Frontline Amivantamab Plus Chemo Receives Positive EU CHMP Opinion for EGFR Exon 20 Insertion+ NSCLC

Nicolas Girard, MD, PhD

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of amivantamab-vmjw (Rybrevant) plus carboplatin and pemetrexed for the frontline treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations, according to a news release.¹

The positive opinion was supported by results from the phase 3 PAPILLON study (NCT04538664), in which amivantamab plus chemotherapy (n = 153) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) in patients with NSCLC harboring EGFR exon 20 insertions compared with chemotherapy alone (n = 155), meeting the study’s primary end point.¹ Amivantamab plus carboplatin and pemetrexed elicited a median PFS of 11.4 months (95% CI, 9.8-13.7) vs 6.7 months (95% CI, 5.6-7.3) with chemotherapy alone (HR, 0.40; 95% CI, 0.30-0.53; P < .001).^2,3

As of the March 2024 analysis, the overall survival (OS) results were immature, with 44% of pre-specified deaths for the final analysis reported; however, there is currently no trend towards a detriment that was observed.³ An interim OS analysis also shows a favorable trend for patients treated with amivantamab plus chemotherapy compared with those on chemotherapy alone (HR = 0.675; 95% CI, 0.42%-1.09%; P = .106).¹

"The PAPILLON study results represent an important advancement in the EGFR exon 20 insertion NSCLC treatment landscape, demonstrating significantly improved PFS with first-line amivantamab plus chemotherapy vs chemotherapy alone,” trial investigator Nicolas Girard, MD, PhD, professor of respiratory medicine at Versailles Saint Quentin University, and head of medical oncology at the Curie-Montsouris Thorax Institute, the Institut Curie, in Paris, France, stated in the release.¹ “Notably, we observed improvements in functional status and reduction in lung cancer-related symptoms, underscoring the potential of this regimen to redefine standards of care for these patients, offering hope for improved quality of life and patient-relevant treatment outcomes."

Amivantamab targets tumors with activating and resistance EGFR mutations and MET mutations and amplifications by harnessing the immune system and this positive CHMP opinion positions the agent as the first fully-human EGFR-MET bispecific antibody in the first-line treatment of EGFR exon 20 insertion-mutated NSCLC.¹

There is an unmet need for additional novel therapies for the treatment of patients with NSCLC, specifically for patients with EGFR exon 20 insertion driver mutations, given the substantial disease impact. EGFR exon 20 insertion mutations are the third most prevalent activating EGFR mutation and are linked to a real-world 5-year OS rate as low as 8%. This underscores this current need for targeted treatment strategies.¹

Notably, the FDA recently approved amivantamab plus carboplatin and pemetrexed on March 1, 2024, for the frontline treatment of locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations, as detected by an FDA-approved test.³

“Lung cancer remains the leading cause of cancer-related mortality in Europe. As patients living with EGFR exon 20 insertion-mutated NSCLC face a particularly poor prognosis, the need for innovative combinations in the frontline setting is vital,” Henar Hevia, senior director, EMEA Therapeutic Area Lead, Oncology, Johnson & Johnson Innovative Medicine, said in the press release.¹ “At Johnson & Johnson, we are dedicated to the development and delivery of novel, targeted therapies aimed to address specific disease pathways, with the ultimate goal of ensuring each patient receives the right treatment at the right time."

The randomized, open-label PAPILLON trial randomly assigned patients with newly diagnosed advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations to receive either amivantamab in combination with chemotherapy or chemotherapy alone. The primary end point of the trial was PFS as assessed by an independent review committee. Secondary end points included overall response rate, PFS after first subsequent therapy, duration of response, time to subsequent therapy, OS. Patients initially treated with chemotherapy alone could receive amivantamab monotherapy in the second-line setting upon disease progression.¹

Regarding safety, the combination of amivantamab and chemotherapy demonstrated a safety profile similar to that of the individual agents, with a 7% rate of treatment-related discontinuations. Both treatment arms showed comparable rates of overall adverse events (AEs) and AEs leading to death. However, the rate of grade 3 or higher AEs were more frequent with amivantamab and chemotherapy compared with chemotherapy alone (75% vs 54%).¹

Serious AEs occurred in 37% of patients receiving amivantamab and chemotherapy compared with 31% observed in the chemotherapy arm. Furthermore, increased EGFR and MET-related AEs were noted with amivantamab and chemotherapy treatment, though they were primarily grades 1 and 2; chemotherapy-associated hematologic and gastrointestinal toxicities were similar, except for transient neutropenia. Pneumonitis was reported in 3% of patients receiving amivantamab and chemotherapy.¹

“Today’s positive opinion represents the culmination of years of work and our team’s commitment to the lung cancer community. We will continue to focus on redefining treatment paradigms, starting from the very first line of therapy, with a goal of improving survival rates and overall patient outcomes.” Kiran Patel, MD, vice president, Clinical Development, Solid Tumours, Johnson & Johnson Research & Development, LLC, said in the news release.1 “Through our extensive research and development efforts, we are pioneering novel approaches and targeting key pathways implicated in lung cancer progression, with the ultimate goal of transforming clinical outcomes for patients with EGFR-mutated NSCLC.”

References

1. Johnson & Johnson receives positive CHMP opinion for Rybrevant® (amivantamab) in combination with chemotherapy for the first-line treatment of patients with advanced non-small cell lung cancer with activating EGFR exon 20 insertion mutations. Johnson & Johnson. News release. April 26, 2024. Accessed April 26, 2024. https://www.jnj.com/media-center/press-releases/johnson-johnson-receives-positive-chmp-opinion-for-rybrevant-amivantamab-in-combination-with-chemotherapy-for-the-first-line-treatment-of-patients-with-advanced-non-small-cell-lung-cancer-with-activating-egfr-exon-20-insertion-mutations
2. Zhou C, Tang KJ, Chul B, et al. Amivantamab plus chemotherapy in NSCLC with EGFR exon 20 insertions. N Engl Med. 2023;389(22):2039-2051. doi:10.1056/NEJMoa2306441
3. FDA approves amivantamab-vmjw for EGFR exon 20 insertion-mutation non-small cell lung cancer indications. FDA. March 1, 2024. Accessed April 26, 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