EGFR exon 20 insertion is a rare submutation in the EGFR gene that affects the treatment of NSCLC. According to the DelveInsight’s estimations, the total market size of EGFR NSCLC was USD 2,100 million in 2023. There are two novel agents have been approved for this mutation in the US: RYBREVANT (amivantamab) and EXKIVITY (mobocertinib). RYBREVANT is a bispecific antibody that targets both the extracellular domain of EGFR and the MET gene, a common resistance mechanism to conventional EGFR TKIs. It received accelerated approval from the US FDA in May 2021 for treating adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. In March 2024, the US FDA recently approved amivantamab in combination with chemotherapy for first-line treatment of patients with NSCLC with EGFR Exon20ins mutations. This FDA action converts the May 2021 accelerated approval to a full approval based on the confirmatory Phase III PAPILLON study.

In May 2024, Johnson & Johnson announced the submission of an application for the extension of the RYBREVANT marketing authorization (line extension) to the European Medicines Agency (EMA) seeking approval of SC amivantamab in combination with lazertinib for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR ex19del or L858R mutations and as monotherapy in adult patients with advanced NSCLC with activating EGFR exon 20 insertion mutations after failure of platinum-based therapy based on the PALOMA-3 data. Johnson & Johnson will submit regulatory applications seeking the approval of SC amivantamab in other markets, including the United States

The data presented at ASCO showed that, in total, 418 patients were randomized (SC, n = 206; IV, n = 212); 416 received ≥1 dose. At a median follow-up of 7.0 months, PALOMA-3 met both co-primary endpoints. ORR was 30.1% (95% CI, 24–37) in the subcutaneous arm and 32.5% (95% CI, 26–39) for IV (relative risk, 0.92; p = 0.001), meeting the noninferiority criteria. The median duration of response (DoR) was longer for SC amivantamab + lazertinib vs IV (median, 11.2 vs 8.3 months among confirmed responders). A favorable PFS trend was observed for SC amivantamab + lazertinib over IV (median, 6.1 vs 4.3 months). OS was notably longer for SC amivantamab + lazertinib vs IV. At 12 months, 65% were alive in the SC arm vs 51% for IV. IRRs were ~5-fold lower in the SC arm: 13% vs 66% for IV, primarily Grade 1-2 (0.5% vs 4% Grade ≥3, respectively). Overall, 81% received prophylactic anticoagulants, with venous thromboembolic events (VTE) reported by 9% in the SC arm vs 14% for IV. Across both arms, VTE incidence was 10% for patients who received prophylactic anticoagulants vs. 21% for patients who did not. Severe bleeding risk was low among all pts receiving anticoagulants (1% Grade ≥3).

KOL insights- “The PALOMA-3 data show that subcutaneous amivantamab offers shorter infusion times and lower rates of infusion-related reactions and venous thromboembolism with pharmacokinetics and efficacy comparable to the current IV administration.” –Expert Opinion.

“We are always exploring innovative approaches to meet the urgent needs of patients living with EGFR-mutated non-small cell lung cancer and these compelling findings reinforce the potential for a new route of administration for amivantamab”–Expert Opinion.

Conclusion-

Subcutaneous (SC) administration of amivantamab has demonstrated comparable pharmacokinetics (PK) and objective response rates (ORR) to its intravenous (IV) form. Notably, SC amivantamab exhibited longer duration of response (DoR), progression-free survival (PFS), and overall survival (OS) compared to the IV formulation, indicating that the administration route or formulation may influence treatment outcomes. Additionally, the safety profile of SC amivantamab is improved, with reduced rates of infusion-related reactions (IRR) and venous thromboembolism (VTE). Implementing prophylactic anticoagulation effectively reduces VTE risk and is safe for patients. Data from the PALOMA-3 trial suggest that SC RYBREVANT (amivantamab) may offer advantages over the IV formulation. Furthermore, the Phase III MARIPOSA study, which evaluated first-line treatment with RYBREVANT and lazertinib in high-risk EGFR-mutant advanced NSCLC patients, supports the potential benefits of the SC formulation. Introducing SC amivantamab could enhance overall safety and reduce IRRs, potentially leading physicians to prefer this regimen over TAGRISSO if it maintains similar efficacy.