Byoung Chul Cho, MD, PhD
Dacomitinib holds promise for the treatment of metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN), according to a phase II clinical trial presented at the 2014 AACR Annual Meeting. The study found that response was associated with two factors: no defects in PI3K signaling and no sign of excessive inflammation.
Investigators acknowledged that this is a phase II study and that results need to be confirmed in phase III clinical trials. They plan to optimize chances of success by enrolling patients in phase III according to biomarker data found in phase II— no alterations in the PI3K pathway and no over-expression of proinflammatory cytokines, explained lead author Byoung Chul Cho, MD, PhD, associate professor, Yonsei Cancer Center, Seoul, the Republic of Korea.
Dacomitinib is an irreversible pan-HER kinase inhibitor that blocks the activity of HER1/EGFR, HER2, and HER4. Most SCCHNs express elevated levels of EGFR, suggesting that this drug will work, Cho said.
The phase II trial enrolled 48 patients who had recurrent and/or metastatic SCCHN despite treatment with platinum-containing chemotherapy. Patients received 45 mg of oral dacomitinib once daily.
Response assessed according to RECIST criteria showed that 10 patients (21%) had a partial response and 31 patients had stable disease (65%). After a median follow-up of 8.4 months, median progression- free survival (PFS) was 3.9 months and median overall survival was 8.2 months.
Genetic analysis of tumor samples identified markers associated with response. These included mutations in either PIK3CA or PTEN, which were associated with lower PFS. Median PFS in patients with these mutations was 2.5 months versus 5.4 months in patients without them (P
= .013). Further, two patients lacking these mutations had a median PFS of 13.1 months and 18.9 months, respectively.
PFS was also worse in patients with high levels of expression of genes linked to inflammation, including IL6, IL8, PTGS2, and PLA2G2A, versus those with low levels. Median PFS was 1.9 months versus 6.8 months, respectively (P
= .001). Patients with low gene expression of these cytokines tended to have higher response rates (overall response rate = 40% vs 0% for those with high expression) and unusually long durations of response (18.9 months vs 5.4 months, respectively).
“If our results are confirmed in phase III clinical trials, dacomitinib could provide a new targeted treatment option for a disease for which new therapies are desperately needed,” Cho said in a press release. “We are conducting further biomarker analysis to better define patients most likely to respond.”
Dacomitinib has also been examined in lung cancer, but has not had success in late-stage studies. Two phase III trials investigating dacomitinib were unable to meet their primary endpoints. In the first of these trials, ARCHER 1009, dacomitinib failed to improve PFS compared with erlotinib (Tarceva) in the second- and third-line setting for patients with non–small cell lung cancer. Notably, EGFR status was not in the inclusion criteria for this trial. In the second study, NCIC CTG BR.26, dacomitinib failed to improve OS versus placebo in patients with advanced NSCLC following progression on standard therapies, including EGFR inhibitors.
The ongoing phase III ARCHER 1050 trial is comparing dacomitinib with gefitinib (Iressa) as a first-line treatment for patients with EGFRpositive advanced NSCLC. The primary outcome measure is PFS.
Kim HS, Kwon HJ, Ahn MJ, et al. A phase II and biomarker study of an irreversible pan-human EGF receptor (HER) tyrosine kinase inhibitor, dacomitinib, in patients with recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M-SCCHN). Presented at: 2014 AACR Annual Meeting; April 5-9, 2014; San Diego, CA. Abstract CT229.