Summary Background We aimed to assess the effect of afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from two open-label, ...randomised, phase 3 trials. Methods Previously untreated patients with EGFR mutation-positive stage IIIB or IV lung adenocarcinoma were enrolled in LUX-Lung 3 (n=345) and LUX-Lung 6 (n=364). These patients were randomly assigned in a 2:1 ratio to receive afatinib or chemotherapy (pemetrexed-cisplatin LUX-Lung 3 or gemcitabine-cisplatin LUX-Lung 6), stratified by EGFR mutation (exon 19 deletion del19, Leu858Arg, or other) and ethnic origin (LUX-Lung 3 only). We planned analyses of mature overall survival data in the intention-to-treat population after 209 (LUX-Lung 3) and 237 (LUX-Lung 6) deaths. These ongoing studies are registered with ClinicalTrials.gov , numbers NCT00949650 and NCT01121393. Findings Median follow-up in LUX-Lung 3 was 41 months (IQR 35–44); 213 (62%) of 345 patients had died. Median follow-up in LUX-Lung 6 was 33 months (IQR 31–37); 246 (68%) of 364 patients had died. In LUX-Lung 3, median overall survival was 28·2 months (95% CI 24·6–33·6) in the afatinib group and 28·2 months (20·7–33·2) in the pemetrexed-cisplatin group (HR 0·88, 95% CI 0·66–1·17, p=0·39). In LUX-Lung 6, median overall survival was 23·1 months (95% CI 20·4–27·3) in the afatinib group and 23·5 months (18·0–25·6) in the gemcitabine-cisplatin group (HR 0·93, 95% CI 0·72–1·22, p=0·61). However, in preplanned analyses, overall survival was significantly longer for patients with del19-positive tumours in the afatinib group than in the chemotherapy group in both trials: in LUX-Lung 3, median overall survival was 33·3 months (95% CI 26·8–41·5) in the afatinib group versus 21·1 months (16·3–30·7) in the chemotherapy group (HR 0·54, 95% CI 0·36–0·79, p=0·0015); in LUX-Lung 6, it was 31·4 months (95% CI 24·2–35·3) versus 18·4 months (14·6–25·6), respectively (HR 0·64, 95% CI 0·44–0·94, p=0·023). By contrast, there were no significant differences by treatment group for patients with EGFR Leu858Arg-positive tumours in either trial: in LUX-Lung 3, median overall survival was 27·6 months (19·8–41·7) in the afatinib group versus 40·3 months (24·3–not estimable) in the chemotherapy group (HR 1·30, 95% CI 0·80–2·11, p=0·29); in LUX-Lung 6, it was 19·6 months (95% CI 17·0–22·1) versus 24·3 months (19·0–27·0), respectively (HR 1·22, 95% CI 0·81–1·83, p=0·34). In both trials, the most common afatinib-related grade 3–4 adverse events were rash or acne (37 16% of 229 patients in LUX-Lung 3 and 35 15% of 239 patients in LUX-Lung 6), diarrhoea (33 14% and 13 5%), paronychia (26 11% in LUX-Lung 3 only), and stomatitis or mucositis (13 5% in LUX-Lung 6 only). In LUX-Lung 3, neutropenia (20 18% of 111 patients), fatigue (14 13%) and leucopenia (nine 8%) were the most common chemotherapy-related grade 3–4 adverse events, while in LUX-Lung 6, the most common chemotherapy-related grade 3–4 adverse events were neutropenia (30 27% of 113 patients), vomiting (22 19%), and leucopenia (17 15%). Interpretation Although afatinib did not improve overall survival in the whole population of either trial, overall survival was improved with the drug for patients with del19 EGFR mutations. The absence of an effect in patients with Leu858Arg EGFR mutations suggests that EGFR del19-positive disease might be distinct from Leu858Arg-positive disease and that these subgroups should be analysed separately in future trials. Funding Boehringer Ingelheim.
Summary Background Platinum-based chemotherapy is the standard first-line treatment for patients with advanced non-small-cell lung cancer. However, the optimum number of treatment cycles remains ...controversial. Therefore, we did a systematic review and meta-analysis of individual patient data to compare the efficacy of six versus fewer planned cycles of platinum-based chemotherapy. Methods All randomised trials comparing six versus fewer planned cycles of first-line platinum-based chemotherapy for patients with advanced non-small-cell lung cancer were eligible for inclusion in this systematic review and meta-analysis. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients with an objective response, and toxicity. Statistical analyses were by intention-to-treat, stratified by trial. Overall survival and progression-free survival were compared by log-rank test. The proportion of patients with an objective response was compared with a Mantel-Haenszel test. Prespecified analyses explored effect variations by trial and patient characteristics. Findings Five eligible trials were identified; individual patient data could be collected from four of these trials, which included 1139 patients—568 of whom were assigned to six cycles, and 571 to three cycles (two trials) or four cycles (two trials). Patients received cisplatin (two trials) or carboplatin (two trials). No evidence indicated a benefit of six cycles of chemotherapy on overall survival (median 9·54 months 95% CI 8·98–10·69 in patients assigned to six cycles vs 8·68 months 8·03–9·54 in those assigned to fewer cycles; hazard ratio HR 0·94 95% CI 0·83–1·07, p=0·33) with slight heterogeneity between trials (p=0·076; I2 =56%). We recorded no evidence of a treatment interaction with histology, sex, performance status, or age. Median progression-free survival was 6·09 months (95% CI 5·82–6·87) in patients assigned to six cycles and 5·33 months (4·90–5·62) in those assigned to fewer cycles (HR 0·79, 95% CI 0·68–0·90; p=0·0007), and 173 (41·3%) of 419 patients assigned to six cycles and 152 (36·5%) of 416 patients assigned to three or four cycles had an objective response (p=0·16), without heterogeneity between the four trials. Anaemia at grade 3 or higher was slightly more frequent with a longer duration of treatment: 12 (2·9%) of 416 patients assigned to three-to-four cycles and 32 (7·8%) of 411 patients assigned to six cycles had severe anaemia. Interpretation Six cycles of first-line platinum-based chemotherapy did not improve overall survival compared with three or four courses in patients with advanced non-small-cell lung cancer. Our findings suggest that fewer than six planned cycles of chemotherapy is a valid treatment option for these patients. Funding None.
Sotorasib is a first-in-class small molecule that irreversibly inhibits KRAS G12C, locking it in an inactive state, inhibiting oncogenic signaling, and inducing a proinflammatory microenvironment. ...Here, we report the first case of life-threatening hepatitis in a patient with NSCLC shortly after commencing sotorasib, in which biopsy result was consistent with checkpoint inhibitor (CPI) immune-related adverse event, implicating sotorasib as being able to trigger CPI immune hepatitis. Given the large proportion of patients potentially treatable with sequential sotorasib after CPI, coupled with limited trial data, sotorasib-triggered CPI immune-related hepatitis should be considered in patients with sotorasib hepatotoxicity.
Abstract The optimal treatment sequence for patients with metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) continues to evolve, related largely ...to a growing number of breakthroughs and studies in the field. The efficacy of tyrosine kinase inhibitors (TKI) in the treatment of these patients is well established, yet the treatment decision-making process is becoming more complex as our knowledge of EGFR mutations and resistance pathways grows and more treatment options become available. Treating physicians need to consider a growing number of factors. Here we present a step-wise approach to personalizing treatment for patients with EGFR mutation-positive NSCLC, emphasizing some of the real world challenges faced by treating physicians. Decision criteria for selecting the best first-line therapy is reviewed, the importance of re-biopsy upon disease progression to determine the most appropriate next-line therapy is highlighted, and third line therapy and beyond is discussed. An algorithm designed to optimize sequencing strategies for prolonging survival and maintaining quality of life in our patients with EGFR mutation-positive NSCLC is presented.
Selpercatinib and pralsetinib are RET inhibitors with substantial activity in advanced RET-rearranged NSCLC. We present a case of pralsetinib-related pneumonitis and leptomeningeal and brain ...metastases progression during treatment suspension for pneumonitis. During recovery, selpercatinib administration led to rapid neurologic response and complete intracranial response and allowed pneumonitis resolution. This case supports the safety of selpercatinib in patients with pneumonitis on pralsetinib and highlights its marked efficacy in leptomeningeal disease.
The TIGER-3 (NCT02322281) study was initiated to compare the efficacy and safety of rociletinib, a third-generation EGFR tyrosine kinase inhibitor (TKI) that targets EGFR T790M and common ...EGFR-activating mutations, versus chemotherapy in patients with NSCLC who progressed on first- or second-generation EGFR TKIs.
Patients with advanced or metastatic EGFR-mutated NSCLC with disease progression on standard therapy (previous EGFR TKI and platinum-based chemotherapy) were randomized to oral rociletinib (500 or 625 mg twice daily) or single-agent chemotherapy (pemetrexed, gemcitabine, docetaxel, or paclitaxel).
Enrollment was halted when rociletinib development was discontinued in 2016. Of 149 enrolled patients, 75 were randomized to rociletinib (n = 53: 500 mg twice daily; n = 22: 625 mg twice daily) and 74 to chemotherapy. The median investigator-assessed progression-free survival (PFS) was 4.1 months (95% confidence interval CI: 2.6–5.4) in the rociletinib 500-mg group and 5.5 months (95% CI: 1.8–8.1) in the 625-mg group versus 2.5 months (95% CI: 1.4–2.9) in the chemotherapy group. An improved PFS was observed in patients with T790M-positive NSCLC treated with rociletinib (n = 25; 500 mg and 625 mg twice daily) versus chemotherapy (n = 20; 6.8 versus 2.7 mo; hazard ratio = 0.55, 95% CI: 0.28–1.07, p = 0.074). Grade 3 or higher hyperglycemia (24.0%), corrected QT prolongation (6.7%), diarrhea (2.7%), and vomiting (1.3%) were more frequent with rociletinib than chemotherapy (0%, 0%, 1.4%, and 0%, respectively).
Rociletinib had a more favorable median PFS versus chemotherapy but had higher rates of hyperglycemia and corrected QT prolongation in patients with advanced EGFR-mutated NSCLC who progressed on previous EGFR TKI. Incomplete enrollment prevented evaluation of the primary efficacy end point.
Optimal management of people with advanced NSCLC depends on accurate identification of predictive markers. Yet, real-world data in this setting are limited. We describe the impact, timeliness, and ...outcomes of molecular testing for patients with advanced NSCLC and good performance status in England.
In collaboration with Public Health England, patients with stages IIIB to IV NSCLC, with an Eastern Cooperative Oncology Group performance status of 0 to 2, in England, between June 2017 and December 2017, were identified. All English hospitals were invited to record information.
A total of 60 of 142 invited hospitals in England participated in this study and submitted data on 1157 patients. During the study period, 83% of patients with advanced adenocarcinoma underwent molecular testing for three recommended predictive biomarkers (EGFR, ALK, and programmed death-ligand 1). A total of 80% of patients with nonsquamous carcinomas on whom biomarker testing was performed had adequate tissue for analysis on initial sampling. First-line treatment with a tyrosine kinase inhibitor was received by 71% of patients with adenocarcinoma and a sensitizing EGFR mutation and by 59% of those with an ALK translocation. Of patients with no driver mutation and a programmed death-ligand 1 expression of greater than or equal to 50%, 47% received immunotherapy.
We present a comprehensive data set for molecular testing in England. Although molecular testing is well established in England, timeliness and uptake of targeted therapies should be improved.
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