Irreversible EGFR inhibitors: clinical data

EGFR inhibitors, such as gefitinib and erlotinib, are used widely in the treatment of advanced non-small cell lung cancer (NSCLC) in both first and subsequent lines of treatment. However, de-novo or acquired resistance limits the efficacy of these agents. Irreversible inhibitors of the EGFR have been developed in an attempt to limit the impact of resistance, especially that caused by the exon 20 T790M mutation. Clinical data are available for several irreversible EGFR tyrosine kinase inhibitors, including EKB 569, neratinib, canertinib, afatinib, and PF299804. However, only afatinib and PF299804 are continuing to undergo development in NSCLC and further discussion will be limited to these drugs. Afatinib (BIBW2992) is an irreversible inhibitor of both EGFR and Her2 tyrosine kinases. In a phase 2 study carried out in Taiwan and the USA, afatinib was evaluated in patients whose tumors were known to have an activating EGFR mutation, and who were either chemo-naïve or had previously received one line of chemotherapy. The primary endpoint of this open label, single arm study was response rate (RR), with secondary endpoints that included progression free survival (PFS), overall survival (OS), safety, and clinical benefit. Treatment was with afatinib 50 mg daily, but a high rate of dose reductions for adverse events resulted in this being reduced to 40 mg daily for the final 30 patients in the trial. 129 patients were accrued, 68 of whom were chemo-naive. The CR + PR rate was 61%, and the CR + PR +SD rate was 86%. Median PFS was 13.9 and 10.5 months in the first and second line settings respectively. Common toxicities included diarrhea, rash and nail changes. Following on from these results, two phase 3 studies are underway evaluating afatinib as first line therapy in patients with stage 3B or 4 adenocarcinoma and activating EGFR mutations. The first is an open label study comparing afatinib (40 mg daily) to chemotherapy with cisplatin and pemetrexed, with a primary endpoint of progression free survival. This study completed accrual in early 2011, and results are awaited. The other is a study of similar design which is still accruing patients, using cisplatin and gemcitabine as the chemotherapy comparator. Afatinib has been evaluated in a double blind, placebo controlled phase 3 study in patients with stage 3B or 4 adenocarcinoma of the lung who had progressed following treatment with 1 or 2 lines of chemotherapy (including a platinum) and at least 12 weeks of treatment with erlotinib or gefitinib. The primary endpoint of the study was OS, with PFS, response, quality of life and safety as secondary endpoints. 585 patients were randomised to afatinib or placebo (2:1 in favour of afatinib) between 5/2008 and 9/2009. Median OS was similar in both arms (placebo 11.9 months, afatinib 10.7 months, HR 1.07, p=0.74) despite a better RR (13% vs. 0.5%), and better PFS (3.3 vs. 1.1 months) in the afatinib treated patients. Unexpectedly, for a population that had received 2 or 3 lines of treatment prior to study entry, 60 to 70% of patients had chemotherapy subsequent to study treatment, and this may have confounded the survival results. In a sub-group analysis, those patients whose tumors were likely to have had EGFR mutations based on clinical features (CR/ PR and or duration of >48weeks with prior EGFR TKI) seemed to derive more benefit from afatinib. However, the results of EGFR mutation analysis will be required to understand these observations. Ongoing studies with afatinib are evaluating its role in tumors with Her2 overexpression, and the benefit of continuing afatinib beyond the time of objective progression, in combination with chemotherapy, in patients who have had prior chemotherapy and EGFR TKIs. PF299804 is an irreversible inhibitor of EGFR, Her2, and Her4, with clinical data available in the 1st line, 2nd / 3rd line, and refractory (post EGFR TKI) settings. In a phase 2 study untreated patients with advanced adenocarcinoma were clinically selected (never or light ex smokers, Asian, or non Asian but K-Ras wild type). 74 patients were enrolled between 3/2009 and 5/2010 and treated with PF299804 at 45 mg daily (later modified to a starting dose of 30 mg daily with dose escalation if tolerated). EGFR mutations occurred in 34 of 42 (81%) patients with available samples. Overall RR was 42% in all patients and 55% in those with known EGFR mutations. PFS data remain immature. Common toxicities included rash, diarrhea, hand foot syndrome and stomatitis. PF299804 has also been compared to erlotinib in a randomized phase 2 study in patients who had received 1 or 2 lines of prior chemotherapy, but not otherwise selected. The primary endpoint was PFS. 188 patients were randomized between 10/2008 and 11/2009. Median PFS was 12.4 months in the PF299804 arm and 8.3 months in the erlotinib arm (HR 0.68, p=0.019), while response rates were 17% and 4% in these arms respectively. EGFR mutations were present in 20% in the PF299804 arm and 12% in the erlotinib arm. Toxicities were similar to those observed in other PF299804 studies, though rash and diarrhea were more common than with erlotinib. Patient reported outcomes indicate that these toxicities were tolerable and improved over time. In the refractory setting, data are available from two phase 2 studies, one performed in Korea, the other in the USA. Both included patients who had previously been treated with at least one line of chemotherapy as well as erlotinib or gefitinib, and whose tumours were either K-Ras wild type or EGFR mutant. In the Korean study, amongst 43 patients a RR of 17% was observed, with median PFS of 15 weeks. In the US study, amongst 66 patients RR was 5%, with PFS of 11 and 19 weeks in the absence and presence of an EGFR mutation respectively. In both studies, patient reported outcomes indicate that adverse effects did not have a major impact on patients, and that some disease related symptoms may have improved with treatment. A double blind phase 3 study (NCIC BR26) comparing PF299804 to placebo in patients who have progressed following 1 or 2 lines of chemotherapy as well as erlotinib or gefitinib is currently accruing.