Positive Tepotinib Data Underscore Value of Liquid Biopsies in Non-Small Cell Lung Cancer

Xiuning Le, MD, PhD

In the phase II VISION study, tepotinib demonstrated promising responses and tumor shrinkage in patients with non–small cell lung cancer (NSCLC) who harbor the MET exon 14 skipping mutation in 99 evaluable patients, which included 66 patients who were entered into the study based on results from a liquid biopsy assay.

Tepotinib, an oral MET inhibitor, induced an objective response rate of 46.5% (95% CI, 36.4%-56.8%) in the VISION study. The median duration of response was 11.1 months (95% CI, 7.2-not evaluable), and the disease control rate was 65.7% (95% CI, 55.4%-74.9%).

The MET exon 14 skipping mutation occurs in approximately 3% to 4% of patients with NSCLC and more frequently in older adults. The mutation is also mutually exclusive with other frequently occurring genomic alterations. These mutations are often determined by tissue biopsies, but this trial uniquely demonstrated that this mutation can also be detected with a liquid biopsy assay and will produce the same benefit among patients.

“For this older patient population, this is important because you don't want to repeat the [tissue] biopsy to do the testing,” said Xiuning Le, MD, PhD. “If it can be with a very convenient blood draw, then you can detect if the patient has MET exon 14 and subsequently confer the benefit.”

In the liquid biopsy cohort of patients, the objective response rate was 48.5% (95% CI, 36.0%-61.1%) versus 50.0% with tissue biopsy (95% CI, 36.8%-63.2%). The median duration of response was 9.9 months in the liquid biopsy cohort (95% CI, 7.2-NE) versus 14.0 months in the tissue biopsy cohort (95% CI, 7.3-NE), and the disease control rate was 65.2% (95% CI, 52.4%-76.5%) versus 69.7% (95% CI, 57.1%-80.4%), respectively.

In an interview with Targeted Oncology, Le, of The University of Texas MD Anderson Cancer Center, discussed the results of the phase II VISION study. She also highlighted the role of liquid biopsy in this space.

TARGETED ONCOLOGY: What was the rationale for this study?

Le: In the last, I will say 2 decades, we know a subset of lung cancers have the oncogene driver. If we can target appropriately those patients who derive significant benefit. So met exon 14 is a newer target. It becomes very clear in the last 5 years or so that for those patients, their tumors are dependent on my METexon 14 The idea is, if the MET exon 14 is skipped out due to the mutation, the MET signaling just keeps going to drive the cancer cells growth. That's how it turned into a lung cancer.

Tepotinib, the small molecule inhibitor, is a specially designed small molecule that's an oral drug, once a day, [which is] very convenient. The drug targets the intracellular part of the MET, even with the 14 skipped. Tepotinib still works because it is an optimized molecule for MET exon 14 and also for MET amplification, and the molecule is very potent. In the cell culture system, you only need a nanomolar in order to achieve a complete suppression and in patients. We also know this is very efficacious with more than 99% of target engagement. That's the idea of why we have established this oncogene driver. We have a smart designed small molecule inhibitor, so we wanted to test if this molecule will work in this patient population.

TARGETED ONCOLOGY: How was this study designed?

Le: This trial is a single-arm trial. The hypothesis is very strong, and the biology is completely laid out by the scientific community. Using a single-arm [design] rather than having a chemotherapy comparison arm is ethical because we don't want to deprive half of the patients who have to go on to chemotherapy, so it's a single-arm design.

Nowadays, I think the field, including the FDA, accept targeted therapy, and we can use this type of trial design because MET exon 14 is not a very common alteration in lung cancer. This trial is a single-arm [study] but multicenter. We have over 130 sites globally enrolling patients in order for us to have a good cohort of patients to know if our hypothesis holds true.

TARGETED ONCOLOGY: What were the results?

Le: The trial is massively positive. What we've seen is, in the first 99 patients we can report on, the response rate is 46%. When we talk about response rates, the tumor has to shrink by 30%, and we call that a real response. In the 99 patients, we have 90% of tumor shrinkage, really showing the hypothesis was correct. The small molecule inhibitor worked on those tumors and induced tumor shrinkage. Some patients are shrinking more, and some tumors are shrinking less, but this is a positive results showing tepotinib works for this patient population.

TARGETED ONCOLOGY: What did the safety profile look like for this agent?

Le: For tepotinib, we see the same signal of safety with the phase 1 portion of the trial. It is very well tolerated, even for the older patient population. The toxicities are the class effect meaning that for most of the inhibitors, because of how it inhibits oncogenic MET, it also inhibits normal MET.

We see peripheral edema. We see patients have some nausea or upset gastrointestinal. We saw occasionally patient shave impaired liver function, but those are manageable and occur in a relatively small subset of patients.

TARGETED ONCOLOGY: What population of patients with NSCLC have the MET exon 14 skipping mutation?

Le: The median age for MET exon 14 skipping mutations is 74 years old. In comparison, if we think about EGFR-mutant NSCLC or ALK-rearranged NSCLC, the patient population is much older because EGFR-mutant patients are more around 50 to 60 years old; ALK patients are even younger, around 40 to 50 years old. For this patient population, it's so important to have a chemotherapy pill rather than trying to convince, say, a 78-year old to go through the very harsh traditional chemotherapy.

TARGETED ONCOLOGY: What are the implications of the data from this study?

Le: Tepotinib has been approved in Japan for clinical use that happened in March 2020. The FDA gave us the Breakthrough [Therapy designation] for evaluation to see if tepotinib will be applicable for MET exon 14-positive patients. We're hopeful that we can push tepotinib to the patient front sometime later this year.

TARGETED ONCOLOGY: Are there any next steps planned for this trial?

Le: We're not planning on phase 3 because we think for a targeted therapy showing this much definitive efficacy, it is enough to convince the FDA to allow us to use this in the patient population in the near future. However, I think the field is constantly moving on. We show in this trial that the duration of response is 11 months, meaning if you're a patient and you get on to the study, I can tell you [there should be] 90% tumor shrinkage. Then if that happened, I will tell you, you can be on the drug for about a year, but what after that 1 year of benefit. When the tumor progresses, do we have combinations? Do we have newer agents to tackle the resistance? I think that will be the big question for the field coming up.

TARGETED ONCOLOGY: What else would you like to highlight from this study?

Le: I think 1 particular point to stress from this trial is we also allowed the patients to be enrolled based on their liquid biopsy and based on their bladder tumor marker, so we had 66 patients [from this]. They had MET exon 14 detected in the blood. When we compare the liquid cohort versus the tumor biopsy cohort, we see completely the same response.

For this older patient population, this is important because you don't want to repeat the [tissue] biopsy to do the testing. If it can be with a very convenient blood draw, then you can detect if the patient has MET exon 14 and subsequently confer the benefit. I think that's very important information coming out from this study.

Furthermore, for this 66-patient cohort, we started to see that we can truly use the circulating tumor DNA to monitor the disease. In this paper, we show that in a subset of patients, the MET exon 14 disappeared in their blood, and that coincides with the CT scan showing the significant tumor shrinkage.

Another note is this way to monitor the disease. Now we're waiting to see when the data is more mature to see if that will coincide with the disease progression. Can we help to predict when we need something else? What's the resistant mechanism? I think that's a very interesting part of we're looking forward to in the data.

TARGETED ONCOLOGY: Do you see the role of liquid biopsy becoming more prevalent in lung cancer?

Le: I will say yes because I think liquid biopsy and tissue biopsy are complementary to each other. Liquid biopsy is very convenient and very non-invasive to the patient, and it can be done at multiple time points. Over the course of treatment, however, there are information we cannot learn from the liquid biopsy. For example, certain immunotherapy-related markers, like PD-L1, cannot be done because the sequencing fragments are much smaller than the real tissue DNA sequencing.

Certain research cannot be done just by liquid biopsy, but I think liquid biopsy will become more and more important, both in the clinical practice and also in the translational research.