Adding chemotherapy to gefitinib significantly prolongs survival in patients who have EGFR-mutant non-small cell lung cancer (NSCLC) with brain metastases, according to results from the BRAIN GAP trial published in JAMA Network Open.¹

In this phase 3 randomized-controlled multicenter trial from China, Xue Hou and his co-researchers set out to assess the safety and efficacy of gefitinib alone vis a vis gefitinib with pemetrexed with platinum chemotherapy in 161 in treatment-naive patients with non–small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation and brain metastases. Majority of the study subjects had adenocarcinoma. The various types of EGFR mutations included exon 19 deletions in ~53%, exon 21 L858R point mutations in 43.5%, while nearly 4% had uncommon EGFR mutations. Intracranial lesions, numbering ≥4, were present in ~61% patients, while around 40% had 1-3 lesions. The trial was conducted from January 2016 to August 2021. The mean age of the study subjects was 55 years; women comprised more than half of them (54%). At baseline, 25.5% were smokers. Intracranial progression-free survival (iPFS), PFS, intracranial and overall objective response rate (ORR), overall survival (OS) and safety were the parameters measured.

Eighty-one patients received gefitinib alone, while 80 patients received gefitinib + chemotherapy.

iPFS, which was also the primary outcome measure, was found to be significantly longer among patients treated with gefitinib + chemotherapy compared to those who received only gefitinib; 15.6 months vs 9.1 months, respectively with hazard ratio of 0.36. Similarly, the median overall PFS also improved with gefitinib + chemotherapy (16.3 months) than with gefitinib alone (9.5 months) with HR of 0.39. The overall survival in the gefitinib combination group was 35 months and in the monotherapy group it was 28.9 months with HR of 0.65.

Patients in the gefitinib + chemotherapy group had higher intracranial ORR (85.0%) compared to patients in the gefitinib alone group (63.0%). The overall ORR was again much better with gefitinib + chemotherapy (80.0%) vs gefitinib alone (64.2%).

Grade 3 or higher adverse events such as nausea, diarrhea, anorexia, neutropenia and raised ALT levels occurred more often in the combination group than in the monotherapy group; 40.0% and 21.0%, respectively. 

Gefitinib + pemetrexed and carboplatin chemotherapy has shown similar favorable results in EGFR-mutant advanced NSCLC patients without brain metastasis in an earlier phase 3 trial carried out at Tata Memorial Center in 2020.²

This study conducted in a similar patient group but with brain metastasis has shown that addition of chemotherapy to gefitinib significantly improved overall and intracranial progression-free survival. The response rates were also better. Hence, gefitinib + chemotherapy may be a potential cost-effective substitute for osimertinib, which is a 3rd-generation EGFR tyrosine kinase inhibitor (TKI) and is currently the first-line therapy for advanced NSCLC with EGFR mutations, especially when osimertinib is inaccessible due to its exorbitant cost.

These findings may be especially germane to resource-crunched countries like India where out of pocket health expenditure still constitutes more than 50% of the health care costs. Compared to osimertinib, the 1st-generation EGFR-TKI gefitinib, is widely available and more affordable.

References

1. Hou X, et al. Gefitinib plus chemotherapy vs gefitinib alone in untreated EGFR-mutant non-small cell lung cancer in patients with brain metastases: the GAP BRAIN open-label, randomized, multicenter, phase 3 study. JAMA Netw Open. 2023 Feb 1;6(2):e2255050. doi: 10.1001/jamanetworkopen.2022.55050.
2. Noronha V, et al. Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer. J Clin Oncol. 2020 Jan 10;38(2):124-136. doi: 10.1200/JCO.19.01154.