FDA Considers Subcutaneous Amivantamab in EGFR-Mutated NSCLC

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A biologics license application for subcutaneous amivantamab combined with recombinant human hyaluronidase has been submitted to the FDA for NSCLC indications.

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  • The FDA has received a biologics license application (BLA) submission for amivantamab-vmjw (Rybrevant) and recombinant human hyaluronidase for subcutaneous administration (SC amivantamab).
  • The submission is for all currently approved or submitted indications of intravenous amivantamab in select patients with non–small cell lung cancer (NSCLC).
  • Data from the phase 3 PALOMA-3 study (NCT05388669) support the BLA submission.

A BLA for a fixed combination of amivantamab with recombinant human hyaluronidase for SC amivantamab has been submitted to the FDA for all currently approved or submitted indications of IV amivantamab in certain patients with NSCLC.1

The BLA submission is supported by data from the phase 3 PALOMA-3 study in which SC amivantamab demonstrated comparable overall response rates (ORR) to IV administration in patients with NSCLC with EGFR exon 19 deletion or L858R mutations. Further, amivantamab given SC also led to a significantly shorter administration time and a 5-fold reduction in infusion-related reactions.

Longer overall survival (OS), progression-free survival (PFS), and duration of response (DOR) was also seen with SC amivantamab, according to findings presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting and published in the Journal of Clinical Oncology.

Lung Cancer: © Crystal Light - stock.adobe.com

Lung Cancer: © Crystal Light - stock.adobe.com

“As seen in the PALOMA-3 study, with its significantly shorter administration time and five-fold reduction in infusion-related reactions, alongside longer overall survival, progression-free survival and duration of response, I look forward to seeing how subcutaneous amivantamab can make a meaningful difference in clinical practice,” Natasha B. Leighl, MD, medical oncologist at the Princess Margaret Cancer Centre in Toronto, Canada, and clinical trial investigator on PALOMA-3, told Targeted OncologyTM.

Data from the phase 2 PALOMA-2 (NCT05498428) study also support this BLA. The study is evaluating SC amivantamab in select patient populations where IV amivantamab has been previously submitted for approval and is intended to support dosing schedules of every 2 and every 3 weeks.

“We saw last year as a result from the MARIPOSA trial [NCT04487080], amivantamab plus lazertinib is doing better than the historical standard of care, which is osimertinib. Now, the question is how to move forward with the administration of this combination. It can be done intravenously, for sure. But given the fact that these patients are usually young patients, still working, wanting to have a normal quality of life? Well, it's good to have this formulation in terms of organizational purposes. It can be done at home, for sure,” said Nicolas Girard, MD, pneumologist specializing in thoracic oncology at the Institut Curie in Paris, France. Girard is an investigator on the PALOMA-2 study and presented findings at this year’s ASCO meeting.

About the PALOMA Studies

PALOMA-3 is an open-label, randomized, phase 3 trial which enrolled 418 patients with EGFR-mutated advanced or metastatic NSCLC after progression on osimertinib (Tagrisso) and chemotherapy.

Here, investigators are evaluating the pharmacokinetics (PK), efficacy, and safety of SC amivantamab given in combination with lazertinib (Leclaza) compared with IV amivantamab and lazertinib in this patient population. The coprimary PK end points being evaluated were trough concentration (Ctrough) and C2 area under the curve. Key secondary end points included ORR and PFS, and OS was an exploratory end point of the study.

According to findings presented at ASCO this year, in total, 206 patients received SC amivantamab and 212 received the IV form. The median age of those enrolled was 61 years, female patients made up 67%, 61% were Asian, and patients received a median of 2 prior lines of therapy.2

At a median follow-up of 7.0 months, the study’s 2 primary end points were met. Geometric mean ratios (GMRs) for SC amivantamab with lazertinib vs IV for Ctrough were 1.15 (90% CI, 1.04-1.26) for C2D1 and 1.43 (90% CI, 1.27-1.61) for C4D1. The GMR for C2 AUCD1-D15 was 1.03 (90% CI, 0.98-1.09).

In the patients given SC amivantamab, the ORR was 30.1% (95% CI, 24%-37%) compared with 32.5% (95% CI, 26%-39%) for IV (relative risk, 0.92; P =.001). This met the noninferiority criteria. Additionally, the median DOR was longer with SC amivantamab and lazertinib at 11.2 months compared with 8.3 months with IV amivantamab, and a favorable PFS trend was seen for the SC arm vs the IV arm at a median of 6.1 months vs 4.3 months (HR, 0.84; P =.20). OS rates were also longer for those treated with SC amivantamab vs IV (HR, 0.62; 95% CI, 0.42-0.92; nominal P =.017).

PALOMA-2, an open-label, phase 2 study, also sought to assess the efficacy, safety, and PK of first-line SC amivantamab given in combination with lazertinib and/or chemotherapy for the treatment of patients with EGFR-mutated advanced or metastatic NSCLC. In cohort 1, 68 patients were enrolled. In cohort 6, 58 patients were included. In cohort 1, prophylactic anticoagulation for the first 4 months of treatment was recommended, and in cohort 6, it was mandatory.

The primary end point of the study was ORR as assessed by the investigator per RECIST v1.1.

Findings also presented at ASCO showed there to be a comparable response rate among patients in this study treated with SC amivantamab and lazertinib vs those treated with the IV formulation in the MARIPOSA study.3 Additionally, SC amivantamab treatment correlated with significantly lower rates of infusion-related reactions, as well as and shorter treatment time vs with the IV formulation.

Amivantamab is already approved in the US, Europe, and in other markets globally as monotherapy for adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.1 In the US, the agent is also approved for use in combination with chemotherapy for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test.

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://tinyurl.com/2ftpswhv
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(suppl 16):LBA8505. doi:10.1200/JCO.2024.42.16_suppl.8505
3. Late-breaking results from PALOMA-2 study of subcutaneous amivantamab in combination with lazertinib show clinically meaningful antitumor response and improved safety profile in patients with EGFR-mutated non-small cell lung cancer. News release. Johnson & Johnson. June 3, 2024. Accessed June 17, 2024. https://tinyurl.com/mpdnatsf
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