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

A Type II extension of indication application seeking the approval of amivantamab (Rybrevant) in combination with carboplatin and pemetrexed for the frontline treatment of adult patients with advanced non–small cell lung cancer (NSCLC) and activating EGFR exon 20 insertion mutations has been submitted to the European Medicines Agency (EMA).¹

The application is based on findings from the phase 3 PAPILLON trial (NCT04538664), which met its primary end point in that amivantamab/chemotherapy regimen significantly improved progression-free survival (PFS) over chemotherapy alone in this patient population.² The toxicity profile of the combination was consistent with what has been observed with each agent alone.

“People living with advanced or metastatic NSCLC with activating EGFR exon 20 insertion mutations generally face a poor survival probability, and new treatment options are urgently needed from the very first line of therapy,” Martin Vogel, EMEA Therapeutic Area Lead Oncology at Janssen-Cilag GmbH, stated in a press release.¹ “Today’s submission to the EMA highlights our deep commitment to change the trajectory of lung cancer, through earlier intervention with targeted treatment options for eligible patients.”

In December 2021, the European Commission granted a conditional marketing authorization to amivantamab for use in adult patients with advanced NSCLC harboring activating EGFR exon 20 insertion mutations after platinum-based chemotherapy had failed.³ The regulatory decision was supported by findings from the phase 1 CHRYSALIS study (NCT02609776) in which the fully-human bispecific antibody elicited an overall response rate (ORR) of 37% (95% CI, 28%-46%) by investigator assessment in this population, with a median duration of response of 12.5 months (95% CI, 6.5-16.1).

In May 2021, the FDA granted accelerated approval to amivantamab for use in the same population.⁴ PAPILLON is the confirmatory study needed for continued approval of the agent in this indication.

The trial enrolled patients with histologically or cytologically confirmed, locally advanced or metastatic, nonsquamous NSCLC and documented activating EGFR exon 20 insertion mutations.⁵ Patients were required to have measurable disease by RECIST v1.1 criteria and an ECOG performance status of 0 or 1. They also needed to agree to undergo pretreatment tumor biopsy and provide baseline and longitudinal samples.

Amivantamab was administered intravenously at a dose of 1400 mg once weekly up to day 1 of cycle 2 and then 1750 mg on day 1 of each 21-day cycle for thereafter. In both arms, patients were given pemetrexed at 500 mg/m2 on day 1 of each 21-day cycle, in combination with carboplatin at an area under the concentration-time curve of 5 mg/mL per minute on day 1 of each 21-day cycle for up to 4 cycles. Pemetrexed was continued in the maintenance setting until disease progression.

Those assigned to the control arm were permitted to receive amivantamab in the second-line setting following confirmed progressive disease.

In addition to PFS by blinded independent central review assessment and RECIST v1.1 criteria serving as the trial’s primary end point, secondary end points comprised ORR, PFS after first subsequent therapy, time to symptomatic progression, and overall survival.

“PAPILLON is the first randomized phase 3 study to read out in patients with NSCLC and EGFR exon 20 insertion mutations. Pending approval, this creates an opportunity to make a significant improvement to the standard of care for this patient population, where high unmet medical needs remain,” Kiran Patel, MD, vice president of clinical development in solid tumors at Janssen Research & Development, LLC, stated in the press release.¹ “We look forward to working with the EMA to bring this potential new indication to the lung cancer community as soon as possible.”

In August 2023, a supplemental biological license application (sBLA) seeking expanded approval of amivantamab plus carboplatin/pemetrexed in the first-line treatment of this population was submitted to the FDA.⁶ The sBLA was supported by PAPILLON findings.

References

1. Janssen submits application to the European Medicines Agency for Rybrevant (amivantamab) in combination with chemotherapy for the first-line treatment of adult patients with advanced non-small cell lung cancer with activating EGFR exon 20 insertion mutations. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. October 6, 2023. Accessed October 6, 2023. https://www.investor.jnj.com/files/doc_news/2023/Oct/06/amivantamab-papillon-ema-filing-release.pdf
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 October 6, 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. Janssen EMEA receives conditional marketing authorisation for Rybrevant (amivantamab), the first treatment approved for patients with advanced non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. December 10, 2021. Accessed October 6, 2023. https://www.businesswire.com/news/home/20211210005550/en/Janssen-EMEA-Receives-Conditional-Marketing-Authorisation-for-RYBREVANT%C2%AE-%E2%96%BC-amivantamab-the-First-Treatment-Approved-for-Patients-With-Advanced-Non-Small-Cell-Lung-Cancer-NSCLC-With-EGFR-Exon-20-Insertion-Mutations...
4. FDA approves first targeted therapy for subset of non-small cell lung cancer. News release. FDA. May 21, 2021. Accessed October 6, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-subset-non-small-cell-lung-cancer#:~:text=Today%2C%20the%20U.S.%20Food%20and,EGFR)%20exon%2020%20insertion%20mutations.
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 September 11, 2023. Accessed October 6, 2023. https://clinicaltrials.gov/study/NCT04538664
6. 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 October 6, 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