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Adding chemotherapy to gefitinib increases PFS, OS, toxicity in NSCLC subset
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The addition of pemetrexed and carboplatin chemotherapy to gefitinib significantly extended PFS and OS for patients with advanced non-small cell lung cancer and EGFR-sensitizing mutations, according to results of a randomized phase 3 study published in Journal of Clinical Oncology.
However, clinically relevant serious toxicities occurred twice as often with the combination regimen than with gefitinib alone, the researchers reported.
“Despite having identified the molecular target and using drugs that specifically bind to the target, cure and long-term remission [in molecularly driven NSCLC] elude us,” Vanita Noronha, MD, MBBS, professor in the department of medical oncology at Tata Memorial Hospital in Mumbai, India, and colleagues wrote. “Resistance inevitably develops within 8 to 12 months. Various strategies have been attempted to decrease the emergence of resistance. One strategy involves combining cytotoxic chemotherapy with an EGFR tyrosine kinase inhibitor.”
The open-label study by Noronha and colleagues included 350 patients with advanced, chemotherapy-naive, EGFR-mutated NSCLC recruited between August 2016 and August 2018. Eighteen percent of patients had brain metastases and 21% has an ECOG performance status of 2.
The researchers stratified patients by performance status and EGFR mutation type (exon 19 vs. exon 18 or 21) and randomly assigned them 1:1 to gefitinib (Iressa, AstraZeneca) 250 mg orally once per day alone (n = 176; median age, 56 years; range, 27-78) or with 500 mg/m2 IV pemetrexed and IV carboplatin area under the curve 5 every 3 weeks for four cycles (n =174; median age, 54 years; range, 27-75). The combination regimen was followed by maintenance 500 mg/m2 IV pemetrexed every 3 weeks.
PFS served as the primary endpoint, and OS, toxicity and response rate served as secondary endpoints. The investigators evaluated survival endpoints in the intention-to-treat population.
Median follow-up was 17 months (range, 7-30).
Among patients treated with gefitinib and chemotherapy, 139 (80%) completed all four cycles of pemetrexed and carboplatin.
Results showed objective response rates of 75.3% (95% CI, 68.3-81.1) among patients in the combination group and 62.5% (95% CI, 55.1-69.3) in the gefitinib-only group.
Patients in the combination group had significantly longer estimated median PFS (16 months; 95% CI, 13.5-18.5) than those in the gefitinib-only group (8 months; 95% CI, 7.1-8.9). Researchers observed an HR for disease progression or death of 0.51 (95% CI, 0.39-0.66).
At the time of analysis, 122 patients (34.9%) had died, including 42 in the combination group and 80 in the gefitinib-only group. The combination group had significantly longer estimated median OS than the gefitinib group (not reached vs. 17 months; HR = 0.45; 95% CI, 0.31-0.65).
Half of patients in the combination group (50.6%; 95% CI, 43-58.2) experienced grade 3 or higher toxicities — mostly due to chemotherapy-induced myelosuppression and nephrotoxicity — compared with 25.3% (95% CI, 19.4-32.4) of those in the gefitinib group (P < .001).
The researchers noted the study’s limitations, including the fact that it was conducted at a single center, enrolled a high proportion of nonsmokers and used an open-label design.
“Adding pemetrexed and carboplatin chemotherapy to gefitinib significantly prolonged PFS and OS, but also increased toxicity,” the researchers wrote. “The combination of gefitinib, pemetrexed and carboplatin represents a new standard first-line therapy for EGFR-mutant NSCLC.” – by Jennifer Byrne
Disclosures: Noronha reports research funding to her institution from Amgen, Dr. Reddy’s Laboratories and Sanofi. Please see the study for all other authors’ relevant financial disclosures.
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