In a phase I/IIa study reported in the Journal of Clinical Oncology, Piotrowska et al found that the EGFR tyrosine kinase inhibitor zipalertinib showed activity and an acceptable safety profile in previously treated patients with advanced non–small cell lung cancer (NSCLC) and EGFR exon 20 insertions.

As stated by the investigators: “Although several agents targeting EGFR exon 20 insertions have recently been approved by the U.S. Food and Drug Administration, toxicities related to the inhibition of wild-type EGFR are common with these agents and affect overall tolerability. Zipalertinib is an oral EGFR tyrosine kinase inhibitor with a novel pyrrolopyrimidine scaffold leading to enhanced selectivity for EGFR [exon 20]-mutant vs wild-type EGFR….”

Study Details

In the international trial, 73 evaluable patients with recurrent or metastatic disease who had received prior platinum-based chemotherapy were given zipalertinib at doses of 30, 45, 65, 100, or 150 mg twice daily, with treatment beginning between December 2019 and October 2021. Overall, 23 patients received ≤ 65 mg, 39 received 100 mg (expansion cohort), and 11 received 150 mg twice daily. Data cutoff was in May 2022. Patients had received a median of two prior systemic therapies (range = 1–9 therapies); 36% had received previous non–exon 20 insertion EGFR tyrosine kinase inhibitors, and 4% had received previous exon 20 insertion tyrosine kinase inhibitors. 

Adverse Events

Enrollment to the 150-mg twice-daily group was stopped after the first 11 patients entered the trial, because of excess dose reductions (n = 3), treatment discontinuations (n = 3), and occurrence of adverse events meeting criteria for dose-limiting toxicity outside the dose-limiting toxicity evaluation period.

Among all patients, the most common treatment-related adverse events of any grade were rash (in 80% of patients), paronychia (32%), diarrhea (30%), and fatigue (21%). The most common treatment-related grade ≥ 3 adverse events included anemia (10%), increased aspartate aminotransferase (4%), and diarrhea (3%). No cases of grade ≥ 3 treatment-related rash or diarrhea were observed among patients receiving 100 mg or less of zipalertinib twice daily. Treatment-related adverse events led to discontinuation of treatment in six patients, including pneumonitis in two, hepatic toxicity in two, fatigue in one, and allergic reaction in one. No treatment-related deaths were observed.

Responses

Among all 73 patients, objective responses (all partial) were observed in 28 patients (38.4%), with responses observed at all dose levels. Stable disease was observed in an additional 42 patients (57.5%). Objective response was observed in 16 of 39 patients (41.0%) who received 100 mg twice daily, with stable disease observed in an additional 22 (56.4%). At a median follow-up of 11 months, the median duration of response was 10 months (95% confidence interval [CI] = 6 months to not estimable) across all doses; at data cutoff, the median response duration had not been reached for responders receiving 100 mg twice daily. Median progression-free survival was 10 months (95% CI = 6–12 months) among all patients, 12 months (95% CI = 5 months to not estimable) among those receiving 100 mg twice daily, and 8 months (95% CI = 5–13 months) among those receiving ≤ 65 mg twice daily.

The investigators concluded: “Zipalertinib has encouraging preliminary antitumor activity in heavily pretreated patients with EGFR exon 20 insertion–mutant NSCLC, with an acceptable safety profile, including low frequency of high-grade diarrhea and rash.”

Zofia Piotrowska, MD, of Massachusetts General Hospital, is the corresponding author of the Journal of Clinical Oncology article.

Disclosure: The study was funded by Cullinan Oncology, Inc. For full disclosures of the study authors, visit ascopubs.org.