The combination of osimertinib (Tagrisso) and gefitinib (Iressa) produced an objective response rate (ORR) of 82.1% (95% CI, 65.5%-92.5%) and suppressed the emergence of second-site EGFR resistance mutations as first-line therapy in patients with EGFR-mutated non–small cell lung cancer (NSCLC), according to data from a phase 1/2 study presented in a poster session at the
Among 39 efficacy-evaluable patients, best response was a partial response in 32 (82.1%), stable disease in 6 (15.4%), and progressive disease in 1 (2.6%). At a median follow-up of 60.8 months, the median progression-free survival (PFS) was 18.4 months (95% CI, 14.6-32.0), with 12- and 24-month PFS rates of 71.1% (95% CI, 53.9%-82.5%) and 46.5% (95% CI, 30%-61.4%), respectively. At a median follow-up of 72.4 months, the median overall survival (OS) was 44.4 months (95% CI, 29.3-53.7), with 12- and 24-month OS rates of 89.7% (95% CI, 74.9%-96%) and 76.3% (95% CI, 59.3%-86.9%), respectively.
The investigator-initiated, Dana-Farber Cancer Institute–led phase 1/2 study enrolled patients with newly diagnosed, stage IV NSCLC (AJCC 7th edition) harboring an EGFR exon 19 deletion or L858R mutation, an ECOG performance status of 0 or 1, and no prior systemic therapy; asymptomatic, untreated central nervous system (CNS) metastases were permitted. Study findings were presented by lead author Julia K. Rotow, MD, of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts, who discussed the
In the concurrent-dosing cohort, dose escalation began with gefitinib 250 mg plus osimertinib 40 mg daily (dose level 1; n = 3), then gefitinib 250 mg plus osimertinib 80 mg daily (dose level 2; n = 3), before expanding to that regimen in 36 additional patients; a protocol amendment later allowed intrapatient dose escalation to osimertinib 80 mg. A separate alternating-dosing cohort (n = 6) was terminated early because of evolving first-line standards of care and excluded from the efficacy analysis. The primary end point was safety during dose escalation and feasibility, defined as receipt of combination therapy for at least 6 months, during dose expansion; secondary and exploratory end points included ORR, PFS, OS, and genomic mechanisms of resistance.
Among the 42 patients in the safety set, the median age was 62 years (range, 39-79); 66.7% were female, 92.9% had adenocarcinoma histology, and EGFR mutations were exon 19 deletion in 57.1% and L858R in 42.9%. Baseline CNS metastases were present in 47.6% of patients (19.0% untreated), and TP53 co-mutations were identified in 47.6%. Thirty-nine patients, those treated at dose level 2 or in the expansion cohort, were included in the efficacy analysis; 4 remained on treatment as of data cutoff.
Of 39 efficacy-evaluable patients, 32 developed acquired treatment resistance, and 29 (90.6%) underwent resistance profiling (11 tissue-based sequencing, 9 with both tissue- and ctDNA-based testing, and 9 ctDNA-based only, 4 of which were nondiagnostic). No known EGFR second-site acquired resistance mutations, including T790M or C797S, were detected in any profiled sample. One EGFR variant of uncertain significance (V1047M), not known to be oncogenic, was identified in a post-treatment specimen.
Among 25 patients with an identifiable resistance mechanism or unknown result, bypass pathway alterations were each detected in a minority of samples, including PIK3CA alterations, KRAS amplification, EGFR amplification, BRAF alterations, and MET amplification (8% each), small cell transformation (5%), and beta-catenin or ERBB4 alterations (4% each); the mechanism remained unknown in 56% of samples. The 2 patients with EGFR amplification (11-fold and 6-fold copy number gain) each had a co-occurring bypass alteration, in KRAS (6-fold copy number gain) or BRAF (16-fold copy number gain). Despite the absence of second-site EGFR resistance mutations, investigators noted that the median PFS observed with the combination was comparable to historical data reported with osimertinib monotherapy.
Patients received a median of 13 cycles of gefitinib and 23 cycles of osimertinib. The protocol-defined feasibility threshold, completion of 6 cycles with 2 or fewer doses held per cycle in at least 80% of patients, was met by 56% of patients, below the prespecified criterion. Investigators noted that treatment was nonetheless clinically manageable, with most patients receiving a prolonged period of combination therapy supported by dose modification and supportive care.
The most common treatment-related adverse effects (TRAEs) of any grade were diarrhea (92.9%), dry skin (69.0%), acneiform rash (50.0%), paronychia (47.6%), and skin/subcutaneous events (47.6%); grade 3 events included diarrhea (14.3%), maculopapular rash (7.1%), alanine aminotransferase level increase (7.1%), and aspartate aminotransferase level increase (4.8%). Overall, 54.8% of patients had a grade 3 TRAE and 16.7% a grade 4 TRAE; 1 patient (2.4%) had a grade 5 adverse effect (pulmonary embolism), attributed as unrelated to either study drug. Dose interruptions for TRAEs occurred in 33.3% of patients for osimertinib and 46.2% for gefitinib, reductions in 12.8% and 28.2%, and discontinuations in 7.7% and 35.9%, respectively. Drug-induced pneumonitis occurred in 2 patients (4.8%), and reduced left ventricular ejection fraction attributed to the study drugs occurred in 5 patients (11.9%); treatment was held transiently in 2 of those patients, both of whom resumed and tolerated osimertinib monotherapy.
Dual EGFR-targeted strategies remain an active area of investigation in frontline EGFR-mutated NSCLC; at the same meeting, an
