Analysis Highlights Acquired Resistance Mechanisms in METex14+ NSCLC

Mark M. Awad, MD, PhD

The clinical need to identify patients with MET exon 14 skipping (METex14)-mutated non—small cell lung cancer (NSCLC) and understand the characteristics of these cancers has grown in light of the recent regulatory approval of capmatinib (Tabrecta) in this indication, said Mark M. Awad, MD, PhD.

The accelerated approval was based on findings from the phase 2 GEOMETRY mono-1 study,¹ in which capmatinib led to a 67.9% objective response rate (95% CI, 47.6-84.1) in treatment-naïve patients with METex14-mutant NSCLC.

The FoundationOne CDx assay was simultaneously approved as a companion diagnostic for capmatinib to detect tumor mutations that lead to METex14 skipping.

During the 2020 ASCO Virtual Scientific Program, Awad presented findings from a study in which 60,495 samples from patients with NSCLC underwent next-generation sequencing—based hybrid-capture genomic profiling to identify METex14 skipping alterations and potential acquired resistance mechanisms.²

METex14 alterations were found in 2.3% of samples. Moreover, 32% of METex14-altered samples showed an MDM2 amplification, and 19% showed a CDK4 amplification. MET co-amplifications were present in 12% of cases.

Additionally, potential acquired resistance mechanisms such as secondary MET alterations and alterations in EGFR, ERBB2, KRAS, and PI3K pathways were identified.

"Since this is a relatively new target in lung cancer, it's been more important to try to understand the characteristics of these cancers, to see what other mutations may be present within the genome, and identify the other factors that may regulate response or resistance to immunotherapy or targeted therapies," said Awad. "By understanding resistance mechanisms, perhaps we can design better trials to delay [their] emergence. Then, if we do encounter acquired resistance, we can develop strategies to overcome those mechanisms."

In an interview with OncLive, Awad, clinical director of the Thoracic Oncology Treatment Center and physician at Dana-Farber Cancer Institute, and an assistant professor of medicine at Harvard Medical School, discussed the findings from the study, the importance of identifying patients with METex14 mutations, and the importance of understanding acquired resistance in NSCLC.

OncLive: What was the rationale for conducting this study?

Awad: This was a collaboration with Foundation Medicine where, in over 60,000 patients with NSCLC, we found METex14 mutations in over 1300 cases. This is an important and emerging subset of lung cancer to identify, especially now because we have an FDA-approved targeted therapy for patients with METex14-mutant NSCLC.

Could you discuss the data that led to the approval of capmatinib for patients with METex14-mutated NSCLC?

Over the years, many drugs have gone through clinical development for patients with MET-dysregulated cancers. Some of these drugs include agents such as crizotinib (Xalkori), tepotinib (Tepmetko), and savolitinib. In May 2020, capmatinib became the first FDA-approved drug for patients with METex14-mutant NSCLC.

That approval was based on data from the GEOMETRY mono-1 study in patients with METex14-mutant NSCLC who had not previously received a MET inhibitor. Based on the response rate and progression-free survival [seen in the GEOMETRY mono-1 study], we know drugs such as [capmatinib] have the potential to make meaningful differences for our patients.

What were the objectives of the analysis you conducted?

We had several goals for this study. We know many different types of mutations can be identified that can impact METex14, some of which lie in the flanking intronic sequences. One of the goals of this study was to see if certain mutations correlated more with other co-mutations or genomic abnormalities.

We were also looking to develop a better sense of factors, such as PD-L1 expression and tumor mutational burden, in this molecular lung cancer subtype.

In patients who had serial biopsies and underwent sequencing, we also tried to identify putative mechanisms of acquired resistance to MET kinase inhibitors with the hope that, by developing a greater understanding of acquired resistance mechanisms, we might be able to develop drugs to either overcome or, ideally, prevent resistance.

What do we know about acquired resistance to MET inhibitors?

What we found in this study, as well as what has been recently described in some other work in this space, is that mechanisms of resistance in METex14-mutant NSCLC are varied and can be complex.

Some patients develop on-target acquired resistance mutations. This means that MET mutates again, leading to secondary mutations within the MET kinase domain. This is particularly seen in certain recurring positions, such as D1228, Y1230, L1195, and others. We also see a subset of patients who develop acquired amplification of the MET mutation.

Additionally, we see a number of possible off-target resistance mechanisms or bypass track activations, such as amplification of wild-type KRAS or EGFR, other HER family receptors, and BRAF or other MAP kinase pathway molecules. This increases the complexity of resistance mechanisms in this subtype of lung cancer. Hopefully, we'll develop a strategy to develop improved therapies and prevent resistance from emerging.

What are the key findings from this study?

In this analysis of over 1300 patients with METex14-mutant NSCLC, we conducted a very comprehensive description of the co-mutational analyses within these cancers. We found that, although these cancers tend to have a lower tumor mutation burden compared to MET wild-type NSCLC, they have very high PD-L1 expression. A large subset, almost half, of patients with METex14-mutant NSCLC will have greater than 50% PD-L1 expression. We need to learn a little bit more and develop biomarkers within this subset to identify whether there are certain patients who will benefit from checkpoint inhibitors or not. Hopefully this analysis will help provide a greater framework for looking at some of these immune markers within METex14-mutant NSCLC.

We also saw that several patients with paired biopsies who were sequenced developed new resistance mutations over time at positions D1228, Y1230, L1195, and others, as well as bypass track resistance mechanisms in other MAP kinase pathway proteins or genes, including KRAS, BRAF, EGFR, or other HER family receptors.

This highlights the complexity of resistance but also a potential path forward for targeting resistance or developing combination strategies to delay the emergence of resistance.

How do you expect these findings to impact clinical practice?

This study showed that these mutations are not uncommon in NSCLC. [METex14 mutations] represent a small proportion of the total lung cancer population, but there are thousands of these cases in the United States and globally. As such, it is important to test patients for these alterations because we now have targeted therapies that are approved to treat patients with this type of lung cancer.

The other big takeaway is the importance of understanding resistance mechanisms to targeted therapies in this population and other subsets of lung cancer. Through studying resistance mechanisms, we've been able to develop successful strategies to overcome resistance in many cases. That is the hope for this subtype of lung cancer as well.

References

1. Wolf J, Seto T, Han JY, et al. Capmatinib (INC280) in METΔex14-mutated advanced non-small cell lung cancer (NSCLC): efficacy data from the phase II GEOMETRY mono-1 study. J Clin Oncol. 2019;37(suppl 15; abstr 9004). doi:10.1200/JCO.2019.37.15_suppl.9004
2. Awad MM, Lee JK, Madison R, et al. Characterization of 1,387 NSCLCs with MET exon 14 (METex14) skipping alterations (SA) and potential acquired resistance (AR) mechanisms. J Clin Oncol. 2020;38(suppl 15; abstr 9511). doi:10.1200/JCO.2020.38.15_suppl.9511