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In patients with locally advanced non–small-cell lung cancer who have undergone concurrent chemotherapy and radiation therapy, the use of durvalumab in the year after completing treatment significantly prolonged disease-free and overall survival as compared with placebo.

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 The standard treatment for stage III non-small cell lung cancer (NSCLC) is platinum-based concurrent chemoradiotherapy (CCRT), followed by durvalumab (anti-programmed death ligand-1 antibody) maintenance therapy. Biomarkers related to immune-related pneumonitis during durvalumab maintenance therapy after CCRT for stage III NSCLC have not yet been identified. Methods We evaluated 88 cytokines/chemokines at three time points, before concurrent chemoradiotherapy (pre-CCRT), post-radiotherapy, and six weeks after durvalumab administration, using a multiplex assay (Bio-Plex system) in 29 patients who provided consent for the blood biomarker study, categorizing them into Grade 0–1 and Grade 2 or higher pneumonitis groups. Results At pre-CCRT, no significant changes were observed; however, at post-radiotherapy, significant changes in TNFRSF8/sCD30 were observed in the group with Grade 2 or higher pneumonitis. Moreover, six weeks after durvalumab administration, significant changes were observed in TNFRSF8/sCD30, in addition to TNFSF12, IL-1Ra, CXCL9/CXCL10/CXCL11, IFN-γ, and CCL19. Conclusion Although no biomarkers predicting Grade 2 or higher pneumonitis before CCRT were identified, the relationship between radiotherapy and TNFRSF8/sCD30 as well as the relationship between durvalumab administration and various cytokines/chemokines is reported for the first time in stage III NSCLC. In particular, the CXCL family, including CXCL9, CXCL10, and CXCL11, is considered highly significant in pneumonitis with durvalumab maintenance therapy after CCRT for stage III NSCLC. Further large-scale studies are needed to establish biomarkers for patients with NSCLC who receive durvalumab maintenance therapy after CCRT.

Immune-related adverse events (irAEs) and hyperprogressive disease (HPD) are serious problems arising in the early period of monotherapy (MT) with programmed cell death protein 1 (PD-1) and programmed cell death ligand1 (PD-L1) inhibitors. However, the frequency and clinical features of these problems in patients receiving combination therapy (CT) with cytotoxic chemotherapy in addition to these agents remain unclear. We retrospectively screened patients with pathologically confirmed advanced or recurrent non-small cell lung cancer (NSCLC) who had received PD-1/PD-L1 inhibitors at Kurume University Hospital between February 2016 and March 2020. We recruited 210 patients, of whom 172 (81.9%) had received PD-1/PD-L1 inhibitor MT and 38 (18.1%) had received CT. The incidence of irAE during the 3 months after treatment initiation was significantly higher in the MT group (57 of 172, 33.1%) than in the CT group (6 of 38, 15.8%) (p = 0.049). During the same period, the incidence of pneumonitis was also higher in the MT group (18 of 172, 10.9%) than in the CT group (0 of 38) (p = 0.049). A similar trend was observed in patients who had received these treatments on a first line basis. The HPD rate was significantly lower in the CT group (1 of 34, 2.9%) than in the MT group (25 of 142, 17.6%) (p = 0.031). The incidences of HPD and irAE, especially pneumonitis, during 3 months after treatment initiation were relatively lower in the CT group than in the MT group. The mechanisms underlying these differences warrant further study.

Cytokine release syndrome (CRS) is a systemic inflammatory disease caused by a variety of factors, including infections and certain drugs. A 70‐year‐old man who was diagnosed with a postoperative recurrence of lung adenocarcinoma received nivolumab, ipilimumab, pemetrexed and carboplatin every 3 weeks for two cycles followed by nivolumab and ipilimumab, which resulted in a partial response. Four days after the dose of nivolumab, the patient returned with diarrhea and fever. The patient was diagnosed with COVID‐19 infection accompanied by severe colitis. Although intensive care was performed, the patient suddenly went into cardiopulmonary arrest. Examination revealed an abnormally high interleukin‐6 level, suggesting CRS. This is the first report of a patient with CRS accompanied with COVID‐19 infection during treatment with ICIs. Cytokine release syndrome (CRS) is a systemic inflammatory disease caused by a variety of factors, including infections and certain drugs. Here, we report a case of non‐small cell lung cancer with CRS caused by COVID‐19 infection during treatment with nivolumab and ipilimumab. Fever is a common event in cancer patients, especially in COVID‐19‐infected patients, but when fever develops during cancer immunotherapy, CRS should always be kept in mind. Cytokine release syndrome (CRS) is a systemic inflammatory disease caused by a variety of factors, including infections and certain drugs. Here, we report a case of non‐small cell lung cancer with CRS caused by COVID‐19 infection during treatment with nivolumab and ipilimumab. Fever is a common event in cancer patients, especially in COVID‐19‐infected patients, but when fever develops during cancer immunotherapy, CRS should always be kept in mind.

Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were developed to target the EGFR T790M resistance mutation in non-small cell lung cancer (NSCLC) patients resistant to first- or second-generation EGFR-TKIs. To investigate the efficacy of afatinib treatment for EGFR T790M-positive NSCLC patients showing resistance to osimertinib and alterations in somatic mutations and tumor mutation burden (TMB) in plasma circulating tumor DNA (ctDNA) during afatinib treatment, we conducted a prospective study using Cancer Personalized Profiling by deep Sequencing (CAPP-Seq). Nine NSCLC patients with EGFR T790M mutation who showed resistance to third-generation EGFR-TKIs were enrolled in this study and treated with afatinib. Plasma samples were collected before treatment, 4 weeks after treatment, and at disease progression. The mutation profile and TMB in plasma ctDNA were analyzed by CAPP-Seq. The objective response rate and median progression-free survival associated with afatinib were 0% and 2.0 months, respectively. The C797S mutation-mediated resistance to osimertinib was observed in one patient and following afatinib treatment in two patients; the C797S mutations occurred in the same allele as the T790M mutation. After afatinib treatment, afatinib-sensitive mutant alleles, such as ERBB2, and TMB decreased. We have demonstrated that detection of mutant allele frequency and TMB of ctDNA by CAPP-Seq could help determine the effectiveness of and resistance to afatinib. Although afatinib monotherapy for T790M-positive NSCLC resistant to osimertinib was less effective, the action for multiclonal mutant alleles and TMB might contribute to further treatment strategy.

Background Pembrolizumab is a first-line therapy for certain patients with advanced/metastatic non-small cell lung cancer (NSCLC). Combining pembrolizumab with other immunotherapies may enhance tumor cell killing and clinical outcomes. Epacadostat is a selective inhibitor of indoleamine 2,3-dioxygenase 1, an immuno-regulatory enzyme involved in tryptophan to kynurenine metabolism that inhibits T cell-mediated immune responses. Methods In this randomized phase II study, patients with metastatic NSCLC expressing high (≥ 50%) programmed death-ligand 1 (PD-L1) levels received pembrolizumab 200 mg every 21 days plus oral epacadostat 100 mg twice daily (combination) or matching placebo (control). The primary objective was objective response rate (ORR); secondary objectives were progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety/tolerability. Results 154 patients were randomized (77 per group). Median (range) follow-up was 6.8 months (0.1–11.4) and 7.0 months (0.2–11.9) in the combination and control groups, respectively Confirmed ORR was similar between groups (combination: 32.5%, 95% CI 22.2–44.1; control: 39.0%, 95% CI 28.0–50.8; difference: − 6.5, 95% CI − 21.5 to 8.7; 1-sided P  = 0.8000). Median (range) DOR was 6.2 months (1.9 + to 6.5 +) and not reached (1.9 + to 8.6 +) in the combination and control groups, respectively. Although not formally tested, median PFS was 6.7 and 6.2 months for the combination and control groups, respectively, and median OS was not reached in either group. Circulating kynurenine levels increased from C1D1 to C2D1 ( P  < 0.01) in the control group and decreased from C1D1 to C2D1 ( P  < 0.01) in the combination group but were not normalized in most patients. The most frequent serious adverse events (AEs) (≥ 2%) were pneumonia (4.0%), anemia (2.7%), atelectasis (2.7%) and pneumonitis (2.7%) in the combination group and pneumonia (3.9%), pneumonitis (2.6%) and hypotension (2.6%) in the control group. Two deaths due to drug-related AEs were reported, both in the control group. Conclusions Addition of epacadostat to pembrolizumab therapy for PD-L1–high metastatic NSCLC was generally well tolerated but did not demonstrate an improved therapeutic effect. Evaluating higher doses of epacadostat that normalize kynurenine levels when given in combination with checkpoint inhibitors may be warranted. Trial registration ClinicalTrials.gov, NCT03322540. Registered 10/26/2017.

Tepotinib is a highly selective MET tyrosine kinase inhibitor (TKI) that has demonstrated robust and durable clinical activity in patients with MET exon 14 (METex14) skipping non–small‐cell lung cancer (NSCLC). In the Phase II VISION study, patients received oral tepotinib 500 mg once daily. The primary endpoint was an objective response by an independent review committee (IRC) according to RECIST v1.1 criteria. The secondary endpoints included duration of response (DOR), progression‐free survival (PFS), overall survival (OS), and safety. Here we report the analysis of the efficacy and safety of tepotinib in all Japanese patients with advanced METex14 skipping NSCLC from VISION (n = 38) with >18 months' follow‐up. The median age of the Japanese patients was 73 years (range 63–88), 39.5% of patients were ≥75 years old, 68.4% were male, 55.3% had a history of smoking, 76.3% had adenocarcinoma, and 10.5% of patients had known brain metastases at baseline. Overall, the objective response rate (ORR) was 60.5% (95% confidence interval (CI): 43.4, 76.0) with a median DOR of 18.5 months (95% CI: 8.3, not estimable). ORR in treatment‐naïve patients (n = 18) was 77.8% (95% CI: 52.4, 93.6), and in patients aged ≥75 years (n = 15), ORR was 73.3% (95% CI: 44.9, 92.2). The most common treatment‐related adverse event (AE) with any grade was blood creatinine increase (65.8%), which resolved following tepotinib discontinuation. Other common treatment‐related AEs were peripheral edema (60.5%), hypoalbuminemia (34.2%), diarrhea (28.9%), and nausea (15.8%). In summary, tepotinib demonstrated robust and durable clinical activity irrespective of age or therapy line, with a manageable safety profile in Japanese patients with METex14 skipping NSCLC enrolled in VISION. This manuscript presents an extended analysis of efficacy and safety of tepotinib in all Japanese patients from the VISION study with >18 months’ follow‐up. Tepotinib provides robust and durable clinical activity, irrespective of age or therapy line. In addition, tepotinib was well tolerated with mostly mild‐to‐moderate adverse events and a low rate of treatment discontinuations, confirming the manageable safety profile of tepotinib in this population, with no new safety signals.

The global phase III KEYNOTE‐407 (NCT02775435) trial showed that pembrolizumab plus chemotherapy prolonged overall and progression‐free survival (OS/PFS) versus placebo plus chemotherapy in patients with metastatic squamous non‐small‐cell lung cancer (NSCLC). We present outcomes of patients from Japan enrolled in KEYNOTE‐407. Patients were randomized 1:1 to receive pembrolizumab 200 mg or placebo with paclitaxel 200 mg/m2 every 3 weeks (Q3W) or nab‐paclitaxel 100 mg/m2 (weekly) plus carboplatin area under the concentration‐time curve of 6 mg/mL/min Q3W for four cycles, followed by pembrolizumab or placebo Q3W for a total of 35 cycles. Primary end‐points were OS and PFS per RECIST version 1.1 by blinded independent central review. Fifty patients were randomized at Japanese sites (pembrolizumab plus chemotherapy, n = 22; placebo plus chemotherapy, n = 28). Median follow‐up time at data cut‐off (May 9, 2019) was 15.1 (range, 0.5–24.0) months. Median OS (95% confidence interval [CI]) was 17.3 (12.5–not reached) versus 11.0 (8.6–19.5) months in the pembrolizumab plus chemotherapy versus placebo plus chemotherapy group (hazard ratio [HR] 0.56; 95% CI, 0.27–1.15). Median PFS (95% CI) was 8.3 (6.1–13.0) versus 7.2 (3.9–8.8) months (HR 0.65; 95% CI, 0.35–1.23). Grade 3–5 adverse events (AEs) occurred in 86% and 75% of patients, respectively. There were three fatal AEs, two of which were treatment‐related (one from each treatment group, pneumonitis and pulmonary hemorrhage). Efficacy and safety outcomes were consistent with the global study and support the use of pembrolizumab plus chemotherapy in Japanese patients with metastatic squamous NSCLC. Pembrolizumab plus platinum‐based chemotherapy prolonged overall survival and progression‐free survival, and provided durable clinical benefit with manageable safety versus placebo plus chemotherapy in Japanese patients with metastatic squamous non‐small‐cell lung cancer (NSCLC) in the phase III KEYNOTE‐407 study. These data support the continued use of pembrolizumab plus platinum‐based chemotherapy as first‐line treatment for metastatic squamous NSCLC in Japanese patients.

We report two cases of adrenal insufficiency (AI) occurring during neoadjuvant treatment with pembrolizumab for breast cancer. In the first case, a 53-year-old female presented with a chief complaint of poor oral intake and fatigue. In the second case, a 46-year-old female presented with a chief complaint of fever, poor oral intake, and general fatigue and was admitted with a diagnosis of pneumonia. Her symptoms did not improve during treatment for pneumonia. After that, two patients were diagnosed with pembrolizumab-induced adrenal insufficiency and were treated with hydrocortisone with improvement in their symptoms. AI due to pembrolizumab use is a relatively rare adverse event, but if it is detected late, it can be potentially life-threatening. In both cases, there were clear changes in the common terminology criteria for adverse events (CTCAE) grade at the time of diagnosis of AI. It may be useful for early detection of AI. The CTCAE version 5.0 was used to assess the severity of adverse events.