Gefitinib vs Gefitinib Plus Pemetrexed and Carboplatin Chemotherapy in EGFR-Variant Lung Cancer—Long-Term Results of a Randomized Clinical Trial

Abstract

This randomized clinical trial examines whether adding chemotherapy with pemetrexed and carboplatin to gefitinib improves survival among patients with epidermal growth factor receptor (EGFR)–variant non–small cell lung cancer.

We previously reported that adding chemotherapy to gefitinib improved progression-free survival (PFS) (hazard ratio [HR], 0.51; 95% CI, 0.39-0.66) and overall survival (OS) (HR, 0.45; 95% CI, 0.31-0.65) among patients with epidermal growth factor receptor (EGFR)–variant non–small cell lung cancer (NSCLC).¹

Methods

Details of this randomized clinical trial (RCT) have been published¹ and are included in the trial protocol (Supplement 1). In brief, we enrolled adults (aged ≥18 years) with advanced treatment-naive NSCLC harboring EGFR-sensitizing variations in exons 19, 21, 18 and Eastern Cooperative Oncology Group performance status 0 to 2. Randomization was 1:1 to gefitinib or gefitinib plus chemotherapy, comprising 4 cycles of pemetrexed plus carboplatin, then pemetrexed maintenance until progression or adverse effects. Additional details on the methods are shown in Supplement 2.

Results

We recruited 350 patients; 174 were randomized to gefitinib plus chemotherapy, and 176 were randomized to gefitinib alone. At a median follow-up of 5.0 years (95% CI, 4.9-5.1 years), there were 165 deaths in the gefitinib group and 147 deaths in the gefitinib plus chemotherapy group. Median OS was 17.6 months (95% CI, 15.3-21.5) in the gefitinib group vs 27.5 months (95% CI, 24.8-30.8) in the gefitinib plus chemotherapy group (P < .001) (Figure 1). The 5-year OS was 4.42% (95% CI, 1.98-8.39) in the gefitinib group and 13.04% (95% CI, 8.27-18.9) in the gefitinib plus chemotherapy group (HR, 0.58; 95% CI, 0.46-0.72). Gefitinib plus chemotherapy improved outcomes regardless of EGFR variation type and brain metastases.

Figure 1. Overall Survival Among Patients Who Received Gefitinib vs Gefitinib Plus Pemetrexed and Carboplatin Chemotherapy.

Chemotherapy is defined generally as pemetrexed plus carboplatin or more specifically as 4 cycles of pemetrexed plus carboplatin, then pemetrexed maintenance until progression or adverse effects.

The 5-year PFS was 1.71% (95% CI, 0.47%-4.54%) in the gefitinib group and 6.67% (95% CI, 3.54%-11.15%) in the gefitinib plus chemotherapy group (HR, 0.53; 95% CI, 0.42-0.65; P < .001). There were 175 progression events in the gefitinib group and 161 in the gefitinib plus chemotherapy group; 131 of 176 patients (74.4%) in the gefitinib group and 100 of 174 patients (57.5%) in the gefitinib plus chemotherapy group received further therapy. The details of treatment received according to lines are shown in Figure 2. Repeat tumor biopsy and molecular testing at first progression were performed in 117 patients (62 in the gefitinib group and 55 in the gefitinib plus chemotherapy group). T790M variation was noted in 16 patients (25.9%) in the gefitinib group and 9 patients (16.4%) in the gefitinib plus chemotherapy group at first progression.

Figure 2. Details of Treatment Received According to Lines of Therapy.

Chemotherapy is defined generally as pemetrexed plus carboplatin or more specifically as 4 cycles of pemetrexed plus carboplatin, then pemetrexed maintenance until progression or adverse effects.

Discussion

With availability of higher generation tyrosine kinase inhibitors (TKIs), the outcomes of EGFR-variant NSCLC have steadily improved. Unfortunately, access to third-generation agents like osimertinib is limited in low- and middle-income countries (LMICs). This RCT found that PFS and OS benefits of adding chemotherapy to gefitinib were sustained at 5 years, confirming our earlier results reported at median follow-up of 17 months.¹

Three other studies have explored the strategy of adding chemotherapy to TKI. NEJ009^2,3 and GAP brain⁴ added chemotherapy to gefitinib; FLAURA2⁵ added chemotherapy to osimertinib. All 3 reported a PFS benefit. OS improvement was reported in the initial NEJ009 article,² GAP,⁴ and our study. FLAURA2⁵ results are immature for OS interpretation.

Interestingly, updated NEJ009 results showed numerically but not statistically significant OS improvement.³ This may be attributed to access to osimertinib, which was limited in our setting; hence, PFS gains from chemotherapy addition translated into OS benefit. Second, only 74% of patients in the gefitinib group received postprogression therapy, similar to our previous experience,⁶ for various reasons like performance status deterioration or patient choice. This underlines the importance of administering the best treatment upfront. Third, ethnic differences in Japanese patients’ pharmacokinetics and pharmacodynamics might have resulted in differential results. In addition the recent results of MARIPOSA study suggest that amivantamab and lazertinib are also an option now in EGFR-variant NSCLC.

Ours was a single-center study. Access to osimertinib was limited postprogression. However, this reflected the general population in LMICs like India. It is precisely in this situation that adding chemotherapy to gefitinib improves outcomes.

Supplement 1.

Trial Protocol

Supplement 2.

eAppendix. Supplemental Methods

eReference

Supplement 3.

Data Sharing Statement