FDA Approves Rybrevant Plus Chemo for Front-Line Treatment of NSCLC with EGFR Exon 20 Insertion Mutations

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The FDA has approved Johnson & Johnson’s Rybrevant (amivantamab-vmjw) combined with carboplatin and pemetrexed for the frontline treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC) that harbors EGFR exon 20 insertion mutations, as detected by an FDA-approved test.^1,2 The agency also granted a traditional approval to Rybrevant for adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease progressed on or following platinum-based chemotherapy. The FDA previously granted accelerated approval to this indication in May 2021 based on findings from the confirmatory Phase III PAPILLON (NCT04538664) study.

“When aiming for the best possible treatment outcomes, a targeted approach should be used in the first line for patients with EGFR exon 20 insertion mutations, as this is a commonly applied practice for patients with NSCLC harboring other molecular driver alterations,” said study investigator Joshua K. Sabari, MD, an oncologist at NYU Langone’s Perlmutter Cancer Center, in a press release. “The results observed in the PAPILLON study showed significant improvement in progression-free survival, supporting the use of this regimen as the potential standard-of-care in the first-line treatment of these patients.”²

Results from the randomized, open-label, multicenter PAPILLON trial showed that Rybrevant combined with chemotherapy significantly improved progression-free survival (PFS) compared with chemotherapy alone, at a median of 11.4 months compared with 6.7 months.

Overall survival (OS) data were immature at the data cutoff, with 44% of prespecified deaths reported, but there were no observed trends indicating a detrimental outcome with the Rybrevant plus chemotherapy combination.

PAPILLON enrollment criteria included having treatment-naive, locally advanced, or metastatic NSCLC harboring EGFR exon 20 insertion mutations with measurable disease by RECIST v1.1 criteria; an ECOG performance status of 0 or 1; and acceptable organ and bone marrow function. The trial’s primary endpoint was PFS as evaluated by blinded independent central review, with other efficacy measures that included overall response rate, duration of response, and OS.

Patients with active interstitial lung disease or a history of the condition were excluded from the trial. Investigators randomly assigned 308 patients 1:1 to receive Rybrevant with chemotherapy or chemotherapy alone.

Rybrevant was administered intravenously at a dose of 1400 mg in patients weighing less than 80 kg, or 1750 mg in patients weighing 80 kg or more, once weekly for four weeks and then every three weeks at doses of 1750 mg or 2100 mg, respectively, beginning at week seven. Treatment with the combination continued until disease progression or intolerable toxicity. Patients in the chemotherapy-alone arm whose disease progressed were allowed to switch to treatment with Rybrevant alone.

Adding Rybrevant to chemotherapy produced an ORR of 67% compared with 36% with chemotherapy alone. Four percent of patients who responded to Rybrevant had a complete response and 63% had a partial response compared to 1% and 36%, respectively, in the chemotherapy-alone cohort. Median duration of response with Rybrevant plus chemotherapy was 10.1 months compared with 5.6 months in the chemotherapy cohort.

In terms of safety, 37% of those administered the Rybrevant combination experienced serious adverse events (AEs), with 4.6% of patients experiencing fatal AEs that included pneumonia, cerebrovascular accident, cardiorespiratory arrest, COVID-19, sepsis, and death not otherwise specified. AEs led to dose reductions or interruptions in 36% and 64% of patients, respectively, in the dosing groups, with 11% permanently discontinuing Rybrevant because of an AE.

“For patients with lung cancer and their families, each breakthrough in treatment provides not only a new option, but a potential lifeline. The approval of Rybrevant plus chemotherapy heralds a promising new first-line treatment option for patients newly diagnosed with non-small cell lung cancer where their driver mutation is an EGFR exon 20 insertion,” Marcia Horn, executive director of the Exon 20 Group and CEO of ICAN, International Cancer Advocacy Network, said in the release. “This new regimen is a major advance over chemotherapy alone. We’ve seen first-hand the extended survival that Exon 20 Group patients experienced on Rybrevant plus chemotherapy in the PAPILLON study, and we’re delighted that this historic treatment option, which specifically targets the EGFR exon 20 insertion mutation, has been approved.”²

References

1. FDA approves amivantamab-vmjw for EGFR exon 20 insertion-mutation non-small cell lung cancer indications. FDA. March 1, 2024. Accessed March 4, 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

2. RYBREVANT® (amivantamab-vmjw) in Combination With Chemotherapy Is the First FDA Approved Therapy for First-line Treatment of Patients With Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations. Johnson & Johnson. News release. March 1, 2024. Accessed March 4, 2024. https://www.jnj.com/media-center/press-releases/rybrevant-amivantamab-vmjw-in-combination-with-chemotherapy-is-the-first-fda-approved-therapy-for-first-line-treatment-of-patients-with-non-small-cell-lung-cancer-with-egfr-exon-20-insertion-mutations