FDA Approval Sought for Amivantamab Plus Chemo in EGFR Exon 20 Insertion+ NSCLC

A supplemental biologics license application (sBLA) seeking the expanded approval of amivantamab-vmjw (Rybrevant) in combination with carboplatin plus pemetrexed for use in the frontline treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations has been submitted to the FDA.¹

The sBLA is based on findings from the phase 3 PAPILLON trial (NCT04538664), which met its primary end point when the combination resulted in a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs carboplatin/pemetrexed alone in this patient population.² The toxicity profile of the regimen was noted to be comparable to what has been reported with each agent alone.

In May 2021, the FDA granted accelerated approval to amivantamab for use in adult patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease progressed on or following platinum-based chemotherapy.³ In the phase 1 CHRYSALIS trial (NCT02609776), amivantamab (n = 81) elicited an overall response rate (ORR) of 40% (95% CI, 29%-51%) by blinded independent central review and RECIST v1.1 criteria, with a median duration of response of 11.1 months (95% CI, 6.9-not evaluable).⁴

The sBLA submission is intended to satisfy the requirements for the accelerated approval, confirming the clinical benefit reported with amivantamab in CHRYSALIS.1 The Janssen Pharmaceutical Companies of Johnson & Johnson shared plans to submit the PAPILLON data for presentation at an upcoming meeting.²

“PAPILLON is the first randomized phase 3 study in patients with NSCLC with EGFR exon 20 insertion mutations to show clinically meaningful results. This creates an opportunity to make a significant improvement to the standard of care for this patient population with high unmet medical need,” Kiran Patel, MD, vice president of Clinical Development in Solid Tumors at Janssen Research & Development, LLC, stated in a press release.1 “We look forward to working with the FDA through the RTOR pathway in pursuit of an approval for [amivantamab] plus chemotherapy as we simultaneously progress the development of this novel bispecific antibody in additional patient populations.”

The randomized, open-label, phase 3 study enrolled patients with histologically or cytologically confirmed locally advanced or metastatic nonsquamous NSCLC.⁵ Patients were required to have a documented primary EGFR exon 20 insertion activating mutation and measurable disease by RECIST v1.1 criteria. They also needed to have an ECOG performance status of 0 or 1, agree to undergo tumor biopsy prior to treatment, and provide longitudinal blood samples at baseline.

Participants in the investigative arm received the bispecific antibody intravenously, at a dose of 1400 mg once weekly up to day 1 of cycle 2, then at a dose of 1750 mg on day 1 of each 21-day cycle thereafter. If patients weighed 80 kg or greater, they received the agent at 1750 mg once weekly up to day 1 of cycle 2, followed by 2100 mg on day 1 of each cycle thereafter.

Those in both arms received pemetrexed at 500 mg/m² on day 1 of each cycle, plus up to 4 cycles of carboplatin at an area under the concentration-time curve of 5 mg/mL per minute on day 1 of each cycle. Pemetrexed was continued as maintenance therapy until progressive disease (PD).

In addition to PFS serving as the trial’s primary end point, key secondary end points comprised ORR, PFS after first subsequent treatment, time to symptomatic progression, and overall survival. Those in the control arm were permitted to receive amivantamab in the second-line setting following confirmation of PD.

In March 2020, the FDA granted breakthrough therapy designation to amivantamab for this patient population.⁶

References

1. Janssen submits supplemental biologics license application to the US Food and Drug Administration seeking approval of Rybrevant (amivantamab-vmjw) in combination with chemotherapy for the first-line treatment of patients with locally advanced or metastatic EGFR exon 20 insertion mutation-positive non-small cell lung cancer. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. August 25, 2023. Accessed August 25, 2023. https://www.prnewswire.com/news-releases/janssen-submits-supplemental-biologics-license-application-to-the-us-food-and-drug-administration-seeking-approval-of-rybrevant-amivantamab-vmjw-in-combination-with-chemotherapy-for-the-first-line-treatment-of-patients-with-l-301910074.html?tc=eml_cleartime
2. Treatment with Rybrevant (amivantamab-vmjw) plus chemotherapy resulted in statistically significant and clinically meaningful improvement in progression-free survival in patients with newly diagnosed EGFR exon 20 insertion mutation-positive non-small cell lung cancer. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. July 17, 2023. Accessed August 25, 2023. https://www.prnewswire.com/news-releases/treatment-with-rybrevant-amivantamab-vmjw-plus-chemotherapy-resulted-in-statistically-significant-and-clinically-meaningful-improvement-in-progression-free-survival-in-patients-with-newly-diagnosed-egfr-exon-20-insertion-mutati-301878443.html
3. RYBREVANT (amivantamab-vmjw) receives FDA approval as the first targeted treatment for patients with non-small cell lung cancer with EGFR exon 20 insertion mutations. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. March 21, 2021. Accessed August 25, 2023. https://www.jnj.com/rybrevanttm-amivantamab-vmjw-receives-fda-approval-as-the-first-targeted-treatment-for-patients-with-non-small-cell-lung-cancer-with-egfr-exon-20-insertion-mutations
4. FDA grants accelerated approval to amivantamab-vmjw for metastatic non-small cell lung cancer. FDA. May 21, 2021. Accessed August 25, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-amivantamab-vmjw-metastatic-non-small-cell-lung-cancer
5. A study of combination amivantamab and carboplatin-pemetrexed therapy, compared with carboplatin-pemetrexed, in participants with advanced or metastatic non-small cell lung cancer characterized by epidermal growth factor receptor (EGFR) exon 20 insertions (PAPILLON). ClinicalTrials.gov. Updated June 29, 2023. Accessed August 25, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04538664
6. Janssen announces US FDA breakthrough therapy designation granted for JNJ-6372 for the treatment of non-small cell lung cancer. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. March 10, 2020. Accessed August 25, 2023. https://www.jnj.com/janssen-announces-u-s-fda-breakthrough-therapy-designation-granted-for-jnj-6372-for-the-treatment-of-non-small-cell-lung-cancer