The most common grade 3 adverse events with afatinib were diarrhea (14.4%), rash (16.2%), stomatitis/mucositis (8.3%) and paronychia (11.4%), with one case of grade 4 stomatitis/mucositis (0.4%). There were four deaths related to afatinib.
The duration of treatment likely had an impact on adverse events, as patients received 16 cycles of afatinib (median, 336 days) vs. just 6 cycles of chemotherapy, Dr. Yang pointed out. Drug-related adverse events leading to discontinuation were reported in 7.9% of patients who were given afatinib and in 11.7% of those given cisplatin plus pemetrexed chemotherapy.
Acquired Resistance Anticipated
Finally, Dr. Solomon said that "as impressive as the progression free survival seen with afatinib is ... all these patients eventually develop acquired resistance." He highlighted a recent study in which the T790M secondary mutation was implicated as a mechanism of acquired resistance to second-generation irreversible TKI inhibitors in a clinical case and in an in vitro cell culture model (Mol. Cancer Ther. 2012;11:784-91).
Patrice Wendling/IMNG Medical Media
Benjamin Solomon, Ph.D.
"While the mechanisms of resistance may not completely overlap with the mechanisms of resistance due to first-generation inhibitors, we know at least in the case of afatinib and also dacomitinib [Pfizer] that T790M, potentially in association with amplification of the EGFR gene, is in part responsible," he said. This may be particularly troublesome in the clinical setting, "where it’s probably difficult to achieve high-enough concentrations of afatinib to inhibit T790M."
Dr. Yang reported serving as a consultant or advisor and receiving honoraria from Boehringer Ingelheim, the study sponsor. Several coauthors had financial relationships with firms including Boehringer Ingelheim. Dr. Solomon reports serving as a consultant or advisor to AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Lilly, Pfizer, and Roche.
* This story was updated 6/29/2012.