SC04.03 Sequencing of EGFR Tyrosine Kinase Inhibitors

Abstract

Treatment of EGFR-mutant (EGFRm) lung cancer with specific EGFR TKIs, such as gefitinib, erlotinib or afatinib, has opened the door to the precision medicine in the management of advanced non-small cell lung cancer with remarkable tumor shrinkage and improvement in progression-free survival (PFS) and quality of life compared to standard chemotherapy. Despite such a remarkable initial clinical response with EGFR TKIs in patients with EGFR+ NSCLC, however, the disease eventually comes back with the emergence of acquired resistance and median PFS is ∼ 1 year. The most common mechanism of resistance is acquisition of the T790M gatekeeper mutation and the 3rd-generation EGFR TKIs irreversibly inhi bit mutant EGFR, esp. T790M, with sparing wild-type(WT) EGFR. There are several EGFR mutant specific inhibitors (EMSIs) under development including AZD9291, CO-1686, BI1482694 /HM61713, ASP8273, etc. All these 3rd-generation EGFR TKIs have shown a promising early clinical efficacy in T790M(+) EGFRm NSCLC patients with ORR of ca. 60% and PFS of 9.6 – 10.3 months and appear to be well tolerated. Based upon these encouraging early results many confirmatory phase 3 trials(e.g., NCT02151981, NCT02322281) comparing to the standard chemotherapy in the 2nd-line setting are underway. It is very tempting that one might like to move the 3rd-generation EGFR TKI to 1st-line setting. The development of the 3rd-generation agents as the first-line therapy for patients with EGFRm disease has already started. Recently AZD9291 demonstrated an encouraging clinical activity and a manageable tolerability profile in 1st-line: confirmed objective response rate of 77% (95% CI 64, 87) and mPFS of 19.3 months (investigator-assessed). Currently it is being compared with the 1st/2nd-generation EGFR TKI in the 1st-line setting. The Phase III FLAURA study (NCT02296125), comparing AZD9291 80 mg once daily versus current standard of care EGFR-TKIs for treatment-naïve patients, is enrolling. Though the preliminary result in the 1L setting is quite provocative, extreme caution needs to be exerted since the currently available data are not mature enough to determine which agent is the best in its class and only from a small subset of patients. Though it is hoped that the T790M-mediated resistance can be delayed or prevented by using the EMSIs in the TKI-naïve setting, it is also possible that other less well known escape mechanisms might emerge. Given that EMSI works well after failing 1st/2nd-generation EGFR TKI I believe it seems to be a more reasonable approach to investigate if EMSI in the TKI-naïve setting is more effective than 1st/2nd-generation EGFR TKI followed by EMSI when failing 1st/2nd-generation EGFR TKI with acquired resistance. One of the biggest questions to emerge in the era of next-generation inhibitors that have activity against the basic driver oncogene is whether it makes sense to use this approach before the development of acquired resistance to prevent it from occurring in the first place. Can its use in the 1st-line(TKI-naïve) setting prevent the development of acquired resistance and lead to a longterm control of the disease? Considering the well-known genomic heterogeneity with its possible association with resistance to EGFR TKIs we need better understanding of the biology and resistance mechanisms to this class of new generation EGFR TKIs in order to develop better strategies for subsequent therapies to overcome the resistance including how to best sequence the available EGFR TKIs in the clinic as well as combination therapies. It is fair to say that during the past few years we’ve clearly made another progress in the management of NSCLC patients with EGFRm, including those who failed previous EGFR TKIs. However, the currently available data are not mature enough to determine which agent is the best in its class, with the notable differences primarily related to toxicity and we’re not there yet and still lots of unanswered questions remain and further researches are warranted. 1. DR Camidge, et al. Acquired resistance to TKIs in solid tumors: learning from lung cancer. Nat Rev Clin Oncol 2014;11: 473-481. 2. SS Ramalingam, et al. The Next Generation of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in the Treatment of Lung Cancer. Cancer 2015;121:E1-E6. 3. GR Oxnard et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M. Nature Med 2015;21:560-564. 4. LV Sequist et al. Heterogeneity Underlies the Emergence of EGFR T790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor. Cancer Discov 2015;5(7): 713-22. 5. CM Lovly et al. Shades of T790M: Intratumor Heterogeneity in EGFR -Mutant Lung Cancer. Cancer Discov 2015;5(7): 694-6. 6. S Ramalingam, et al. ELCC 2016; Abstract LBA1_PR. EGFR TKI, Resistance, Sequence