Is the third generation EGFR TKIs the solution for making EGFR mutant NSCLC a curable disease?

Much promise and encouragement has been linked to the treatment of patients with advanced NSCLC harboring EGFR mutations. The first generation EGFR TKIs (e.g., erlotinib/gefitinib) gave promise as single agent therapy in the first-line setting (1). The second generation EGFR TKI with covalent irreversible binding to the receptor and with the potential to target heterodimers of the Erb-B receptors gave further promise regarding response, progression-free survival and overall survival, particularly in patients with exon 19 deletions (2-4). However, while significant improvement in outcome was achieved with these agents, no reports on cure have yet been seen! The main reason for that is the development of acquired resistant abnormalities with the most common resistant mechanism the development of T790M mutations (5). Most recently we learned about the third generation EGFR TKIs, which are designed to target the activating EGFR mutations as well as the resistance T790M mutation. AZ 9291 is one of these third generation EGFR TKIs and the results from the phase I/II study in patients with advanced NSCLC with EGFR Mutation and acquired resistance was presented at ASCO Annual Meeting 2014 by Dr. Janne et al. with very promising efficacy results in patients with T790M mutations (RSP: 64% and DCR: 94%) (6). The drug was well tolerated without any serious side effects. As a matter of fact, the new generation EGFR TKIs spares the EGFR wild type and, therefore, the patients will not suffer from the “traditional” EGFR side effects such as skin rash, diarrhea, hypomagnesemia, etc. Thus, much improvement has been achieved in this particular subgroup of advanced NSCLC patients. The current question is whether this therapy is enough to achieve long-term remissions and eventually cure by itself? Another question is of course whether the new generation EGFR TKIs is better than the previous generations in first-line therapy? A crucial element in this discussion is the fact that T790M mutations are not the only resistant mechanism. Several other mechanisms have been identified and more mechanisms for resistance to EGFR TKIs are expected to be learned in the future. Among already well known resistant mechanisms are activation of the MET pathway, transition to small cell carcinoma morphology, and based on preclinical data a possible role of FGFR, Mer and Axl as part of the acquired resistance to EGFR TKIs (5,7). Thus, while the development of the new generation EGFR TKIs represent a significant achievement in the fight for “curable” EGFR mutant tumors, most likely a partnership with other agents will be needed in order to achieve the goal.

Acknowledgements

Disclosure: The author declares no conflict of interest.

References

1. Hirsch FR, Jänne PA, Eberhardt WE, et al. Epidermal growth factor receptor inhibition in lung cancer: status 2012. J Thorac Oncol 2013;8:373-84. [PubMed]
2. Katakami N, Atagi S, Goto K, et al. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol 2013;31:3335-41. [PubMed]
3. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31:3327-34. [PubMed]
4. Yang JC, Sequist LV, Schuler MH, et al. Overall survival (OS) in patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring common (Del19/L858R) epidermal growth factor receptor mutations (EGFR mut): Pooled analysis of two large open-label phase III studies (LUX-Lung 3 [LL3] and LUX-Lung 6 [LL6]) comparing afatinib with chemotherapy (CT). ASCO Meeting Abstracts 2014;32:8004.
5. Cortot AB, Jänne PA. Molecular mechanisms of resistance in epidermal growth factor receptor-mutant lung adenocarcinomas. Eur Respir Rev 2014;23:356-66. [PubMed]
6. Janne PA, Ramalingam SS, Yang JC, et al. Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor-resistant non-small cell lung cancer (NSCLC). ASCO Meeting Abstracts 2014;32:8009.
7. Ware KE, Hinz TK, Kleczko E, et al. A mechanism of resistance to gefitinib mediated by cellular reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop. Oncogenesis 2013;2:e39. [PubMed]