In the past the prognosis for patients with Neurotrophic tyrosine receptor kinase (NTRK) fusion cancer, was poor as the cancer did not respond well to most available therapies. But now a new class of drug, recently approved by the FDA and now available in more than 40 countries, is offering new hope to TRK fusion cancer patients with no other satisfactory alternative treatment options. John Battersby reports.
Long-term data on larotrectinib (Vitrakvi™) confirm sustained clinical benefit of greater than four years in patients with TRK fusion cancer regardless of tumour type and age
TRK fusion cancer occurs when an NTRK gene fuses with another unrelated gene, producing a chimeric TRK protein. The altered protein, or TRK fusion protein, becomes constitutively active or overexpressed, triggering a signalling cascade. These TRK fusion proteins are oncogenic drivers promoting cell growth and survival, leading to TRK fusion cancer (1). TRK fusion cancer is not limited to certain types of tissues and can occur in any part of the body. TRK fusion cancer occurs in various adult and paediatric solid tumours with varying frequency, including lung, thyroid, GI cancers (colon, cholangiocarcinoma, pancreatic and appendiceal), sarcoma, CNS cancers (glioma and glioblastoma), salivary gland cancers (secretory carcinoma of the salivary gland) and paediatric cancers (infantile fibrosarcoma and soft tissue sarcoma) where the frequency can be as high as 90% depending on the series investigated; making them almost pathognomonic of these disease states (2,3).
Solid tumour cancers have traditionally been classified by location, for example: breast and lung cancer. But TRK fusion cancers are unusual in that they can grow almost anywhere in the body; the thyroid, soft tissue, lung, colon, and most dangerously the brain and central nervous system (CNS). Many cancers present in middle age or later but NTRK fusion cancers can strike at any age, and a high proportion of patients are children.
Which is why the latest update on the ongoing trials for larotrectinib is good news for CNS and paediatric patients with TRK fusion cancer.
The targeted therapy larotrectinib (marketed by Bayer under the brand name Vitrakvi™) is a selective TRK inhibitor which targets TRK A, B and C. These are proteins which are involved in the development and maintenance of the nervous system. The rearranged, or fusion, state creates a chimeric oncoprotein which drives oncogenesis and this is the process larotrectinib is designed to shut down by binding to and inhibiting the TRK family of proteins. Because it targets the gene mutation that causes the cancer it can treat NTRK cancers wherever they occur in the body.
Larotrectinib was given preliminary approval by the FDA in 2019 in the tumour agnostic fashion for any cancer with an NTRK fusion, across any age including paediatric patients and infants. Rather than a single trial the regulatory data set the approval was based on was the pooled results of three trials of patients treated with larotrectinib. Those trials have been ongoing and the latest updates were presented by David S. Hong, M.D., (Professor of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center) at the 2021 American Society of Clinical Oncology annual meeting. The updates support and build on the generally positive conclusions of the original data; particular for the overall response rate (ORR), duration of response and progression-free survival (PFS). These outcomes compared favourably with, and indeed exceeded the outcomes of other contemporary, next generation, targeted TKI therapies for EGFR and ALT for instance (4).
Report Highlights at a glance
Highlights from the report on pooled data from 3 clinical trials (NCT02576431, NCT02122913, NCT02637687) of patients with TRK fusion–positive cancers treated with larotrectinib.
| Baseline Characteristics | Patient population by tumor type (n = 218): soft tissue sarcoma, 26%; infantile fibrosarcoma, 20%; thyroid, 13%; salivary gland, 11%; lung, 9%; colon, 4%; melanoma, 3%; breast, 3%; and other, 3% NTRK gene fusion (N = 218): NTRK1, 44%; NTRK2, 3%; and NTRK3, 53% |
| Conclusions: Efficacy | In all evaluable patients (n = 206), the overall response rate (ORR) was 75%, including 45 (22%) complete responses, 109 (53%) partial responses, 33 (16%) with stable disease, 13 (6%) with progressive disease, and 6 (3%) not determined; responses were durable with a median progression-free survival (PFS) of 35.4 months and a median duration of response of 49.3 months. Median overall survival (OS) was not reached. The 36-month rates for duration of response, PFS, and OS were 54%, 48%, and 77%, respectively. In patients with central nervous system metastases (n = 15), the ORR was 73%, including 11 (73%) partial responses, 2 (13%) with stable disease, and 2 (13%) with progressive disease. |
| Conclusions: Safety | There were no new or unexpected safety signals. Treatment-related adverse events (TRAEs) were predominantly grade 1 to 2. Grade 3 and 4 TRAEs were reported in 18% of patients, with the most common being decreased neutrophil count (7%), increased aminotransferase (3%), and increased aspartate aminotransferase (2%). |
The updates included waterfall plots, an ordered histogram depicting the best percentage change in tumour size with positive values representing increase in size of tumour and negative values representing shrinkage of tumour. The waterfall plots were broken down by cancer type giving a good indication of the likely response for any particular histology. Notably, the majority of patients, across histological types showed tumour shrinkage.
The swimmer plots, which show each study subject’s response to treatment over the course of the study, were also broken down by histology. Many of the swimmer plots showed very early response to treatment, often by the first radiologic follow up. In many cases the responses are still ongoing; for upwards of four years now for some of the paediatric patients.
The safety profile was consistent with that of the overall safety population previously reported and no new safety signals were identified. The majority of treatment-related adverse events (TRAEs) reported were primarily Grade 1 or 2, with 18% of patients reporting Grade 3 or 4 TRAEs. Two percent of patients discontinued larotrectinib due to TRAEs and no treatment-related deaths were reported. To summarise, this was a presentation of updated data, covering a larger cohort of patients ranging in age from one month to 82 years who had a NTRK fusion. The study found that larotrectinib was highly active, and achieved durable disease control with a very good safety profile (4).
The latest updated results have shown that the likelihood of response to larotrectinib is high, the likelihood of prolonged duration of response allowing the patient will be able to stay on the drug is high, and compared to other therapies the tolerability of this drug is very favourable. All of which underline the importance of testing for NTRK fusion, it might be comparatively rare but if found it can be significant for the patient now that we have a targeted therapy.
Testing for genomic alterations is becoming more common and is increasingly used to guide treatment selection. In some countries testing for actionable alterations is already the accepted standard of practice for certain tumours, such as, anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) rearrangements in advanced non-small cell lung cancer (NSCLC) (5-7). And there is growing evidence that screening for a broader range of biomarkers could be beneficial. Studies on the impact of genomic testing indicate that as many as 30% to 49% of patients who undergo tumour genomic profiling can have an actionable alteration (8,9). If patients are found to have an actionable alteration it means that they may be able to be matched to either an approved or investigational therapy.
References:
1. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/ntrk-gene-fusion
2. Okimoto RA, Bivona TG. Cancer Discov. 2016;6(1):14-16.
3. Vaishnavi A, et al. Cancer Discov. 2015;5(1):25-34.
4. Hong et al, (Long-term efficacy and safety of larotrectinib in an integrated data set of patients with TRK fusion cancer), Journal of Clinical Oncology, Volume 39, Issue 15_suppl https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.3108
5. Stransky N, et al. Nat Commun. 2014:5:4846. doi:10.1038/ncomms5846.
6. Lim C, et al. Ann Oncol. 2015;26(7):1415-1421.
7. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer v5.2019. © National Comprehensive Cancer Network, https://www.nccn.org/
8. Massard C, et al. Cancer Discov. 2017;7(6):586-595.
9. Boland GM, et al. Oncotarget. 2015;6(24):20099-20110.
