Investigators are reporting improved progression-free survival (PFS) after treatment with the investigational agent dacomitinib compared with erlotinib in patients with non–small cell lung cancer (NSCLC) experiencing progression during chemotherapy.
Erlotinib, which targets a single member of the HER family, inhibits signaling through competitive, reversible binding at the EGFR tyrosine kinase domain. The pan-HER inhibitor dacomitinib binds irreversibly to the adenosine triphosphate domain of all three kinase-active members of the HER family: EGFR, HER2, and HER4.
Suresh S. Ramalingam, MD, chief of the Thoracic Oncology Division at Emory University in Atlanta, Georgia, and coworkers randomized 188 patients to receive either 45 mg of oral dacomitinib or 150 mg of oral erlotinib once daily. In addition to having had no prior HER-directed therapy, patients enrolled in the phase II study had an ECOG performance status of 0 to 2 and had received one or two prior chemotherapy regimens. The primary endpoint of the study was PFS.
The study found that the median PFS w as 2.86 months in the dacomitinib arm versus 1.91 months in the erlotinib group (hazard ratio [HR] = 0.66; 95% CI, 0.47- 0.91; two-sided P = .012).
An improvement in PFS was noted in most clinical and molecular subgroups (Table). In patients with KRAS wild-type tumors, the median PFS was 3.71 months and 1.91 months for the dacomitinib and erlotinib treatment arms, respectively (HR = 0.55; 95% CI, 0.35-0.85; two-sided P = .006). Patients with KRAS wild-type/EGFR wild-type tumors receiving dacomitinib had a median PFS of 2.21 months compared with 1.84 months for patients treated with erlotinib (HR = 0.61; 95% CI, 0.37-0.99; two-sided P = .043).
Median overall survival was similar in the dacomitinib and erlotinib groups: 9.53 months in patients treated with dacomitinib and 7.44 months in patients who received erlotinib (HR = 0.80; 95% CI, 0.56-1.13; two-sided P = .205).
Treatment-related adverse events were more common with dacomitinib, primarily grade 1 and 2, and frequently involved skin and gastrointestinal events.
“The results documented here for dacomitinib suggest that irreversible pan-HER inhibition may offer a new treatment option for patients with advanced NSCLC, potentially representing an effective alternative to reversible inhibition of EGFR,” Ramalingam et al wrote.
The researchers suggested that the superior outcomes with dacomitinib might be due to its mechanism of action, “which potentially includes more complete inhibition of HER signaling by receptor homoand heterodimerization through targeting of all three kinase-active HER receptors and permanent blockade of signaling by covalent receptor modification.”
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. 2012;30(27):3337-3344.
http://cancerfocus.org/forum/showthread.php?t=842
While Tarceva "reversibly" binds to EGFR (Her1), Afatinib "irreversibly" binds to EGFR (Her1) and EGFR type 2 (Her2), preventing their activation and hopefully inhibiting the unwanted signaling pathways. While Dacomitinib binds irreversibly to the domains of all three kinase-active members of EGFR (Her1), EGFR type 2 (Her2) and EGFR type 4 (Her4).
However, the AngioRx Assay for anti-angiogenic agents has assessed previously unanticipated direct and potentiating anti-angiogenic effects of targeted therapy drugs such as Tarceva (and Iressa) at the tyrosine kinase level.