Summary Background Alectinib—a highly selective, CNS-active, ALK inhibitor—showed promising clinical activity in crizotinib-naive and crizotinib-resistant patients with ALK -rearranged ( ALK ...-positive) non-small-cell lung cancer (NSCLC). We aimed to assess the safety and efficacy of alectinib in patients with ALK -positive NSCLC who progressed on previous crizotinib. Methods We did a phase 2 study at 27 centres in the USA and Canada. We enrolled patients aged 18 years or older with stage IIIB–IV, ALK -positive NSCLC who had progressed after crizotinib. Patients were treated with oral alectinib 600 mg twice daily until progression, death, or withdrawal. The primary endpoint was the proportion of patients achieving an objective response by an independent review committee using Response Evaluation Criteria in Solid Tumors, version 1.1. Response endpoints were assessed in the response-evaluable population (ie, patients with measurable disease at baseline who received at least one dose of study drug), and efficacy and safety analyses were done in the intention-to-treat population (all enrolled patients). This study is registered with ClinicalTrials.gov , number NCT01871805 . The study is ongoing and patients are still receiving treatment. Findings Between Sept 4, 2013, and Aug 4, 2014, 87 patients were enrolled into the study (intention-to-treat population). At the time of the primary analysis (median follow-up 4·8 months IQR 3·3–7·1), 33 of 69 patients with measurable disease at baseline had a confirmed partial response; thus, the proportion of patients achieving an objective response by the independent review committee was 48% (95% CI 36–60). Adverse events were predominantly grade 1 or 2, most commonly constipation (31 36%), fatigue (29 33%), myalgia 21 24%), and peripheral oedema 20 23%). The most common grade 3 and 4 adverse events were changes in laboratory values, including increased blood creatine phosphokinase (seven 8%), increased alanine aminotransferase (five 6%), and increased aspartate aminotransferase (four 5%). Two patients died: one had a haemorrhage (judged related to study treatment), and one had disease progression and a history of stroke (judged unrelated to treatment). Interpretation Alectinib showed clinical activity and was well tolerated in patients with ALK -positive NSCLC who had progressed on crizotinib. Therefore, alectinib could be a suitable treatment for patients with ALK -positive disease who have progressed on crizotinib. Funding F Hoffmann-La Roche.
Summary Background Limited evidence exists to show that adding a third agent to platinum-doublet chemotherapy improves efficacy in the first-line advanced non-small-cell lung cancer (NSCLC) setting. ...The anti-PD-1 antibody pembrolizumab has shown efficacy as monotherapy in patients with advanced NSCLC and has a non-overlapping toxicity profile with chemotherapy. We assessed whether the addition of pembrolizumab to platinum-doublet chemotherapy improves efficacy in patients with advanced non-squamous NSCLC. Methods In this randomised, open-label, phase 2 cohort of a multicohort study (KEYNOTE-021), patients were enrolled at 26 medical centres in the USA and Taiwan. Patients with chemotherapy-naive, stage IIIB or IV, non-squamous NSCLC without targetable EGFR or ALK genetic aberrations were randomly assigned (1:1) in blocks of four stratified by PD-L1 tumour proportion score (<1% vs ≥1%) using an interactive voice-response system to 4 cycles of pembrolizumab 200 mg plus carboplatin area under curve 5 mg/mL per min and pemetrexed 500 mg/m2 every 3 weeks followed by pembrolizumab for 24 months and indefinite pemetrexed maintenance therapy or to 4 cycles of carboplatin and pemetrexed alone followed by indefinite pemetrexed maintenance therapy. The primary endpoint was the proportion of patients who achieved an objective response, defined as the percentage of patients with radiologically confirmed complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by masked, independent central review, in the intention-to-treat population, defined as all patients who were allocated to study treatment. Significance threshold was p<0·025 (one sided). Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned study treatment. This trial, which is closed for enrolment but continuing for follow-up, is registered with ClinicalTrials.gov , number NCT02039674. Findings Between Nov 25, 2014, and Jan 25, 2016, 123 patients were enrolled; 60 were randomly assigned to the pembrolizumab plus chemotherapy group and 63 to the chemotherapy alone group. 33 (55%; 95% CI 42–68) of 60 patients in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 (29%; 18–41) of 63 patients in the chemotherapy alone group (estimated treatment difference 26% 95% CI 9–42%; p=0·0016). The incidence of grade 3 or worse treatment-related adverse events was similar between groups (23 39% of 59 patients in the pembrolizumab plus chemotherapy group and 16 26% of 62 in the chemotherapy alone group). The most common grade 3 or worse treatment-related adverse events in the pembrolizumab plus chemotherapy group were anaemia (seven 12% of 59) and decreased neutrophil count (three 5%); an additional six events each occurred in two (3%) for acute kidney injury, decreased lymphocyte count, fatigue, neutropenia, and sepsis, and thrombocytopenia. In the chemotherapy alone group, the most common grade 3 or worse events were anaemia (nine 15% of 62) and decreased neutrophil count, pancytopenia, and thrombocytopenia (two 3% each). One (2%) of 59 patients in the pembrolizumab plus chemotherapy group experienced treatment-related death because of sepsis compared with two (3%) of 62 patients in the chemotherapy group: one because of sepsis and one because of pancytopenia. Interpretation Combination of pembrolizumab, carboplatin, and pemetrexed could be an effective and tolerable first-line treatment option for patients with advanced non-squamous NSCLC. This finding is being further explored in an ongoing international, randomised, double-blind, phase 3 study. Funding Merck & Co.
Summary Background There is a major unmet need for effective treatments in patients with squamous cell carcinoma of the lung. LUX-Lung 8 compared afatinib (an irreversible ErbB family blocker) with ...erlotinib (a reversible EGFR tyrosine kinase inhibitor), as second-line treatment for patients with advanced squamous cell carcinoma of the lung. Methods We did this open-label, phase 3 randomised controlled trial at 183 cancer centres in 23 countries worldwide. We enrolled adults with stage IIIB or IV squamous cell carcinoma of the lung who had progressed after at least four cycles of platinum-based-chemotherapy. Participants were randomly assigned (1:1) to receive afatinib (40 mg per day) or erlotinib (150 mg per day) until disease progression. The randomisation was done centrally with an interactive voice or web-based response system and stratified by ethnic origin (eastern Asian vs non-eastern Asian). Clinicians and patients were not masked to treatment allocation. The primary endpoint was progression-free survival assessed by independent central review (intention-to-treat population). The key secondary endpoint was overall survival. This trial is registered with ClinicalTrials.gov , NCT01523587. Findings 795 eligible patients were randomly assigned (398 to afatinib, 397 to erlotinib). Median follow-up at the time of the primary analysis of progression-free survival was 6·7 months (IQR 3·1–10·2), at which point enrolment was not complete. Progression free-survival at the primary analysis was significantly longer with afatinib than with erlotinib (median 2·4 months 95% CI 1·9–2·9 vs 1·9 months 1·9–2·2; hazard ratio HR 0·82 95% CI 0·68–1·00, p=0·0427). At the time of the primary analysis of overall survival (median follow-up 18·4 months IQR 13·8–22·4), overall survival was significantly greater in the afatinib group than in the erloinib group (median 7·9 months 95% CI 7·2–8·7 vs 6·8 months 5·9–7·8; HR 0·81 95% CI 0·69–0·95, p=0·0077), as were progression-free survival (median 2·6 months 95% CI 2·0–2·9 vs 1·9 months 1·9–2·1; HR 0·81 95% CI 0·69–0·96, p=0·0103) and disease control (201 51% of 398 patients vs 157 40% of 397; p=0·0020). The proportion of patients with an objective response did not differ significantly between groups (22 6% vs 11 3%; p=0·0551). Tumour shrinkage occurred in 103 (26%) of 398 patients versus 90 (23%) of 397 patients. Adverse event profiles were similar in each group: 224 (57%) of 392 patients in the afatinib group versus 227 (57%) of 395 in the erlotinib group had grade 3 or higher adverse events. We recorded higher incidences of treatment-related grade 3 diarrhoea with afatinib (39 10% vs nine 2%), of grade 3 stomatitis with afatinib (16 4% vs none), and of grade 3 rash or acne with erlotinib (23 6% vs 41 10%). Interpretation The significant improvements in progression-free survival and overall survival with afatinib compared with erlotinib, along with a manageable safety profile and the convenience of oral administration suggest that afatinib could be an additional option for the treatment of patients with squamous cell carcinoma of the lung. Funding Boehringer Ingelheim.
PDF
