FDA Receives BLA Seeking Approval for Subcutaneous Amivantamab in EGFR+ NSCLC

FDA Receives BLA Seeking Approval for Subcutaneous Amivantamab in EGFR+ NSCLC

A biologics license application (BLA) has been received by the FDA to seek approval of the fixed combination of amivantamab-vmjw (Rybrevant) and recombinant human hyaluronidase (subcutaneous amivantamab) for potential use in all currently approved or submitted indications of the intravenous (IV) formulation in some patients with EGFR-positive non–small cell lung cancer (NSCLC).¹

The BLA is supported by data from the phase 3 PALOMA-3 trial (NCT05388669), which evaluated subcutaneous amivantamab in combination with lazertinib (Leclaza) vs the IV formulation plus lazertinib in patients with advanced NSCLC harboring EGFR mutations who experienced disease progression on or after treatment with osimertinib (Tagrisso) and chemotherapy. Findings, which were presented at the 2024 ASCO Annual Meeting and published in the Journal of Clinical Oncology, showed that subcutaneous amivantamab plus lazertinib generated noninferior pharmacokinetics and responses compared with the IV formulation.^2,3

At day 1 of cycle 2, the observed serum concentration at steady state (C_trough) for subcutaneous amivantamab was noninferior to the IV formulation (geometric mean ratio, 1.15; 90% CI, 1.04-1.26), as was the area under the concentration-time curve at cycle 2 (C2 AUC; geometric mean ratio, 1.03; 90% CI, 0.98-1.09), meeting the trial’s co-primary end points.

Additionally, patients in the subcutaneous arm (n = 206) achieved an overall response rate (ORR) of 30% (95% CI, 24%-37%) compared with 33% (95% CI, 26%-39%) for patients in the IV arm (n = 212; relative risk [RR], 0.92; 95% CI, 0.70-1.23; P = .001). The confirmed ORRs were 27% (95% CI, 21%-33%) and 27% (95% CI, 21%-33%), respectively (RR, 0.99; 95% CI, 0.72-1.36; P < .001).

In the subcutaneous arm, best responses included complete response (CR; 0.5%), partial response (PR; 30%), stable disease (SD; 45%), and progressive disease (PD; 18%). In the IV arm, the respective CR, PR, SD, and PD rates were 0.5%, 32%, 38%, and 20%. Notably, 7% of patients in the subcutaneous arm and 9% of patients in the IV arm were not evaluable for best response. The disease control rate was 75% (95% CI, 69%-81%) for subcutaneous amivantamab vs 71% (95% CI, 64%-77%) for the IV formulation. The median time to response was 1.5 months (range, 1.5-6.9) and 1.5 months (range, 1.2-9.9), respectively.

"[Amivantamab] administered intravenously is a foundational treatment for patients with EGFR-mutated NSCLC," Kiran Patel, MD, vice president, Clinical Development, Solid Tumors, Johnson & Johnson Innovative Medicine, stated in a news release.¹ "This subcutaneous option, administered in approximately 5 minutes, is a clinically important advancement that could transform the treatment experience for patients, oncologists and nursing staff. We look forward to working with the FDA and global regulators in the review of these applications."

In May 2021, the FDA granted accelerated approval to amivantamab monotherapy for the treatment of adult patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.⁴ In March 2024, the regulatory agency granted full approval to the agent for this indication and also approved amivantamab in combination with carboplatin and pemetrexed for the first-line treatment of patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations, as detected by an FDA-approved test.⁵

PALOMA-3 was a global, randomized trial evaluating the subcutaneous formulation of amivantamab in patients with locally advanced or metastatic NSCLC with documented EGFR exon 19 deletions or exon 21 L858R mutations. Patients were required to have disease progression on or after treatment with osimertinib and platinum-based chemotherapy, irrespective of treatment order. An ECOG performance status of 0 or 1 was also required.²

Patients were randomly assigned 1:1 to receive subcutaneous amivantamab at 1600 mg (2240 mg for patients with a body weight of at least 80 kg) once per week for 4 weeks, then once every 2 weeks thereafter, in combination with lazertinib at 240 mg per day; or IV amivantamab at 1050 mg (1400 mg for those with a body weight of at least 80 kg) once per week for 4 weeks, then once every 2 weeks thereafter, plus lazertinib at 240 mg per day.

Stratification factors included brain metastases (yes vs no), EGFR mutation type (exon 19 deletion vs exon L858R mutation), race (Asian vs non-Asian), and type of last therapy (osimertinib or chemotherapy).

Along with the co-primary end points of C_trough and C2 AUC, secondary end points included ORR (noninferiority), progression-free survival (PFS; superiority), duration of response (DOR), patient satisfaction, and safety. Overall survival (OS) was an exploratory end point.

Additional data showed that at a median follow-up of 7.0. months, the median DOR was 11.2 months (95% CI, 6.1–not evaluable [NE]) for patients in the subcutaneous arm vs 8.3 months (95% CI, 5.4-NE) for those in the IV arm.

Patients in the subcutaneous arm experienced a median PFS of 6.1 months (95% CI, 4.3-8.1) vs 4.3 months (95% CI, 4.1-5.7) for the IV arm (HR, 0.84; 95% CI, 0.64-1.10; P = .20). The 6- and 12-month PFS rates for the subcutaneous arm were 50% and 37%, respectively. Those respective rates were 42% and 20% for the IV arm.

An OS benefit was associated with the subcutaneous formulation (HR, 0.62; 95% CI, 0.42-0.92; P = .02). The 6- and 12-month OS rates were 85% and 65% for the subcutaneous arm, respectively, compared with 75% and 51% for the IV arm, respectively.

The median duration of treatment was 4.7 months (range, 0.1-13.2) in the subcutaneous arm vs 4.1 months (range, 0-13.2) in the IV arm. Regarding safety, any-grade treatment-emergent adverse effects (TEAEs) occurred in 99% of patients in both arms. The rates of grade 3 or higher TEAEs and serious TEAEs in the subcutaneous arm were 52% and 29%, respectively. In the IV arm, those respective rates were 56% and 30%. TEAEs led to death in 3% of patients treated with subcutaneous amivantamab vs 5% of patients given the IV formulation. In the experimental arm, TEAEs leading to dose interruptions of any agent, dose reductions of any agent, and discontinuations of any agent occurred at rates of 62%, 31%, and 13%, respectively. Those respective rates were 60%, 25%, and 14% in the control arm.

The most common any-grade AEs of any cause reported in at least 20% of patients in at least 1 of the arms included paronychia (subcutaneous arm, 54%; IV arm, 51%), rash (46%; 43%), dermatitis acneiform (31%; 33%), stomatitis (28%; 33%), diarrhea (21%; 19%), hypoalbuminemia (47%; 37%), peripheral edema (25%; 28%), nausea (39%; 25%), increased alanine aminotransferase (22%; 27%), decreased appetite (22%; 25%), fatigue (21%; 20%), vomiting (21%; 20%), constipation (20%; 20%), headache (20%; 17%), increased aspartate aminotransferase (20%; 21%), and infusion-related reactions (IRRs; 13%; 66%).

Notably, no grade 4 or 5 IRRS occurred in either arm, and most were reported during cycle 1. No patients in the subcutaneous arm were hospitalized due to IRRs; 2 hospitalizations were required in the IV arm. Additionally, no patients in the subcutaneous arm discontinued treatment due to IRRs compared with 4 patients in the IV arm.

Eighty percent of patients (n = 164 of 206) in the subcutaneous arm received prophylactic anticoagulation vs 81% (n = 171 of 210) in the IV arm. In patients who received prophylactic anticoagulation between the 2 arms, 10% experienced venous thromboembolism (VTE); VTE occurred in 21% of patients who did not undergo prophylactic anticoagulation. Bleeding events were also uncommon in the subcutaneous arm (2%) and IV arm (1%) for patients who received prophylactic anticoagulation. Overall, VTE events were less common in the subcutaneous arm (9%) compared with the IV arm (14%), irrespective of prophylactic anticoagulation.

References

1. Subcutaneous amivantamab Biologics License Application submitted to U.S. FDA for patients with EGFR-mutated non-small cell lung cancer. News release. Johnson & Johnson. June 17, 2024. Accessed June 17, 2024. https://www.prnewswire.com/news-releases/subcutaneous-amivantamab-biologics-license-application-submitted-to-us-fda-for-patients-with-egfr-mutated-non-small-cell-lung-cancer-302173613.html
2. Leighl NB, Akamatsu H, Lim SM, et al. Subcutaneous amivantamab vs intravenous amivantamab, both in combination with lazertinib, in refractory EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Primary results, including overall survival (OS), from the global, phase 3, randomized controlled PALOMA-3 trial. J Clin Oncol. 2024;42(supple 17):LBA8505. doi:10.1200/JCO.2024.42.17_suppl.LBA8505
3. Leighl NB, Akamatsu H, Lim SM, et al. Subcutaneous versus intravenous amivantamab, both in combination with lazertinib, in refractory EGFR-mutated NSCLC: primary results from the phase 3 PALOMA-3 study. J Clin Oncol. Published online June 10, 2024. doi:10.1200/JCO.24.01001
4. FDA grants accelerated approval to amivantamab-vmjw for metastatic non-small cell lung cancer. FDA. May 21, 2021. Accessed June 17, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-amivantamab-vmjw-metastatic-non-small-cell-lung-cancer
5. FDA approves amivantamab-vmjw for EGFR exon 20 insertion-mutated non-small cell lung cancer indications. FDA. March 1, 2024. Accessed June 17, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-amivantamab-vmjw-egfr-exon-20-insertion-mutated-non-small-cell-lung-cancer-indications