Since 2020 the US Food and Drug Administration (FDA) has granted approval to several novel precision cancer medicines that target specific cancer causing mutations that may occur in multiple “types” of cancer. 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 increasingly defined by the cancers growth driving mutations or biomarkers. In effect, the biomarker defines the cancer rather than the organ where the cancer began.
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.
Cancer is caused by genetic mutations, and these mutations can be detected in the cancer itself or by measuring circulating tumor DNA, or ctDNA, in the blood. Liquid biopsy detection of ctDNA in the blood allows for personalized cancer surveillance based on an individual’s unique set of tumor mutations.
Traditionally, the most common way to detect the presence of cancer has been through the use of imaging techniques like computerized tomography (CT) scan, magnetic resonance imaging (MRI), and positron emission tomography (PET). However, these imaging tools are limited in their ability to detect molecular residual disease (MRD), or very small traces of cancer in the body. ctDNA can be detected in the blood long before it appears on a CT or MRI scan.
Consult Your Care Team to Discuss Biomarker Testing
A recent study of over 295,000 tumor samples revealed that 21.5% of cancers carry at least one biomarker eligible for these “tissue-agnostic” drugs, with 5.4% of patients lacking standard treatment options now potentially benefiting from these therapies.
Key Findings for Patients:
Eligibility: Biomarkers like TMB-High, MSI-High/MMRd, BRAFV600E mutations, and NTRK/RET fusions are present across many cancer types, including rare cases.
Real-World Benefits: Drugs like pembrolizumab (Keytruda) showed varied effectiveness depending on cancer type, even for the same biomarker.
Rare Mutations: Therapies for NTRK fusions—though effective—are underused due to limited awareness and testing.
Unexpected Opportunities: Some drugs in the same class as approved therapies (e.g., other PD-1 inhibitors or kinase inhibitors) may work for tumors not studied in initial trials.
What This Means for You: These therapies, such as larotrectinib (Vitrakvi) for NTRK fusions and pembrolizumab for MSI-High or TMB-High tumors, highlight the importance of comprehensive biomarker testing. While challenges remain in accessing treatments for rare mutations, the study underscores the potential for broader application of existing drugs.
Recent FDA Approvals
Enhertu
The Food and Drug Administration granted accelerated approval to Enhertu (fam-trastuzumab deruxtecan-nxki) for treatment of adult patients with unresectable, or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment. The approval makes Enhertu the first FDA approved tumor-agnostic HER2-directed antibody drug conjugate (ADC) approved for treatment regardless of a cancers location.
Enhertu is an “antibody drug conjugate” meaning the antibody has a partner to which it’s chemically linked, in this case the chemotherapy drug deruxtecan. Trastuzumab latches on to HER2 on a cancer cells surface and the entire drug is pulled into the cell delivering deruxtecan to kill the cell.
Enhertu was evaluated in 192 adult patients with previously treated advanced HER2-positive (IHC 3+) solid tumors.
- The most impressive responses were seen in women with IHC3+ gynecologic cancers, about 85% of women with endometrial cancer and 75% of women with cervical cancer responded to T-DXd.
- In patients with lung and colorectal cancer, tumors shrank in about half of the patients.
- More than 56% of people with IHC3+ biliary tract cancers had a response.
- 42% of people with salivary gland cancers had a tumor response, including several that lasted beyond 20 months.
- 50% response rates in breast cancer.
Patients with a history of interstitial lung disease (ILD)/pneumonitis, a known complication of treatment with Enhertu and clinically significant cardiac disease were excluded from the trials.
Jemperli (dostarlimab) for dMMR Advanced Solid Cancers
The Food and Drug Administration granted accelerated approval to Jemperli (dostarlimab-gxly) for adult patients with mismatch repair deficient (dMMR) recurrent or advanced solid tumor that have progressed on or following prior treatment.
Microsatellite instability (MSI) is the condition of genetic hypermutability or a predisposition to mutations in cells that results from the bodies impaired DNA mismatch repair (MMR) mechanism. DNA MMR is an essential function and the way the body naturally corrects errors that spontaneously occur during cell division associated DNA replication.
Mismatch Repair Genes work like genetic “spell checkers.” When problems occur in these spell-checking MMR genes, it means that areas of DNA start to become unstable, and the body is unable to correct the errors that occur during DNA replication and consequently accumulate errors. The accumulation of errors causes the creation of novel microsatellite fragments that can be measured. The presence of MSI represents evidence that the MMR function is not working normally and predisposition to developing cancer exists. Several cancers may have MSI-H or dMMR identified when NGS testing is performed.
About Jemperli (dostarlimab)
Jemperli (dostarlimab or TSR-042) is a humanized anti-programmed death (PD)-1 monoclonal antibody that binds with high affinity to the PD-1 receptor and effectively blocks its interaction with the ligands PD-L1 and PD-L2. Jemperli is a novel precision cancer immunotherapy drugs that helps to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD -L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade an attack by the body’s immune cells.
Jemperli was evaluated in the GARNET Trial in 209 patients with dMMR recurrent or advanced solid tumors who progressed following systemic therapy and had no satisfactory alternative treatment. Overall, 41.6% of refractory patients responded to treatment and 9.1% attainted complete disappearance of their cancer. The median response duration was 34.7 months with 95.4% of patients with duration ≥6 months.
Neurotrophic tyrosine receptor kinase (NTRK) gene fusions.
Vitrakvi (larotrectinib) and Rozlytrek (entrectinib) have been approved for patients with the NTRK gene fusion.
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.
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 disorder.
Tissue Agnostic Approval for Keytruda
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.
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:
- About Vitrakvi® (larotrectinib) for soft tissue sarcoma, salivary gland cancer, infantile fibrosarcoma, thyroid cancer, and lung cancer.
- About Keytruda (pembrolizumab) for adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors
- Understanding Precision Cancer Medicine: What Every Patient Should Know
Connect With Others for Support and information
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References
- FDA Grants First “Tissue Agnostic” Accelerated Approval to Keytruda
- Vitrakvi® – Larotrectinib FDA Approved for Treatment of NTRK + Cancers
- 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.
- http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm560040.ht
- https://www.fiercepharma.com/pharma/astrazeneca-daiichi-sankyos-enhertu-wins-historic-her2-tumor-agnostic-nod-fda#google_vignette
- Sledge GW Jr, Yoshino T, et al. Real-world evidence provides clinical insights into tissue-agnostic therapeutic approvals. Nat Commun. 2025 Mar 18;16(1):2646.
