age was 63 years (interquartile range, 57‐67 years), and 78.0% of the patients ultimately underwent surgery. The 3‐year PFS probability was 76.3%. We detected 20 genes with SNVs, indels, or amplifications with a frequency of 10% or more. Genomic alterations in FGF19 showed the strongest association with PFS with a borderline level of statistical significance of P = .00252 (Bonferroni‐adjusted significance level is .0025). Genomic alterations in FGF4, MYEOV, CTTN, and ORAOV1 showed a marginal association with PFS (P < .05). These genomic alterations were all CNAs at chromosome 11q13.3. We have identified new genomic alterations associated with the poor efficacy of ESCC (T1bN0M0). These findings open avenues for the development of new potential treatments for patients with ESCC.