Loading ...

Combining the bispecific antibody amivantamab (Rybrevant) with chemotherapy in the first- or second-line setting offers ongoing benefit to patients with epidermal growth factor receptor (EGFR)–mutated advanced non–small cell lung cancer (NSCLC) even after disease progression, follow-up analyses of two phase 3 trials suggested.

The research — presented over 2 days at the European Lung Cancer Congress 2024 — was accompanied by an exploratory analysis of a third phase 3 trial — MARIPOSA — which indicated that dose interruptions for adverse events do not compromise outcomes with amivantamab.

The US Food and Drug Administration approved amivantamab in 2021 to treat EGFR exon 20 insertion-mutated advanced NSCLC after progression on platinum-based chemotherapy.

The PAPILLON trial, which involved 308 treatment-naive patients with advanced or metastatic NSCLC, explored whether combining the two therapies in the first line would provide a more meaningful benefit over chemotherapy alone.

The initial findings, presented at ESMO 2023, found that patients receiving the combination in the first line had a longer progression-free survival of 11.4 months vs 5.7 with chemotherapy alone. Amivantamab plus chemotherapy was also associated with a lower risk for second progression (hazard ratio [HR], 0.49; P = .001) and a trend toward a lower risk for death (HR, 0.675; P = .106).

The post-progression analysis, presented by Enriqueta Felip, MD, PhD, of Vall d'Hebron University Hospital, Barcelona, Spain, confirmed the progression-free survival benefit of the combination at the 14.9-month follow-up — 11.4 months vs 6.7 (HR, 0.395). Overall, the combination reduced the risk for second disease progression or death by 51% (median progression-free survival not reached vs 17.2 months in the monotherapy group; HR, 0.49).

Felip also revealed that patients receiving the frontline combination had a longer time to treatment discontinuation than those receiving chemotherapy alone (13.2 months vs 7.5 months; HR, 0.38) and had a longer time to initiating a subsequent therapy (17.7 months vs 9.9 months; HR, 0.35).

Among 43 patients in the combination therapy arm who received a subsequent therapy, 30% had chemotherapy, 21% had chemotherapy plus immunotherapy or a vascular endothelial growth factor inhibitor, and 21% were given an EGFR tyrosine kinase inhibitor.

A total of 94 patients in the chemotherapy alone arm had a subsequent therapy, with the majority (76%) receiving amivantamab monotherapy.

The rates of first progression were lower at all sites with the combination, and notably in in the brain, at 5.2% vs 9.0% of the monotherapy group.

Antonio Passaro, MD, PhD, Division of Thoracic Oncology, European Institute of Oncology IRCCS, Milan, Italy, who was not involved in PAPILLON, called the results "very, very impressive," considering the treatment setting.

The most important data to him were the reduction in brain progression seen with the combination therapy.

With primary data from the MARIPOSA-2 trial indicating that amivantamab achieved a very impressive intracranial progression-free survival, this confirms that amivantamab can offer patients a form of brain protection, Passaro told Medscape Medical News.

MARIPOSA-2: Follow-Up Data

The MARIPOSA-2 trial included 657 patients with EGFR-mutated locally advanced or metastatic NSCLC who had progressed on or after treatment with the third-generation tyrosine kinase inhibitor osimertinib.

Study participants were randomized to amivantamab plus chemotherapy; chemotherapy alone; or amivantamab, chemotherapy, and a third-generation tyrosine kinase inhibitor lazertinib.

The post-progression analysis, presented by Ryan D. Gentzler, MD, of the University of Virginia, Charlottesville, Virginia, focused on the first two treatment arms comparing amivantamab plus chemotherapy with chemotherapy alone.

The initial trial, reported at ESMO 2023, found that amivantamab plus chemotherapy was associated with a 52% improvement in progression-free survival vs chemotherapy alone over a median follow-up of 8.7 months.

In the current analysis, the time to treatment discontinuation was significantly longer with the combination (11.0 months vs 4.5 months; HR, 0.37), as was the time to subsequent therapy (12.1 months vs 6.6 months; HR, 0.42), Gentzler reported.

Progression-free survival in the second-line setting was slightly longer in the combination group (13.9 months vs 11.3 months; HR, 0.60).

In both arms, 63% of patients with disease progression and treatment discontinuation received a subsequent (third-line) therapy.

In terms of safety, Gentzler noted there was a higher incidence and severity of hematologic adverse events with amivantamab plus chemotherapy vs chemotherapy alone, but those events largely appeared in cycle 1, with the similar profiles occurring in subsequent cycles.

Overall, he concluded that the combination is "a new standard of care among patients with EGFR-mutant advanced non–small cell lung cancer after disease progression on osimertinib."

Mariposa: Dose Interruption

Finally, Maria Rosario Garcia Campelo, MD, of the University Hospital A Coruña, A Coruña, Spain, reported the exploratory findings from MARIPOSA.

This trial involved 1074 patients with treatment-naive locally advanced or metastatic EGFR-mutant NSCLC, who were randomly assigned to receive amivantamab plus lazertinib, osimertinib alone, or lazertinib alone.

The initial findings, reported at ESMO 2023, revealed that the combination led to a better median progression-free survival after a median follow-up of 22 months — 23.7 months vs 16.6 months for those on osimertinib alone (HR, 0.70) and 18.5 months for those on lazertinib alone.

The study protocol recommended dose interruptions for patients with grade 2 or greater toxicities, defined as "a skipped dose that is not made up."

Among 421 patients who received one or more doses of amivantamab, 49% had a dose interruption within the first 4 months. The interruption had no impact on progression-free survival or other outcomes.

To minimize bias, the researchers compared 188 patients with dose interruptions within the first 4 months with 190 who had no interruptions and found that the baseline characteristics were similar between the two groups.

Adverse events were more frequent during the first 4 months and then declined, Campelo noted, with rash decreasing by approximately 50%, paronychia by around 30%, and diarrhea by approximately 70%.

Campelo also highlighted that no grade 4 or 5 events were reported.

After adjusting for patient age and performance status, Asian race, type of EGFR mutation, and history of brain metastases, the team found that dose interruptions in the first 4 months of amivantamab treatment had no significant impact on progression-free survival vs no interruptions (HR, 1.06).

Campelo said that dose interruptions were a meaningful way of managing adverse events without compromising outcomes.

The post-progression outcomes in these two MARIPOSA trials are encouraging and show us that there's a "clear benefit to amivantamab for patients with classic EGFR mutations," commented Zofia Piotrowska, MD, a lung cancer medical oncologist at Massachusetts General Cancer Center, Boston, Massachusetts.

This trial also "reminds us that there are important toxicities that need to be managed carefully with amivantamab," Piotrowska added, and "raises questions about whether less frequent administration of amivantamab could yield similar efficacy but improved tolerability."

Overall, she noted, this information will be "very helpful for us to bring back to our clinics. When we talk to patients about potentially withholding therapy to manage the toxicity, we can reach for this data and say we don't think that this will impact their long-term outcomes."

PAPILLON, MARIPOSA, and MARIPOSA-2 were funded by Janssen Pharmaceuticals.

Felip declared relationships with AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F Hoffman-La Roche, Genentech, GlaxoSmithKline, Janssen, Medical Trends, Medscape Medical News, Merck Sharp & Dohme, Merck Serono, Novartis, PeerVoice, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, Turning Point Therapeutics, and Grifols.

Gentzler declared relationships with Pfizer, Amgen, Chugai, Merck, AstraZeneca, Janssen, Daiichi Sankyo, Alliance Foundation, Takeda, ECOG/ACRIN, Jounce Therapeutics, Bristol Myers Squibb, NCI, Big Ten Research Consortium, Hoosier Cancer Research Network, SWOG, Helsinn, Clinical Care Options, OncLive, Targeted Oncology, Society for Immunotherapy of Cancer (SITC), International Association for the Study of Lung Cancer (IASLC), Gilead, Mirati, Sanofi, Oncocyte, Jazz Pharmaceuticals, Blueprint Medicines, Thoracic Clinical Trial Working Group, ASCO Scientific Review Committee, Journal of Clinical Oncology, ASCO Meeting Abstracts, and NCI Investigational Drug Steering Committee.

Campelo declared relationships with AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Janssen Oncology, MSD Oncology, Novartis, Pfizer, Roche/Genentech, Takeda, Amgen, Lilly, Sanofi/Aventis, and MSD Oncology.

Passaro declared relationships with AstraZeneca, Bristol Myers Squibb, Eli Lilly, Janssen, Pfizer, Roche, Bayer, Boehringer Ingelheim, Merck Sharp & Dohme, Mundipharma, Daiichi Sankyo, Medscape Medical News, ecancer.

Piotrowska declared relationships with AstraZeneca, Blueprint Medicines, C4Therapeutics, Eli Lilly, Incyte, Medtronic, Cullinan Pearl, Novartis, Spectrum, Takeda, and Tesaro.