Abstract 2781: De novo molecular mechanisms of resistance to mobocertinib
Authors: Vincent Sylvie , Su Zhenqiang , Joshi Adarsh , Penta Kalyani , Zhang Pingkuan 
Published: June 2022

Mobocertinib is an oral tyrosine kinase inhibitor recently approved by the FDA for the treatment of patients (pts) with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations who have progressed on or after platinum-based chemotherapy. To understand the impact of co-occurring genetic alterations on the therapeutic response to mobocertinib, tumors from a subset of 72 platinum-pretreated pts with EGFR exon 20 insertions from the phase 1/2 study (NCT02716116) were collected before treatment and analyzed by next-generation sequencing. More than 200 co-occurring hotspot genetic alterations were detected in 43 pts, with some alterations detected with greater than 20% frequency, such as PTCH1 (67%), HNF1A (58%), TP53 (58%), and GNAQ (35%). In addition to EGFR exon 20 insertion mutations, co-occurring EGFR substitutions were also observed in the exon 20 loop following the C-helix (amino acid positions 770, 771, 772) in 4 pts and L858Q in 1 pt. The pt with the L858Q mutation had a confirmed partial response as assessed by an independent review committee, while the 4 pts with exon 20 substitutions were non-responders (2 had stable disease and 2 had progressive disease as best response). An abnormally high level of mutational burden was seen in 4 pts with EGFR exon 20 insertions, along with alterations in the mismatch repair gene MSH6 and/or the elongation factor MLLT3. Association analysis of mutations reported increased odds of association between the presence of PIK3CA, TP53, and EGFR alterations and a lack of mobocertinib response. Gene amplifications were observed in 12 pts (16%) affecting EGFR (6 pts), MYC (4 pts), CDK4 (3 pts), and CCND1 (2 pts). When assessed for association with lack of response (P values from the Fisher exact test), odds ratios were 2.47 (P=0.66) and 6.34 (P=0.085) for EGFR amplification and any-gene amplification, respectively. When combined, the presence of either PIK3CA mutations or any-gene amplification was associated with a lack of response to mobocertinib treatment with an odds ratio of 12.93. Following adjustment for selected clinical covariates in a multivariate model, the presence of either PIK3CA mutation or gene amplification was an independent predictor of lack of response to mobocertinib (P value of 0.047). Given the retrospective nature of these analyses and the insufficient control of statistical multiplicity, this finding should be considered exploratory. These data suggest that intrinsic genetic alterations, present at baseline in patients with NSCLC harboring an EGFR exon 20 insertion mutation, might impact the response to mobocertinib treatment. The presence of PIK3CA mutations, EGFR gene amplification, or cell cycle regulator MYC-CDK4-CCND1 amplification is associated with lack of response to mobocertinib, which might guide rational combinations for future clinical investigation.

Citation Format: Sylvie Vincent, Zhenqiang Su, Adarsh Joshi, Kalyani Penta, Pingkuan Zhang. De novo molecular mechanisms of resistance to mobocertinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2781.