Targeting NTRK Fusions in Advanced NSCLC Leads Deep Responses

CASE SUMMARY

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 BRAF, NTRK1/2/3, MET, RET, and ERBB2 (HER2). Report from the RNA next-generation sequencing was positive for a TPM3-NTRK3 fusion.

Treatment​

• 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.

5 Months After Initiating Larotrectinib​

• 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 ​

• LFTs normalized.
• Patient continued larotrectinib twice daily without dose reduction or dose hold​.
• Stable disease maintained​.

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

VAMSIDHAR VELCHETI, MD, MBA, FACP, FCCP: We see with other targeted therapies they have a good central nervous system [CNS] penetration,¹ 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.

Vamsidhar Velcheti, MD, MBA, FACP, FCCP​

Professor, Department of Medicine

Director, Thoracic Medical Oncology Program

NYU Grossman School of Medicine​

New York, New York

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

TRK fusions are usually seen in younger patients, younger female patients especially.² 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].³

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].⁴ 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].³ So, we need to manage the weight gain here with a glucagon-like peptide-1 receptor agonist, which works quite well [in my experience].

REFERENCES:

1. Sharma A, Singer L, Kumthekar P. Updates on molecular targeted therapies for intraparenchymal CNS metastases. Cancers (Basel). 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. ESMO Open. 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. N Engl J Med. 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. JCO Precis Oncol. 2022;6:e2100418. doi:10.1200/PO.21.00418