MET Overexpression as a Predictive Biomarker in Post-Osimertinib NSCLC

Benjamin Besse, MD, PhD

The combination of lazertinib (Leclaza) and amivantamab (Rybrevant) in patients with EGFR-mutated non–small cell lung cancer (NSCLC) whose disease progressed on or after treatment with osimertinib (Tagrisso) demonstrated activity, according to updated findings from a treatment-naïve cohort from the phase 1/1b study CHRYSALIS trial (NCT02609776).1

Of the patients enrolled in cohort D with MET overexpression as identified by immunohistochemistry (IHC), the overall response rate was 61% and the median progression-free survival (PFS) was 12.2 months vs 14% and 4.2 months among patients with low MET expression.

The safety data reported in this cohort was also consistent with previous reports with no new safety signals identified.

These findings show that MET overexpression by IHC may be a predictive biomarker for response to the combination of lazertinib and amivantamab in this patient population. According to Besse, this biomarker will be further evaluated in the CHRYSALIS-2 trial (NCT04077463)

In an interview with Targeted Oncology^TM, Benjamin Besse, MD, PhD, professor of medical oncology at Université Paris-Saclay and Head of Clinical Research at Gustave Roussy discussed recent data from the phase 1/1b CHRYSALIS-2 of amivantamab and lazertinib in patients with EGFR-mutated NSCLC.

Targeted Oncology: Can you discuss the background of the CHRYSALIS-2 study in NSCLC?

Besse: This study is about finding efficacy of a combination of 2 drugs against EGFR, including lazertinib, a third-generation brain penetrant [tyrosine kinase inhibitor], and amivantamab, an antibody that targets EGFR. In our work, we studied the efficacy of the combination in patients with EGFR-mutated non–small cell lung cancer harboring exon 19 or exon 21 mutations that received osimertinib and then had resistance to osimertinib. In this situation, you usually give platinum-based chemotherapy. Here, we gave the combination of lazertinib plus amivantamab and the response rate in 101 patients evaluable for response was 30% with a median PFS of 5.7 months.

Please discuss the findings of the biomarker analysis of cohort D of the CHRYSALIS-2 study.

Part of the patients derived a strong benefit from this combination and the goal was to train a signature on the tissue to find who were the patients that benefited the most to this combination. In this cohort, all the patients had a mandatory biopsy before receiving the combination, so after the exposure of osimertinib. Seventy-seven patients got a biopsy and, in this tissue, we trained signatures. The signature that was the most positive was the expression by the tumor cells that have the protein MET on the surface of the cell. It's a simple test, immunohistochemistry, and the threshold for positivity was a 3 plus staining in at least 25% of the cells. We defined a met-positive group and a met-negative group. Thirty-six percent of the patients were considered MET-positive. In the MET-positive group, in this population, the response rate to lazertinib plus amivantamab was 61% and the median PFS 12.2 months. When met was negative, the response rate was 14% and the median PFS was 4.2 months.

This biomarker seems to discriminate between 2 populations, 1 with a high response and high benefit to the combination, and it needs to be confirmed. Two new cohorts will open and enroll patients to confirm this data. Additionally, we collected plasma before starting the combination and under plasma, you can analyze the circulating tumor DNA by NGS and define if you have a molecular mechanism of resistance towards osimertinib. This is what we did in 20 patients. With 19 patients, we found that there were molecular mechanisms of resistance dependent on EGFR and MET and in 20 patients, one was independent and the other, it was not found, but what is interesting is that response rate of the combination was roughly similar and MET of the resistance mechanism.

What advice do you have for community oncologists?

The data are quite convincing to conclude that we have an interesting signature to predict the efficacy of this combination. It has to be confirmed and later we will have how we use it in the current landscape of the treatment of EGFR-mutated non–small cell lung cancer. In the future, since we may have this combination in the first-line if the MARIPOSA trial [NCT04487080] is positive, it may be an option with the combination of chemotherapy and osimertinib. If we have many options, it is always good to have predictive biomarkers.

Were any of these data particularly surprising?

Not surprising. It's reassuring, because when you use an antibody that targets both EGFR and MET, you expect that the expression of the targets on the tumor cells will be predictive of efficacy, and this is what we have seen. I would say that 1 of the strengths of the study is that this MET evaluation was done on a fresh biopsy, meaning just before starting the combination. I would say we have an accurate reflection of the expression of MET on the tumor if we have used the archive tissue pre osimertinib, probably, the results would not have been so clear cut.

What are the next steps for research in this space?

The next step for the study is to confirm the predictive value in other cohorts, a cohort with the combination, the same combination, but also a cohort only with amivantamab. Later, we will see what we can do with this predictive signature in the new landscape of the treatment if we have this combination first-line, if the MARIPOSA trial [NCT04487080] is positive, or if we have a new combination, like chemotherapy plus osimertinib.

For a community oncologist, what are the key takeaways from this research?

The key takeaways are that today, amivantamab is available only for a small subgroup of EGFR mutated non–small cell lung cancer in those patients with exon 20 insertion of EGFR. But given the activity of the combination in the other patients with more classical EGFR mutations, it's very likely that this combination will be in our hands [soon] to treat these patients either in first-line, either maybe after failure of osimertinib, and it will be good to have a signature in this very near future to select the best patients for this treatment.

REFERENCE:

Besse B, Baik CS, Marmarelis ME, et al. Predictive biomarkers for treatment with amivantamab plus lazertinib among EGFR-mutated NSCLC in the post-osimertinib setting: Analysis of tissue IHC and ctDNA NGS. J Clin Oncol. 2023;41(16):9013. doi:10.1200/JCO.2023.41.16_suppl.9013