PALOMA-2 Trial Advances SC Amivantamab, Lazertinib for Advanced NSCLC With EGFR Mutations to the First Line

Pharmacy Times interviewed Nicolas Girard, MD, PhD, the head of the Curie-Montsouris Thorax Institute, Institut Curie, and professor of respiratory medicine at the Versailles Saint Quentin University inFrance, on the results of the PALOMA-2 trial (NCT05498428), which assessed subcutaneous amivantamab (Rybrevant;Johnson & Johnson) combined with lazertinib (Leclaza;Yuhan and Janssen Biotech) as a first-line treatment in patients with advanced non-small cell lung cancer (NSCLC) with EGFR exon 19 deletion (ex19del) or L858R mutations. These data, which were featured in a late-breaking presentation at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, showed a comparable response rate for subcutaneous amivantamab and lazertinib compared to the intravenous formulation in the MARIPOSA study (NCT04487080), which established the combination of amivantamab and lazertinib as superior to osimertinib (Tagrisso; AstraZeneca).

Pharmacy Times: What is the current standard of care in the first line for advanced non-small cell lung cancer with EGFR ex19del or L858R mutations, and how does subcutaneous amivantamab combined with lazertinib compare?

Nicolas Girard, MD, PhD: In the treatment of patients with common EGFR mutations or metastatic [NSCLC], the historical standard of care is osimertinib, which is a third generation [tyrosine kinase inhibitor (TKI)] that demonstrated a benefit vs the previous treatments, [which are] first second generation TKIs.

We have new options for these patients that show that we can do better than those osimertinib through combination. The first combination is chemotherapy plus osimertinib, the so called FLAURA2 [NCT04035486] regimen, leading to increase the median PFS from 19 months with osimertinib monotherapy to 24 months with chemotherapy plus osimertinib.

The second combination that demonstrated a similar benefit is the MARIPOSA regimen, combining a third generation TKI pretty similar to osimertinib, that is lazertinib, with a bispecific EGFR monoclonal antibody, that is amivantamab. So, the combination of amivantamab with lazertinib is another standard of care option for the first-line treatment of these patients.

Obviously, when we do this kind of combination, we need to combine the TKI with an intravenous drug, chemotherapy, the FLAURA2 regimen, or amivantamab in the MARIPOSA regimen. The advantage of the MARIPOSA regimen being chemo-free first-line treatment, leading in the global strategy for these patients to be able to deliver chemotherapy in later lines.

Back to this MARIPOSA regimen. Amivantamab is usually delivered, in the landmark study, intravenously, and we have seen during the ASCO 2024 meeting data with a subcutaneous formulation for amivantamab. The advantage is obviously the quality of life of patients and the optimization of hospital resources. Based on the data, we see that the subcutaneous formulation of amivantamab is actually reducing the risk of toxicity, especially administration-related reactions, which are observed in two-thirds of the patients with the intravenous formulation vs 15% with the subcutaneous formulation.

PALOMA-2 enrolled 126 patients who were treatment naive for EGFR mutant [NSCLC], did receive this combination of amivantamab subcutaneous plus lazertinib, and there was also recommended mandatory thromboembolism prophylaxis, as these events are frequent in EGFR [NSCLC]. Very interesting to see that in PALOMA-2, the response rates to amivantamab subcutaneous plus lazertinib was in line with that reported in the landmark MARIPOSA trial; it was 77% of patients who did show a response on the target lesion. So this is a next step for amivantamab plus lazertinib, subcutaneous formulation, better safety profile, and similar efficacy. We also saw during the meeting data from the PALOMA-3 study in the later line setting with the same combination, and in those patients, again, we had a similar efficacy pharmacokinetics, and the better safety with the subcutaneous formulation of amivantamab.

PALOMA-2 enrolled 126 patients who were treatment naive for EGFR mutant NSCLC. Image Credit: © Royalty-Free - stock.adobe.com

Pharmacy Times: What are current challenges in the treatment of advanced NSCLC, and how might subcutaneous amivantamab plus lazertinib help to address some of these challenges?

Girard: Well, the challenges in the management of [NSCLC] with common EGFR mutations is that, now that we have additional options, [what] will be the sequencing of these options. When to position amivantamab in the treatment strategy, when to position chemotherapy with probably the need to stratify patients based on the general condition, the status of the disease, number of metastatic sites, presence of [central nervous system (CNS)] disease, and also probably the biology of the tumor.

Based on the data from the MARIPOSA trial that we saw at ASCO 2024, we feel that the magnitude of benefit with the combination of amivantamab plus lazertinib vs osimertinib is similar whatever are the subgroups that are studied, especially in patients with characteristics associated with poor outcomes, such as liver [metastases], CNS disease, co-mutation in the tumor, or positive [circulating tumor DNA (ctDNA)] at the time of diagnosis.

So, we see that we can improve the outcomes of the patients whatever are the characteristic features, including patients with an expected poor prognosis with a single agent osimertinib. So, right now, we have several sequences that are possible. We may start with osimertinib, a single agent, and then have the opportunity to deliver the MARIPOSA-2 regimen, which is chemo plus amivantamab. We have the opportunity of a sequence of osimertinib, then chemo, then amivantamab plus lazertinib based on PALOMA-3. We have, obviously, MARIPOSA as a way to have an early exposure to the amivantamab and lazertinib combination, and giving the opportunity to deliver chemotherapy in a later line setting, possibly optimized with combination—we have some data with ivonescimab (AK112/SMT112; Akeso Inc), a bispecific VEGF antibody, and then we have the FLAURA2 regimen in the first-line setting, with the opportunity of rechallenge with chemotherapy, possibly associated with amivantamab MARIPOSA-2 or in the PALOMA-3 setting without chemotherapy.

Pharmacy Times: What are next steps after the phase 2 PALOMA-2 study?

Girard: We have the phase 3 PALOMA-3 trial conducted in patients in a later line setting, but being a registrational study, given the pharmacokinetic equivalence and efficacy data that have been generated. So hopefully the next step for amivantamab is to move to subcutaneous, probably for a majority of patients who are able to receive it, not only just in the hospital, but hopefully also for patients at home.

To me, it's a major change in the way we manage patients with EGFR mutant [NSCLC]. We have improved efficacy, and we have the opportunity still to have patients at home with at-home delivery of the treatment. So again, given the fact that those patients are usually young patients continuing to work and having daily activity, it's a way to maintain the quality of life.