Pemetrexed plus gefitinib improves PFS in EGFR–mutated NSCLC

The addition of gefitinib to a pemetrexed-based treatment extended PFS in East Asian patients with EGFR mutation–positive nonsquamous non–small cell lung cancer, according to results from a randomized phase 2 trial.

Treatment with pemetrexed (Alimta, Eli Lilly) has become the standard of care in treating locally advanced or metastatic NSCLC; however, studies have suggested potential synergy between the chemotherapy regimen and EGFR tyrosine kinase inhibitors.

“Low thymidylate synthase expression is predictive of pemetrexed efficacy in patients with NSCLC, and gefitinib (Iressa, AstraZeneca) suppresses thymidylate synthase expression in NSCLC cell lines,” James Chih-Hsin Yang, MD, PhD, director of the department of oncology and the department of medical research at National Taiwan University Hospital, and colleagues wrote. “Pemetrexed plus EGFR TKIs may offer several advantages, including avoiding potential antagonism, nonoverlapping toxicity, and preserving the ability to treat patients with platinum-based therapy after progression.”

Because no randomized trials have confirmed these advantages, the researchers compared the addition of pemetrexed to gefitinib to determine if the combination therapy effectively prolonged PFS in 195 treatment-naive patients from 35 sites in China, Japan, Korea and Taiwan with stage IV or recurrent nonsquamous NSCLC and activating EGFR mutations.

Yang and colleagues randomly assigned patients 2:1 to receive 500 mg/m² IV pemetrexed on day 1 of every 21-day cycle with 250 mg oral gefitinib once daily (n = 129) or the gefitinib regimen alone (n = 66). Fifty-five percent of patients harbored EGFR exon 19 deletions and 39% had exon 21 L858R point mutations.

PFS served as the primary endpoint. Time to progressive disease, OS, tumor responsive rates, DOR and safety served as secondary endpoints.

Researchers evaluated these endpoints in the intent-to-treat population, which included 126 patients (mean age, 62 years) from the combination arm and all 66 patients (mean age, 61 years) from the gefitinib-alone arm who received at least one dose of study drug.

Patients treated with the combination therapy demonstrated a superior median PFS of 15.8 months, compared with 10.9 months in the gefitinib-only group (HR = 0.68; 95% CI, 0.48-0.96).

Results of a subgroup analysis showed that the addition of pemetrexed to gefitinib extended PFS in patients with exon 19 deletion (median, 17.1 months vs. 11.1 months; HR = 0.67; 95% CI, 0.43-1.05) and exon 21 L858R point mutation (median, 12.6 months vs. 10.9 months; HR = 0.58; 95% CI, 0.33-1.01).

Patients treated with the combination therapy also demonstrated longer median time to progressive disease (16.2 vs. 10.9 months; HR = 0.66; 95% CI, 0.47-0.93) and median duration of response (15.4 vs. 11.3 months; HR = 0.74; 95% CI, 0.5-1.08).

Tumor response rates did not differ among groups. In addition, OS data were immature at the time of the analysis.

The most common drug-related adverse events in the gefitinib-plus-pemetrexed arm included diarrhea (44%), increased AST (41%) and ALT (38%), and dermatitis acneiform (38%). The most common toxicities in the gefitinib-alone arm included diarrhea (48%), dermatitis acneiform (43%) and dry skin (35%).

A significantly greater proportion of patients in the combination arm experienced at least one treatment-related grade 3 or grade 4 adverse event (42% vs. 19%; P = .001).

In total, 33% the combination therapy arm and 15% of the monotherapy experienced gefitinib interruption as a result from adverse events, and 43% of patients required pemetrexed dose delay. However, the “modest increase in toxicity was clinically manageable,” Yang and colleagues wrote.

“If the combination of pemetrexed plus EGFR TKI is used in the first-line setting, platinum-based therapies may still be used after progression,” they added. “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.” – by Kristie L. Kahl

Disclosure: Cheng reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.