Approval of Inhibitor Larotrectinib Across Tumor Types– Are We Ready for the Era of Tissue-Agnostic Targeted Cancer Therapy?
By Nina Lapke, Biomedical Informatics Scientist of ACT Genomics
During the past years, precision medicine has seen major advances. More and more patients who may benefit from new therapies are now identified based on specific traits, or markers, of their tumors. However, clinical trials generally focus on specific cancer types, and a tested drug will only obtain approval for those cancer types. Therefore, a marker-positive patient with breast cancer who could benefit from a drug approved for lung cancer may not have access to that drug.
In 2017, pembrolizumab (Keytruda) was the first drug to be approved by the United States Food and Drug Administration (USFDA) as a tissue-agnostic drug, meaning that the drug can be prescribed for tumors independent of their origin . Shortly after that, in late 2018, the TRK inhibitor larotrectinib (Vitrakvi) was the second tissue-agnostic and age-agnostic cancer drug to receive USFDA approval . Larotrectinib is indicated for adults and children whose tumor is positive for the marker neurotrophic receptor tyrosine kinase (NTRK) gene fusion. The antitumoral activity of larotrectinib in clinical trials was phenomenal, with 75% of patients responding to the treatment and tolerable side effects . The drug is effective across involved NTRK genes and fusion partners. The approval gives hope to patients with certain cancer types, e.g., secretory breast carcinoma, for which NTRK gene fusions occur in as many as 90% of patients. Some patients with other cancer types, such as breast or colorectal cancer, could also be eligible for treatment, although the proportion of NTRK gene fusions in these cancer types is considerably lower .
What are possible challenges of larotrectinib integration into clinical practice, and are we on our way to the era of tissue-agnostic cancer therapy?
Specific testing for NTRK gene fusions to identify patients who can benefit from larotrectinib could be useful for tumor types for which a majority of patients is expected to be eligible for larotrectinib treatment. In contrast, it will be more feasible for tumor types for which most patients are not expected to benefit from larotrectinib to perform NTRK testing as part of more comprehensive testing. Such comprehensive testing could identify other treatment options as well. To ensure that eligible patients with common tumor types know that they could benefit from larotrectinib treatment, comprehensive testing would need to become a standard in clinical practice. Although NTRK analysis may be integrated into existing clinical assays using next-generation sequencing, accessibility could remain an issue for many patients around the world.
Subsequent studies recruiting larger numbers of patients may be needed to prove that the effects of larotrectinib are truly tissue-independent. For the initial studies, only 55 patients were treated, and the patient number per tumor type was low . This is relevant since some drugs work better in some cancer types than in others, but conclusions about tumor type-specific effectivity require many patients to be studied. An example of such a drug that is vemurafenib, which showed an excellent performance in melanoma but worked less well in colorectal cancer patients, even though all patients had sensitizing BRAF mutations [5, 6].
Therefore, it may turn out that the effectivity of drugs labeled as tissue-agnostic could somewhat differ across cancer types.
Lastly, as with all cancer drugs, there is the issue of patients developing treatment resistance. However, new drugs to address such larotrectinib resistance are already being tested, and results are eagerly awaited.
The approval of larotrectinib certainly represents a major milestone on the journey to tissue-agnostic therapy. Even though some challenges remain, this approval will be a life-changing event for many patients eligible for larotrectinib therapy. And with clinical trials combining patients of various cancer types according to their tumor markers becoming more popular, it is only a matter of time until other tissue-agnostic drugs will obtain approval, driving further personalization of cancer therapy and improving patient outcomes.
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