Optimizing the Sequence of Anti-EGFR–Targeted Therapy in EGFR-Mutant Lung Cancer

Abstract

Metastatic EGFR-mutant lung cancers are sensitive to the first- and second- generation EGFR tyrosine kinase inhibitors (TKIs), gefitinib, erlotinib, and afatinib, but resistance develops. Acquired resistance (AR) to gefitinib or erlotinib occurs most commonly (>50%) via the emergence of a second-site EGFR mutation, T790M. Two strategies to overcome T790M-mediated resistance are dual inhibition of EGFR with afatinib plus the anti-EGFR antibody, cetuximab (A+C), or mutant-specific EGFR inhibition with AZD9291. A+C and AZD9291 are now also being tested as first-line therapies, but whether these therapies will extend progression-free survival or induce more aggressive forms of resistance in this setting remains unknown. We modeled resistance to multiple generations of anti-EGFR therapies preclinically in order to understand the effects of sequential treatment with anti-EGFR agents on drug resistance and determine the optimal order of treatment. Using a panel of erlotinib/afatinib-resistant cells including a novel patient-derived cell line (VP-2), we found that AZD9291 was more potent than A+C at inhibiting cell growth and EGFR signaling in this setting. 4 of 4 xenograft-derived A+C-resistant cell lines displayed in vitro and in vivo sensitivity to AZD9291, but 4 of 4 AZD9291-resistant cell lines demonstrated cross-resistance to A+C. Addition of cetuximab to AZD9291 did not confer additive benefit in any preclinical disease setting. This work, emphasizing a mechanistic understanding of the effects of therapies on tumor evolution, provides a framework for future clinical trials testing different treatment sequences. This paradigm is applicable to other tumor types in which multiple generations of inhibitors are now available.

A Phase Ib/II Study of Afatinib in Combination with Nimotuzumab in Non–Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib

“…Recently, third-generation EGFR TKI, AZD9291 and rociletinib demonstrated robust and durable response in both T790M-positive and -negative patients (43,44). Moreover, Meador and colleagues reported that secondary resistance to afatinib plus cetuximab can be overcome by AZD9291 (45). However, given the heterogeneity of T790M-negative EGFR TKI-resistant tumor, dual targeting of EGFR with afatinib plus nimotuzumab still has therapeutic option for patients who developed resistance to EGFR TKIs.…”

Liposomal curcumin and its application in cancer

“…Even so, 5-year survival rate is only 16%, though new drugs of anti-lung cancer such as angiogenesis-targeted drugs, epidermal growth factor receptor (EGFR)-targeted drugs, protein peptides of anti-lung cancer and lung cancer antibody drugs were developed. [97][98][99][100][101][102] Recently, a study reported that nanoliposomes using sodium hyaluronate and trimethyl CS form polymer-glycerosomes that can effectively deliver CUR to lung so as to improve the therapeutic index of CUR. 103 Recently, many studies reported that CUR liposomes have anticancer activity.…”

2,4-Diarylamino-pyrimidines as kinase inhibitors co-targeting IGF1R and EGFRL858R/T790M

“…10 Tyrosine Kinase Inhibitor dose-escalation investigations also suggested that sustained activation of Akt could induce insensitivity against drugs 1 and 2 in H1975 NSCLC cells. 5,11 A similar independent study demonstrated that amplification of Insulin-like Growth Factor 1 Receptor (IGF1R) was involved in over-activation of Akt. A selective IGF1R inhibitor BMS536924 (5) successfully restored the drug sensitivity to 4 in the WZ4002-Resistant (WZR) NSCLC cells, and a combination of 4 with 5 completely prevented the emergence of drug-resistant clones in the experimental system.…”

“…Significantly, a concentration of 1.0 µM of 8g resulted in complete inhibition of Akt activation, which has been demonstrated to be closely related to resistance against the 2 nd and 3 rd generation EGFR inhibitors. 5,11,12 On the other hand, compound 1 selectively inhibited the phosphorylation of EGFR L858R/T790M , while its effect on IGF1R was minor; and compound 6 strongly inhibited the activation of IGF1R, but barely affected the phosphorylation of EGFR L858R/T790M . Neither 1 nor 6 could completely suppress activation of Akt at high concentrations in H1975-IGF1R cells.…”