Tumor Analyses Reveal Squamous Transformation and Off-Target Alterations As Early Resistance Mechanisms to First-line Osimertinib inEGFR-Mutant Lung Cancer

Abstract

Patterns of resistance to first-line osimertinib are not well-established and have primarily been evaluated using plasma assays which cannot detect histologic transformation and have differential sensitivity for copy number changes and chromosomal rearrangements. Experimental Design:To characterize mechanisms of resistance to osimertinib, patients with metastatic EGFR-mutant lung cancers who received osimertinib at Memorial Sloan Kettering and had next-generation sequencing performed on tumor tissue before osimertinib initiation and after progression were identified.Results: Among 62 patients who met eligibility critieria, histologic transformation, primarily squamous transformation, was identified in 15% of first-line osimertinib cases and 14% of laterline cases. Nineteen percent (5/27) of patients treated with first-line osimertinib had off-target genetic resistance (2 MET amplification, 1 KRAS mutation, 1 RET fusion, and 1 BRAF fusion) whereas 4% (1/27) had an acquired EGFR mutation (EGFR G724S). Patients with squamous transformation exhibited considerable genomic complexity; acquired PIK3CA mutation, chromosome 3q amplification and FGF amplification were all seen. Patients with transformation had shorter time on osimertinib and shorter survival compared to patients with on-target resistance. Initial EGFR sensitizing mutation, time on osimertinib treatment and line of therapy also influenced resistance mechanism that emerged. The compound mutation EGFR S768 + V769L and the mutation MET H1094Y were identified and validated as resistance mechanisms with potential treatment options. Conclusion:Histologic transformation and other off-target molecular alterations are frequent early emerging resistance mechanisms to osimertinib and are associated with poor clinical outcomes.Research.

Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer

“…Our analysis was also limited to genetic alterations detected through different assays and did not assess for nongenetic mechanisms of resistance that may additionally have a role in RET fusion-positive lung cancer. While histologic transformationdsuch as from adenocarcinoma to squamous cell or small-cell histology as identified in resistant EGFR-mutant or ALK fusion-positive lung cancer 24,25,[36][37][38][39] dwas not observed in our series, we speculate that this was likely due to the relatively low frequency of such events and a small number of cases analyzed herein. Despite these limitations, our study offers important early insights into the relative prevalence and spectrum of mechanisms of resistance to RET-selective inhibitors.…”

“…Indeed, the preponderance of resistant cases without RET resistance mutations is striking when compared with EGFR-mutant or ALK fusion-positive NSCLC, where w50%e60% of resistance to next-generation TKIs is driven by target-independent mechanisms. 25,30 This observation highlights the importance of identifying putative potentially targetable RET-independent resistance drivers, with the ultimate goal of designing new treatment approaches.…”

“…MET amplification is an established mechanism of resistance to EGFR inhibitors in EGFR-mutant NSCLC and has been identified in up to 20% of EGFR TKI-resistant biopsies. [23][24][25] Notably, a combination of EGFR and MET inhibitors, such as osimertinib plus savolitinib or osimertinib plus capmatinib, is able to effectively overcome this MET-driven resistance in clinic. 33,34 Similarly, MET amplification can mediate resistance to next-generation ALK inhibitors in ALK fusionpositive lung cancer.…”

“…MET amplification is a recurrent bypass signaling pathway across oncogenic drivers, such as in NSCLC with EGFR mutations or ALK fusions. [23][24][25][26] We identified MET amplification in three post-RET TKI cases (15%), none of which harbored a concomitant RET resistance mutation ( Supplementary Table S2, available at https://doi. org/10.1016/j.annonc.2020.09.015).…”

<p>G-MDSCs-Derived Exosomal miRNA-143-3p Promotes Proliferation via Targeting of ITM2B in Lung Cancer</p>

“…Lung cancer is a major cause of cancer-related mortality. 1 The progression of lung cancer is closely associated with immune factors and the tumor microenvironment and involves suppression of immune protection. Myeloid-derived suppressor cells (MDSCs) are heterogeneous immune suppressive cells of the myeloid lineage.…”