UC Davis

Background

Onalespib is a novel heat shock protein 90 inhibitor (HSP90i). Previous preclinical and clinical studies with HSP90i have demonstrated activity in EGFR-mutant non-small cell lung cancer (NSCLC). This study sought to determine the safety and tolerability of onalespib plus erlotinib in EGFR-mutant NSCLC and to evaluate the preliminary efficacy of the combination in epidermal growth factor receptor exon 20 insertion (EGFRex20ins) NSCLC.

Patients and methods

Standard 3+3 dose escalation was followed by a phase II expansion in EGFRex20ins. The phase II component targeted a response rate of 25% versus a background rate of 5%. Prospective next-generation sequencing (NGS) of 70 cancer-related genes, including EGFR, via plasma circulating tumor DNA (ctDNA) was performed. Toxicity was graded by Common Terminology Criteria for Adverse Events (CTCAE), version 4, and response was determined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1.

Results

Eleven patients were treated (nine dose escalation, two dose expansion). Two dose-limiting toxicities (DLTs) occurred in dose level (DL) 0 and zero in DL -1 (minus). In 10 EGFRex20ins patients, no responses were observed, median progression-free survival was 5.4 months (95% confidence interval, 0.9-5.7), and the disease control rate (DCR) was 40% (median, 3.5 months). EGFRex20ins was detected in nine of 10 ctDNA samples at baseline; on-treatment ctDNA clearance was not observed. Grade 3 diarrhea was the predominant toxicity in 45% of patients. The recommended phase II dose is DL -1 (minus): erlotinib 150 mg orally every morning and onalespib 120 mg/m² intravenously on days 1, 8, and 15 every 28 days.

Conclusion

Overlapping toxicities of erlotinib and onalespib, mainly diarrhea, limited the tolerability of this combination, and limited clinical activity was observed, so the trial was closed early. Plasma EGFRex20ins ctDNA was detected in the majority of patients; failure to clear ctDNA was consistent with lack of tumor response (NCT02535338).