Zipalertinib Offers Promising Oral Option for EGFR Exon 20+ NSCLC
Zipalertinib shows promising efficacy and safety for advanced NSCLC with EGFR exon 20 mutations, offering a much-needed oral treatment option.
Illustration of lungs: © yodiyim - stock.adobe.com
For patients with advanced non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations, the treatment landscape is poised for a significant shift. At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, Helena Yu, MD, presented compelling results from the phase 2b part of the REZILIENT 1 study (NCT04036682), highlighting the efficacy and favorable tolerability of zipalertinib, a novel oral EGFR tyrosine kinase inhibitor (TKI).
EGFR exon 20 insertion mutations are a distinct subtype of EGFR-mutant lung cancer, representing about 1% to 2% of NSCLC diagnoses in the US. While the EGFR-MET bispecific antibody amivantamab (Rybrevant) is currently the only approved agent for this patient population, its intravenous administration and associated toxicities create a clear unmet need for effective oral therapies.
"Many of our targeted therapies in lung cancer are oral therapies, which, of course, oftentimes are better tolerated and certainly a patient preference, if possible," Yu, medical oncologist at Memorial Sloan Kettering Cancer Center, said in an interview with Targeted OncologyTM. "So, there is definitely an unmet need to find an oral targeted therapy for this population."
The REZILIENT 1 study enrolled 244 patients with metastatic or locally advanced NSCLC with EGFR exon 20 insertion mutations. Notably, patients with stable, untreated brain metastases were permitted. Zipalertinib was administered orally at 100 mg twice daily.
The study included 2 cohorts: patients who had progressed on platinum-based chemotherapy but had not received prior exon 20-targeted treatment (n = 143), and those who had received both platinum-based chemotherapy and prior exon 20-targeted therapy, including amivantamab (n = 101). The primary end points were confirmed overall response rate (ORR) and duration of response (DOR) by independent central review.
Promising Responses Across Diverse Patient Groups
Helena Yu, MD
Overall, the confirmed ORR for the entire treated population was 35.2% (95% CI, 28.2-42.8), with a median DOR of 8.8 months (95% CI, 8.3-12.7). However, Yu highlighted important distinctions within the cohorts.
- Platinum-only pretreated patients: This group, who had not received prior EGFR exon 20-targeted therapy, showed a higher ORR of 40% (95% CI, 31-49) with a median DOR of 8.8 months (95% CI, 8.3-12.7).
- Prior amivantamab-only patients: Patients who had only received prior amivantamab demonstrated an ORR of 30% (95% CI, 15-49), but notably, a very long median DOR of 14.7 months (95% CI, 4.2-not evaluable [NE]). This suggests that zipalertinib may be an effective subsequent treatment option even after amivantamab, addressing concerns about cross-resistance.
- Prior other investigational oral exon 20 TKIs: In patients who had received other oral exon 20-targeted therapies like zipalertinib, the ORR was 14% (95% CI, 3-36) with a median DOR of 4.2 months (95% CI, 3.9-NE).
A significant finding was the similar response rates and DOR observed in patients with brain metastases, indicating ziplertinib's excellent central nervous system (CNS) penetration.
"I think that this drug, zipalertinib, has very good CNS penetration," Yu confirmed. The median progression-free survival (PFS) for the total population was 9.4 months (95% CI, 7.4-10.0), with 9.5 months for those without prior EGFR-directed therapy (95% CI, 7.7-11.5), and 7.3 months for those with prior amivantamab or other targeted therapies (95% CI, 5.3-9.7). Overall survival data are still maturing.
Favorable Safety Profile and Patient Quality of Life
Beyond efficacy, zipalertinib demonstrated a favorable safety profile. The rate of treatment discontinuation due to treatment-related toxicities was low at 8.2%. Common EGFR wild-type toxicities like paronychia and rash were infrequent, with rash occurring in only 30% of patients at any grade.
Yu emphasized the importance of an oral option, not just for accessibility but also for improved patient quality of life.
"Amivantamab, while being very effective, has significant EGFR- and MET-directed [adverse events]. They have significant rates of rash and paronychia. I think the MET targeting toxicities, including the edema, really are limiting for some patients." Zipalertinib's targeted inhibition and lower rates of these adverse [events] could be particularly beneficial for older or frail patients.
Future Directions: Accelerated Approval and First-Line Exploration
The immediate goal for zipalertinib is to achieve accelerated FDA approval based on these registrational phase 2b data. Looking forward, the REZILIENT 3 study (NCT05973773) is already underway, investigating zipalertinib in the first-line setting, comparing chemotherapy alone to chemotherapy plus zipalertinib.
"When we find something active, our next goal is, can we move it up in the lines of sequencing?" Yu noted. The potential for zipalertinib to serve as an effective oral, well-tolerated treatment option, especially after amivantamab and with good CNS penetration, represents a crucial advancement for patients with EGFR exon 20-positive NSCLC.
