Summary Background Afatinib, an irreversible ErbB-family blocker, has shown preclinical activity when tested in EGFR mutant models with mutations that confer resistance to EGFR tyrosine-kinase ...inhibitors. We aimed to assess its efficacy in patients with advanced lung adenocarcinoma with previous treatment failure on EGFR tyrosine-kinase inhibitors. Methods In this phase 2b/3 trial, we enrolled patients with stage IIIB or IV adenocarcinoma and an Eastern Cooperative Oncology Group performance (ECOG) performance score of 0–2 who had received one or two previous chemotherapy regimens and had disease progression after at least 12 weeks of treatment with erlotinib or gefitinib. We used a computer-generated sequence to randomly allocate patients (2:1) to either afatinib (50 mg per day) or placebo; all patients received best supportive care. Randomisation was done in blocks of three and was stratified by sex and baseline ECOG performance status (0–1 vs 2). Investigators, patients, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival (from date of randomisation to death), analysed on an intention-to-treat basis. This study is registered with ClinicalTrials.gov , number NCT00656136. Findings Between May 26, 2008, and Sept 21, 2009, we identified 697 patients, 585 of whom were randomly allocated to treatment (390 to afatinib, 195 to placebo). Median overall survival was 10·8 months (95% CI 10·0–12·0) in the afatinib group and 12·0 months (10·2–14·3) in the placebo group (hazard ratio 1·08, 95% CI 0·86–1·35; p=0·74). Median progression-free survival was longer in the afatinib group (3·3 months, 95% CI 2·79–4·40) than it was in the placebo group (1·1 months, 0·95–1·68; hazard ratio 0·38, 95% CI 0·31–0·48; p<0·0001). No complete responses to treatment were noted; 29 (7%) patients had a partial response in the afatinib group, as did one patient in the placebo group. Subsequent cancer treatment was given to 257 (68%) patients in the afatinib group and 153 (79%) patients in the placebo group. The most common adverse events in the afatinib group were diarrhoea (339 87% of 390 patients; 66 17% were grade 3) and rash or acne (305 78% patients; 56 14% were grade 3). These events occurred less often in the placebo group (18 9% of 195 patients had diarrhoea; 31 16% had rash or acne), all being grade 1 or 2. Drug-related serious adverse events occurred in 39 (10%) patients in the afatinib group and one (<1%) patient in the placebo group. We recorded two possibly treatment-related deaths in the afatinib group. Interpretation Although we recorded no benefit in terms of overall survival with afatinib (which might have been affected by cancer treatments given after progression in both groups), our findings for progression-free survival and response to treatment suggest that afatinib could be of some benefit to patients with advanced lung adenocarcinoma who have failed at least 12 weeks of previous EGFR tyrosine-kinase inhibitor treatment. Funding Boehringer Ingelheim Inc.
Summary Background Two phase II trials in patients with previously-treated advanced non-small-cell lung cancer suggested that gefitinib was efficacious and less toxic than was chemotherapy. We ...compared gefitinib with docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer who had been pretreated with platinum-based chemotherapy. Methods We undertook an open-label phase III study with recruitment between March 1, 2004, and Feb 17, 2006, at 149 centres in 24 countries. 1466 patients with pretreated (≥one platinum-based regimen) advanced non-small-cell lung cancer were randomly assigned with dynamic balancing to receive gefitinib (250 mg per day orally; n=733) or docetaxel (75 mg/m2 intravenously in 1-h infusion every 3 weeks; n=733). The primary objective was to compare overall survival between the groups with co-primary analyses to assess non-inferiority in the overall per-protocol population and superiority in patients with high epidermal growth factor receptor (EGFR)-gene-copy number in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT00076388. Findings 1433 patients were analysed per protocol (723 in gefitinib group and 710 in docetaxel group). Non-inferiority of gefitinib compared with docetaxel was confirmed for overall survival (593 vs 576 events; hazard ratio HR 1·020, 96% CI 0·905–1·150, meeting the predefined non-inferiority criterion; median survival 7·6 vs 8·0 months). Superiority of gefitinib in patients with high EGFR-gene-copy number (85 vs 89 patients) was not proven (72 vs 71 events; HR 1·09, 95% CI 0·78–1·51; p=0·62; median survival 8·4 vs 7·5 months). In the gefitinib group, the most common adverse events were rash or acne (360 49% vs 73 10%) and diarrhoea (255 35% vs 177 25%); whereas in the docetaxel group, neutropenia (35 5% vs 514 74%), asthenic disorders (182 25% vs 334 47%), and alopecia (23 3% vs 254 36%) were most common. Interpretation INTEREST established non-inferior survival of gefitinib compared with docetaxel, suggesting that gefitinib is a valid treatment for pretreated patients with advanced non-small-cell lung cancer. Funding AstraZeneca.
Abstract Background Standard treatment for unresectable stage III non-small cell lung cancer (NSCLC) is concurrent chemo-radiation (CRT). A regimen of induction carboplatin and gemcitabine followed ...by CRT was developed at the McGill University Health Centre to prevent delays in treatment initiation. We report the long-term outcomes with this regimen based on a pooled analysis of both protocol patients from a phase II study and non-protocol patients. Methods and materials Outcomes and toxicity data were retrieved for 142 patients with stage III NSCLC: 43 patients treated on protocol between January 2003 and November 2004, and 101 patients treated off-protocol between December 2004 and August 2013. Patients received 2 cycles of carboplatin AUC=5 IV on day 1 and gemcitabine 1000mg/m2 IV on days 1 and 8 every 3 weeks, followed on day 50 by CRT, 60Gy/30 over 6 weeks, concomitantly with 2 cycles of paclitaxel 50mg/m2 IV and gemcitabine 100mg/m2 IV on days 1 and 8 every three weeks. Results The median overall survival was 23.2 months. With a median follow-up of 23.8 months, the 3, 4 and 5 year overall survival was 38%, 30%, and 26% respectively. The median and 5-year progression-free survival rates were 12.5 months and 25% respectively. Rates of grade ≥ 3 hematological, esophageal and respiratory toxicity were 20%, 10% and 10% respectively. Forty-eight patients received further lines of chemotherapy. Conclusion The present analysis affirms the favorable toxicity profile of this novel induction chemotherapy, without apparent compromise in clinical outcomes when compared to regimens using immediate concurrent CRT.
Abstract Background This analysis examined outcomes in the phase 3 trial of nab -paclitaxel ( nab -P) plus carboplatin (C) vs solvent-based P (sb-P) plus C in a subset of patients with advanced ...non-small cell lung cancer (NSCLC) and diabetes. Patients and Methods Patients with stage IIIB/IV NSCLC received nab -P 100 mg/m2 on days 1, 8, and 15 or sb-P 200 mg/m2 on day 1, both with C at an area under the curve of 6 mg•min/mL on day 1 every 3 weeks. Overall response rate (ORR) and progression-free survival (PFS) were determined by blinded, independent, centralized review. P values were based on chi-square test for ORR and log rank test for overall survival (OS) and PFS. Results Of the 1052 randomized patients in the phase III trial, 61 had diabetes according to prespecified terms ( nab -P/C, 31; sb-P/C, 30). ORR for nab -P/C vs sb-P/C in this subset was 52% vs 27% (relative risk ratio, 1.935; P = .046), median PFS was 10.9 vs 4.9 months (hazard ratio HR, 0.420; P = .016), and median OS was 17.5 vs 11.1 months (HR, 0.550; P = .057). Treatment differences in PFS remained significant ( P ≤ .036) after adjusting for histology, region, stage, race, and age and also remained significant in OS for histology ( P = .039). Patients with diabetes experienced lower rates of grade ≥ 3 neutropenia and peripheral neuropathy and higher rates of thrombocytopenia and anemia with nab -P/C vs sb-P/C. Conclusions nab -P/C demonstrated improved efficacy and manageable tolerability in patients with advanced NSCLC and diabetes.
Summary Background The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive ...non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting. Methods This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov , number NCT01466660. Findings Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3–33·9). Progression-free survival (median 11·0 months 95% CI 10·6–12·9 with afatinib vs 10·9 months 9·1–11·5 with gefitinib; hazard ratio HR 0·73 95% CI 0·57–0·95, p=0·017) and time-to-treatment failure (median 13·7 months 95% CI 11·9–15·0 with afatinib vs 11·5 months 10·1–13·1 with gefitinib; HR 0·73 95% CI 0·58–0·92, p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 13% of 160 patients given afatinib vs two 1% of 159 given gefitinib) and rash or acne (15 9% patients given afatinib vs five 3% of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 9% of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure. Interpretation Afatinib significantly improved outcomes in treatment-naive patients with EGFR -mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population. Funding Boehringer Ingelheim.
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.
High risk patients with metastatic non small cell lung cancer (NSCLC) including patients with performance status (PS) 2 or elderly with comorbidities do poorly on combination chemotherapy regimens. ...We evaluated a sequential treatment with Vinorelbine followed by Gemcitabine to determine its effect on survival and the toxicity in this patient population.
Forty-two evaluable patients, median age 75, 21 patients with PS 2 and 21 patients with PS 0 or 1, 37 patients with stage IV and five patients with stage III B NSCLC entered the trial. They received Vinorelbine 30
mg/m
2, i.v., on days 1
+
8 every 3 weeks followed by Gemcitabine 1000
mg/m
2, i.v., on days 1
+
8 every 3 weeks, each for two cycles for stable disease or one cycle after best response. Then stable patients continued until progressive disease on Vinorelbine or Gemcitabine according to the patient's preference.
A total of 126 cycles of Vinorelbine were administered to 42 patients, median of three cycles per patient and 74 cycles of Gemcitabine, median of 1.0 cycle per patient. Sixteen patients (38%) achieved PR, 11 patients on Vinorelbine, 5 patients on Gemcitabine; 12 patients (26%) had stable disease, 7 patients on Vinorelbine, 5 patients on Gemcitabine. Of 24 patients with progressive disease on Vinorelbine, 3 patients (12.5%) responded to Gemcitabine. Median time-to-first progression was 3.5 months, median survival was 8 months, 1-year survival was 12 patients (28.5%). No grade 3 or 4 toxicities were reported.
This sequential treatment offers excellent palliative treatment with minimal toxicity for high-risk patients with metastatic NSCLC.
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