Health & Medical Cancer & Oncology

Advanced NSCLC With EGFR Mutations

Advanced NSCLC With EGFR Mutations

Second-generation, Irreversible EGFR TKIs


The second-generation of EGFR TKIs have the advantage of forming covalent, irreversible bonds with the target, which should increase their effectiveness through a prolonged inhibition of EGFR signaling. It is hypothesized that the prolonged and irreversible inhibition of the receptor has the potential for further improvement in response to treatment over the first-generation TKIs such as erlotinib and gefitinib. In particular, in preclinical studies irreversible TKIs effectively killed cells with acquired resistance to first-generation TKIs. Several irreversible oral TKIs that target simultaneously multiple members of the EGFR family are currently in clinical development for NSCLC, including afatinib, dacomitinib and neratinib.

Afatinib


The activity of afatinib as first- or second-line therapy for NSCLC patients with tumors harboring EGFR mutations was evaluated in a Phase II single-arm study (LUX-LUNG 2). Response rate was 61%, with a disease control rate of 82%. Median PFS was 10.1 months. The LUX-LUNG 3 trial was an open-label, randomized, Phase III trial comparing afatinib versus cisplatin/pemetrexed as first-line therapy for 345 patients (from North and South America, Europe, Asia and Australia) with advanced adenocarcinoma of the lung harboring EGFR mutations. Afatinib significantly prolonged PFS as compared with chemotherapy (11.1 vs 6.9 months; HR: 0.58; 95% CI: 0.43–0.78; p = 0.001). In 308 patients with common mutations (Del19/L858R), PFS with afatinib was 13.6 months (HR: 0.47; 95% CI: 0.34–0.65; p = 0.001). Moreover, treatment with afatinib was associated with a delay in worsening of lung cancer-related symptoms and improvement in quality of life. These findings were confirmed by the LUX-LUNG 6 study that compared afatinib with cisplatin/gemcitabine in 364 Asian patients with advanced adenocarcinoma of the lung and EGFR mutation. Afatinib significantly improved PFS (11 vs 5.6 months; HR: 0.28; p < 0.0001), response rate (66.9 vs 23.0%; p < 0.0001) and disease control rate (92.6 vs 76.2%; p < 0.0001) as compared with chemotherapy. Moreover, significantly higher number of patients had improvement of cough (p < 0.0003), dyspnea (p < 0.0001) and pain (p = 0.003) with afatinib than with chemotherapy. Finally, a randomized Phase IIb clinical study (the LUX-LUNG 7 study) is evaluating in a head-to-head comparison whether afatinib is better than gefitinib in terms of PFS as first-line therapy of 264 patients with EGFR mutation: the study will have the power to detect a 0.73 HR (corresponding to an improvement in PFS from 10 to 13.7 months) (ClinicalTrials.gov identifier: NCT01466660).

Dacomitinib


Dacomitinib showed antitumor activity in patients with progressive NSCLC after treatment with an EGFR TKI and one or more chemotherapy regimens, and this represented the background to test its potential utility in earlier lines of therapy. A randomized Phase II study compared dacomitinib with erlotinib in 188 patients with advanced NSCLC (30 of whom EGFR mutation positive) pre-treated with one or two prior chemotherapy regimens. PFS (primary end point) was 2.86 months for patients treated with dacominitib and 1.91 months in the erlotinib arm (HR: 0.66; 95% CI: 0.47–0.91; p = 0.012). Median OS was longer for patients treated with dacomitinib than erlotinib, although this difference was not statistically significant (9.53 vs 7.44 months; HR: 0.80; 95% CI: 0.56–1.13; p = 0.205). However, in the small subgroup of patients harboring EGFR mutation, median PFS was 7.44 months for both dacomitinib and erlotinib (HR: 0.46; 95% CI: 0.18–1.18; p = 0.098). A large randomized Phase III clinical study (the ARCHER 1050 study) is comparing dacomitinib and gefitinib in 440 patients with advanced NSCLC and EGFR exon 19/21 mutations. Primary end point is PFS (ClinicalTrials.gov identifier: NCT01774721).

Neratinib


Neratinib has been studied in a Phase II trial to assess the response rate in specific groups of NSCLC patients thought likely to benefit from an irreversible EGFR TKI: patients previously benefiting from first-generation TKI therapy who developed acquired resistance after at least 12 weeks of treatment (arm A if they were EGFR mutation positive or arm B if they were wild-type) and TKI-naïve patients (arm C) with clinical characteristics predicting TKI response (adenocarcinoma and light smoking histories). The response rate was 3% in arm A and 0% in arms B and C. No patients with known T790M responded. Of note, three of four patients with an exon 18 G719X EGFR mutation had a partial response and the fourth had stable disease lasting 40 weeks. The authors supposed that the low activity of neratinib was probably due to insufficient bioavailability related to diarrhea-imposed dose limitation.

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