Treating Patients with MET Alterations: A Q&A with Dr. Ravi Salgia

Posted: February 12, 2020

Ravi Salgia, MD, PhD, is the Arthur & Rosalie Kaplan Endowed Chair in Medical Oncology and the associate director for clinical sciences at City of Hope’s Comprehensive Cancer Center. His many decades of research in MET and other oncogenic drivers has helped further lung cancer research and patient care. In the following interview, Dr. Salgia discusses current and future directions in the treatment of patients with lung cancer with MET alterations.

Q: Is MET a true oncogenic driver?
A: I’ve been working on MET research for a little more than 20 years now. The MET receptor tyrosine kinase was initially described in hereditary papillary renal cell carcinoma as having mutations, which were first seen in the tyrosine kinase domain. Laura Schmidt, PhD, who was at the National Cancer Institute at the time, conducted this research. The mutations that were observed were gain-of-function mutations, and they represented the MET oncogenic driver.

Then, through the work of various brilliant investigators, the hepatocyte growth factor was identified as the ligand for MET. Over time—specifically for the past 20 years—we have been able to study how in lung cancer, MET can be overexpressed, amplified, or mutated. In addition, MET may not be degraded properly, so it is constantly signaling at the cell surface. All of these factors help MET become oncogenic in a normal cell. This took us considerable time to determine. Today, it’s really exciting that MET is a known oncogene.

Q: How viable is MET as a therapeutic target?
A: Very viable. My colleagues and I were among the first research groups to identify the amplification and overexpression of MET in lung cancer, and we were actually the first ones to discover that MET could be mutated in lung cancer. We did that in SCLC first; that was our seminal discovery in 2003. We also identified the exon 14 skipping mutation at that point, and my lab also identified it in NSCLC in 2005. It took us approximately 10 to 12 years to determine that some of these mutations as well as MET amplification could be a potential therapeutic target. Drug companies developed MET inhibitors, and clinical trials were performed. I commend so many researchers who are currently investigating the MET receptor tyrosine kinase as a therapeutic target; it constitutes a very viable target, as mentioned, in lung cancer.

Q: We’re seeing data about exon 14 skipping mutations more frequently. Is this the next phase for research?
A: We first described it in 2003 in SCLC and then in 2005 in NSCLC, but it took us all this time to realize that it is a targetable receptor tyrosine kinase. Now we must determine how MET is important as a resistance mechanism to other therapeutics. How can it be targeted? And are there other mutations? We clearly have identified a large number of mutations of MET in lung cancer, but we do not know if they represent anything for us to target. Th is is a whole branch of MET research, as is further exploration of MET fusions that have recently been identified.

Q: What is the best way to identify MET alterations?
A: MET exon 14 skipping mutations as well as MET mutations and amplifications can be identified through next-generation sequencing, for which there are multiple platforms. MET overexpression can be identified through immunohistochemistry. As we design the next set of trials for identification of future biomarkers, we must keep in mind that, not only can you identify the amplifications, mutations, or the overexpression, but you can also identify the CBL molecule, which is the reason for MET’s inability to be degraded, as a mutation or loss of heterozygosity.

Q: In terms of the agents that might be active against MET, what is your perspective on the roles of crizotinib, capmatinib, and tepotinib?
A: I helped write the initial clinical trial for crizotinib for MET. When I was at Dana Farber Cancer Institute and then at the University of Chicago, we identified crizotinib as a very active drug against MET and MET mutations. Crizotinib has U.S. Food and Drug Administration (FDA) approval but only for exon 14 skipping mutations; we must determine crizotinib’s importance for other genetic or genomic alterations. Capmatinib has yielded durable responses and a manageable safety profile in patients with NSCLC and a MET exon 14 skipping mutation in the GEOMETRY mono-1 phase II trial. I think therapeutic selection should be determined by efficacy but also by duration of response and expected toxicities associated with each agent.

Q: Assuming that capmatinib and tepotinib do get FDA approval like crizotinib, do you think toxicities are going to prove a challenge with those?
A: As you know, immunotherapy is incredibly well tolerated but when toxicities develop, they can be quite challenging. Of course, that holds true for any of the drugs that we use regularly in our clinics. So is that going to be hard to manage? I don’t think so, but I believe we have to understand the potential toxicities and how we can help all of our colleagues in our multidisciplinary teams to best manage them.

Q: How is MET managed when it appears as a resistance mutation?
A: Ideally for any MET alteration that one identifies, we would love to have that patient on a clinical trial. That’s how you make breakthroughs—by understanding the molecular and therapeutic responses to agents that target these drivers, so that you can drive research. If a patient does not qualify for clinical trials, then TKIs should be considered. We are seeing MET amplification more frequently because of the drugs that target EGFR, which is leading us to conclude that MET amplification is not an uncommon mechanism of resistance. We also know that certain chemotherapies, for example cisplatin, can also cause MET amplification and/ or overexpression. So as we think about lung cancer and its responsiveness to therapeutics, when a patient’s disease progresses from standard therapy or TKIs, MET has to be part of the equation in evaluating mechanisms of resistance. MET should be looked at as a de novo molecule in terms of actionable genetic alterations

Q: Combatting therapeutic resistance will start with enrolling patients in clinical trials; then where do we go from there?
A: Heterogeneity becomes an issue. We worry about temporal heterogeneity, that is, the kind of molecular or cellular evolution that can occur over time. But we also worry about spatial heterogeneity— what happens to different metastases. Is the primary lung tumor the same as its metastasis to the brain or its metastasis to the liver? Is the metastasis to the liver the same as metastasis to the brain? Studying resistance in the context of spatial and temporal heterogeneity, especially for lung cancer, is crucial.

Q: What are the effects of brain metastasis on patients with MET alterations?
A: Patients with MET alterations can have brain metastasis. One must determine if stereotactic radiosurgery can be given to solitary metastasis or a number of metastases, or if one should consider oral therapeutics, and whether these oral therapeutics can cross the blood–brain barrier. I do not think enough is known at this moment to recommend a single course of action. There are incidental reports in the literature where one drug might cross the blood–brain barrier as compared to another one, but we need more data and greater understanding about the mechanism of action. Not only do brain metastases become an issue, but every once in a while we see leptomeningeal disease, which also is a serious complication. So how do we treat all of this? It’s an open-ended question for us for now.

Q: What is your current strategy for managing brain metastasis?
A: If it’s a solitary lesion or multiple lesions that can be encompassed by stereotactic radiosurgery, I tend to do that first. If the metastases are too numerous to count, then you have to think potentially about whole-brain radiation therapy (WBRT); however, we tend to reserve WBRT for extreme cases. If there is a very significant metastatic burden in the brain with a lot of edema and potential for herniation, you have to think about neurosurgery. Consequently, I still think a lot about the traditional therapeutic approaches for brain metastasis, but I also determine whether to give an oral TKI. For example, in the literature, there’s a case report about cabozantinib having efficacy against brain metastasis in a patient with a MET alteration. All of these things must be taken into consideration but, ultimately, the way we decide to treat brain metastases is in a multidisciplinary fashion with all of our colleagues weighing in, while at the same time also staying focused on the needs and considerations of the individual patient.

Q: What novel agents, if any, might make a difference regarding CNS efficacy in patients with MET alterations? Are there any ongoing trials for this?
A: Again, it’s an open-ended question for us for now because I don’t think enough is known about how these drugs penetrate the brain and how sustainable they are in the brain and in the spinal fluid. We need to conduct more studies, including prospective clinical trials, to be able to understand this issue. In vivo modeling and other modeling exist to help us determine which drugs can cross the blood–brain barrier, but I think the human blood–brain barrier is complex, and the capacity of cytotoxic agents and TKIs to penetrate into the brain is completely different, so we must study this.

In terms of ongoing trials, I don’t think there is anything specific to this topic. The ongoing trials are much broader. For example, capmatinib and tepotinib are being assessed in ongoing trials that often allow brain metastases. I think those trials should be further refined to include a cohort reserved for patients with brain metastases, once the initial data are reported. The other question is whether agents can be used in combination (such as with bevacizumab) if one has brain metastasis. Those are each important questions to ask in further research. ✦