In the past two decades, the landscape of EGFR-mutant NSCLC treatment has undergone a significant transformation with the advent of targeted therapies. EGFR exon 20 insertion is a rare submutation in the EGFR gene and contributes to only 10-12% of all EGFR mutations. TAGRISSO, a third-generation EGFR TKI, has shown some activity against this mutation in preclinical studies. However, two novel agents have been approved for this mutation in the US: RYBREVANT (amivantamab) and EXKIVITY (mobocertinib). RYBREVANT is a bispecific antibody designed to target both the extracellular domain of EGFR and the MET gene. This approach addresses a common resistance mechanism observed with traditional EGFR TKIs. The drug showed clinical benefits in the patient in the second-line setting.

The company is investigating the drug in the Phase III registrational PAPILLON study in which overall, 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 benefit 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.

Altogether, these findings mark a significant advancement in the management of EGFR exon 20 insertion NSCLC, offering patients improved disease control, enhanced response rates, and a well-managed side effect profile. Amivantamab-chemotherapy has undoubtedly emerged as a game-changing standard of care for this patient population.

KOL insights

“The long-term benefit from amivantamab-chemotherapy and PFS2 benefit for the PAPILLON trial are quite compelling. And in regard to the OS, I am quite thrilled to see the curves. And yes, toxicity is a major issue! Let’s get our dermatologists ready to help us! - Medical Oncologist

“Long waited results of PAPILLON trial mPFS of 11.4 vs 6.7 months. New effective treatment for exon 20 patients who historically had poor outcomes.” Medical Oncologist

“PAPILLON, a clinical trial that saw a new bright spot in one of the unmet medical needs, EGFRex20ins. It is only worthwhile because of the efforts of the clinicians who have taken up the challenge so far.” Medical Oncologist

Conclusion

DelveInsight estimates that approximately 3,000-4,000 patients had exon 20 insertion EGFR mutation in the United States in 2022. The data presented strongly establishes amivantamab-chemotherapy as the new standard of care for first-line treatment in patients with EGFR exon 20 insertion advanced non-small cell lung cancer. This innovative treatment approach has demonstrated compelling advantages, notably a significant improvement in PFS when compared to traditional chemotherapy. Importantly, these benefits were consistently observed across various patient subgroups, underlining its broad applicability. Additionally, amivantamab-chemotherapy exhibited a substantially higher ORR, longer DoR, and more profound tumor size reduction, indicating its capacity to effectively control and shrink tumors. The support for its use as a first-line treatment is further bolstered by longer PFS2, signifying continued disease control. While more data may be needed to fully confirm its impact on overall survival, a favorable interim trend in OS is evident. 

Last year in June 2022, Takeda withdrew its application from Europe due to the EMA’s (European Medicines Agency) request for more clinical data to confirm EXKIVITY’s benefits for second-line patients. More recently, EXKIVITY faced another setback, with Takeda withdrawing it from the market due to underwhelming results in a confirmatory trial. As the dust settles, the spotlight now shines on RYBREVANT, taking the reins as the frontrunner in this arena. With no competitors, Janssen is now the only company marketing the Exon-20 EGFR NSCLC medication. However, companies like Cullinan Oncology/Taiho Oncology, ArriVent BioPharma, and Dizal Pharmaceutical, are aiming at the Exon-20 mutant EGFR NSCLC segment. Apart from the Exon-20 EGFR NSCLC segment, Janssen is aggressively trying to expand RYBREVANT’s label. In coming years, RYBREVANT will have access to a larger patient cohort through the MARIPOSA-2 study, which accounts for up to 90% of all EGFR mutations in NSCLC. However, it is important to note that RYBREVANT may have an uphill struggle against TAGRISSO (a key drug in EGFR NSCLC). 

For more insight into the patient's burden/epidemiology, treatment, and changing market landscape-related advancements, refer to the Epidermal Growth Factor Receptor-Non Small Cell Lung Cancer (EGFR-NSCLC) Market Insight and Forecast Report

Note: The therapeutics segment is experiencing significant NSCLC clinical trial activity, which is further expected to drive Non-Small Cell Lung Caner market growth in the coming years.