Over the past decade, EGFR inhibition has supplanted chemotherapy as the standard first-line treatment of advanced-stage EGFR-mutant non-small-cell lung cancer (NSCLC). However, new findings might prompt renewed use of chemotherapy in this setting.

In an open-label, single-centre phase III trial involving 350 patients with untreated advanced-stage EGFR-mutant NSCLC, the addition of carboplatin and pemetrexed to the first-generation EGFR inhibitor gefitinib resulted in improvements in the objective response rate (75% versus 63% with gefitinib alone; P = 0.01) and the primary end point, progression-free survival (PFS; median 16 months versus 8 months; HR 0.51, 95% CI 0.39–0.66; P < 0.001), with consistent benefit across exploratory patient subgroups. These outcomes are similar to those achieved with the third-generation EGFR inhibitor osimertinib as monotherapy in the FLAURA trial. Interestingly, however, 21% of patients in this trial had a performance status (PS) of 2, whereas all those in FLAURA had a PS ≤1.

In exploratory analyses, the combination therapy was also associated with a prolonged PFS2 (time from randomization to second progression): median 23 months versus 14 months (HR 0.69, 95% CI 0.53–0.92; P < 0.001). Accordingly, at a median follow-up duration of 17 months, the median overall survival (OS) duration was not reached versus 17 months (HR 0.45, 95% CI 0.31–0.65; P < 0.001); the estimated 18-month OS was 74% versus 49%.

Unsurprisingly, the combination regimen was more toxic than gefitinib alone (grade ≥3 adverse event rate of 75% versus 49%), owing mainly to increased myelosuppression, nephrotoxicity and hypokalaemia. Toxicities were, however, mostly manageable.

These results confirm the benefits demonstrated in randomized phase II trials combining gefitinib with carboplatin and pemetrexed, presenting a new first-line treatment option. Whether such regimens will supersede frontline EGFR inhibitor monotherapy remains to be seen, particularly in light of the imminent and reportedly positive OS results of FLAURA.