Results of 2 trials comparing erlotinib, a first-generation reversible tyrosine kinase inhibitor, with second-generation irreversible tyrosine kinase inhibitors (dacomitinib and afatinib) in patients with either advanced non–small cell lung cancer (NSCLC) or squamous cell carcinoma (SCC) were presented in one session.

EGFR Mutant Subset Analysis of ARCHER 1009 Comparing Dacomitinib and Erlotinib

The ARCHER 1009 trial was a randomized, double-blind, phase 3 study in which patients (n = 878) with locally advanced or metastatic NSCLC who had progressed after 1 to 2 prior lines of therapy were randomized 1:1 to receive either dacomitinib 45 mg/d or erlotinib 150 mg/d. Among these patients, 47 treated with dacomitinib and 44 treated with erlotinib had EGFR-mutant NSCLC, and 37 treated with dacomitinib and 39 treated with erlotinib had an EGFR-activating mutation in exon 19 or 21.

It has been previously reported that for the overall study population, dacomitinib was not superior to erlotinib for patients with advanced NSCLC or in patients with KRAS wild-type tumors [Ramalingam SS et al. Lancet Oncol. 2014]. In the present session, Luis Paz-Ares, MD, PhD, Hospital Universitario Virgen del Rocio, Seville, Spain, discussed a subset analysis of patients with EGFR-activating mutations [Paz-Ares L et al. Ann Oncol. 2015].

Among the 91 patients with EGFR mutations, the median progression-free survival (PFS) per independent review was 11.1 months (95% CI, 5.6 to 21.9) with dacomitinib and 10 months (95% CI, 7.4 to 16.6) with erlotinib (HR, 0.935; 95% CI, 0.539 to 1.624; one-sided P = .403). Among the 76 patients with EGFR-activating mutations in exon 19 or 21, the median PFS per independent review was 14.6 months (95% CI, 7.6 to not reached [NR]) with dacomitinib and 9.6 months (95% CI, 7.3 to 16.6) with erlotinib (HR, 0.707; 95% CI, 0.380 to 1.315; one-sided P = .136). Notably, the PFS values per independent review were not mature, as the event rate was 56%.

When PFS was determined per investigator’s assessment, the median PFS for all EGFR mutations was 10.9 months for patients treated with dacomitinib (95% CI, 7.5 to 18.2) and 10 months for patients treated with erlotinib (95% CI, 7.4 to 12.8), with an HR of 0.874 (95% CI, 0.542 to 1.408; one-sided P = .286). Among the 76 patients with EGFR-activating mutations in exon 19 or 21, the median PFS per investigator’s assessment was 13.4 months (95% CI, 9.0 to 19.6) with dacomitinib and 10.0 months (95% CI, 7.4 to 12.8) with erlotinib (HR, 0.749; 95% CI, 0.440 to 1.275; one-sided P = .142). The PFS data by the investigator’s assessment were mature.

For patients with EGFR mutations, overall survival (OS) was 26.6 months (95% CI, 21.6 to NR) with dacomitinib and 28.0 months (95% CI, 16.4 to NR) with erlotinib (HR, 0.976; 95% CI, 0.534 to 1.786; one-sided P = .472). For patients with EGFR-activating mutations in exon 19 or 21, OS was 26.6 months (95% CI, 21.6 to NR) with dacomitinib and 23.2 months (95% CI, 16.0 to NR) with erlotinib (HR, 0.796; 95% CI, 0.405 to 1.565; one-sided P = .256). These OS data were not mature as the trial was still < 50% deaths. The toxicity profile was similar between the EGFR mutation population and the overall patient population.

Overall, the subgroup of patients with the EGFR-activating mutation in exon 19 or 21 appeared to show a trend in favor of dacomitinib for PFS. The activity of dacomitinib in NSCLC with EGFR-activating mutations as a second- and third-line treatment is being reviewed for future presentation.

LUX-Lung 8: Afatinib vs Erlotinib for Squamous Cell Carcinoma

Afatinib has shown activity in patients with SCC of the head/neck and lung. Silvia Novello, MD, PhD, San Luigi Hospital, Orbassano, Italy, discussed the results of the LUX-Lung 8 phase 3 trial [Goss GD et al. Ann Oncol. 2015], based on a poster by Glendwood D. Goss, MD, University of Ottawa, Ottawa, Canada, and colleagues. The LUX-Lung 8 trial prospectively compared afatinib and erlotinib in patients with SCC of the lung after failure of platinum-based first-line chemotherapy. Prof Novello explained that early trial data led researchers to expect that afatinib would have a different efficacy, safety profile, pharmacokinetic interactions, and activity in different mutations, as well as a specific role in overcoming resistance and ability to target other receptors, but not all of the above-mentioned characteristics have been clinically demonstrated.

In the LUX-Lung 8 trial, patients with stage IIIB/IV SCC were randomized 1:1, after being stratified by race to avert any possible imbalance in EGFR mutation. The primary analysis was based on 414 PFS events when 669 patients had been randomized (afatinib n = 335; erlotinib n = 334).

The median PFS was significantly higher for afatinib vs erlotinib (2.4 months vs 1.9 months; HR, 0.822; 95% CI, 0.676 to 0.998; log-rank P = .043). Novello noted that an HR of 0.822 is much less than that required by recent American Society of Clinical Oncology guidelines that define clinically meaningful outcomes [Ellis LM et al. J Clin Oncol. 2014], but she raised the question of how to meet that goal in SCC.

The overall response rate (4.8% vs 3%; P = .23) and disease control rate (45.7% vs 36.8%; P = .02) were higher with afatinib vs erlotinib.

The overall adverse event (AE) profiles were similar, with grade 3 or higher AEs occurring in 50.2% of patients receiving afatinib and in 49.1% of patients receiving erlotinib. Afatinib had a higher incidence of drug-related grade 3 or higher diarrhea (9.7% vs 2.4%) and grade 3 stomatitis (3.3% vs 0%), while erlotinib had a higher incidence of grade 3 rash/acne (5.5% vs 9%). The drug was discontinued due to AEs in 8.8% of the afatinib arm and 4.2% of the erlotinib arm.

Notably, Prof Novello stated that the toxicity was not negligible. At 2 months, 50% of the patients did not benefit from one treatment vs the other. This raises the question of how to select patients who can really benefit from treatment.

More patients had improved global health status (36.4% vs 27.1%; P = .03) and cough (44% vs 33%; P = .01) with afatinib than with erlotinib. Changes in mean scores over time favored afatinib over erlotinib for cough, dyspnea, and physical and role functioning.

Overall, LUX-Lung 8 is the largest prospective trial comparing afatinib vs erlotinib in patients with relapsed/refractory SCC. PFS, tumor shrinkage, overall response rate, and disease control rate were significantly better for afatinib than erlotinib. Afatinib had drug-related AEs more frequently and severely than erlotinib, but rates of discontinuation from AEs were comparable. Notably, this trial was still recruiting when this data analysis occurred.