MARIPOSA Trial Shows PFS Benefit With or Without CNS Disease in NSCLC

Joshua K. Sabari, MD

Assistant Professor, Department of Medicine

NYU Grossman School of Medicine

Director, High Reliability Organization Initiatives

Perlmutter Cancer Center

New York, NY

Targeted Oncology: Could you describe the mechanism of action of amivantamab (Rybrevant) compared with other EGFR-targeted therapies in non–small cell lung cancer (NSCLC)?

Joshua K. Sabari, MD: Amivantamab is a unique therapeutic. It has a different mechanism of action compared with EGFR-TKIs [tyrosine kinase inhibitors]. TKIs are straightforward to think about. You have binding in the membrane and essentially you have cessation of the constitutive activation of a receptor. With amivantamab, it's an EGFR and MET bispecific and the MET entity has an interesting modality potentially targeting resistance. But up front, it allows us to anchor and target EGFR more directly and impacts both intercellularly and intracellularly.¹

It works by 3 different mechanisms of action. First and foremost, you get standard ligand blocking, and that happens in the cell surface. Then you also get receptor internalization and degradation. The reason I became excited about this compound early on was this immunotherapeutic-type activity. All patients with EGFR-mutant lung cancer are going to have resistance at some point to their TKI, whatever generation it is…. This is an agent that potentially has both antibody-dependent cellular trobocytosis as well as antibody-dependent cellular cytotoxicity. By binding the FC receptor, we can bring natural killer cells and macrophages in proximity to the tumor cells, leading to cell death.

We do this in this setting in combination with lazertinib [Lazcluze]. Lazertinib is essentially, in my mind, equivalent to osimertinib [Tagrisso]. It is a third-generation EGFR-TKI. It was approved outside the United States in South Korea, but now [is approved] in the United States in combination with amivantamab.²

What led to the approval of this combination?

The MARIPOSA trial [NCT04487080], which is a randomized phase 3 study looking at 3 arms…. The study goal was to…improve upon osimertinib [by] studying the combination of amivantamab and lazertinib vs osimertinib. Those are the treatment arm and control arm. They added a third arm [lazertinib alone] based on the FDA [asking] how much of this is being driven by lazertinib vs amivantamab?

It’s a 1074-patient study with 2:2:1 randomization, and we enrolled patients with metastatic disease who had an EGFR exon 19 deletion or an [exon 21] L858R mutation. The primary end point was progression-free survival [PFS] via blinded independent central review [BICR], and we're primarily looking at amivantamab/lazertinib vs osimertinib. Some of the stratification factors we looked at was whether a patient had brain metastases or not, whether a patient was Asian, and whether a patient had an exon 19 deletion or an L858R mutation.

The PFS presented over a year ago showed that the amivantamab/lazertinib arm had a median of about 24 months vs 16.6 months with osimertinib alone.³ The lazertinib control arm was similar, in that…18-month range, and we saw updated data at the [2024] World Conference on Lung Cancer showing minor differences between lazertinib and osimertinib, primarily related to some of the skin toxicity as well as some of the gastrointestinal toxicities.⁴ At 12 months, 73% were progression free if they received amivantamab/lazertinib vs 65% if they received osimertinib.³ If you look at the 2-year landmark, 48% were progression free with amivantamab/lazertinib and 34% were progression free on osimertinib. The HR was 0.70 [95% CI, 0.58-0.85; P < .001], a 30% reduction in death or progression in this patient population.

How did patients with brain metastasis respond in this trial?

We looked at those patients with or without brain metastases [in terms of] PFS by BICR. Clearly those without brain metastases as a whole do far better.³ We're seeing a 27.5-month median PFS compared with 18.3 months [for those with brain metastases] with amivantamab/lazertinib. But we see a significant delta [vs osimertinib in both groups]. The curves still separate very nicely, but overall, there is a difference in patients who have brain metastasis. An important aspect of trial design is that these patients all had serial MRIs of their brain performed. We were monitoring the central nervous system [CNS] very closely so we could understand and report what the PFS was.

They studied the extracranial PFS. This is excluding those patients whose disease progressed in the brain only and just looking at extracranial [progression]. This is more equivalent to what we saw [with osimertinib plus chemotherapy] in FLAURA2 [NCT04035486]. The numbers start to get much better: [a median of] 27.5 months for amivantamab/lazertinib vs 18.5 months with osimertinib [HR, 0.68; 95% CI, 0.56-0.83; P < .001].

But to be honest, this is not the way the study was designed. The study was designed to look at intracranial activity, so that's why it's hard to compare cross-trial in this patient population. In the study that we're talking about here, serial brain MRIs were conducted, which was not the standard of care in the osimertinib trials—the FLAURA study [NCT02296125] or the FLAURA2 study. It's important to note that both median PFS estimates increase if you take out CNS-only first sites of progression.

_References:

_{1. Vyse S, Huang PH. Amivantamab for the treatment of EGFR exon 20 insertion mutant non-small cell lung cancer. Expert Rev Anticancer Ther. 2022;22(1):3-16. doi:10.1080/14737140.2022.2016397}

_{2. FDA approves lazertinib with amivantamab-vmjw for non-small lung cancer. FDA. August 20, 2024. Accessed December 24, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lazertinib-amivantamab-vmjw-non-small-lung-cancer}

_{3. Cho BC, Felip E, Spira AI, et al. Amivantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): primary results from MARIPOSA, a phase III, global, randomized, controlled trial. Ann Oncol. 2023;34(suppl 2):S1306. doi:10.1016/j.annonc.2023.10.062}

_{4. Gadgeel S, Cho BC, Lu S, et al. Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced NSCLC: longer follow-up of the MARIPOSA study. J Thorac Oncol. 2024;19(suppl 10):S10-S11. doi:10.1016/j.jtho.2024.09.026}