Encouraging Larotrectinib Data Underscores Importance of Genetic Testing in Metastatic Solid Tumors

Marcia Brose, MD, PhD

Larotrectinib (Vitrakvi) demonstrated durable efficacy in a tumor-agnostic fashion as treatment of patients with TRK fusion-positive solid tumors, and also appeared to be well-tolerated in an analysis presented during the American Society of Clinical Oncology (ASCO) Virtual Scientific Program. These findings underscore the importance of routine genetic testing for patients with solid tumors.

The objective response rate (ORR) was 71% (95% CI< 62-79), and complete responses (CRs) were observed in 12 patients (10%), partial responses in 70 patients (60%). Additionally, 19 patients had stable disease (14%), and 2 had progressive disease (14%). The median duration of response was 35.2 months (95% CI, 21.6-not estimable [NE]), and the median time to response was 1.8 months (range, 0.9-6.0).

Median progression-free survival was 25.8 months (95% CI, 15.2-NE), and the 12-month progression-free survival rate was 61%. The median overall survival data had not yet been reached after median follow-up of 15.8 months, but the overall survival rate at 12 months or longer was 87%.

The safety findings were consistent with prior findings for the overall population. Treatment was discontinued in 8 patients (7%) due to a treatment-emergent adverse event (TEAE), and 1 patient discontinued due to a TEAE related to larotrectinib. Eight TEAE-related deaths (7%) occurred in the study, but the majority of deaths were due to disease progression of an underlying oncological disease or related complications.

The expanded data for this analysis of larotrectinib was comprised of data from a phase 1 in adult patients with cancer (NCT02122913), the phase 2 NAVIGATE study (NCT02576431), and a phase 1/2 in pediatric patients (NCT02637687). Pediatric patients were not included in this analysis.

In an interview with  Targeted Oncology,  Marcia Brose, MD, PhD, director of the Center for Rare Cancers and Personalized Therapy, director of the Thyroid Cancer Therapeutics Program, associate professor of Otorhinolaryngology: Head and Neck Surgery at the Hospital of the University of Pennsylvania, and associate professor of Medicine at Penn Medicine, discussed the importance of conducting genetic testing on all patients with metastatic solid tumors following the exciting data on larotrectinib.

TARGETED ONCOLOGY: Would you like to provide some background to larotrectinib as a treatment for patients with cancer?

Brose: Larotrectinib was 1 of the first drugs that was to be approved for a genetic abnormality in a tumor-agnostic fashion across all tumors and only the second agent to do that because pembrolizumab was the first to be approved across all tumors. Larotrectinib was approved a couple of years ago for TRK fusion cancers. TRK fusions can be extremely rare in some tumor types, but it can be more common and others, and for that reason, if you got tested and you had a TRK fusion, you were then able to get the medication as part of this study. The study that was presented at ASCO is a follow-up. It's an update of data that we've had previously, but over 16 different tumor types were treated.

Our patient patients who have TRK fusion cancers are eligible to receive larotrectinib, and the results in the first study were really quite remarkable with a 76% response rate, and approximately a 10% complete response rate. These data were to follow up to see how the data compared.

TARGETED ONCOLOGY: What were the methods of design, and what tumor types were included in this patient population?

Brose: Any patient who had a TRK fusion, regardless of where it came from, was eligible for this study. In the case of the data set that was presented, we just selected the patients who were adult patients, over 18. These patients had metastatic disease, many of them had failed multiple lines of therapy, and so if they tested positive on a fusion panel, they then received larotrectinib, and that dose was 100 milligrams twice daily. Those are the patients in this study, and for the study design, there were 3 studies that were brought together. There was originally a pediatric trial combined with a phase 1 and phase 2 expansion cohort, excuse me expansion cohort, but the pediatric patients were not included in this analysis.

TARGETED ONCOLOGY: What were the results from this analysis?

Brose: What we found was that the overall response rate was 71%. That was still quite remarkable because it was still over 70%, showing that it was not just the pediatric patients who are getting these really good responses. So that's the first take- home message. The other take- home message is that there was a very good response rate even in patients who had brain metastases. For that reason, again, a notable finding was that patients with metastatic disease in the brain could have responses even in the central nervous system (CNS), which of course is always a concern because we always are concerned that some of the therapies that we have do not penetrate metastasis in the brain. Those were the 2 big take home messages of from this study.

TARGETED ONCOLOGY: In terms of safety, how well tolerated is larotrectinib?

Brose: Larotrectinib is extremely well tolerated, and when we look at the poster from ASCO, we can actually see that there are extremely few grade 3 toxicities that are attributed to larotrectinib. Patients are doing really well. Again, with a 10% complete response rate, in addition to all the other patients who are getting really deep responses, it just blows almost all of the comparative chemotherapies in each of these cancers out of the park.

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

Brose: I think that right now, the most important thing is that the sponsor is working together to create a way for patients to be able to get tested because, at this point, we now have a fantastic drug that's very active. Entrectinib (Rozlytrek) is another drug that's also now FDA-approved for these TRK fusions, but the problem about patients getting these therapies is going to be testing. I think the next step is to try to encourage people across the board that any patients who have metastatic solid tumors should get tested. It's not covered by insurance, so they're now trying to create additional ways for patients to get tested, or in other words, to have support so that that testing can be paid for

TARGETED ONCOLOGY: What are the implications of these data?

Brose: I think the most amazing implications of these data are if you're an oncologist and your patient has metastatic disease, these patients can end up with no evidence of disease. I really think it means that we're in a new ballpark for the responses that we can expect or hope for. I think that ever since I was a fellow, with metastatic disease, the best we could hope for was usually in most cases stable disease. There are a few exceptions to that, but once people had metastatic disease, we really hoped that we could stabilize it, maybe have a little bit of response, and increase overall survival in that perspective. Now that we actually have an opportunity to create really significant responses, we start to get back into the realm of significant changes to people's quality of life, and presumably overall survival will be affected, although that still has to be proven.

The other interesting thing about this is if you're having these great responses, where else can we use these drugs. For instance, if a patient has a large tumor, and we can shrink it considerably, maybe now they can have surgery that they couldn't otherwise have. This has already been shown with larotrectinib in the pediatric population where there are patients who had sarcomas that would not have been amenable to surgery or limb-sparing disease; now they're able to have significant responses, surgeries done with no evidence of disease and clear margins.

These are really spectacular, life-altering types of responses. I think now we're in a range that we can continue to pursue some of these targeted therapies. Our hope is now to get into this new era of really significant improvement in quality of life for even our patients with metastatic disease.

TARGETED ONCOLOGY: In these data, thyroid cancer actually made up 22% of this patient population, so how is larotrectinib impacting that population in particular?

Brose: We've had a lot of success with targeted therapies in thyroid cancers, as you're well aware, and for the last 4 or 5 years, we've really had at least 2 different targeted therapies, sorafenib (Nexavar) and lenvatinib (Lenvima), have been approved. A third drug, cabozantinib (Cabometyx), is now in clinical trials for FDA approval for differentiated thyroid cancer. These are mostly differentiated thyroid cancers that have fusions, and it doesn't tend to be the regular thyroid cancers. However, even though these are very well tolerated drugs and patients can stay on them for many years, they do have side effects. I think now that we have an agent that seems to be even less toxic than those drugs, we are now obligated to get the genetic testing on our thyroid cancer patients prior to starting them on systemic therapy because we wouldn't want to miss the presence of attraction as then we could possibly get them started on this agent that would be less toxic.

TARGETED ONCOLOGY: Is there anything else you would like to highlight from this analysis?

Brose: We now are in a new age, and between CNS responses and responses across the board, I think that all people who treat solid tumors need to start thinking about getting their patients tested. I mean, that is absolutely the most important thing, and we need to get everyone to do it. Remember, in lung cancer it might only be 1% of patients, but there are so many lung cancer patients out there that even 1% is a large number of patients. It really is important to make sure that people understand which tests actually test for the fusion because that's not true of all of the testing and then as much as possible, we're ordering this test on all of our metastatic patients.

TARGETED ONCOLOGY: What did you find most exciting at this year’s meeting?

Brose: I just think that overall our targeted therapies and even a few more of the immunotherapies now are making a huge impact. It's a really exciting time to be in oncology because we're now getting responses, as I said, in the metastatic patient who we used to have lower expectations for. I think that this ASCO is really turning our expectations for those patients, from people who are going to live for maybe a few months to a couple of years to now people who are going to be living several years. I mean, this is really a turning point, and I'm hoping that we'll be able to continue to build on this and years to come.