Alectinib versus crizotinib in untreated ALK-positive non–small-cell lung cancer

Alectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system (CNS) efficacy in the treatment of ALK-positive non-small-cell lung cancer (NSCLC). We investigated alectinib as compared with crizotinib in patients with previously untreated, advanced ALK-positive NSCLC, including those with asymptomatic CNS disease. In a randomized, open-label, phase 3 trial, we randomly assigned 303 patients with previously untreated, advanced ALK-positive NSCLC to receive either alectinib (600 mg twice daily) or crizotinib (250 mg twice daily). The primary end point was investigator-assessed progression-free survival. Secondary end points were independent review committee-assessed progression-free survival, time to CNS progression, objective response rate, and overall survival. During a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression or death occurred in 62 of 152 patients (41%) in the alectinib group and 102 of 151 patients (68%) in the crizotinib group. The rate of investigator-assessed progression-free survival was significantly higher with alectinib than with crizotinib (12-month event-free survival rate, 68.4% [95% confidence interval (CI), 61.0 to 75.9] with alectinib vs. 48.7% [95% CI, 40.4 to 56.9] with crizotinib; hazard ratio for disease progression or death, 0.47 [95% CI, 0.34 to 0.65]; P<0.001); the median progression-free survival with alectinib was not reached. The results for independent review committee-assessed progression-free survival were consistent with those for the primary end point. A total of 18 patients (12%) in the alectinib group had an event of CNS progression, as compared with 68 patients (45%) in the crizotinib group (cause-specific hazard ratio, 0.16; 95% CI, 0.10 to 0.28; P<0.001). A response occurred in 126 patients in the alectinib group (response rate, 82.9%; 95% CI, 76.0 to 88.5) and in 114 patients in the crizotinib group (response rate, 75.5%; 95% CI, 67.8 to 82.1) (P=0.09). Grade 3 to 5 adverse events were less frequent with alectinib (41% vs. 50% with crizotinib). As compared with crizotinib, alectinib showed superior efficacy and lower toxicity in primary treatment of ALK-positive NSCLC. (Funded by F. Hoffmann-La Roche; ALEX ClinicalTrials.gov number, NCT02075840 .)

Acquired Resistance to KRAS (G12C) Inhibition in Cancer

BACKGROUND: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRAS(G12C)). The mechanisms of acquired resistance to these therapies are currently unknown. METHODS: Among patients with KRAS(G12C) -mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRAS(G12C) inhibitors. RESULTS: A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRAS(G12C) allele. Acquired bypass mechanisms of resistance included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN. In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of KRAS mutations that confer resistance to KRAS(G12C) inhibitors. CONCLUSIONS: Diverse genomic and histologic mechanisms impart resistance to covalent KRAS(G12C) inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.)

Continuation of Lorlatinib in ALK-Positive NSCLC Beyond Progressive Disease

INTRODUCTION: Lorlatinib, a potent, selective third-generation ALK tyrosine kinase inhibitor (TKI), exhibited overall and intracranial antitumor activity in patients with ALK-positive NSCLC. METHODS: Retrospective analyses in the ongoing phase 2 trial (NCT01970865) investigated the clinical benefit of continuing lorlatinib beyond progressive disease (LBPD). Patients with previous crizotinib treatment as the only ALK TKI were group A (n = 28); those with at least one previous second-generation ALK TKIs were group B (n = 74). LBPD was defined as greater than 3 weeks of lorlatinib treatment after investigator-assessed progressive disease. Only patients with the best overall response of complete or partial response or stable disease were included. RESULTS: There were no major differences in baseline characteristics between groups. The median duration of treatment for patients who continued LBPD was 32.4 months (group A) and 16.4 months (group B) versus 12.5 months (group A) and 7.7 months (group B) for patients who did not continue LBPD. The median overall survival in group A was not reached (NR) in patients who continued LBPD versus 24.4 months (95% confidence interval [CI]: 12.1-NR); group B\u27s median was 26.5 months (95% CI: 18.7-35.5) in patients who continued LBPD versus 14.7 months (95% CI: 9.3-38.5) in patients who did not continue LBPD. The median overall survival postprogression for groups A and B was NR (95% CI: 21.4-NR) and 14.6 months (95% CI: 11.2-19.2) in patients who continued LBPD and 8.0 months (95% CI: 1.5-NR) versus 5.3 months (95% CI: 2.8-14.3) in patients who did not continue LBPD. CONCLUSIONS: Continuing LBPD is a viable treatment strategy for select patients with ALK-positive NSCLC who progressed on lorlatinib

Clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC

We compared the clinicopathologic characteristics and survival outcomes of 194 ALK+ NSCLC patients who had progressed on crizotinib according to whether they continued crizotinib beyond disease progression or not. Overall survival also favored significantly patients who were able to continue crizotinib beyond disease progression. Multivariate analysis revealed ability to continue crizotinib beyond disease progression is an independent favorable prognostic factor for improved survival outcome.Crizotinib is approved to treat advanced ALK-positive non-small-cell lung cancer (NSCLC), but most patients ultimately develop progressive disease (PD). We investigated whether continuing ALK inhibition with crizotinib beyond PD (CBPD) is clinically beneficial and attempted to identify clinicopathologic characteristics associated with patients who experience clinical benefit. Patients with advanced ALK-positive NSCLC enrolled in two ongoing multicenter, single-arm trials who developed RECIST-defined PD were allowed to continue crizotinib if they were deriving ongoing clinical benefit. In the present retrospective analysis, continuation of CBPD was defined as > 3 weeks of crizotinib treatment after PD documentation. Patients who had PD as best response to initial crizotinib treatment were excluded. Baseline and post-progression characteristics, sites of PD, and overall survival (OS) were compared in patients who continued CBPD versus those who did not. The impact of continuing CBPD on OS after adjusting for potential confounding factors was assessed. Among 194 crizotinib-treated patients with RECIST-defined PD, 120 (62%) continued CBPD. A significantly higher proportion of patients who continued CBPD than patients who did not had an ECOG performance status (PS) of 0/1 at PD (96% versus 82%; P = 0.02). CBPD patients had significantly longer OS from the time of PD [median 16.4 versus 3.9 months; hazards ratio (HR) 0.27, 95% confidence interval (CI): 0.17-0.42; P < 0.0001] and from the time of initial crizotinib treatment (median 29.6 versus 10.8 months; HR 0.30, 95% CI: 0.19-0.46; P < 0.0001). The multiple-covariate Cox regression analysis revealed that CBPD remained significantly associated with improved OS after adjusting for relevant factors. Patients who continued CBPD were more likely to have good ECOG PS (0/1) at the time of PD. Continuing ALK inhibition with crizotinib after PD may provide survival benefit to patients with advanced ALK-positive NSCLC.

Differences in outcome and toxicity between Asian and caucasian patients with lung cancer treated with systemic therapy

10.2217/fon.12.25Future Oncology84451-46

Dacomitinib as first-line treatment in patients with clinically or molecularly selected advanced non-small-cell lung cancer: a multicentre, open-label, phase 2 trial

Background Patients with EGFR-mutant non-small-cell lung cancer generally have a progression-free survival of 9-13 months while being treated with the EGFR tyrosine-kinase inhibitors gefitinib or erlotinib. However, resistance inevitably develops, and more effective EGFR inhibitors are needed. Dacomitinib is a covalent pan-HER inhibitor that has shown clinical activity in patients previously treated with gefitinib or erlotinib. We did a trial of dacomitinib as initial systemic therapy in clinically and molecularly selected patients with advanced non-small-cell lung cancer. Methods In this open-label, multicentre, phase 2 trial, we enrolled treatment-naive patients with advanced lung cancer who had clinical (never-smokers [= 15 years since last cigarette) or molecular (EGFR mutation, regardless of smoking status) characteristics associated with response to EGFR inhibitors. We gave dacomitinib orally once daily (45 mg or 30 mg) until progressive disease, unacceptable toxicity, or patient withdrawal. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.0) to investigate the activity of dacomitinib in all patients with a baseline scan and at least one post-treatment scan, with investigator assessment of response and progression. The primary endpoint was progression-free survival at 4 months in the as-enrolled population, with a null hypothesis of progression-free survival at 4 months of 50% or less. The study is registered with ClinicalTrials. gov, number NCT00818441, and is no longer accruing patients. Findings Between March 11, 2009, and April 1, 2011, we enrolled 89 patients from 25 centres, including 45 (51%) with EGFR-activating mutations in exon 19 (n=25) or exon 21 (n=20). Progression-free survival at 4 months was 76.8% (95% CI 66.4-84.4) in the as-enrolled population, and was 95.5% (95% CI 83.2-98.9) in the EGFR-mutant population. The most common all-grade treatment-related adverse events were diarrhoea in 83 (93%) patients, dermatitis acneiform in 69 (78%) patients, dry skin in 39 (44%) patients, and stomatitis in 36 (40%) patients. Two patients (2%) had grade 4 treatment-related events (one with hypokalaemia and one with dyspnoea). No grade 5 toxicities were recorded. Interpretation Dacomitinib had encouraging clinical activity as initial systemic treatment in clinically or molecularly selected patients with advanced non-small-cell lung cancer.