ESMO 2023: LBA5
Targeted therapies have revolutionized the treatment of EGFR-mutant NSCLC in the last 20 years. However, EGFR exon 20 insertion is a rare and challenging mutation that accounts for only 10-12% of all EGFR mutations. Tagrisso, a third-generation EGFR TKI, has some activity against this mutation in laboratory studies. But two new drugs have been approved for this mutation in the US: Rybrevant (amivantamab) and Exkivity (mobocertinib). Rybrevant is a dual antibody that targets both the outside part of EGFR and the MET gene. This strategy overcomes a common resistance mechanism seen with traditional EGFR TKIs. The drug showed clinical benefits in the patient in the second-line setting.
The company is testing the drug in the Phase III PAPILLON trial in which 308 patients were randomized and at a median follow-up of 14.9 months the median PFS was 11.4 months for the combination vs. 6.7 months for chemotherapy. The 18-month progression-free survival (PFS) rate was 31% for the combination vs. 3% for chemotherapy. The PFS advantage of the combination was consistent across subgroups. Objective response rate (ORR) was 73% for the combination vs. 47% for chemotherapy. Interim overall survival (OS) analysis showed a favorable trend for the combination, despite 66% of chemo-randomized patients whose disease had progressed, receiving second-line amivantamab.
The most common Treatment emergent adverse events (TEAEs) (≥40%) of the combination were neutropenia, paronychia, rash, anemia, infusion-related reactions, and hypoalbuminemia; no new safety signals. Discontinuation of amivantamab due to treatment-related AEs was 7%. The combination achieved superior PFS vs. chemotherapy and the safety profile was consistent with that of each agent. Amivantamab-chemotherapy represents the new standard of care for first-line EGFR exon 20 insertion advanced NSCLC.
These results represent a significant improvement in the treatment of EGFR exon 20 insertion NSCLC, offering patients better disease control, higher response rates, and a manageable side effect profile. Amivantamab-chemotherapy has clearly become a game-changing standard of care for this patient group.
Conclusion
Amivantamab-chemotherapy has emerged as a promising first-line treatment option for patients with EGFR exon 20 insertion advanced non-small cell lung cancer, redefining the standard of care. The robust data underscores its efficacy, with significant improvements in progression-free survival, overall response rate, duration of response, and tumor size reduction. These benefits were consistently observed across various patient subgroups, emphasizing its broad applicability and potential to effectively control and shrink tumors.
While amivantamab-chemotherapy shows a favorable interim trend in overall survival, more data may be needed to confirm its impact in this regard. Meanwhile, the landscape for exon 20 EGFR NSCLC treatment has shifted, with Rybrevant taking the lead following setbacks for other medications like Exkivity. Janssen now stands as the sole marketer of an exon-20 EGFR NSCLC medication, although emerging competitors like Cullinan Oncology/Taiho Oncology, ArriVent BioPharma, and Dizal Pharmaceutical are on the horizon.
Looking ahead, Rybrevant aims to expand its reach, particularly through the MARIPOSA-2 study, which could potentially benefit up to 90% of all EGFR mutations in NSCLC. However, it’s important to acknowledge that Rybrevant may face strong competition, notably from Tagrisso, a key drug in the EGFR NSCLC landscape. The evolving treatment landscape for EGFR exon 20 insertion mutations is an exciting area to watch as new therapies and data continue to shape the future of patient care.
