A phase 2 trial of dacomitinib (PF‐00299804), an oral, irreversible pan‐HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non–small cell lung cancer after failure of prior chemotherapy and erlotinib

Abstract

BACKGROUNDThis phase 2 trial (ClinicalTrials.gov identifier NCT00548093) assessed the efficacy, safety, and impact on health‐related quality of life of dacomitinib (PF‐00299804), an irreversible tyrosine kinase inhibitor (TKI) of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, in patients with KRAS wild‐type non–small cell lung cancer (NSCLC).METHODSPatients with advanced NSCLC, progression on 1 or 2 regimens of chemotherapy and erlotinib, KRAS wild‐type or known EGFR‐sensitizing mutant tumor, and Eastern Cooperative Oncology Group performance status of 0 to 2 received 45 mg of dacomitinib once daily continuously in 21‐day cycles.RESULTSA total of 66 patients enrolled (adenocarcinoma, n = 50; those without adenocarcinoma [nonadenocarcinoma], n = 16). The objective response rate (ORR) for patients with adenocarcinoma (primary endpoint) was 5% (2 partial responses; 1‐sided P = .372 for null hypothesis [H0]: ORR ≤ 5%) and 6% (1 partial response) for patients with nonadenocarcinoma. Responders included: 2 of 25 EGFR mutation‐positive tumors; 1 of 3 EGFR wild‐type with HER2 amplification. Median progression‐free survival was 12 weeks overall (n = 66) and 18 weeks (n = 26) for patients with EGFR mutation‐positive tumors. Common treatment‐related adverse events were of grade 1 or 2 severity, manageable with standard supportive care, and included diarrhea (grade 3 [G3], 12%), acneiform dermatitis (G3, 6%), exfoliative rash (G3, 3%), dry skin (G3, 0%), fatigue (G3, 3%), and stomatitis (G3, 2%). Six patients (9%) discontinued due to treatment‐related adverse events. By patient report, NSCLC symptoms of dyspnea, cough, and pain (chest, arm/shoulder) showed improvement first observed after 3 weeks on therapy.CONCLUSIONSDacomitinib demonstrated preliminary activity and acceptable tolerability in heavily pretreated patients, and may offer benefit in molecularly defined patient subsets. Cancer 2014;120:1145–1154. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Gastrointestinal toxicities of first and second-generation small molecule human epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer

“…Dacomitinib has shown significant therapeutic efficacy in NSCLC, specifically to tumours that have not previously responded to conventional single receptor inhibitors, and also against tumours with mutations developed for acquired resistance of targeted therapies [37][38][39]. Dacomitinib is currently in phase III clinical trials, and the most commonly reported adverse event among all trials has been diarrhoea, commonly resulting in dose reductions and patient withdrawal from clinical trials [38,39,[42][43][44] (Table 3).…”

Biomarkers in Lung Adenocarcinoma: A Decade of Progress

“…39,61,62 Acquired PIK3CA mutations have been described in 5% of relapsed lung ACAs, 31 but are also seen in concert with EGFR (and other driver gene) mutations in untreated samples. 63 The mechanisms underpinning a morphologic transformation to small cell carcinoma are unknown.…”

10-year long-term survival of a metastaticEGFR-mutated nonsmall cell lung cancer patient

“…Second generation EGFR TKIs, such as afatinib and dacomitinib, failed to overcome significant acquired resistance to erlotinib and gefitinib [7]. CO1686 and AZD9291 are third generation EGFR TKI which can irreversibly bind to EGFR sensitising mutations, as well as the acquired T790M mutation, with high selectivity as compared to wild-type EGFR [8].…”