Chemo Regimen Boosts Gefitinib in EGFR-Mutant Lung Cancer, But at What Cost?

Addition of a pemetrexed-carboplatin chemotherapy regimen to gefitinib led to a survival benefit in patients with EGFR-mutant advanced non–small-cell lung cancer (NSCLC), according to a phase III study (abstract 9001) presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago. EGFR-directed oral tyrosine kinase inhibitors are the first-line therapy for this population, but resistance occurs within 8 to 12 months, leading to efforts to develop strategies to delay onset of resistance.

One approach is to add chemotherapy, in the hopes that this will create synergy through inducing apoptosis and suppressing AKT and Erk phosphorylation, which are believed to play a role in resistance.

The study included 350 chemotherapy-naive patients who were randomized to gefitinib daily or gefitinib combined with IV pemetrexed-carboplatin every 3 weeks for 4 cycles. Following that, patients in the combination group underwent maintenance IV pemetrexed every 3 weeks.

The median patient age was 54 years; 48% were women, and 84% had never smoked. Twenty-one percent had an ECOG performance status of 2, and 18% had brain metastases. The median follow-up in surviving patients was 17 months.

The combination therapy group had an overall response rate of 75.3%, compared with 65.2% in the gefitinib-only group (P = .01). The median depth of response was −56.4% and −43.5%, respectively (P = .002).

The combination therapy group had a greater estimated median PFS (16 months vs 8 months; hazard ratio for disease progression or death, 0.51; 95% CI, 0.39–0.66) and a better 18-month overall survival rate (78.3% vs 48.7%).  

More patients in the combination group experienced clinically relevant grade 3 or higher toxicities (50.6% vs 25.3%; P < .001), with anemia, neutropenia, thrombocytopenia, febrile neutropenia, hypokalemia, and nephrotoxicity being the most common.

“This study demonstrated an improvement in progression-free survival, which was pretty impressive, with doubling of PFS from 8 to 16 months. It also demonstrated an overall survival improvement, which was also pretty impressive,” said study discussant Ticiana Leal, MD, an assistant professor and thoracic oncology program leader at the University of Wisconsin.

The study authors suggested that the regimen is a new front-line option in these patients, but Leal rang a note of caution. “One of the things that’s concerning when you’re adding chemotherapy to a frontline therapy, the toxicities are certainly higher. What about quality of life?” she asked.

She also had concerns about CNS activity and brain metastases, which are more common in EGFR-mutant NSCLC, given that chemotherapy has low penetration into the CNS.