Larotrectinib

First Approval for Tissue-Agnostic Small-Molecule Inhibitor

On November 26, 2018, the U.S. Food and Drug Administration (FDA) granted accelerated approval to larotrectinib (Vitrakvi) for the treatment of adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation; these patients had to have either metastatic disease or disease progression following treatment, were not candidates for surgical resection, and had to have no satisfactory alternative treatments.^1,2 This approval represents the second tissue-agnostic FDA approval for a cancer therapy and the first for a small-molecule inhibitor.

[Editor’s Note: The first FDA approval for a tissue-agnostic cancer treatment was for the checkpoint inhibitor pembrolizumab.³ Pembrolizumab is approved for unresectable or metastatic, microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options or with MSI-H or dMMR colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.]

Indication

“The indication for larotrectinib does not stipulate prior therapy as a requirement for treatment,” David S. Hong, MD, Professor and Deputy Chair in the Department of Investigational Therapeutics and Associate Vice President of Clinical Research at MD Anderson Cancer Center, Houston, told JNCCN 360. “The data that led to the approval of larotrectinib were derived from studies of patients who were mostly refractory to other standard therapies.”

Larotrectinib is indicated for the treatment of adults and children with solid tumors that harbor specific abnormalities, specifically NTRK gene fusions. “The question of if and when to determine the presence of such an abnormality has not been definitively answered,” Dr. Hong noted. “My personal approach is that at some point, most patients with advanced, metastatic cancer—either before selection of a first-line regimen or on disease progression—should have next-generation sequencing (NGS), which may include DNA or RNA sequencing. Some NTRK gene fusions might be missed with DNA techniques, but the majority are captured,” Dr. Hong said.

Somewhat surprisingly, Dr. Hong pointed out, NGS is not ordered for many patients, even those for whom there are several potentially targetable mutations or molecular abnormalities, such as patients with lung cancer. Instead, Dr. Hong observed that testing for these patients is often performed by local pathology groups that do point mutation analysis or fluorescent in situ hybridization (FISH) analysis for oncogenic drivers such as ALK-ROS1.

NTRK Gene Fusion

The definition of an NTRK fusion is an NTRK gene fused to another partner, “representing an abnormal receptor that makes the tumor exquisitely, oncogenically addicted to that pathway,” Dr. Hong explained. This occurs when a portion of the chromosome containing NTRK breaks off and joins a gene on another chromosome, yielding a fusion protein that drives oncogenesis.⁴ The three NTRK genes (containing the kinase domains of TRK1, TRK2, TRK3) can have multiple, different partners.

“Although we haven’t identified all the possible partners, the most common is the ETV6 gene, often seen in rare salivary gland (mammary analog secretory carcinoma [MASC]) tumors. There is a FISH test to identify the NTRK-EBT6 gene fusion,⁵ but generally, the only way to capture these fusions is with broad NGS,” Dr. Hong told JNCCN 360.

Key Clinical Clues

From the perspective of the genomic landscape, most patients with NTRK gene fusions have that specific fusion alone, with no other molecular abnormalities. According to Dr. Hong, “if you are a community oncology practitioner and you have a young, patient who does not smoke with non–small cell lung cancer (NSCLC) and all the point mutation studies (eg, EGFR, KRAS, RAS, ALK-ROS1, BRAF, etc) have turned up nothing, you should consider ordering some sort of fusion analysis. Although these fusions are rare in lung cancer, the clue is the absence of other drivers. The culprit may be a fibroblast growth factor (FGF) pathway aberration,⁶ but it may be an NTRK fusion gene. If that’s the case, I will start that patient on an NTRK inhibitor, like larotrectinib or entrectinib.⁷”*

Patient Demographics

Dr. Hong acknowledged that ordering NGS for every patient is currently unrealistic. “Patient demographics may help narrow the focus,” he suggested. “Patients with NTRK gene fusions tend to be on the younger side compared with the age of individuals who are diagnosed with cancer,” he emphasized. “Significantly, there are no other molecular abnormalities or mutations identified that drive malignancy.”

MSI Status

Dr. Hong noted that the MSI status of the tumor might also provide a clue to the presence of an NTRK gene fusion: Those with MSI-high tumors tend to have a higher incidence of NTRK gene fusions. “We’ve noticed that most patients with gastrointestinal tumors who qualify for our trial because of NTRK gene fusion also have tumors that are MSI-high,” Dr. Hong said. In general, MSI-high tumors respond well to immunotherapy. “If a patient with an MSI-high tumor is not responding to or has progressive disease on pembrolizumab, for example, it would make sense to look for an NTRK gene fusion,” Dr. Hong explained.

Tumor Types

NTRK gene fusions are found in rare tumors, such as MASC, a subset of salivary gland tumors. Dr. Hong observed that it is often difficult to distinguish tumors these from more common salivary or parotid tumors. Nevertheless, more than 90% of these MASC tumors harbor an NTRK gene fusion.^8,9 Although the histology is the same for salivary tumors, MASC tumors can also occur in the breast.

In addition, NTRK gene fusions may be found in sarcomas (including fibrous sarcomas) and nerve-sheath tumors.^8,9 For instance, Dr. Hong noted, in gastrointestinal stromal tumors, “if neither KIT nor BRAF is identified, there’s a good chance that the tumor harbors an NTRK gene fusion.”

In thyroid cancer, if the patient is young (up to 39 years of age) and no other oncogenic driver (eg, BRAF, RET) is identified, “it would be prudent to look for an NTRK gene fusion,” Dr. Hong advised.

In the more common cancer types, such as NSCLC and colorectal cancer (non-MSI–high), the incidence of an NTRK gene fusion is less than 1%.^8,9 Nevertheless, Dr. Hong stressed that “an NTRK gene fusion is more likely and should be investigated in young patients whose testing shows no other molecular drivers of oncogenesis.” Finally, as many as 3% of glioblastomas may harbor an NTRK gene fusion.¹⁰

Evolving Trial Data

“Every time I present the integrated data set from larotrectinib studies,”¹¹ Dr. Hong stated, “the findings get better. The response rate is still around 75% to 80%; the duration of response is 49.3 months; progression-free survival is 35.4 months; and overall survival at 22.3 months has not yet been reached.¹² The overall survival at 36 months is 77%. I have patients who have been on the trial for 5.5 years. Some of these individuals were told initially that their survival would be about 6 months,” he reported.

“I tell patients who are eligible and are receiving larotrectinib that they’re lucky. Yes, metastatic disease is not curable, but with this drug, there’s a 20% chance of having a complete response,” Dr. Hong told JNCCN 360. “And, you can be on larotrectinib for 3 years without evidence of disease.”

Adverse Events

As with any drug, larotrectinib is associated with some adverse events.* The most common reaction is dizziness, and it is considered an on-target side effect (related to the binding of the TRK receptor). However, Dr. Hong said, for many patients, the dizziness improves with time.

“These TRK receptors were originally characterized as neural receptors, which control functions such as proprioception and appetite,” Dr. Hong explained. Patients on NTRK inhibitors also tend to gain weight. “Initially, we thought the weight gain was related to better tumor control with treatment (ie, reduced cachexia),” he recalled. “However, we have since realized that patients feel hungrier and eat more while on treatment.” There is also a pain syndrome that has been described as the achiness one might feel after working out, Dr. Hong noted, describing the sensation from the patient’s perspective. This pain may be mild to significant and is most often reported when a dose has been delayed or missed, “almost like a withdrawal phenomenon,” Dr. Hong said.

There have been some reports of bone fractures with another NTRK gene fusion inhibitor, entrectinib.¹³* However, Dr. Hong told JNCCN 360, he hasn’t seen this happen with larotrectinib. Additionally, liver function test values can be increased with these agents but “can usually be reversed by holding and potentially reducing the dose. The concern is usually because of the risk for drug interactions, but this doesn’t seem to be a major issue.”

For Eligible Patients at Any Age

“Overall, this treatment is well tolerated,” Dr. Hong said.” I have patients who have been on therapy for 5+ years. The only patients who might be considered ineligible for treatment—if their tumor harbors an NTRK gene fusion—are those with preexisting liver dysfunction. And, although I don’t have data to support this observation, dizziness seems to be worse in older than younger patients. So, that might be something to watch for in older individuals,” he speculated. “That said, I would not hesitate to use an NTRK inhibitor in an eligible patient of any age because the potential for efficacy is outstanding.”

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*Please check back periodically to see new Spotlights focused on other NTRK-related topics such as entrectinib, management of adverse events, and other pertinent subjects.

Disclosures

David S. Hong, MD, has received research or grant funding from AbbVie, Adaptimmune, Aldi-Norte, Amgen, AstraZeneca, Bayer, BMS, Daiichi Sankyo, Deciphera, Eisai, Erasca, Fate Therapeutics, Genentech, Genmab, Infinity, Kite, Kyowa, Lilly, Loxo, Merck, MedImmune, Mirati, Mologen, Navier, NCI-CTEP, Novartis, Numab, Pfizer, Pyramid Bio, SeaGen, Takeda, Turning Point Therapeutics, Verstatem, and VM Oncology. He has also received reimbursement for travel accommodations or expenses from Bayer, Genmab, AACR, ASCO, SITC, and Telperian. In addition, Dr. Hong has served as a consultant, speaker, or advisor to Adaptimmune, Alpha Insights, Acuta, Alkermes, Amgen, Aum Biosciences, Atheneum, Axiom, Barclays, Baxter, Bayer, Boxer Capital, BridgeBio, CDR-life AG, COR2ed, COG, Ecor1, Genentech, Gilead, GLG, Group H, Guidepoint, HCW Precision, ImmunoGen, Infinity, Janssen, Liberium, Medscape, Numab, Oncologia Brasil, Pfizer, Pharma Intelligence, POET Congress, Prime Oncology, Seattle Genetics, ST Cube, Takeda, Tavistock, Telperian, Trieza Therapeutics, Turning Point, WebMD, and Ziopharm. He also is the founder of OncoResponse.

References

1. S. Food and Drug Administration. FDA approves larotrectinib for solid tumors with NTRK gene fusions. Available at https://www.fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions. Accessed August 10, 2021.
2. Larotrectinib (Vitrakvi). FDA prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/210861s006lbl.pdf. Accessed August 10, 2021.
3. S. Food and Drug Administration. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-first-tissuesite-agnostic-indication. Accessed August 10, 2021.
4. Boldt C. Targeted therapy larotrectinib shows marked responses in patients with NTRK gene fusions, limited response in non-fusion mutations. April 28, 2020. Available at https://www.mdanderson.org/publications/cancer-frontline/targeted-therapy-larotrectinib-shows-marked-responses-in-patient.h00-159381156.html. Accessed August 3, 2021.
5. Solomon JP, Benayed R, Hechtman JF, et al. Identifying patients with NTRK fusion cancer. Ann Oncol 2019;30(suppl 8):viii16–viii22.
6. Chu QS. Targeting non-small cell lung cancer: driver mutation beyond epidermal growth factor mutation and anaplastic lymphoma kinase fusion. Ther Adv Med Oncol. January 23, 2021 (early release online).
7. S. Food and Drug Administration. FDA approves entrectinib for NTRK solid tumors and ROS-1 NSCLC. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984433/. Accessed August 10, 2021.
8. Westphalen CB, Krebs MG, Le Tourneau C, et al. Genomic context of NTRK1/2/3 fusion-positive tumours from a large real-world population. npj Precision Oncology 2021;5:69.
9. Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 2018;15:731–747.
10. Torre M, Vasudevaraja V, Serrano J, et al. Molecular and clinicopathologic features of gliomas harboring NTRK fusions. Acta Neuropathol Commun 2020;8:107.
11. 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;378:731–739.
12. Hong DS, Shen L, van Tilburg CM, et al. Long-term efficacy and safety of larotrectinib in an integrated dataset of patients with TRK fusion cancer. J Clin Oncol 2021;39(suppl):Abstract 3108.
13. Desai AV, Robinson GW, Basu EM, et al. Updated entrectinib data in children and adolescents with recurrent or refractory solid tumors, including primary CNS tumors. J Clin Oncol 2021;38(suppl 15):Abstract 107.