by Dr. C.H. Weaver M.D. updated 12/2020

In 2020 the US Food and Drug Administration (FDA) granted approval to the precision cancer medicines Vitrakvi (larotrectinib) and Rozlytrek (entrectinib) for treatment of adults and pediatric patients 12 years of age and older with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion.

Vitrakvi was the second “tissue agnostic” drug approved for the treatment of cancer in 2020. A “tissue agnostic” FDA approval also occurred for Keytruda (pembrolizumab) for adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment.

These tissue agnostic approvals represent a major paradigm shift in how doctors and their patients will need to think about cancer treatment. Until recently we thought of cancer as being defined by its location in the body - moving forward it will be defined by cancer driving mutations or biomarkers. In effect, the biomarker defines the cancer rather than the organ where the cancer began.

The approval of Rozlytrex for patients with the NTRK gene fusion marks the third FDA approval of a “tissue agnostic” cancer therapy based on a biomarker frequently found across different tumor types versus the location in the body where the tumor originated.

According to the FDA Commissioner Dr. Scott Gottlieb, M.D. "These approvals mark another step in an important shift toward treating cancers based on their tumor genetics rather than their site of origin in the body.”

The shift away from organ specific treatments creates some unique challenges for cancer patients and their doctors and provides hope to many individuals with hard to treat cancers who can now look to genomic testing as another way to identify their available treatment options.

About Rozlytrek

Rozlytrek was evaluated in 54 adult patients with NTRK-positive cancers at various doses and schedules in one of three clinical trials: ALKA, STARTRK-1 (NCT02097810) and STARTRK-2 (NCT02568267). Identification of positive NTRK gene fusion status was determined in local laboratories or a central laboratory using nucleic acid-based tests prior to enrollment.

Among the 54 adult patients, the overall response rate was 57% and the response duration was 6 months or longer for 68% of patients and 12 months or longer for 45% of patients. The most common cancers treated in the trial were sarcoma, non-small cell lung cancer (NSCLC), thyroid, and colorectal cancer.

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The most common side effects occurring in at least 20% of patients were fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, cognitive impairment, increased weight, cough, vomiting, pyrexia, arthralgia, and vision disorders.

Tissue Agnostic Approval for Keytruda

Keytruda (pembrolizumab) for adult and pediatric patients with 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.

The approval was based on data from 149 patients with MSI-H or dMMR cancers enrolled across five clinical trials. Ninety patients had colorectal cancer and 59 patients were diagnosed with one of 14 other cancer types. Patients were treated with Keytruda until unacceptable side effects, or disease progression that was either symptomatic, rapidly progressive, required urgent intervention, or associated with a decline in performance status. A maximum of 24 months of treatment was administered.

The response rate (ORR) to treatment was 39.6% and responses lasted six months or more for 78% percent of those who responded to Keytruda. There were 11 complete responses and 48 partial responses. ORR was similar irrespective of whether patients were diagnosed with colorectal cancer or a different cancer type (46% across the 14 other cancer types).

The identification of MSI-H or dMMR tumor status for the majority of patients (135/149) was prospectively determined using local laboratory-developed, investigational polymerase chain reaction (PCR) tests for MSI-H status or immunohistochemistry (IHC) tests for dMMR. For 14 of the 149 patients, MSI-H status was determined in a retrospective assessment of 415 patients’ tumor samples using a central laboratory-developed PCR test.

Additional Recommended Reading:


  1. FDA Grants First “Tissue Agnostic” Accelerated Approval to Keytruda
  2. Vitrakvi® - Larotrectinib FDA Approved for Treatment of NTRK + Cancers
  3. US Food and Drug Administration. FDA approves third oncology drug that targets a key genetic driver of cancer, rather than a specific type of tumor. August 15, 2019.