Addition of Pemetrexed/Carboplatin to Gefitinib in Advanced EGFR-Mutant NSCLC


Key Points

  • The addition of pemetrexed/carboplatin to gefitinib increased progression-free and overall survival.
  • The combination treatment was associated with greater toxicity.

In an Indian single-center phase III trial reported in the Journal of Clinical Oncology, Noronha et al found that the addition of pemetrexed/carboplatin to gefitinib improved progression-free and overall survival in first-line treatment of advanced EGFR-mutant non–small cell lung cancer (NSCLC), but toxicity was worse with the combined therapy.

Study Details

In the open-label trial, 350 patients at Tata Memorial Center, Mumbai were randomly assigned between 2016 and 2018 to receive gefitinib 250 mg per day (n = 176) or gefitinib plus pemetrexed 500 mg/m2 and carboplatin area under curve = 5 every 3 weeks for four cycles (n = 174); patients in the combination group also received maintenance pemetrexed every 21 days in the absence of progression. Brain metastases were present in 18% of patients, and 21% of patients had Eastern Cooperative Oncology Group performance status of 2.

The primary endpoint was progression-free survival.

Progression-Free Survival

Median follow-up was 17 months (range = 7–30 months). Radiologic response rates were 75% in the combination group vs 63% in the gefitinib group (P = .01). Estimated median progression-free survival was 16 months vs 8 months (hazard ratio [HR] = 0.51, P < .001). Combination treatment was associated with benefit among subgroups examined, including subgroups according to age, sex, exon 19 or other mutation, performance status, and brain metastases status. Estimated median overall survival was not reached vs 17 months (HR = 0.45, P <.001).

Adverse Events

Grade ≥ 3 adverse events occurred in 75.0% of the combination group vs 49.9% of the gefitinib group (P < .001). Clinically relevant grade ≥ 3 adverse events occurred in 51% vs 25% (P < .001). The increased grade ≥ 3 toxicity in the combination group was primarily due to hematologic toxicity (anemia in 19% vs 1%, neutropenia in 16% vs 0%, febrile neutropenia in 11% vs 0%), nephrotoxicity (renal dysfunction in 6% vs 0%), and hypokalemia (8% vs 1%).

The investigators concluded, “Adding pemetrexed and carboplatin chemotherapy to gefitinib significantly prolonged [progression-free survival] and [overall survival] but increased toxicity in patients with NSCLC.”

Kumar Prabhash, MBBS, MD, DM, of the Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the Tata Memorial Center Research Administration Council and grants from Dr. Reddy’s Laboratories, Fresenius Kabi India, Alkem Laboratories, Natco Pharma, BDR Pharmaceuticals, and Lung Cancer Consortium India. For full disclosures of the study authors, visit

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