MA09.03 Identification of Mechanisms of Acquired Resistance to Poziotinib in EGFR Exon 20 Mutant Non-Small Cell Lung Cancer (NSCLC)

Abstract

period, DL1 was further assessed. 3 (50%) of 6 patients at DL1 experienced a DLT (grade 3 headaches and body pain, grade 3 neutropenia, grade 3 rash, one each). One patient was enrolled at DL -1 and did not have a DLT. The most common treatment-related adverse events (TRAEs) included pleural effusion (n¼9), diarrhea (n¼8), rash (n¼7), AST elevation (n¼6), ALT elevation (n¼6), most of which were grade 1 or 2. 4/4/1 patients had grade 1/2/3 pleural effusion, respectively. 7 (70%) patients had grade 3 TRAEs. No grade 4 or 5 toxicities were observed. Eight (80%) patients had a partial response (including 1 unconfirmed partial response) and 2 had stable disease. Median PFS was 27.2 months; median OS was not reached. The recommended phase II dose was determined as osimertinib 80 mg QD and dasatinib 70 mg QD. Pharmacokinetics (PK) analysis is being performed and will be presented. Due to slow accrual after approval of osimertinib in firstline, the trial was closed to enrollment. Conclusion: The combination of dasatinib and osimertinib demonstrated encouraging anticancer activity. Median PFS is longer than what is historically reported with osimertinib alone in first-line setting, although definitive conclusions cannot be drawn given the small sample size. The tolerability of the combination was limited by TRAEs, but they were generally manageable with dasatinib dose reductions and supportive measures.

Tackling Drug Resistance in EGFR Exon 20 Insertion Mutant Lung Cancer

“… 38 While insufficient dosing due to toxicity may contribute to short-term responses in patients, early data from the use of poziotinib in EGFR Ex20ins patients suggests rapid acquisition of drug resistance, and the specific mechanisms of resistance have some overlap with those observed to arise in classical mutant EGFR NSCLC treated with approved EGFR inhibitors. 39 Therefore, it is important to consider and anticipate the potential routes of drug resistance in order to achieve durable responses in patients with Ex20ins mutations.…”

“…Despite having only recently been evaluated in clinical trials, clinical mechanisms of resistance have already been reported for some of the aforementioned Ex20ins TKIs. 39 Here we will outline the currently known resistance mechanisms to poziotinib and other Ex20ins TKIs focusing on on-target mechanisms and compensatory bypass mechanisms of resistance described in the literature ( Figure 2 ). An overview of genomic alterations, mutations, amplifications and copy number losses which are present at baseline or occur at relapse post-TKI treatment in Ex20ins patients are summarized in Table 2 .…”

“…An overview of genomic alterations, mutations, amplifications and copy number losses which are present at baseline or occur at relapse post-TKI treatment in Ex20ins patients are summarized in Table 2 . 39–41 We also outline potential therapeutics and druggable targets, which could be utilised to overcome TKI resistance.…”

“…Studies Presented in the Table Utilized Different Sample Collection Methods, Elamin et al Evaluated Tumour Specimens Pre-Poziotinib and on Progression from 20 Patients Who Responded to Poziotinib. 39 Riess et al and Montenegro et al Were Observational Studies to Identify the Most Common Co-Occurring Genetic Alterations at Baseline from Formalin Fixed Embedded Ex20ins NSCLC Tumour Specimens from 263 (Riess et al) 40 and 104 (Montenegro et al) 41 Patients Genetic Alteration Genetic Alteration (Prevalence %) Baseline/Post-Treatment Confers Poziotinib Resistance (Confirmed/Putative/Unknown) Ref Mutation EGFR T790M (10%) Post-treatment Confirmed (T790M)/putative (V774A, D770, PIK3CA E545K and MAP2K2 S94L) Elamin et al 39 EGFR V774A (5%) EGFR D770A (5%) PIK3CA E545K (5%) MAP2K2 S94L (5%) Amplification MET amplification (5%) Post-treatment Putative EGFR amplification (10%) CDK6 amplification (10%) Mutation TP53 (56%) Baseline Unknown Riess et al 40 CDKN2A (22%) CDKN2B (16%) RB1 (11%) CTNNB1 (5–10%) PIK3CA (5–10%) Amplification NKX2-1 (14%) Baseline Unknown NFKBIA (5–10%) MDM2 (5–10%) MYK (5–10%) CDK4 (5–10%) Mutation TP53 (51%) Baseline <...>…”

“… Mechanisms of EGFRex20ins TKI resistance. Evidence from the use of poziotinib in patients and in pre-clinical models 39 suggests drug resistance can be driven by ( A ) acquisition of secondary on-target mutations in EGFR or ( B ) mutations or amplification in other oncogenic pathway proteins that result in activation of compensatory bypass pathways including the PI3K/AKT pathway, RAS/MAPK pathway, alternative RTKs and cell cycle genes. …”