Randomized Phase 2 Trial of Pharmacodynamic Separation of Pemetrexed and Intercalated Erlotinib Versus Pemetrexed Alone for Advanced Nonsquamous, Non-small-cell Lung Cancer

Abstract

Background: Pharmacodynamic separation of pemetrexed and erlotinib avoids negative cellular interactions and results in antitumor synergy in erlotinib-resistant non-small-cell lung cancer (NSCLC) cells, independent of EGFR (epidermal growth factor receptor) genotype.

Patients and methods: Patients with platinum-treated metastatic nonsquamous NSCLC were randomly assigned 1:2 to pemetrexed alone (500 mg/m² provided intravenously on day 1) or pemetrexed followed by erlotinib (150 mg provided orally once daily on days 2-17) every 21 days. EGFR genotype was centrally confirmed by Sequenom multiplex oncogenotyping assay. The primary end point was progression-free survival (PFS), which would be considered promising for future study if median PFS was ≥ 4.5 months.

Results: Of 83 patients enrolled, 79 were randomized to either pemetrexed alone (n = 27) or in combination (n = 52). Fifty-nine (79%) of 75 eligible patients had tumors with confirmed EGFR genotype: 7 with activating mutations and 52 wild type. Median PFS was 4.7 and 2.9 months in the combination and pemetrexed-alone groups, respectively. In patients with EGFR wild-type tumors, median PFS was 5.3 and 3.5 months in the combination and pemetrexed-alone groups, respectively. Objective response rate (29% vs. 10%, P = .17), 6-month PFS (45% vs. 29%, P = .26), and 12-month PFS (23% vs. 10%, P = .28) were all higher in the combination arm. Rash (67% vs. 26%, P = .0007) and diarrhea (44% vs. 11%, P = .003) were significantly more common in the combination arm.

Conclusion: In patients with unselected or EGFR wild-type advanced nonsquamous NSCLC, pharmacodynamic separation of pemetrexed and intercalated erlotinib had promising antitumor activity without new safety concerns. The combination merits further evaluation as maintenance or second-line therapy against new standards in patients with EGFR wild-type advanced NSCLC.

Keywords: EGFR wild type; Multiplex genotyping; Plasma circulating tumor DNA; Randomized phase 2 study; Second line.

Figure 1

Study Schema. Eligible Patients Were Randomized 2:1 to Arms B and A, Respectively, Stratified by Gender, Performance Status (0 or 1 vs. 2), and Smoking History. Treatment: Arm A, Pemetrexed 500 mg/m² provided Intravenously on Day 1; Arm B, Pemetrexed and Erlotinib 150 mg Orally Once Daily on Days 2 to 17. One Cycle = 3 Weeks. Fifty Patients in Arm B Were Needed to Detect an Increase in Median PFS by 50%, ie, Estimate ~ 3 to 4.5 months Abbreviation: PFS = progression-free survival.

Figure 2

Kaplan-Meier Curves for PFS. PFS for Second-line Treatment With Pemetrexed and Erlotinib or Pemetrexed Alone in Patients With Molecularly Unselected NSCLC (A) or Patients With EGFR Wild-type NSCLC (B) Abbreviations: EGFR = epidermal growth factor receptor; HR = hazard ratio; NSCLC = non–small-cell lung cancer; PFS = progression-free survival.