In the phase III OPTIMAL study, which was conducted in China, first-line single-agent erlotinib (Tarceva) given to patients with advanced non-small cell lung cancer (NSCLC) extended median progression-free survival (PFS) to 13.1 months, a highly significant increase over a PFS of 4.6 months with gemcitabine/carboplatin, reported Caicun Zhou, MD, of Tongji University in Shanghai, at the 35th ESMO Congress, held October 8-12 in Milan, Italy.¹

The study, which included a population expected to be sensitive to inhibitors of the epidermal growth factor receptor (EGFR), was the first trial to compare erlotinib head-to-head with a platinum doublet regimen. Investigators screened 549 patients with NSCLC for EGFR-activating mutations, requiring that patients have exon 19 deletions or exon 21 point mutations, as these genetic variations are associated with particular sensitivity to anti-EGFR agents. They randomly assigned 165 patients to receive erlotinib (150 mg/d) or gemcitabine (1,000 mg/m²) plus carboplatin (AUC 5), which is standard first-line treatment for NSCLC in China.

Consistent Benefit

In the intent-to-treat analysis, erlotinib reduced the risk of progression by 84% (P < .0001) over gemcitabine/carboplatin. All subgroup analyses heavily favored erlotinib, with hazard ratios ranging from 0.13 to 0.27.

"Consistent benefit was observed regardless of histology, smoking history, age, gender, or disease stage," Dr. Zhou reported.

In addition to improvements in PFS, the erlotinib-treated patients also had a significantly higher response rate (83% vs 36%; P < .0001) and disease control rate (96% vs 82%; P = .002). The overall survival data are not yet mature.
Erlotinib was highly effective regardless of the mutation type as well, though longer PFS was observed in patients with exon 19 deletions. Baseline c-MET amplification status was not predictive of efficacy in either arm.

Safety Data

Safety data confirmed the favorable tolerability profile of erlotinib, with a lower incidence of adverse events and serious adverse events vs gemcitabine/carboplatin. However, grade 1-2 rash was observed in about 70% of patients receiving the EGFR inhibitor. Grade 3-4 rash was rare, and there were no unexpected toxicities.

After the presentation, Tony Mok, MD, who led the pivotal IPASS trial (see story here) of gefitinib (Iressa), commented from the audience that OPTIMAL was "an excellent study" that produced "an outstanding hazard ratio." He added, "Although the PFS of the control arm at 4.6 months is shorter than expected, I have no doubt that this is a significantly positive trial." ■

References

1. Zhou C, Wu Y-L, Chen G, et al: Efficacy results from the randomized phase III OPTIMAL (CTONG 0802) study comparing first-line erlotinib versus carboplatin plus gemcitabine in Chinese advanced non-small cell lung cancer patients with EGFR activating mutations. 35th ESMO Congress. Abstract LBA13. Presented October 9, 2010.

2. Maemondo M, Inoue A, Kobayashi K, et al: Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362:2380-2388, 2010.