Phase II Study Suggests Advantage of Irreversible Pan-HER Inhibition in Advanced NSCLC


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Dacomitinib is a new tyrosine kinase inhibitor that forms irreversible covalent bonds with the ATP domain of each of the three kinase-active members of the HER family—EGFR/HER1, HER2, and HER4. Agents such as erlotinib (Tarceva) and gefitinib (Iressa), which are of proven benefit in advanced non–small cell lung cancer (NSCLC), are reversible tyrosine kinase inhibitors that selectively target EGFR/HER1 through competitive binding at the tyrosine kinase domain. In preclinical studies, dacomitinib showed greater HER kinase inhibition and antitumor activity than these agents in sensitive and resistant cell lines and in NSCLC xenograft models.

A randomized phase II trial recently reported by Ramalingam and colleagues in Journal of Clinical Oncology suggests that dacomitinib may have greater activity than erlotinib in advanced NSCLC.1 The trial is the first to directly compare an irreversible pan-HER tyrosine kinase inhibitor with a reversible EGFR-selective tyrosine kinase inhibitor.

Baseline Imbalances

In the phase II study, 188 patients with advanced NSCLC who had progressed after one or two chemotherapy regimens for advanced disease and had received no prior EGFR-targeted therapies received dacomitinib at 45 mg (n = 94) or erlotinib at 150 mg (n = 94) once daily.

Although treatment groups were well balanced for most baseline characteristics, there were some imbalances that may have contributed to differences in study outcomes. A higher proportion of dacomitinib-treated patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 vs 0, 1 (20% vs 3%) and had received two prior chemotherapy regimens (40% vs 29%). Further, there were some imbalances in mutation distribution, notably a greater proportion of KRAS wild-type (any EGFR mutation status) tumors in the erlotinib group and a greater proportion of EGFR mutant tumors (against which EGFR inhibitors have greater activity) in the dacomitinib group.

Overall, KRAS mutational status in the dacomitinib group was wild-type in 61%, mutant in 18%, and unknown in 21%, and that status in the erlotinib group was 68%, 15%, and 17%, respectively. EGFR mutational status in the dacomitinib group was wild-type in 62%, mutant in 20%, and unknown in 18%, and that in the erlotinib group was 69%, 12%, and 19%, respectively.

Progression-free Survival Improvements

Overall, median progression-free survival—the primary outcome measure—was significantly prolonged in the dacomitinib group (2.86 vs 1.91 months), with a hazard ratio [HR] of 0.66 (95% confidence interval [CI] = 0.47–0.91, P = .012) based on a stratified log-rank test with EGFR mutation status, KRAS mutation status, and ECOG performance status as stratification factors. The unadjusted hazard ratio in the total population was 0.66 (P = .009).

The improvement in progression-free survival with dacomitinib was observed across most clinical and molecular subgroups. In patients with KRAS wild-type/EGFR any status tumors, median progression-free survival durations were 3.71 months with dacomitinib and 1.91 months with erlotinib (HR = 0.55, 95% CI = 0.35–0.85, P = .006). In those with KRAS wild-type/EGFR wild-type tumors, median progression-free survival durations were 2.21 months and 1.84 months, respectively (HR = 0.61, 95% CI = 0.37–0.99, P = .043). Progression-free survival hazard ratios for dacomitinib vs erlotinib in molecular subgroup comparisons were 0.99 (95% CI = 0.45–2.17) in the KRAS mutant subgroup, 0.70 (95% CI = 0.47–1.05) in the EGFR wild-type subgroup, and 0.46 (95% CI = 0.18–1.18) in the EGFR mutant subgroup.

The objective response rate was higher with dacomitinib (17.0%, including one complete response, vs 5.3%, P = .011), as were clinical benefit rate (response plus stable disease ≥ 24 weeks, 29.8% vs 14.9%, P = .014) and median duration of response (16.56 months, range = 3.15–23.95+ months, vs 9.23 months, range = 5.69–16.58 months).

An analysis of median overall survival (performed after 80% of patients had died) showed a nonsignificant increase with dacomitinib (9.53 vs 7.44 months, HR = 0.80, 95% CI = 0.56-1.13, P = .205) on a stratified log-rank test with EGFR mutation status, KRAS mutation status, and ECOG performance status as stratification factors.

More Adverse Events

The greater apparent activity of dacomitinib was accompanied by higher rates of adverse events expected with EGFR tyrosine kinase inhibitors (eg, diarrhea and skin effects), although most such adverse events were of grade 1 or 2. The most common adverse events of any grade with dacomitinib were diarrhea (73% vs 48% with erlotinib), acneiform dermatitis (65% vs 57%), and stomatitis (29% vs 11%). The most common grade 3 adverse events with dacomitinib were diarrhea (12% vs 4%) and acneiform dermatitis (11% vs 6%). One dacomitinib patient had four grade 4 adverse events, consisting of anemia, increased ALT, increased AST, and increased blood creatinine, which were considered to be drug-related. One erlotinib patient had a drug-related grade 4 adverse event (pneumonia).

Adverse events requiring treatment withdrawal and dose reductions were more common in the dacomitinib group. Among 7 dacomitinib-treated patients (7.5%) discontinuing treatment due to adverse events, 5 had grade 1 to 3 dermatologic toxicity (4 during the first month of treatment), 1 had grade 2 diarrhea, and 1 had grade 3 dehydration. Two erlotinib recipients (2.1%) discontinued treatment due to adverse events (grade 2 nausea and grade 2 malaise). Treatment-related dose reductions occurred in 40.9% of the dacomitinib group (1 reduction in 31.2%, 2 reductions in 7.5%, and 3 reductions in 2.2%) and 17% of the erlotinib group (1 reduction in all patients).

As related by the investigators, although the progression-free survival improvement with dacomitinib in the total population may have been affected by between-group baseline imbalances, the superiority of dacomitinib is strongly suggested by the significance of the between-group difference on the stratified log-rank test coupled with the significant unadjusted hazard ratio for the overall population. Further, dacomitinib’s relative benefit is indicated by the fact that subgroup results were consistently distributed around the overall hazard ratio. Additional benefit of dacomitinib was observed in the subset analysis of patients with KRAS wild-type/EGFR wild-type tumors, suggesting that the benefit of dacomitinib was not solely driven by the disproportionate number of patients with mutant EGFR in the dacomitinib group.

As stated by the authors, “[The] results raise the possibility that patients with KRAS wild-type/EGFR any status NSCLC may particularly benefit from dacomitinib…. Given the degree of benefit reported here for patients with KRAS wild-type/EGFR any status or KRAS wild-type/EGFR wild-type tumors, and the uncertainty surrounding KRAS as a predictor of response in NSCLC, there is clearly a need for prospective studies of the role of KRAS in tumor response to pan-HER inhibition.”

The phase III ARCHER 1009 trial is underway to compare dacomitinib and erlotinib as second- or third-line therapy in advanced NSCLC. The trial includes the coprimary endpoints of progression-free survival in all patients and in patients with KRAS wild-type/EGFR any status tumors to permit evaluation of dacomitinib in an unselected population and to assess the relationship between KRAS molecular status and treatment outcome. ■

Reference

1. Ramalingam SS, Blackhall F, Krzakowski M, et al: Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol 30:3337-3344, 2012.

 


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