Adding Pemetrexed to Gefitinib Improves PFS in EGFR-Mutated NSCLC

The combination of pemetrexed and gefitinib offered improved progression-free survival (PFS) over gefitinib alone in East Asian patients with advanced nonsquamous non–small-cell lung cancer (NSCLC) and activating EGFR mutations, according to a new randomized, open-label study.

EGFR tyrosine kinase inhibitors (TKIs) including gefitinib have been shown to improve outcomes in patients with EGFR-mutated NSCLC. “Given their different mechanisms of action, combination treatment with EGFR-TKIs and chemotherapy may further improve outcomes,” wrote study authors led by James Chih-Hsin Yang, MD, PhD, of National Taiwan University Hospital in Taipei. Previous trials of such combinations have not shown clinical benefit, however, though this could have been because of antagonism between the agents used or because wild-type EGFR patients were included.

The new study used pemetrexed along with gefitinib to avoid potential antagonism, because the drugs have non-overlapping toxicity profiles, and so that platinum-based chemotherapy might still be used following disease progression. The study randomized patients at 35 sites in China, Japan, Korea, and Taiwan to either pemetrexed plus gefitinib (129 patients) or gefitinib alone (66 patients); results were published online ahead of print in the Journal of Clinical Oncology.

The median PFS in the combination group was 15.8 months, compared with 10.9 months with gefitinib monotherapy; this yielded an adjusted hazard ratio of 0.68 (95% CI, 0.48–0.96; one-side P = .014; two-sided P = .029). The survival curves stayed largely similar for 7 to 8 months, after which point they diverged in favor of the combination regimen.

The PFS advantage was seen in subgroups based on type of EGFR mutation, with both exon 19 deletion and exon 21 L858R point mutations seeing benefit with pemetrexed and gefitinib. Overall survival data was not yet mature, and tumor response rates did not differ between the two groups.

Most patients in both groups reported at least one treatment-emergent adverse event (94% in combination group and 92% in monotherapy group). Grade 3/4 treatment-emergent adverse events were more frequent with the combination, at 42% vs 19% (P = .001). There were two study drug-related deaths in the combination group (pneumonitis and interstitial lung disease). Five patients in the gefitinib monotherapy group discontinued the treatment because of an adverse event, compared with 19 in the combination group, but this was not statistically significant.

“The modest increase in toxicity was clinically manageable,” the authors wrote. “The combination of pemetrexed and an EGFR-TKI may be a new treatment option for patients with EGFR mutation-positive nonsquamous NSCLC that could improve clinical outcomes compared with the current standard of care.”