Santiago Ponce Aix

Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial.

BACKGROUND The tyrosine kinase inhibitor erlotinib improves the outcomes of patients with advanced non-small-cell lung carcinoma (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations. The coexistence of the T790M resistance mutation with another EGFR mutation in treatment-naive patients has been associated with a shorter progression-free survival to EGFR inhibition than in the absence of the T790M mutation. To test this hypothesis clinically, we developed a proof-of-concept study, in which patients with EGFR-mutant NSCLC were treated with the combination of erlotinib and bevacizumab, stratified by the presence of the pretreatment T790M mutation. METHODS BELIEF was an international, multicentre, single-arm, phase 2 trial done at 29 centres in eight European countries. Eligible patients were aged 18 years or older and had treatment-naive, pathologically confirmed stage IIIB or stage IV lung adenocarcinoma with a confirmed, activating EGFR mutation (exon 19 deletion or L858R mutation). Patients received oral erlotinib 150 mg per day and intravenous bevacizumab 15 mg/kg every 21 days and were tested centrally for the pretreatment T790M resistance mutation with a peptide nucleic acid probe-based real-time PCR. The primary endpoint was progression-free survival. The primary efficacy analysis was done in the intention-to-treat population and was stratified into two parallel substudies according to the centrally confirmed pretreatment T790M mutation status of enrolled patients (T790M positive or negative). The safety analysis was done in all patients that have received at least one dose of trial treatment. This trial was registered with ClinicalTrials.gov, number NCT01562028. FINDINGS Between June 11, 2012, and Oct 28, 2014, 109 patients were enrolled and included in the efficacy analysis. 37 patients were T790M mutation positive and 72 negative. The overall median progression-free survival was 13·2 months (95% CI 10·3-15·5), with a 12 month progression-free survival of 55% (95% CI 45-64). The primary endpoint was met only in substudy one (T790M-positive patients). In the T790M-positive group, median progression-free survival was 16·0 months (12·7 to not estimable), with a 12 month progression-free survival of 68% (50-81), whereas in the T790M-negative group, median progression-free survival was 10·5 months (9·4-14·2), with a 12 month progression-free survival of 48% (36-59). Of 106 patients included in the safety analysis, five had grade 4 adverse events (one acute coronary syndrome, one biliary tract infection, one other neoplasms, and two colonic perforations) and one died due to sepsis. INTERPRETATION The BELIEF trial provides further evidence of benefit for the combined use of erlotinib and bevacizumab in patients with NSCLC harbouring activating EGFR mutations. FUNDING European Thoracic Oncology Platform, Roche.

Randomized phase III trial of erlotinib versus docetaxel in patients with advanced squamous cell non-small cell lung cancer failing first line platinum-based doublet chemotherapy stratified by Veristrat good versus Veristrat poor. The European Thoracic Oncology Platform (ETOP) EMPHASIS-lung trial.

Introduction Docetaxel and erlotinib are registered second‐line treatments for wild‐type EGFR NSCLC. Previous studies suggested a predictive value of the VeriStrat test in second‐line therapy of NSCLC, classifying patients as either VeriStrat good or VeriStrat poor. EMPHASIS‐lung aimed at exploring this predictive effect in patients with squamous cell NSCLC. The trial closed prematurely because of low accrual and results from other trials. Our analysis includes an exploratory combined analysis with results from the PROSE trial. Methods EMPHASIS‐lung was a randomized phase III multicenter trial exploring the differential effect of second‐line erlotinib versus docetaxel on progression‐free survival (PFS) in VeriStrat good versus VeriStrat poor patients with squamous cell NSCLC. Results A total of 80 patients were randomized, with 72.5% categorized as VeriStrat good. Patient characteristics were balanced between VeriStrat status and treatment groups. The median PFS times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 4.1 and 1.6 months, respectively, versus 1.9 and 2.1 months, respectively, in the VeriStrat poor cohort. The median overall survival (OS) times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 7.8 and 8.4 months, respectively, and 4.4 and 5.2 months, respectively, in the VeriStrat poor cohort. An additional exploratory analysis was performed; in it, 47 patients from the squamous cell subgroup of PROSE were included in a combined analysis, contributing with 45 PFS and 41 OS events. Conclusions The final analysis of EMPHASIS‐lung did not show a differential effect on PFS for erlotinib versus docetaxel stratified by VeriStrat status. Similarly, in the combined analysis, no significant treatment by VeriStrat status interaction was observed (interaction p = 0.24 for PFS and 0.45 for OS, stratified by study).

Updated Efficacy Analysis Including Secondary Population Results for OAK: A Randomized Phase III Study of Atezolizumab versus Docetaxel in Patients with Previously Treated Advanced Non–Small Cell Lung Cancer

Introduction: The efficacy and safety of atezolizumab versus the efficacy and safety of docetaxel as second‐ or third‐line treatment in patients with advanced NSCLC in the primary (n = 850) and secondary (n = 1225) efficacy populations of the randomized phase III OAK study (respectively referred to as the intention‐to‐treat [ITT] 850 [ITT850] and ITT1225) at an updated data cutoff were assessed. Methods: Patients received atezolizumab, 1200 mg, or docetaxel, 75 mg/m2, intravenously every 3 weeks until loss of clinical benefit or disease progression, respectively. The primary end point was overall survival (OS) in the ITT population and programmed death‐ligand 1–expressing subgroup. A sensitivity analysis was conducted to evaluate the impact of subsequent immunotherapy use in the docetaxel arm on the observed survival benefit with atezolizumab. Results: Atezolizumab demonstrated an OS benefit versus docetaxel in the updated ITT850 (hazard ratio [HR] = 0.75, 95% confidence interval: 0.64–0.89, p = 0.0006) and the ITT1225 (HR = 0.80, 95% confidence interval: 0.70–0.92, p = 0.0012) after minimum follow‐up times of 26 and 21 months, respectively. Improved survival with atezolizumab was observed across programmed death‐ligand 1 and histological subgroups. In the immunotherapy sensitivity analysis, the relative OS benefit with atezolizumab was slightly greater in the ITT850 (HR = 0.69) and ITT1225 (HR = 0.74) than the conventional OS estimate. Fewer patients receiving atezolizumab experienced grade 3 or 4 treatment‐related adverse events (14.9%) than did patients receiving docetaxel (42.4%); no grade 5 adverse events related to atezolizumab were observed. Conclusions: The results of the updated ITT850 and initial ITT1225 analyses were consistent with those of the primary efficacy analysis demonstrating survival benefit with atezolizumab versus with docetaxel. Atezolizumab continued to demonstrate a favorable safety profile after longer treatment exposure and follow‐up.

Atezolizumab Treatment Beyond Progression in Advanced Non-Small Cell Lung Cancer: Results From the Randomized, Phase III OAK Study

Introduction: Cancer immunotherapy may alter tumor biology such that treatment effects can extend beyond radiographic progression. In the randomized, phase III OAK study of atezolizumab (anti–programmed death‐ligand 1) versus docetaxel in advanced NSCLC, overall survival (OS) benefit with atezolizumab was observed in the overall patient population, without improvement in objective response rate (ORR) or progression‐free survival (PFS). We examine the benefit‐risk of atezolizumab treatment beyond progression (TBP). Methods: Eight hundred fifty patients included in the OAK primary efficacy analysis were evaluated. Atezolizumab was continued until loss of clinical benefit. Docetaxel was administered until Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) disease progression (PD)/unacceptable toxicity; no crossover to atezolizumab was allowed. ORR, PFS, post‐PD OS, target lesion change, and safety were evaluated. Results: In atezolizumab‐arm patients, ORR was 16% versus 14% and median PFS was 4.2 versus 2.8 months per immune‐modified RECIST versus RECIST v1.1. The median post‐PD OS was 12.7 months (95% confidence interval [CI]: 9.3–14.9) in 168 atezolizumab‐arm patients continuing TBP, 8.8 months (95% CI: 6.0–12.1) in 94 patients switching to nonprotocol therapy, and 2.2 months (95% CI: 1.9–3.4) in 70 patients receiving no further therapy. Of the atezolizumab TBP patients, 7% achieved a post‐progression response in target lesions and 49% had stable target lesions. Atezolizumab TBP was not associated with increased safety risks. Conclusions: Within the limitations of this retrospective analysis, the post‐PD efficacy and safety data from OAK are consistent with a positive benefit‐risk profile of atezolizumab TBP in patients performing well clinically at the time of PD.

P1.34: First-Line Afatinib vs Gefitinib for Patients With EGFR Mutation-Positive Non-Small-Cell Lung Cancer: The LUX-Lung 7 Trial: Track: Advanced NSCLC

Background The irreversible ErbB family blocker afatinib and the reversible EGFR TKI gefitinib are approved for first-line treatment of advanced EGFRm+ NSCLC. This phase IIb trial prospectively compared afatinib versus gefitinib in this setting. Method Patients with stage IIIB/IV EGFRm+ adenocarcinoma received afatinib (40 mg/day) or gefitinib (250 mg/day) until disease progression or beyond if deemed beneficial. Co-primary endpoints were: progression-free survival (PFS), time to treatment failure (TTF), and overall survival (OS). Other endpoints included objective response rate (ORR), adverse events (AEs) and patient-reported outcomes (PROs; EQ-5D utility and EQ-VAS scores). In case of grade ≥3/selected grade 2 drug-related AEs the dose of afatinib could be reduced to 30 mg or 20 mg (minimum). Results 319 patients were randomized (afatinib: 160; gefitinib: 159). Baseline characteristics were generally balanced (afatinib versus gefitinib): female: 56.8 vs 66.7%; Asian: 58.8 vs 55.3%; Del19 mutation: 58.1 vs 58.5%. PFS (HR [95% CI] 0.73 [0.57-0.95]; p=0.017) and TTF (0.73 [0.58-0.92]; p=0.007) were significantly improved with afatinib versus gefitinib, with consistent effects by mutation type and race (Asian/non-Asian) subgroups. Afatinib significantly improved ORR versus gefitinib (70.0 vs 56.0%; p=0.008); median duration of response was 10.1 versus 8.4 months. OS is not yet mature. The most common grade ≥3 drug-related AEs were diarrhea (12.5%) and rash/acne (9.4%) with afatinib and elevated ALT/AST (8.8%) with gefitinib. Drug-related interstitial lung disease was reported in 0 and 4 patients treated with afatinib and gefitinib, respectively. Rates of discontinuation due to treatment-related AEs were the same in each arm (6.3%). There was no significant/clinically meaningful difference in baseline to post-baseline mean EQ-5D (afatinib: 0.72 to 0.77; gefitinib: 0.73 to 0.80; p=0.142) or EQ-VAS (afatinib: 69.7 to 74.5; gefitinib: 71.2 to 76.0; p=0.203) with afatinib and gefitinib. 39% of patients in the afatinib arm had at least dose reduction from 40 mg. Dose reduction of afatinib did not negatively impact PFS (<40mg vs ≥40mg HR [95% CI]: 1.34 [0.90-2.00]; p=0.144) but the incidence and severity of treatment-related AEs was lower following dose reduction (pre- and post-dose reduction [in the 63/160 patients who had a reduction] diarrhea: 25.4 to 9.5%; rash/acne: 20.6 to 3.2%). Dose reduction of afatinib did not diminish its effects on PROs (EQ-5D <40 mg: 0.69 to 0.74, ≥40 mg: 0.73 to 0.77; EQ-VAS <40 mg: 72.4 to 70.5, ≥40 mg: 68.6 to 75.4). Conclusion Afatinib significantly improved PFS, TTF and ORR versus gefitinib in EGFRm+ NSCLC patients. AEs were manageable and treatment-related discontinuations were low in both arms. Improvements in PROs were similar in patients treated with afatinib or gefitinib. Dose reduction of afatinib reduced the incidence and severity of treatment-related AEs without compromising efficacy or PROs.