EP. 2B: The Impact of Updated Sub-Analysis Data on the Role of Larotrectinib for NTRK Fusion-positive Thyroid Cancer

Fusions between neurotrophic receptor tyrosine kinase (NTRK) genes and other gene partners have been studied as a component of oncogenesis in numerous solid tumor types. Across these various tumor types, treatment with tropomyosin receptor kinase (TRK) inhibitors has the potential to provide therapeutic benefit and may improve patient outcomes.

An oral, selective pan-TRK inhibitor, larotrectinib, was first approved in November 2018 following the results of 3 pivotal clinical trials: LOXO-TRK-14001 (NCT02122913), NAVIGATE (NCT02576431), and SCOUT (NCT02637687). In August of the following year, the FDA also approved entrectinib based on data from numerous studies: ALKA-372-001 (EudraCT, 2012–000148–88), STARTRK-1 (NCT02097810), and STARTRK-2 (NCT02568267). The initial approval and key safety and efficacy data for both of these agents are explored in “Targeting the TRK Pathway in Pediatric or Adult Patients with Advanced or Surgically Resectable NTRK Fusion-positive Solid Tumors,” the first article in a new Precision Medicine Perspectives series.

In this series, "Advances in the Treatment of NTRK Fusion-positive Cancers," key experts in the management of patients with NTRK fusion-positive cancers consider the evolving role of TRK inhibitors in the therapeutic landscape and reflect on potential challenges or unmet needs affecting this patient population.

Ahead, Steven G. Waguespack, MD, professor in the Department of Endocrine Neoplasia and Hormonal Disorders at The University of Texas MD Anderson Cancer Center in Houston, TX, discusses his presentation of extended safety and efficacy data on larotrectinib of patients with thyroid cancer at the 2021 American Thyroid Association Annual Meeting. Dr Waguespack further considers how the results of this recent pooled analysis may affect the treatment paradigm for patients with NTRK fusion-positive cancers.

Targeted Oncology™: How have NTRK inhibitors such as larotrectinib affected clinical outcomes and quality of life in patients who have NTRK fusion-positive solid tumors such as thyroid cancer?

WAGUESPACK: Selective NTRK inhibitors such as larotrectinib have really become game-changers in the treatment of various solid tumors. Larotrectinib, in particular, was FDA approved in a tissue-agnostic fashion, meaning that its use is approved in any tumor that harbors a fusion involving 1 of the NTRK genes. What that means is that you're treating an NTRK fusion-positive cancer, not just “breast cancer” or “sarcoma” or “thyroid cancer”. These fusions are found in a lot of rare cancers, including thyroid cancer, which is my area of expertise. It has really changed the landscape because the selective NTRK inhibitors are very effective for treating these tumors; many of them are very rare tumors without previous good standard-of-care [treatments]. The response to treatment is very rapid, so the treatment works; you see the tumor shrinking very early on, and more importantly, the patients tolerate treatment very well. These drugs are associated with generally mild and manageable adverse effects (AEs), with very few severe adverse effects that warrant reducing the dose or stopping the drug altogether.

Targeted Oncology™: At the 2021 American Thyroid Association Annual Meeting, you presented some of the long-term data from the different trials in patients with NTRK fusion-positive locally advanced or metastatic thyroid cancer. Can you describe the demographics of patients who were included in the trials?

WAGUESPACK: At the 2021 ATA meeting, I was fortunate to present, on behalf of my colleagues, the results of a pooled analysis of thyroid cancer patients who were treated in 1 of 3 different clinical trials during the development of larotrectinib.

A note about NTRK fusions and thyroid cancer: they are fairly rare. If you look at adult patients with papillary thyroid carcinoma (PTC), NTRK fusions are found in about 6%. These NTRK fusions are primarily found in younger patients. We tend to see them more in patients with a younger onset of disease, but they can be found across the age spectrum from very early childhood through late adulthood. They're found in various subtypes of thyroid cancer as well, but predominantly, we're seeing it in the PTC subtype.

In terms of the demographics of the patients in the 3 studies, there were a total of 29 patients. About 69% of them had PTC, 24% had anaplastic thyroid carcinoma (ATC), and the remaining 7% had follicular thyroid carcinoma. One caveat is that the studies did not require a centralized review of the pathology. On subsequent analysis, it became clear that there were also 3 patients who had another subtype of thyroid cancer called poorly differentiated thyroid carcinoma, and for the purpose of this study, 2 of those patients had been classified as ATC and 1 as PTC.

The median age of the patients was approximately age 60, but the patients on study ranged from age 6 all the way through age 80. In terms of their treatment background, 55% of these patients had already received prior systemic therapy, and 31% had received 2 or more prior lines of therapy. Systemic therapy included some type of chemotherapy or oral targeted agent. The vast majority of the patients with differentiated thyroid carcinoma had been treated with radioactive iodine. Also included in the analysis were 4 patients, or 14%, who had brain metastases.

Targeted Oncology™: How do the response rates of these patients with thyroid cancer treated with larotrectinib compare with the response rates of patients with thyroid cancer who have been treated with other targeted therapies?

WAGUESPACK: What's incredible about the larotrectinib data is the significant response rate that is seen in the patients. When looking at the pooled analysis of these 3 trials, the objective response rate was 71% across all the patients. If you specifically look at the patients with the differentiated thyroid carcinomas, who typically respond better to treatment, the objective response rate was 86%.

Historically, there are only 2 other FDA-approved therapies specifically for thyroid cancer, lenvatinib and sorafenib. These are oral multikinase inhibitors. When looking at the lenvatinib phase 3 data, the objective response rate was 65%. That particular study didn't include anaplastic thyroid carcinoma. If we compare apples to apples, the response rate for lenvatinib in patients with PTC was 65% whereas with larotrectinib, it's 86%. Sorafenib doesn't perform as well; the objective response rate for sorafenib was only 12%, and that was in patients with differentiated thyroid carcinoma.

There's only 1 study I'm aware of that uses immunotherapy specifically for advanced thyroid cancer, and that was with pembrolizumab, which is an anti–PD-1 inhibitor. The objective response rate in that study was quite disappointing: it was only 9%.

Targeted Oncology™: What are the differences between the response rates that were seen in patients with differentiated thyroid cancer compared with those patients with ATC? What may be unique about these different types of thyroid cancer that could explain why response rates are so different?

WAGUESPACK: Among the various subtypes of thyroid cancers, there’s PTC and follicular thyroid carcinoma, which are called well-differentiated thyroid carcinomas. As these tumors evolve, they develop additional somatic mutations that make them more aggressive clinically. They tend to metastasize more, progress more, and they tend to lose the ability to respond to radioactive iodine as they progress down this continuum of differentiation.

After the well-differentiated thyroid carcinomas, you have the poorly differentiated thyroid carcinomas. Further down the road are the frankly anaplastic, or undifferentiated, thyroid carcinomas. The big difference in terms of why we see a differential in response rate is the fact that ATCs tend to have multiple somatic mutations, whereas the well-differentiated thyroid carcinomas will typically just have 1 molecular driver.

As an example, patients with TRK-fusion positive PTC are most likely to just have that single NTRK fusion, whereas patients with ATC have that NTRK fusion, but their tumors usually harbor other mutations, such as TERT promoter, TP53, or PIK3CA mutations, which increase the aggressiveness of that tumor. The thought is that a single-agent TRK inhibitor such as larotrectinib is just not sufficient to treat a patient with ATC because there are other genes that are modifying the tumor’s ability to respond to that treatment.

Still, looking at the larotrectinib data, the objective response rate in ATC was 29%. Among ATC-specific trials, there was a single-arm agent trial with lenvatinib, which was closed due to futility because the threshold of a 15% objective response rate was not reached.

We don’t necessarily know if any of these other patients—for example, patients with ATC—had a BRAF mutation. It’s unlikely because we don’t usually see a combination of an NTRK fusion with a BRAF mutation. A BRAF-mutated ATC can respond quite beautifully to selective inhibition of BRAF and MEK. Looking at a recent paper published on that experience, the overall objective response rate was about 56% in patients with BRAF-mutated ATC who were treated with dabrafenib and trametinib.

Targeted Oncology™: Looking at the safety results of this trial, 7% of patients in the analysis had grade 3 or higher AEs that were related to larotrectinib. What were the AEs that were observed in the study? Did they resolve? What can we learn from them?

WAGUESPACK: The good news is that the AE profile is very, very good. When looking at the overall drug-related AE profile, it tends to be mild. What we specifically see with this drug are myalgias and dizziness. That is a testament to the fact that TRK signaling is throughout the nervous system, so it’s not unexpected that a selective TRK inhibitor might cause some neurological AEs. Some other AEs that were seen more consistently included abnormalities in white counts and hemoglobin and elevation of liver function studies.

There were very few grade 3 or higher AEs that were felt to be larotrectinib-related. Specifically, there were only 2 patients who had a grade 3 AE, and both of those patients had abnormalities with either decreased hemoglobin or decreased white blood cell count. These AEs do resolve with a drug hold or dose reduction. Only 2 patients had to do a dose reduction, and there were no patients who discontinued treatment due to an AE.

There were 2 patients who died on trial, but they died of progressive cancer, and that was not felt to be larotrectinib-related.

Targeted Oncology™: As results from these trials continue to emerge, are there other outcomes that you are looking forward to seeing?

WAGUESPACK: There are a lot of long-term outcomes that I’d be interested in learning more about. There’s a lot of interest in looking more at the molecular genotype of these tumors to see if there are other somatic mutations that might predict poor response to larotrectinib. In thyroid cancer, we primarily see fusions only in NTRK1 and NTRK3, and it would be interesting to look at whether the specific NTRK gene or the fusion partner gene leads to a difference in response or duration of response. I think that is 1 of the most interesting things that’ll probably be looked at.

The duration of response with this treatment is really excellent, and in these patients, 84% were still responding at 24 months after treatment, so I think we’ll all be interested to see how long this lasts. Of course, we anticipate that some patients may progress because of acquired resistance due to other mutations that can occur in the NTRK genes, so I think it’ll be interesting to see more of the longer-term outcomes.

In a different thought process, when we start patients with solid tumors on systemic therapy, there’s no thought of stopping that therapy. We usually continue it until they progress, and then you switch to another line of therapy. Given some of the responses seen with larotrectinib—particularly the 2 complete responses, at least radiographically—I think it would also be interesting to know whether there are some patients who have this great response who could withdraw from therapy and maintain that response. That’s another interesting long-term outcome that I would personally like to learn more about.

Targeted Oncology™: How might this data affect your clinical practice? Does it change how or when you prescribe larotrectinib for patients with NTRK fusion-positive thyroid cancer?

WAGUESPACK: Absolutely. Drugs like larotrectinib really are game-changers because they’re so effective. They have a very rapid onset of response and are well-tolerated. I can only speak from a thyroid cancer perspective, but I think it teaches me—and all of us—that, when you see a patient with an advanced thyroid cancer, or really any solid tumor that might harbor an NTRK fusion, physicians should first look for it. I think that more people are now aware of these fusions and are looking for them. Next-generation RNA sequencing is the ideal way to look for an NTRK fusion, so we’re doing more molecular profiling to specifically look for these targetable fusions.

In my mind, it’s also making drugs like larotrectinib a first-line therapy for tumors that harbor NTRK fusions; that’s changing our treatment algorithm. It’s also a game changer because these tumors respond so quickly, and the question now becomes: can we use these drugs in a neoadjuvant setting? Obviously, a patient could present with very locally advanced thyroid cancer, and if we find they harbor an NTRK fusion, then we can offer them up-front systemic therapy; historically, we would just go straight to surgery and radioactive iodine.

Speaking of radioactive iodine, there is accumulating evidence that the use of a selective TRK inhibitor might allow the tumor to concentrate the radioactive iodine more effectively. There’s now interest in exploring using these drugs to enhance radioiodine sensitivity. Drugs like larotrectinib, now that they’re on the scene, have really changed the thought process of how we treat patients with advanced thyroid cancers.

Targeted Oncology™: Considering how NTRK fusions exist across cancer types, how do you see the availability of a drug like larotrectinib affecting treatment approaches? With more long-term data on larotrectinib and as more agents are developed, how do you see treatment approaches evolving in the coming years?

WAGUESPACK: This is really changing how we think about the management of advanced thyroid cancer. In the pre-2018 historical perspective, which is when larotrectinib got FDA approved, a patient with PTC would present with their disease, and usually, if it had spread distantly, they also would have a lot of lymph node disease. We would treat that with surgery, and then we'd give radioactive iodine, which, for advanced cases of PTC, is most often not curative. We would then watch patients who have this distant disease. The good news is that, for most cases of PTC, we can afford to watch and wait for several years before it progresses and before we need to do something.

When their disease progressed or became symptomatic, or when we were worried that they were getting closer to a life-threatening situation, we would then offer 1 of the oral tyrosine kinase inhibitors, lenvatinib or sorafenib, which, particularly for lenvatinib, can be quite effective. I didn’t really talk about the AE profile, but these drugs can be very difficult to take. Often, these patients will be on these drugs for a prolonged time and there’s a cumulative toxicity. Eventually, the cancer would progress, and patients would need to go on second- and third-line therapies.

Now, this is how we think about things: if you have that same patient with metastatic PTC, we do tumor profiling to first look for an NTRK fusion and other fusions that can be present, such as RET fusions (for which selective inhibitors are available), and of course, we also look for BRAF mutations. We now consistently molecularly profile the tumors; we may still watch and wait before we start systemic therapy, but when we have a drug such as larotrectinib that is very effective with very minimal AEs, the thought is, "Well, might we start systemic therapy earlier than we would have before?" As we learn more about the ability of larotrectinib to potentially increase radioiodine uptake, it may also enter the treatment algorithm a little earlier.