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Spotlight

This roundtable series evaluates genomic testing and NTRK-targeted treatment in patients with thyroid cancer as discussed by participants at virtual live events.

Therapeutic Options for NTRK-Mutated Thyroid Cancer

A 49-year-old woman presented to her primary care physician with complaints of progressive dyspnea on moderate exertion and intermittent episodes of blurred vision and headaches​. The patient is a never-smoker with no history of chronic comorbidities or prescription medications, and a negative family history for malignancy. She was diagnosed with metastatic non–small cell lung cancer (NSCLC).

Pre-treatment liver function tests (LFTs): alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and bilirubin were within normal limits​. Broad-based molecular profiling was repeated on archival biopsy tissue for

Report from the RNA next-generation sequencing was positive for a 

The patient initiated larotrectinib (Vitrakvi) orally twice daily and had a sustained partial response after 6 cycles.

Intermittent episodes of arthralgia and myalgia responded to over-the-counter non-steroidal anti-inflammatory drugs.

LFTs: Mildly elevated ALT (70 U/L) and AST (45 U/L); normal bilirubin concentration (0.7 mg/dL)​

18FFludeoxyglucose (FDG) PET/CT scan: reduced FDG avidity in lung and hilar lymph nodes

MRI of the brain: 40% reduction in target lesion size​​

11 Months After Initiating Larotrectinib 

Patient continued larotrectinib twice daily without dose reduction or dose hold​.

Targeted Oncology: What initial approach would you consider in a patient such as this?

: We see with other targeted therapies they have a good central nervous system [CNS] penetration,

 so unless these patients come in and they're very symptomatic, I try to delay radiation and start them on a tyrosine kinase inhibitor (TKI) as fast as possible. And then once I started them on a TKI, the scans usually show a significant improvement. So, I just continue to monitor them very closely and make sure you can induce a maximum response.

What stands out with the use of larotrectinib in this patient population?

fusions are usually seen in younger patients, younger female patients especially.

 The age distribution is interesting, [we see a median age of 48.5 years (range, 0.3-76)], for the most part and this is represented in [various trials].

There are not a lot of patients [in a phase 2 adult and young adult basket trial (NCT02576431) and phase 1 adult trial (NCT02122913)] with CNS metastases at baseline, but even those kinds of patients have a good depth of response, but in the whole patient group, [a PR was seen in 67% of patients with an overall response rate of 73% (95% CI, 45%-92%) and 3 patients had a complete response].

 These are seen in patients with thyroid cancer as well.

How do you manage increased body weight with this therapy?

This might sound trivial, but this is important to be aware. This is very different than [other targeted therapies] because you have food retention here instead of weight loss, but this weight gain is because of the increased appetite [from this therapy].

 So, we need to manage the weight gain here with a glucagon-like peptide-1 receptor agonist, which works quite well [in my experience].

1. Sharma A, Singer L, Kumthekar P. Updates on molecular targeted therapies for intraparenchymal CNS metastases. 

 2021;14(1):17. doi:10.3390/cancers14010017

2. Viñal D, Martínez D, Higuera O, de Castro J. Genomic profiling in non-small-cell lung cancer in young patients. A systematic review. 

. 2021;6(1):100045. doi:10.1016/j.esmoop.2020.100045

3. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. 

. 2018;378(8):731-739. doi:10.1056/NEJMoa1714448

4. Drilon A, Tan DSW, Lassen UN, et al. Efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase fusion-positive lung cancers. 

. 2022;6:e2100418. doi:10.1200/PO.21.00418

During a Case-Based Roundtable® event, Vamsidhar Velcheti, MD, MBA, FACP, FCCP, discussed the role of larotrectinib in a patient with NTRK fusion–positive cancer. 

Targeting NTRK Fusions in Advanced NSCLC Leads Deep Responses

Lori Wirth, MD, of Massachusetts General Hospital, discusses efficacy of larotrectinib in patients with advanced thyroid cancer

Response to Larotrectinib in NTRK+ Thyroid Cancer Differs By Subtype

Lori J. Wirth, MD, associate professor of medicine at Harvard Medical School and medical director of the Center for Head and Neck Cancers at Massachusetts General Hospital, discusses the outcomes of treatment with larotrectinib (Vitrakvi) for patients with 

 fusion–positive advanced thyroid cancer.

Wirth says that advanced thyroid cancer was the most common malignancy in adult patients enrolled in the phase 1 and 2 trials (NCT02576431, NCT02122913, and NCT02637687) investigating larotrectinib in solid tumors with an 

 fusion. In those with papillary or follicular thyroid cancer, the objective response rate (ORR) was 86% (95% CI, 64%-97%), including some complete responses to larotrectinib. The median progression-free survival (PFS) in these patients was not reached and the 24-month PFS rate was 84% in this population.

However, Wirth notes that in the trials, patients with anaplastic thyroid cancer and an NTRK fusion did not have as high response rates. The ORR of 29% (95% CI, 4%-71%) was still favorable considering the poorer treatment outcomes for patients with advanced anaplastic thyroid cancer, but the responses were also not as durable. The median PFS in this subpopulation was 2.2 months.

 In patients with advanced thyroid cancer harboring an 

 fusion, the efficacy of larotrectinib is very good. So in this series of larotrectinib phase 1 and 2 trials, first of all, I think it’s important to note that the diagnosis of thyroid cancer was the most common adult solid tumor diagnosis that was enrolled in the larotrectinib series. So when you’re thinking about 

 fusion–positive cancers, you definitely want to think about thyroid cancer. But, in the larotrectinib [trial of] patients with thyroid cancer, when patients had papillary thyroid cancer or follicular thyroid cancer, their ORR was 86%. These responses were very durable; in that patient population. The median PFS at the last report still had not yet been reached, but at 24 months, the PFS rate in those patients was 84%. We’re seeing really durable responses, very high response rates, even a small handful of patients achieving a complete response.

Unfortunately, in patients in the larotrectinib trials who had 

 fusion–positive anaplastic thyroid cancer, they did not have responses that were nearly as good as the papillary and follicular thyroid cancer patients. Their ORR was 29%, which doesn’t sound all that bad for anaplastic thyroid cancer, but even when patients did have responses, those responses were very short lived. The median PFS was just 2.2 months in the patients with anaplastic thyroid cancer. So, patients with differentiated thyroid cancer that’s 

 fusion positive have phenomenal responses, whereas it’s not the case unfortunately, [for patients] with NTRK fusion–positive anaplastic thyroid cancer.

Lori J. Wirth, MD, discusses the outcomes of treatment with larotrectinib for patients with NTRK fusion–positive advanced thyroid cancer.

Lori Wirth, MD, associate professor of medicine at Harvard Medical School and medical director for the Center for Head and Neck Cancers at Massachusetts General Hospital, discusses the subanalysis of patients with thyroid cancer in clinical trials for larotrectinib (Vitrakvi).

The LOXO-TRK-14001 (NCT02122913), SCOUT (NCT01595529), and NAVIGATE (NCT02576431) single-arm trials of larotrectinib in patients with a variety of cancer types led to its approval by the FDA for patients with solid tumors and an 

 fusion mutation when the tumor is metastatic or not resectable and there are no other treatments available. According to Wirth, a subset analysis of 29 adult and pediatric patients with thyroid cancer showed that these patients had some of the best responses to larotrectinib.

Of the total 28 evaluable patients with thyroid cancer with 

 fusions, the overall response rate (ORR) was 71%, but when only considering patients with differentiated thyroid cancer, including papillary and follicular thyroid carcinoma, larotrectinib showed extremely high efficacy, with an ORR of 86%.

In 7 patients with anaplastic thyroid cancer, however, the ORR was only 29%. Wirth says the duration of response in these patients was also lower than in patients with differentiated thyroid cancer. For all 28 patients, the overall median time to response was 1.9 months (range, 1.6-3.7) with a Kaplan-Meier estimated 24-month duration of response (DOR) of 81% (95% CI, 60-100).

Wirth observed patients from the trials who continued to receive larotrectinib therapy for over 4 years, citing the high duration of response and tolerability of the therapy.

 There were 3 different trials that pooled the data, and there have been several recent presentations. The most recent presentation of the thyroid cancer patient population was done by Steve Waguespack, [MD], at the American Thyroid Association meeting this year in 2021. One of the things that I think is really important to highlight about that analysis is that of the adults enrolled across the larotrectinib trials, there were 2 solid tumors that were most commonly represented in the larotrectinib trials, and those 2 solid tumors were thyroid cancer and soft tissue sarcomas.

Differentiated thyroid cancer really is a poster child for 

-driven malignancies. There were 29 patients with thyroid cancer that were enrolled across the larotrectinib trials. What we saw in the patients with differentiated thyroid cancer: the ORR was 86%. There were also 7 patients that were enrolled who had anaplastic thyroid cancer with 

 fusions. In those patients, we didn't see quite as high a response rate; the response rate was only 29% in anaplastic thyroid cancer, not only do we see a lower ORR, but also the responses were relatively short-lived, whereas in the patients with differentiated thyroid cancer, the responses in general were really quite durable. So, the median DOR, median progression-free survival hadn't even been reached yet. But we're seeing patients remain on larotrectinib with thyroid cancer beyond 57 months and in some cases, there have been patients enrolled in the trial and ongoing remaining in response beyond 4 years. So, the activity really is very good, and the responses are also really quite durable.

Lori Wirth, MD, discusses the subanalysis of patients with thyroid cancer with NTRK fusion mutations in clinical trials for larotrectinib. 