The addition of pembrolizumab, an anti–PD-1 antibody, to a platinum–taxane chemotherapy combination significantly prolonged progression-free and overall survival among patients with untreated ...squamous cell lung cancer, regardless of the level of tumor PD-L1 expression.
In the FLAURA trial Japanese subset, osimertinib significantly improved median PFS versus standard-of-care (gefitinib) in patients with previously untreated EGFR (exon 19 deletion or L858R) ...mutation-positive advanced or metastatic NSCLC.
Abstract
Background
The FLAURA study was a multicenter, double-blind, Phase 3 study in which patients with previously untreated epidermal growth factor receptor mutation-positive advanced non-small-cell lung carcinoma were randomized 1:1 to oral osimertinib 80 mg once daily or standard-of-care (gefitinib 250 mg or erlotinib 150 mg, once daily) to compare safety and efficacy. In the overall FLAURA study, significantly better progression-free survival was shown with osimertinib versus standard-of-care.
Methods
Selected endpoints, including progression-free survival (primary endpoint), overall survival, objective response rate, duration of response and safety were evaluated for the Japanese subset of the FLAURA study.
Results
In Japan, 120 eligible Japanese patients were randomized to osimertinib (65 patients) or gefitinib (55 patients) treatment from December 2014 to June 2017. Median progression-free survival was 19.1 (95% confidence interval, 12.6, 23.5) and 13.8 (95% confidence interval, 8.3, 16.6) months with osimertinib and gefitinib, respectively (hazard ratio, 0.61; 95% confidence interval, 0.38, 0.99). Median overall survival was not reached in either treatment arm (data were immature). In the osimertinib and gefitinib arms, objective response rate was 75.4% (49/65) and 76.4% (42/55), and median duration of response from onset was 18.4 (95% confidence interval, not calculated) and 9.5 (95% confidence interval, 6.2, 13.9) months, respectively. The incidence of adverse events was similar in the two groups. The frequency of Grade ≥3 interstitial lung disease and pneumonitis in the two groups were the same (one patient).
Conclusions
As the first-line therapy, osimertinib showed significantly improved efficacy versus gefitinib in the Japanese population of the FLAURA study. No new safety concerns were raised.
Clinical trial registration
NCT02296125 (ClinicalTrials.gov)
Recently, immune checkpoint inhibitors (iCIs) have been used to treat cancers. Once some of the iCIs for the treatment of hepatocellular carcinoma (HCC) are certified in clinical trials, they are ...likely be administered to HCC patients with hepatitis C virus (HCV). However, the immunopathogenesis of HCV after the administration of iCIs has not been clarified. We experienced a lung cancer patient with HCV infection treated by nivolumab, programmed cell death 1 (PD-1) antibody. HCV-RNA gradually decreased after the start of nivolumab treatment. However, no increase in transaminase was observed during the decline of HCV-RNA. It was thought that HCV-specific cytotoxic T lymphocytes (CTLs) were activated by iCIs.
We evaluated the efficacy and safety of fosnetupitant (FosNTP) versus fosaprepitant (FosAPR) for preventing highly emetogenic chemotherapy-induced nausea and vomiting. This phase III study was the ...first head-to-head comparison between two different neurokinin-1 receptor antagonists in combination with palonosetron and dexamethasone.
Patients scheduled to receive cisplatin-based chemotherapy were randomly assigned 1:1 to FosNTP 235 mg or FosAPR 150 mg in combination with palonosetron 0.75 mg and dexamethasone. The primary end point was overall (0-120 hours) complete response (CR; no emetic event and no rescue medication) rate, stratified by sex and age category, to show the noninferiority of FosNTP to FosAPR (noninferiority margin, -10% for the difference in the overall CR rate).
Overall, 795 patients were randomly assigned, of whom 785 received the study drug (FosNTP N = 392
FosAPR N = 393) and were evaluated for efficacy and safety. The overall CR rate was 75.2% versus 71.0%, respectively (Mantel-Haenszel common risk difference, 4.1%; 95% CI, -2.1% to 10.3%), demonstrating noninferiority of FosNTP to FosAPR. The CR rates in the acute (0-24 hours), delayed (24-120 hours), and beyond delayed (120-168 hours) phases, and at 0-168 hours were 93.9% versus 92.6%, 76.8% versus 72.8%, 86.5% versus 81.4%, and 73.2% versus 66.9%, respectively. The incidence rates of treatment-related adverse events with FosNTP versus FosAPR were 22.2% versus 25.4%, whereas adverse events or treatment-related adverse events relevant to injection site reactions were 11.0% versus 20.6% (
< .001) and 0.3% versus 3.6% (
< .001), respectively.
FosNTP demonstrated noninferiority to FosAPR, with a favorable safety profile and lower risk for injection site reactions. Thus, FosNTP is valuable in the prophylaxis of acute, delayed, and beyond delayed chemotherapy-induced nausea and vomiting.
Background
Immune-related adverse events (irAEs) comprise a distinct spectrum of auto-inflammatory manifestations triggered due to immune checkpoint inhibitors (ICI). Current data on the association ...of irAEs with outcomes in NSCLC treated with nivolumab are limited.
Methods and objectives
We pooled data from 531 metastatic NSCLC patients from five centers treated with nivolumab after failing platinum-based chemotherapy. The primary objective was to investigate the relationship between irAEs with clinical benefit to nivolumab as well as to elucidate patterns of irAE-related ICI discontinuations and their impact on survival.
Results
33.0% (173/531) of patients treated with nivolumab were noted to have an irAE. Patients with irAEs had a significantly longer median PFS 6.1 vs. 3.1 months, HR 0.68 95% CI (0.55–0.85);
p
= 0.001 and OS 14.9 vs. 7.4 months, HR 0.66 95% CI (0.52–0.82);
p
< 0.001) compared to those without irAEs. In multivariate analysis, the presence of irAEs showed a significantly better PFS HR 0.69, 95% CI (0.55–0.87);
p
= 0.002 and a trend for better OS HR 0.62, 95% CI (0.55–1.03);
p
= 0.057. Patients with permanent ICI discontinuation secondary to index irAE had a significantly shorter median PFS 2.3 vs. 6.6 months, HR 1.74 95% CI (1.06–2.80);
p
= 0.02 and median OS 3.6 vs. 17.6 months; HR 2.61 95% CI (1.61–4.21);
p
< 0.001 compared to those that did not have permanent ICI discontinuation.
Conclusions
Our pooled exploratory analysis demonstrates improved clinical benefit to nivolumab in NSCLC patients experiencing irAEs. We also observed negative impact of irAE-related treatment discontinuation on survival in this group of patients.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Pembrolizumab, a humanized monoclonal IgG4 antibody directed against programmed death-1, is an immune checkpoint inhibitor that has been introduced for the treatment of non-small-cell lung cancer. ...However, immune checkpoint inhibitors may cause severe immune-related adverse events. We herein present a case of lung cancer with complete atrioventricular block associated with acute myocarditis, which developed 16 days after the administration of pembrolizumab. The clinical course of this case suggested a strong need for close cardiac monitoring when pembrolizumab is administered on an outpatient basis.
Background First-line treatment of nonsquamous non-small cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination therapy together with immune checkpoint inhibitors (ICIs). ...However, phase III studies of combinations of cytotoxic chemotherapy and ICIs have included only patients with maintained organ function, not those with renal impairment. Methods Cytotoxic chemotherapy-naïve advanced nonsquamous NSCLC patients aged 20 years or older with impaired renal function (creatinine clearance of 15 to 45 mL/min) are prospectively registered in this single-arm phase II study and receive combination therapy with carboplatin, nanoparticle albumin-bound (nab-) paclitaxel, and atezolizumab. Individuals with known genetic driver alterations including those affecting EGFR, ALK, ROS1, BRAF, MET, RET, and NTRK are excluded. We plan to enroll 40 patients over 2 years at 32 oncology facilities in Japan. The primary end point is confirmed objective response rate. Discussion If the study demonstrates efficacy and safety of carboplatin/nab-paclitaxel/atezolizumab, then this combination regimen may become a treatment option even for nonsquamous NSCLC patients with impaired renal function. Trial registration Registered with Japan Registry for Clinical Trials on 25 February 2021 (jRCTs071200102). Keywords: Clinical trial, Nonsquamous non-small cell lung cancer, Immune checkpoint inhibitor, Chemotherapy, Renal impairment
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
MET mutations leading to exon 14 skipping (METΔex14) are strong molecular drivers for non–small‐cell lung cancer (NSCLC). Capmatinib is a highly potent, selective oral MET inhibitor that showed ...clinically meaningful efficacy and a manageable safety profile in a global phase II study (GEOMETRY mono‐1, NCT02414139) in patients with advanced METΔex14‐mutated/MET‐amplified NSCLC. We report results of preplanned analyses of 45 Japanese patients according to MET status (METΔex14‐mutated or MET‐amplified) and line of therapy (first‐ 1L or second‐/third‐line 2/3L). The starting dose was 400 mg twice daily. The primary endpoint was the objective response rate (ORR) assessed by a blinded independent review committee. A key secondary endpoint was duration of response (DOR). Among METΔex14‐mutated patients, in the 1L group, one patient achieved partial response (DOR of 4.24 months) and the other had stable disease. In the 2/3L group, the ORR was 36.4% (95% confidence interval CI 10.9%‐69.2%), median DOR was not evaluable, and progression‐free survival was 4.70 months. One patient (2/3L group) showed partial resolution of brain lesions per independent neuroradiologist review. In MET‐amplified patients with a MET gene copy number of ≥10, the ORR was 100% (2/2 patients) in the 1L group and 45.5% (5/11 patients) in the 2/3L group, with DOR of 8.2 and 8.3 months, respectively. Common treatment‐related adverse events among the 45 Japanese patients were blood creatinine increased (53.3%), nausea (35.6%), and oedema peripheral (31.1%); most were grade 1/2 severity. In conclusion, capmatinib was effective and well tolerated by Japanese patients with METΔex14/MET‐amplified NSCLC, consistent with the overall population.
We describe results for Japanese patients enrolled in a global phase II study (GEOMETRY mono‐1, NCT02414139), which investigated the efficacy and safety of capmatinib in patients with advanced non–small‐cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations (METΔex14). Capmatinib was effective and well tolerated by Japanese patients. The results are consistent with those observed in the overall population enrolled in GEOMETRY mono‐1.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The global phase 3 IMpower010 study evaluated adjuvant atezolizumab versus best supportive care (BSC) following platinum‐based chemotherapy in patients with resected stage IB–IIIA non‐small cell lung ...cancer (NSCLC). Here, we report a subgroup analysis in patients enrolled in Japan. Eligible patients had complete resection of histologically or cytologically confirmed stage IB (tumors ≥4 cm)–IIIA NSCLC. Upon completing 1–4 cycles of adjuvant cisplatin‐based chemotherapy, patients were randomized 1:1 to receive atezolizumab (fixed dose of 1200 mg every 21 days; 16 cycles or 1 year) or BSC. The primary endpoint of the global IMpower010 study was investigator‐assessed disease‐free survival, tested hierarchically first in patients with stage II–IIIA NSCLC whose tumors expressed programmed death‐ligand 1 (PD‐L1) on ≥1% of tumor cells, then in all randomized patients with stage II–IIIA NSCLC, and finally in the intention‐to‐treat (ITT) population (stage IB–IIIA NSCLC). Safety was evaluated in all patients who received atezolizumab or BSC. The study comprised 149 enrolled patients in three populations: ITT (n = 117; atezolizumab, n = 59; BSC, n = 58), all‐randomized stage II–IIIA (n = 113; atezolizumab, n = 56; BSC, n = 57), and PD‐L1 tumor cells ≥1% stage II–IIIA (n = 74; atezolizumab, n = 41; BSC, n = 33). At the data cutoff date (January 21, 2021), a trend toward disease‐free survival improvement with atezolizumab vs BSC was observed in the PD‐L1 tumor cells ≥1% stage II–IIIA (unstratified hazard ratio HR, 0.52; 95% confidence interval CI, 0.25–1.08), all‐randomized stage II–IIIA (unstratified HR, 0.62; 95% CI, 0.35–1.11), and ITT (unstratified HR, 0.61; 95% CI, 0.34–1.10) populations. Atezolizumab‐related grade 3/4 adverse events occurred in 16% of patients; no treatment‐related grade 5 events occurred. Adjuvant atezolizumab showed disease‐free survival improvement and a tolerable toxicity profile in Japanese patients in IMpower010, consistent with the global study results.
This manuscript reports a subgroup analysis of Japanese patients in the global phase 3 IMpower010 study evaluating adjuvant atezolizumab vs best supportive care (BSC) following platinum‐based chemotherapy in resected stage IB‐IIIA non‐small cell lung cancer. Disease‐free survival (DFS) improvement with atezolizumab versus BSC was observed in the Japanese stage II‐IIIA population with PD‐L1 expression on ≥1% of tumor cells; in the Japanese all‐randomized stage II‐IIIA and ITT (stage IB‐IIIA) populations, unstratified DFS hazard ratios favored atezolizumab vs BSC. Adjuvant atezolizumab had a tolerable toxicity profile in Japanese patients in IMpower010, consistent with the global study results.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
p62/SQSTM1 is a selective substrate of autophagy, and aberrant accumulation of p62 has been observed in various pathological conditions. To understand the roles p62 plays in non‐small‐cell lung ...cancer (NSCLC), we carried out immunohistochemical analyses of p62 expression in a cohort of patients with annotated clinicopathological data. As analyses of murine and human hepatocellular carcinomas suggested a correlation between p62 and Nrf2 accumulations, we also examined NRF2 expression in the same cohort. The expression of NRF2 and p62 was examined by immunohistochemical methods in 109 NSCLC cases, which included patients with adenocarcinoma (n = 72), squamous cell carcinoma (n = 31), and large cell carcinoma (n = 6). Accumulation of NRF2 and p62 was detected in 34% and 37% of NSCLC patients, respectively. The accumulations of p62 and NRF2 did not correlate with each other, but both were associated with worse lung cancer‐specific survival (P = 0.0003 for NRF2; P = 0.0130 for p62). NRF2 status had an impact on NSCLC prognosis irrespective of histology types, but p62 status did so particularly in adenocarcinoma (P = 0.037). Multivariate analysis indicated that positive immunoreactivities of NRF2 and p62 were both independent factors predicting worse lung cancer‐specific survival (P < 0.0001 for NRF2 and P = 0.04 for p62). This study revealed that both NRF2 and p62 are independent prognostic factors for NSCLC. The prognostic impact of p62 status was pronounced in adenocarcinoma patients, suggesting that molecular mechanisms underlying cancer evolution differ between adenocarcinoma and squamous cell carcinoma. (Cancer Sci 2012; 103: 760–766)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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