Zipalertinib Elicits Early Clinical Activity in EGFR Exon 20+ NSCLC


Patients with recurrent or metastatic non–small cell lung cancer with EGFR exon 20 insertions achieved a confirmed objective response rate of 38.4% with zipalertinib.

Zipalertinib Elicits Early Clinical Activity in EGFR Exon 20+ NSCLC

Zipalertinib Elicits Early Clinical Activity in EGFR Exon 20+ NSCLC

Data from a phase 1/2a trial (NCT04036682) showed that heavily pretreated patients with recurrent or metastatic non–small cell lung cancer (NSCLC) with EGFR exon 20 insertion experienced antitumor activity following treatment with zipalertinib (CLN-081, TAS6417).

During the dose escalation portion of the study, patients (n = 73) received the irreversible EGFR TKI orally twice a day in 21-day cycles at dose levels of 30 mg (n = 8), 45 mg (n = 1), 65 mg (n = 14), 100 mg (n = 13), and 150 mg (n = 11). In the phase 2a expansion part, patients were given 65 mg or less (n = 23) 100 mg (n = 39), or 150 mg (n = 11) of zipalertinib. However, the maximum-tolerated dose was not defined, and the 150 mg dose level stopped enrolling after there were 3 dose reductions, 3 drug discontinuations, and additional dose-limiting toxicity (DLT) criteria were met outside the 21-day evaluation period in the first 11 patients.

Across all dose levels, patients achieved a confirmed objective response rate (ORR) of 38.4% (95% CI, 27%-49%) and all responses were partial. Confirmed partial responses (PRs) in the 65 mg or less, 100 mg, and 150 mg groups were 35.0%, 41.0%, and 36.4%, respectively. Overall, stable disease (SD) was observed in 57.5% of patients and 4.1% experienced progressive disease. Additionally, the median time to response in the overall population was 1.5 months (range, 1.5-6.2).

Overall, patients experienced a median progression-free survival (PFS) of 10 months (95% CI, 6-12), and those treated at the 65 mg twice daily or less and 100 mg twice daily dose levels experienced a median progression-free survival of 8 months (95% CI, 5-13) and 12 months (95% CI, 5-not calculable [NC]), respectively. At a median follow-up of 11 months, the median duration of response (DOR) was 10 months (95% CI, 6-NC) for all patients. At the May 9, 2022, data cutoff, the median DOR was not reached for those in the 65 mg or less and 100 mg groups. At a 6-week disease assessment, 74% of patients overall experienced tumor regression.

Patients enrolled in the trial were 18 years of age or older, with a median age of 64 years (range, 36-82). Patients with spinal cord compression, a history of drug-induced pneumonitis, or active infection were excluded from the study.

Nearly all patients received previous platinum-based chemotherapy (96%) and were mostly female (56%). Additionally, patients had an ECOG performance score of 0 (30%) or 1 (70%); a history of CNS metastases (38%); received a prior PD-1 or PD-L1 inhibitor (55%); and received a previous EGFR inhibitor (40%) of either afatinib (Gilotrif) or gefitinib (Iressa; 18%), osimertinib (Tagrisso; 18%), or poziotinib and/or mobocertinib (Exkivity; 4%).

Additionally, the median number of previous systemic therapies received was 2 (range, 1-9), with most patients receiving 1 (30%) or 2 (44%). In terms of EGFR exon 20 insertions, patients had helical (3%), near-loop (71%), far-loop (12%), and undetermined (14%) mutations.

As of the data cutoff, 33% of patients remain on study treatment and results are still maturing.

Investigators also noted that PRs were observed with zipalertinib in 31% of patients (n = 26) who had prior treatment with a non–EGFR exon 20 insertion inhibitor. Of 3 patients previously treated with another exon 20 insertion–directed TKI, 2 experienced a PR and 1 had SD. When examining near-loop exon 20 insertions (n = 52) vs far-loop insertions (n = 9) in an exploratory analysis, the ORRs were 41.5% vs 22%, respectively.

Moreover, zipalertinib demonstrated activity in patients with central nervous system (CNS) target lesions. Among the 3 patients with measurable target lesions in the brain, 1 experienced a systemic and intracranial PR, 1 experienced systemic and intracranial SD, and the third experienced CNS progression at cycle 3.

Currently, mobocertinib and amivantamab-vmjw (Rybrevant) have FDA accelerated approvals for this patient population. Notably, on the trial, those receiving 100 mg or less of zipalertinib did not experience grade 3 or higher diarrhea and rash, adverse effects (AEs) that are frequently seen with EGFR exon 20 insertion–specific TKIs.

In the overall population, treatment-related rash occurred in 80% of patients (grade 1, 70%; grade 2, 28%; grade 3, 2%), and diarrhea occurred in 30% of patients (grade 1, 68%; grade 2, 23%; grade 3, 9%). The most common any grade treatment-related AEs (TRAEs) were rash (80%), paronychia (32%), diarrhea (30%), fatigue (21%), anemia (19%), and dry skin (18%).

Grade 3 or higher TRAEs occurred in 23% of patients and 6 patients experienced DLTs—4 at the 150 mg level and 1 each at the 100 mg and 65 mg levels. TRAEs led to dose reduction and discontinuation in 14% and 8% of patients, respectively, with discontinuations occurring due to pneumonitis (n = 2), hepatic toxicity (n = 2), fatigue (n = 1), and allergic reaction (n = 1). There were no treatment-related deaths, and TRAEs were generally reversible and manageable with standard supportive care.


Piotrowska Z, Tan DSW, Smit EF, et al. Safety, tolerability, and antitumor activity of zipalertinib among patients with non-small-cell lung cancer harboring epidermal growth factor receptor exon 20 insertions. J Clin Oncol. Published online June 29, 2023. doi:10.1200/JCO.23.00152

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