In a randomized trial involving patients with previously untreated advanced non–small-cell lung cancer, pembrolizumab was associated with a higher response rate, longer progression-free and overall ...survival, and fewer adverse events than was platinum-based chemotherapy.
Approximately 23 to 28% of patients with advanced non–small-cell lung cancer (NSCLC) have a high level of programmed death ligand 1 (PD-L1) expression, which is defined as membranous PD-L1 expression on at least 50% of tumor cells, regardless of the staining intensity (i.e., a PD-L1 tumor proportion score of 50% or greater).
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Data from the phase 1 KEYNOTE-001 and phase 3 KEYNOTE-010 studies indicated that patients with advanced NSCLC and a PD-L1 tumor proportion score of 50% or greater were more likely than those with lower tumor proportion scores to have a response to pembrolizumab, a highly selective, humanized . . .
Introduction: Platinum-based chemotherapy had long played a role as standard therapy for the first-line treatment of advanced or recurrent non-small cell lung cancer (NSCLC). However, immune ...checkpoint inhibitors such as pembrolizumab, a monoclonal antibody that prevents programmed death protein 1 (PD-1) receptor, have brought a paradigm shift in this field.
Areas covered: In this article, we review the relevant literatures and ongoing trials on the first-line treatment of pembrolizumab. Especially, in two pivotal phase III trials, KEYNOTE-024 and −189, both pembrolizumab monotherapy and combined pembrolizumab plus chemotherapy significantly prolonged overall survival (OS) compared to the existing platinum-based chemotherapy. Currently, multiple trials with combination therapy of pembrolizumab and other agents have been conducted, and further evidences are expected to be created.
Expert opinion: Immune checkpoint inhibitors that block the PD-1/PD-L1 pathway are essential drugs for advanced or recurrent NSCLC, among which pembrolizumab becomes one of the standards of care in the first-line of NSCLC. For further improvement in efficacy of pembrolizumab, it is necessary to clarify the identification of biomarkers exclusive to PD-L1 expression, predictive factors for patients who benefit most from the agent.
Summary Background Alectinib, a potent, highly selective, CNS-active inhibitor of anaplastic lymphoma kinase (ALK), showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP ...trial in Japanese patients with ALK -positive non-small-cell lung cancer. Given those promising results, we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib. Methods J-ALEX was a randomised, open-label, phase 3 trial that recruited ALK inhibitor-naive Japanese patients with ALK -positive non-small-cell lung cancer, who were chemotherapy-naive or had received one previous chemotherapy regimen, from 41 study sites in Japan. Patients were randomly assigned (1:1) via an interactive web response system using a permuted-block method stratified by Eastern Cooperative Oncology Group performance status, treatment line, and disease stage to receive oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was progression-free survival assessed by an independent review facility. The efficacy analysis was done in the intention-to-treat population, and safety analyses were done in all patients who received at least one dose of the study drug. The study is ongoing and patient recruitment is closed. This study is registered with the Japan Pharmaceutical Information Center (number JapicCTI-132316). Findings Between Nov 18, 2013, and Aug 4, 2015, 207 patients were recruited and assigned to the alectinib (n=103) or crizotinib (n=104) groups. At data cutoff for the second interim analysis, 24 patients in the alectinib group had discontinued treatment compared with 61 in the crizotinib group, mostly due to lack of efficacy or adverse events. At the second interim analysis (data cutoff date Dec 3, 2015), an independent data monitoring committee determined that the primary endpoint of the study had been met (hazard ratio 0·34 99·7% CI 0·17–0·71, stratified log-rank p<0·0001) and recommended an immediate release of the data. Median progression-free survival had not yet been reached with alectinib (95% CI 20·3–not estimated) and was 10·2 months (8·2–12·0) with crizotinib. Grade 3 or 4 adverse events occurred at a greater frequency with crizotinib (54 52% of 104) than alectinib (27 26% of 103). Dose interruptions due to adverse events were also more prevalent with crizotinib (77 74% of 104) than with alectinib (30 29% of 103), and more patients receiving crizotinib (21 20%) than alectinib (nine 9%) discontinued the study drug because of an adverse event. No adverse events with a fatal outcome occurred in either treatment group. Interpretation These results provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard of care for the first-line treatment of ALK -positive non-small-cell lung cancer. The dose of alectinib (300 mg twice daily) used in this study is lower than the approved dose in countries other than Japan; however, this limitation is being addressed in the ongoing ALEX study. Funding Chugai Pharmaceutical Co, Ltd.
Molecular agents targeting the epidermal growth factor receptor (EGFR)‐, anaplastic lymphoma kinase (ALK)‐ or c‐ros oncogene 1 (ROS1) alterations have revolutionized the treatment of oncogene‐driven ...non‐small‐cell lung cancer (NSCLC). However, the emergence of acquired resistance remains a significant challenge, limiting the wider clinical success of these molecular targeted therapies. In this study, we investigated the efficacy of various molecular targeted agents, including erlotinib, alectinib, and crizotinib, combined with anti‐vascular endothelial growth factor receptor (VEGFR) 2 therapy. The combination of VEGFR2 blockade with molecular targeted agents enhanced the anti‐tumor effects of these agents in xenograft mouse models of EGFR‐, ALK‐, or ROS1‐altered NSCLC. The numbers of CD31‐positive blood vessels were significantly lower in the tumors of mice treated with an anti‐VEGFR2 antibody combined with molecular targeted agents compared with in those of mice treated with molecular targeted agents alone, implying the antiangiogenic effects of VEGFR2 blockade. Additionally, the combination therapies exerted more potent antiproliferative effects in vitro in EGFR‐, ALK‐, or ROS1‐altered NSCLC cells, implying that VEGFR2 inhibition also has direct anti‐tumor effects on cancer cells. Furthermore, VEGFR2 expression was induced following exposure to molecular targeted agents, implying the importance of VEGFR2 signaling in NSCLC patients undergoing molecular targeted therapy. In conclusion, VEGFR2 inhibition enhanced the anti‐tumor effects of molecular targeted agents in various oncogene‐driven NSCLC models, not only by inhibiting tumor angiogenesis but also by exerting direct antiproliferative effects on cancer cells. Hence, combination therapy with anti‐VEGFR2 antibodies and molecular targeted agents could serve as a promising treatment strategy for oncogene‐driven NSCLC.
We found that VEGFR2 blockade augmented the anti‐tumor effects of molecular targeted agents in oncogene‐driven NSCLC, particularly in EGFR/ALK/ROS1‐driven NSCLC. We also identified 2 mechanisms underlying the synergistic effects of anti‐VEGFR2 therapy with molecular targeted agents. VEGFR2 blockade not only inhibited tumor angiogenesis but also exerted direct antiproliferative effects on cancer cells.
Trastuzumab emtansine (T-DM1), an anti–erb-b2 receptor tyrosine kinase 2 (HER2) antibody-drug conjugate, has been shown to significantly improve survival in HER2-positive breast cancer. We report a ...phase II trial of T-DM1 monotherapy in relapsed NSCLC with documented HER2 positivity (an immunohistochemistry IHC score of 3+, both an IHC score of 2+ and fluorescence in situ hybridization positivity, or exon 20 mutation). This study was terminated early because of limited efficacy. The demographic characteristics in the 15 assessable patients were as follows: median age, 67 years; male sex, 47%; performance status of 0 to 1, 80%; HER2 status IHC 3+, 33%; HER status IHC 2+/fluorescence in situ hybridization–positive, 20%; and exon 20 mutation, 47%. The median number of delivered cycles was 3 (range 1–11). One patient achieved a partial response with an objective response rate of 6.7% (90% confidence interval: 0.2–32.0). With a median follow-up time of 9.2 months, the median progression-free survival time and median survival time were 2.0 and 10.9 months, respectively. Grade 3 or 4 adverse events included thrombocytopenia (40%) and hepatotoxicity (20%) without any treatment-related deaths. T-DM1 had a limited efficacy for HER2-positive NSCLC in our cohort. Applying the concept of precision medicine to tumors appears challenging; thus, additional molecular approaches are warranted.
Highly efficient organic light-emitting diodes are in urgent demand in applications of new generation full-color displays and solid-state lighting sources. The limitation of device performance is ...greatly affected by extrinsic and intrinsic elements of the light out-coupling process. By elaborately designing emitters as sticklike molecules, horizontal orientation ratios in the range of 86–93% were realized to intrinsically increase the out-coupling factor of electroluminescence devices. These elongated compounds are inclined to lie parallel to substrate in vacuum-deposited thin solid films and regularize their transition dipole moments in a major degree. As consequences of such desirable molecule arrangement, remarkable external quantum efficiencies near 21% for pure blue devices, close to 30% for sky-blue devices, and over 35% for greenish blue devices were respectively achieved. A compatible strategy on devising high-performance emitters for organic electroluminescence is advocated herein.
Crizotinib is the standard of care for advanced non-small cell lung cancer (NSCLC) patients harboring the anaplastic lymphoma kinase (ALK) fusion gene, but resistance invariably develops. Unlike ...crizotinib, alectinib is a selective ALK tyrosine kinase inhibitor (TKI) with more potent antitumor effects and a favorable toxicity profile, even in crizotinib-resistant cases. However, acquired resistance to alectinib, as for other TKIs, remains a limitation of its efficacy. Therefore, we investigated the mechanisms by which human NSCLC cells acquire resistance to alectinib. We established two alectinib-resistant cell lines that did not harbor the secondary ALK mutations frequently occurring in crizotinib-resistant cells. One cell line lost the EML4-ALK fusion gene, but exhibited increased activation of insulin-like growth factor-1 receptor (IGF1R) and human epidermal growth factor receptor 3 (HER3), and overexpressed the HER3 ligand neuregulin 1. Accordingly, pharmacologic inhibition of IGF1R and HER3 signaling overcame resistance to alectinib in this cell line. The second alectinib-resistant cell line displayed stimulated HGF autocrine signaling that promoted MET activation and remained sensitive to crizotinib treatment. Taken together, our findings reveal two novel mechanisms underlying alectinib resistance that are caused by the activation of alternative tyrosine kinase receptors rather than by secondary ALK mutations. These studies may guide the development of comprehensive treatment strategies that take into consideration the various approaches ALK-positive lung tumors use to withstand therapeutic insult.
Immune checkpoint inhibitors (ICIs) have demonstrated long survival for the treatment of advanced non-small cell lung cancer (NSCLC). However, the effect and safety of ICI rechallenge have not been ...fully evaluated. The aim of this study was to investigate the efficacy and safety of ICI rechallenge in NSCLC patients.
We defined 'rechallenge' as re-administration of ICIs for patients who were previously treated with ICIs and discontinued treatment for any reason, and received subsequent chemotherapy. We retrospectively analyzed the histories of 434 patients with advanced NSCLC who received ICIs from December 2015 to December 2017 at seven centers.
A total of 317 patients discontinued the ICI treatment, and 14 patients (4.4%) received ICI rechallenge. All 14 patients discontinued the first ICI due to disease progression. Eight patients received the same kind of ICIs, and six patients received different ICIs. Median progression-free survival and overall survival were 1.5 months 95% confidence interval (CI): 0.8-2.6 and 6.5 months 95% CI: 1.4-19.0, respectively. The objective response rate was 7.1%, and the disease control rate was 21.4%. Two of three patients who achieved at least a stable disease, received radiotherapy between the first and second ICIs. Adverse events were not significantly different compared with the first ICIs.
In this study, the effect of ICI rechallenge was limited. Careful consideration of the administration of ICI rechallenge is necessary. This report involved a small number of cases, so further large prospective studies are warranted to confirm the efficacy of ICI rechallenge and to investigate predictive markers to identify a patient population in which ICI rechallenge is effective.
A 59-year-old man with a high level of antinuclear antibody received nivolumab and ipilimumab plus chemotherapy for lung cancer. Two weeks after the second course, he was admitted with a fever and ...severe fatigue. Laboratory studies showed elevated markers of myocardial damage, and a myocardial biopsy showed inflammatory cell infiltration, damaged myocardial fibers. Myocarditis was diagnosed as an immune-related adverse event (irAE), and high-dose corticosteroids were initiated. However, his cardiac function rapidly worsened, and he died on the fifth day after admission. There is no established treatment strategy for fulminant myocarditis as an irAE, and the further exploration of viable treatment strategies is required.
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