Agnostic Cancer Therapies (PDQ®): Treatment - Health Professional Information [NCI]

Introduction

The U.S. Food and Drug Administration (FDA) has approved both gene- and immune-targeted drugs for tissue-agnostic, genomic biomarker–based indications in patients with lethal solid tumors and blood cancers. High response rates were the basis for these approvals.[1]

Precision medicine has rapidly changed the oncology field. Next-generation sequencing can identify patients with specific gene alterations or immune markers for which there are targeted therapies. Biomarker-based treatments are increasingly emerging, and the FDA has approved the following tissue-agnostic therapies:[1,2]

• Pembrolizumab.
• Dostarlimab.
• Entrectinib.
• Larotrectinib.
• Repotrectinib.
• Dabrafenib in combination with trametinib.
• Selpercatinib.
• Pemigatinib.
• Trastuzumab deruxtecan.

Precision medicine is constantly evolving, and improved diagnostic tools allow for more comprehensive genomic definition of the tumor. Tissue-agnostic targeted therapies are a promising treatment strategy tailored to the specific tumor genomic profile, leading to improved patient survival outcomes.

The list of drugs approved for tumors with genomic alterations will likely expand as understanding of the science driving these cancers continues to advance. As oncology drug development continues to move rapidly, the location where the cancer originated will become less critical.

Companion tests can determine the presence of specific genomic alterations or immune markers. These tests may have been approved by the FDA as part of the agnostic drug approval. Most insurance companies have not required these specific tests before covering the prescribed medications.

References:

1. Adashek JJ, Kato S, Sicklick JK, et al.: Considering molecular alterations as pan-cancer tissue-agnostic targets. Nat Cancer 4 (12): 1622-1626, 2023.
2. Tateo V, Marchese PV, Mollica V, et al.: Agnostic Approvals in Oncology: Getting the Right Drug to the Right Patient with the Right Genomics. Pharmaceuticals (Basel) 16 (4): , 2023.

Microsatellite Instability–High or Mismatch Repair–Deficient Solid Tumors

Pembrolizumab

Indication. Pembrolizumab is indicated for adult and pediatric patients with unresectable or metastatic, microsatellite instability–high (MSI-H)/microsatellite unstable or mismatch repair–deficient (dMMR) solid tumors whose disease progressed after prior treatment and who have no satisfactory alternative treatment options. The MSI-H phenotype is associated with germline defects in the MLH1, MSH2, MSH6, and PMS2 genes and is the primary phenotype observed in tumors from patients with hereditary nonpolyposis colorectal cancer or Lynch syndrome. Patients can also have the MSI-H phenotype because one of these genes was silenced via DNA methylation. Molecular genetic tests look for microsatellite instability in the tumor tissue, and immunohistochemistry tests for the loss of mismatch repair proteins. For more information, see the Immunotherapy section in Colon Cancer Treatment.

Evidence. The U.S. Food and Drug Administration (FDA) approval was based on data from the following five uncontrolled, multicohort, multicenter, single-arm clinical trials that included 149 patients with MSI-H or dMMR cancers:[1][Level of evidence C3]

• KEYNOTE-016 (NCT01876511) (median follow-up, 5.3 months).[2]
• KEYNOTE-164 (NCT02460198) (median follow-up, 31.3 months).[3]
• KEYNOTE-012 (NCT01848834) (median follow-up, 9 months).[4]
• KEYNOTE-028 (NCT02054806) (median follow-up, 9.8 months).[5]
• KEYNOTE-158 (NCT02628067) (median follow-up, 13.4 months).[6]

These trials included 90 patients with colorectal cancer and 59 patients with other cancers who were diagnosed with one of 14 other cancer types. Patients received either 200 mg of pembrolizumab every 3 weeks or 10 mg/kg of pembrolizumab every 2 weeks.

Efficacy. The major efficacy outcome measures were objective response rate, assessed by blinded independent central radiologist review according to RECIST 1.1, and response duration. The pooled objective response rate was 39.6%. A total of 11 patients (7.4%) had a complete response and 48 patients (32.2%) had a partial response. The objective response rate was 36% in patients with colorectal cancer, and 46% in patients with other cancers (95% confidence interval [CI], 33%–59%).[7,8] Responses lasted 6 months or longer for 78% of patients who responded to pembrolizumab.[1]

Identification of biomarker. For most patients (135 of 149), tumor status was prospectively determined using local laboratory-developed, investigational polymerase chain reaction (PCR) (for MSI-H) or immunohistochemistry (for dMMR).[9] For 14 of the 149 patients, MSI-H status was determined in a retrospective assessment of tumor samples from 415 patients using a central laboratory-developed PCR test.

Dostarlimab

Indication. Dostarlimab is indicated for adult patients with dMMR recurrent or advanced solid tumors, as determined by an FDA-approved test, whose disease progressed during or after prior treatment and who have no satisfactory alternative treatment options. This indication is not approved in the pediatric population.

Evidence. GARNET (NCT02715284) was a nonrandomized, multicenter, open-label, multicohort trial that evaluated the efficacy of dostarlimab.[10] The expansion cohorts were as follows:[11,12,13,14][Level of evidence C3]

1. dMMR/MSI-H endometrial cancers.
2. Mismatch repair–proficient or microsatellite stable endometrial cancers.
3. Non-small cell lung cancers.
4. Non-endometrial dMMR/MSI-H and POLE-mutated cancers.
5. High-grade serous, endometrioid, or clear cell ovarian, fallopian tube, or primary peritoneal cancer without BRCA variants.

Efficacy. The efficacy population consisted of 209 patients with dMMR recurrent or advanced solid tumors whose disease progressed after systemic therapy and who had no satisfactory alternative treatment options. The objective response rate was 41.6% (95% CI, 34.9%–48.6%), with a 9.1% complete response rate and a 32.5% partial response rate. The median follow-up was 27.7 months.[10]

Identification of biomarker. The VENTANA MMR RxDx Panel is a companion diagnostic device to select patients with dMMR solid tumors for treatment with dostarlimab.

References:

1. Marcus L, Lemery SJ, Keegan P, et al.: FDA Approval Summary: Pembrolizumab for the Treatment of Microsatellite Instability-High Solid Tumors. Clin Cancer Res 25 (13): 3753-3758, 2019.
2. O'Neil BH, Wallmark JM, Lorente D, et al.: Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced colorectal carcinoma. PLoS One 12 (12): e0189848, 2017.
3. Le DT, Kim TW, Van Cutsem E, et al.: Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164. J Clin Oncol 38 (1): 11-19, 2020.
4. Mehra R, Seiwert TY, Gupta S, et al.: Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012. Br J Cancer 119 (2): 153-159, 2018.
5. Ott PA, Elez E, Hiret S, et al.: Pembrolizumab in Patients With Extensive-Stage Small-Cell Lung Cancer: Results From the Phase Ib KEYNOTE-028 Study. J Clin Oncol 35 (34): 3823-3829, 2017.
6. Marabelle A, Le DT, Ascierto PA, et al.: Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol 38 (1): 1-10, 2020.
7. Lemery S, Keegan P, Pazdur R: First FDA Approval Agnostic of Cancer Site - When a Biomarker Defines the Indication. N Engl J Med 377 (15): 1409-1412, 2017.
8. Boyiadzis MM, Kirkwood JM, Marshall JL, et al.: Significance and implications of FDA approval of pembrolizumab for biomarker-defined disease. J Immunother Cancer 6 (1): 35, 2018.
9. Ren XY, Song Y, Wang J, et al.: Mismatch Repair Deficiency and Microsatellite Instability in Triple-Negative Breast Cancer: A Retrospective Study of 440 Patients. Front Oncol 11: 570623, 2021.
10. André T, Berton D, Curigliano G, et al.: Antitumor Activity and Safety of Dostarlimab Monotherapy in Patients With Mismatch Repair Deficient Solid Tumors: A Nonrandomized Controlled Trial. JAMA Netw Open 6 (11): e2341165, 2023.
11. Moreno V, Roda D, Pikiel J, et al.: Safety and Efficacy of Dostarlimab in Patients With Recurrent/Advanced Non-small Cell Lung Cancer: Results from Cohort E of the Phase I GARNET Trial. Clin Lung Cancer 23 (7): e415-e427, 2022.
12. Oaknin A, Gilbert L, Tinker AV, et al.: Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study. J Immunother Cancer 10 (1): , 2022.
13. Berton D, Banerjee SN, Curigliano G, et al.: Antitumor activity of dostarlimab in patients with mismatch repair-deficient/microsatellite instability–high tumors: A combined analysis of two cohorts in the GARNET study. [Abstract] J Clin Oncol 39 (Suppl 15): A-2564, 2021.
14. Andre T, Berton D, Curigliano G, et al.: Efficacy and safety of dostarlimab in patients (pts) with mismatch repair deficient (dMMR) solid tumors: Analysis of 2 cohorts in the GARNET study. [Abstract] J Clin Oncol 40 (Suppl 16): A-2587, 2022.

Tumor Mutational Burden–High (≥10 Mutations / Megabase) Solid Tumors

Pembrolizumab

Indication. Pembrolizumab is indicated for adult and pediatric patients with unresectable or metastatic tumor mutational burden–high (TMB-H) solid tumors, whose disease progressed after prior treatment and who have no satisfactory alternative treatment options. TMB-H is defined as ≥10 mutations/megabase (mut/Mb), as determined by a U.S. Food and Drug Administration (FDA)-approved test.

Evidence. FDA approval was based on a retrospective analysis of 10 cohorts of patients with various previously treated unresectable or metastatic TMB-H solid tumors enrolled in KEYNOTE-158 (NCT02628067), a multicenter, nonrandomized, open-label trial. Patients received 200 mg of pembrolizumab intravenously every 3 weeks until unacceptable toxicity or documented disease progression.[1,2][Level of evidence C3]

Efficacy. A total of 102 patients (13%) had TMB-H tumors (defined as TMB ≥10 mut/Mb). The objective response rate for these patients was 29% (95% confidence interval, 21%–39%), with a 4% complete response rate and 25% partial response rate.[1] The median follow-up was 13.4 months.[2]

Identification of biomarker. The FoundationOne CDx assay is a companion diagnostic test for pembrolizumab.

References:

1. Marabelle A, Fakih M, Lopez J, et al.: Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol 21 (10): 1353-1365, 2020.
2. Marabelle A, Le DT, Ascierto PA, et al.: Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol 38 (1): 1-10, 2020.

NTRK Gene Fusion–Positive Solid Tumors

Entrectinib

Indication. Entrectinib is indicated for adult and pediatric patients with solid tumors and an NTRK gene fusion without a known acquired resistance variant; with disease that is metastatic or where surgical resection is likely to result in severe morbidity; and who have disease progression after treatment or have no satisfactory standard therapy.

Evidence. Five multicenter single-arm clinical trials evaluated the efficacy of entrectinib in patients with NTRK-positive tumors. Three of these trials evaluated a total of 54 adult patients who received entrectinib at various doses and schedules. Two of these trials evaluated a total of 33 pediatric patients.[1,2][Level of evidence C3]

• ALKA-372-001; adult patients.
• STARTRK-1 (NCT02097810); adult patients.
• STARTRK-2 (NCT02568267); adult patients.
• STARTRK-NG (NCT02650401); pediatric patients.
• TAPISTRY (NCT04589845); pediatric patients.

Efficacy. Among the 54 adult patients, the overall response rate, as determined by independent review, was 57% (95% confidence interval [CI], 43%–71%). The median follow-up was 15 months.[1] Among the 33 pediatric patients, the objective response rate was 70% (95% CI, 51%–84%), and the median duration of response was 25.4 months (95% CI, 14.3–not evaluable). The median follow-up was not defined.[2]

Identification of biomarker. Identification of positive NTRK gene fusion status was determined at local laboratories or a central laboratory using nucleic acid-based tests prior to enrollment. Not all NTRK variants are gene fusions. Entrectinib has not shown clinical efficacy in patients with nonfusion NTRK variants..

Larotrectinib

Indication. Larotrectinib is indicated for adult and pediatric patients with solid tumors and an NTRK gene fusion without a known acquired resistance variant; with disease that is metastatic or where surgical resection is likely to result in severe morbidity; and who have disease progression after treatment and have no satisfactory alternative treatment options.

Evidence. U.S. Food and Drug Administration (FDA) approval was based on data from three multicenter, open-label, single-arm clinical trials: LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431).[3,4][Level of evidence C3]

Efficacy. Among 55 patients with unresectable or metastatic solid tumors harboring an NTRK gene fusion enrolled across the three trials, the overall response rate was 75% (95% CI, 61%–85%). The complete response rate was 22%, and the partial response rate was 53%. The median follow-up was 8.3 months.[3,5]

Identification of biomarker. NTRK gene fusion status was prospectively determined at local laboratories using next-generation sequencing (NGS) or fluorescence in situ hybridization (FISH). Not all NTRK variants are gene fusions. Entrectinib has not shown clinical efficacy in patients with nonfusion NTRK variants..

Repotrectinib

Indication. Repotrectinib is indicated for adult and pediatric patients with an NTRK gene fusion and solid tumors that are locally advanced or metastatic for which surgical resection may cause severe morbidity.

Evidence. FDA approval was based on data from TRIDENT-1 (NCT03093116), a multicenter, single-arm, open-label, multicohort trial.[6,7,8][Level of evidence C3]

Efficacy. In 88 adult patients with locally advanced or metastatic NTRK gene fusion–positive solid tumors, the overall response rate was 58% (95% CI, 41%–73%) for patients who had not received prior NTRK tyrosine kinase inhibitors (TKIs) (n = 40) and 50% (95% CI, 35%–65%) for patients who had previously received NTRK TKIs (n = 48). The median duration of response was not estimable in the TKI-naïve group and was 9.9 months (95% CI, 7.4–13.0) in the TKI-pretreated group. The median follow-up was 24.0 months.[6,8]

Identification of biomarker. NTRK gene fusion status was prospectively determined at local laboratories using NGS, Sanger sequencing, reverse transcription–polymerase chain reaction, or FISH. Not all NTRK variants are gene fusions. Repotrectinib has not shown clinical efficacy in patients with nonfusion NTRK variants.

References:

1. Drilon A, Siena S, Ou SI, et al.: Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1). Cancer Discov 7 (4): 400-409, 2017.
2. Desai AV, Robinson GW, Gauvain K, et al.: Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG). Neuro Oncol 24 (10): 1776-1789, 2022.
3. Drilon A, Laetsch TW, Kummar S, et al.: Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med 378 (8): 731-739, 2018.
4. Laetsch TW, DuBois SG, Mascarenhas L, et al.: Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol 19 (5): 705-714, 2018.
5. U.S. Food and Drug Administration: FDA approves larotrectinib for solid tumors with NTRK gene fusions. U.S. Food and Drug Administration, 2018. Available online. Last accessed January 30, 2025.
6. Drilon A, Camidge DR, Lin JJ, et al.: Repotrectinib in ROS1 Fusion-Positive Non-Small-Cell Lung Cancer. N Engl J Med 390 (2): 118-131, 2024.
7. Solomon BJ, Drilon A, Lin JJ, et al.: Repotrectinib in patients (pts) with NTRK fusion-positive (NTRK+) advanced solid tumors, including NSCLC: Update from the phase I/II TRIDENT-1 trial. [Abstract] Ann Oncol 34 (Suppl 2): A-787-788, 2023.
8. U.S. Food and Drug Administration: FDA grants accelerated approval to repotrectinib for adult and pediatric patients with NTRK gene fusion-positive solid tumors. U.S. Food and Drug Administration, 2024. Available online. Last accessed January 23, 2025.

BRAF V600E Variant–Positive Solid Tumors

Dabrafenib in Combination With Trametinib

Indication. The combination of dabrafenib and trametinib is indicated for adult and pediatric patients aged 6 years or older with unresectable or metastatic solid tumors and a BRAF V600E variant. Patients must have progressive disease after prior treatment and have no satisfactory alternative treatment options. Dabrafenib in combination with trametinib is not indicated for patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition.

Evidence. The U.S. Food and Drug Administration approval was based on data from the following populations:[1,2,3,4,5][Level of evidence C3]

• Two open-label multiple cohort trials included 131 adult patients: BRF117019 (NCT02034110) (median follow-up, 47 weeks), and NCI-MATCH (NCT02465060) protocol H (median follow-up, 23.0 months).[1,2,3]
• One trial included 36 pediatric patients: CTMT212X2101 (NCT02124772) (median follow-up, not defined).[4]

The approval was also supported by results from COMBI-d (NCT01072175), COMBI-v (NCT01597908), and BRF113928 (NCT01336634).[6]

Efficacy. For the 131 adult patients, the overall response rate was 41% (95% confidence interval [CI], 33%–50%). For the 36 pediatric patients, the overall response rate was 25% (95% CI, 12%–42%).[5]

Identification of biomarker. Biomarker status was determined at a Clinical Laboratory Improvement Amendments (CLIA) or CLIA-equivalent laboratory.

References:

1. Subbiah V, Lassen U, Élez E, et al.: Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol 21 (9): 1234-1243, 2020.
2. Wen PY, Stein A, van den Bent M, et al.: Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial. Lancet Oncol 23 (1): 53-64, 2022.
3. Salama AKS, Li S, Macrae ER, et al.: Dabrafenib and Trametinib in Patients With Tumors With BRAFV600E Mutations: Results of the NCI-MATCH Trial Subprotocol H. J Clin Oncol 38 (33): 3895-3904, 2020.
4. Whitlock JA, Geoerger B, Dunkel IJ, et al.: Dabrafenib, alone or in combination with trametinib, in BRAF V600-mutated pediatric Langerhans cell histiocytosis. Blood Adv 7 (15): 3806-3815, 2023.
5. U.S. Food and Drug Administration: FDA grants accelerated approval to dabrafenib in combination with trametinib for unresectable or metastatic solid tumors with BRAF V600E mutation. U.S. Food and Drug Administration, 2022. Available online. Last accessed January 30, 2025.
6. Robert C, Grob JJ, Stroyakovskiy D, et al.: Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. N Engl J Med 381 (7): 626-636, 2019.

RET Gene Fusion–Positive Solid Tumors

Selpercatinib

Indication. Selpercatinib is indicated for adult patients with locally advanced or metastatic solid tumors with a RET gene fusion whose disease meets either of the following criteria: disease progressed during or after prior systemic treatment, or disease with no satisfactory alternative treatment options. This indication is not approved for the pediatric population.

Evidence. Forty-one patients with RET gene fusion–positive tumors (other than non-small cell lung cancer [NSCLC] and thyroid cancer) with disease progression during or after prior systemic treatment or who had no satisfactory alternative treatment options were evaluated in the multicenter, open-label, multicohort LIBRETTO-001 trial (NCT03157128).[1,2][Level of evidence C3]

Efficacy. For the 41 evaluable patients with cancers other than NSCLC or thyroid cancer, the objective response rate was 44% (95% confidence interval, 28%–60%). A total of 16 patients had a partial response and 2 patients had a complete response, with a median follow-up of 14.9 months.[1,2]

Identification of biomarker. Clinical Laboratory Improvement Amendments (CLIA) or CLIA-equivalent locally obtained molecular testing was performed at a certified laboratory, with the use of either next-generation sequencing, fluorescence in situ hybridization, or polymerase chain reaction assay.

References:

1. Subbiah V, Wolf J, Konda B, et al.: Tumor agnostic efficacy of selpercatinib in patients with RET fusion+ solid tumors: A global, multicenter, registrational trial update (LIBRETTO-001). [Abstract] J Clin Oncol 40 (Suppl 16): A-3094, 2022.
2. Subbiah V, Wolf J, Konda B, et al.: Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol 23 (10): 1261-1273, 2022.

FGFR1-Rearranged Myeloid / Lymphoid Neoplasms

Pemigatinib

Indication. Pemigatinib is indicated for adult patients with relapsed or refractory myeloid/lymphoid neoplasms (MLNs) with an FGFR1 rearrangement. This indication is not approved for the pediatric population.

Evidence. Twenty-eight patients with relapsed or refractory MLNs with FGFR1 rearrangement were evaluated in the multicenter open-label, single-arm FIGHT-203 trial (NCT03011372). Eligible patients were either not candidates for, or had relapsed disease after, allogeneic hematopoietic stem cell transplant or a disease-modifying therapy (e.g., chemotherapy).[1,2][Level of evidence C3]

Efficacy. For all 28 patients (including three patients without evidence of morphologic disease), the complete cytogenetic response rate was 79% (95% confidence interval [CI], 59%–92%). Among the 18 patients with chronic phase disease in the marrow with or without extramedullary disease (EMD), 14 achieved a complete response (78%; 95% CI, 52%–94%). Among the four patients with blast-phase disease in the marrow with or without EMD, two achieved a complete response (duration, 1+ and 94 days). For the three patients with EMD only, one achieved a complete response (duration, 64+ days) with a median follow-up of 25.3 months.[1,2]

Identification of biomarker. Biomarker identification was performed using local cytogenetics and both local and central fluorescence in situ hybridization results.

References:

1. Verstovsek S, Gotlib J, Vannucchi AM, et al.: FIGHT-203, an ongoing phase 2 study of pemigatinib in patients with myeloid/lymphoid neoplasms (MLNs) with fibroblast growth factor receptor 1 (FGFR1) rearrangement (MLNFGFR1): A focus on centrally reviewed clinical and cytogenetic responses in previously treated patients. [Abstract] Blood 140 (Suppl 1): A-624, 3980-2, 2022.
2. Gotlib J, Kiladjian J, Vannucchi A, et al.: A phase 2 study of pemigatinib (FIGHT-203; INCB054828) in patients with myeloid/lymphoid neoplasms (MLNs) with fibroblast growth factor receptor 1 (FGFR1) rearrangement (MLNFGFR1). [Abstract] Blood 138 (Suppl 1): A-634, 385, 2021.

HER2–Expressing Solid Tumors

Trastuzumab Deruxtecan (T-DXd)

Indication. T-DXd is indicated for adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.[1] This indication is not approved in the pediatric population.

Evidence. One hundred ninety-two adult patients with previously treated unresectable or metastatic HER2-positive (IHC 3+) solid tumors were enrolled in one of the following three multicenter trials:[2,3,4][Level of evidence C3]

• DESTINY-PanTumor02 (NCT04482309).[2]
• DESTINY-Lung01 (NCT03505710).[3]
• DESTINY-CRC02 (NCT04744831).[4]

Efficacy. The objective response rates were as follows:

• 51.4% (95% confidence interval [CI], 41.7%–61.0%) for patients in the DESTINY-PanTumor02 trial.
• 52.9% (95% CI, 27.8%–77.0%) for patients in the DESTINY-Lung01 trial.
• 46.9% (95% CI, 34.3%–59.8%) for patients in the DESTINY-CRC02 trial.

Identification of biomarker. Eligible patients had centrally confirmed HER2 positivity (IHC 3+).

References:

1. U.S. Food and Drug Administration: FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. U.S. Food and Drug Administration, 2024. Available online. Last accessed January 30, 2025.
2. Meric-Bernstam F, Makker V, Oaknin A, et al.: Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. J Clin Oncol 42 (1): 47-58, 2024.
3. Li BT, Smit EF, Goto Y, et al.: Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer. N Engl J Med 386 (3): 241-251, 2022.
4. Raghav KPS, Siena S, Takashima A, et al.: Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-overexpressing/amplified (HER2+) metastatic colorectal cancer (mCRC): Primary results from the multicenter, randomized, phase 2 DESTINY-CRC02 study. [Abstract] J Clin Oncol 41 (Suppl 16): A-3501, 2023.

Potential Emerging Agnostic Targets Not Yet Approved by the U.S. Food and Drug Administration

Tumor Mutational Burden–High (TMB-H) (≥16 Mutations/Megabase [mut/Mb]) Solid Tumors

Atezolizumab

Target and mechanism. Atezolizumab blocks the interaction of programmed death-ligand 1 (PD-L1) with programmed cell death 1 (PD-1) and CD80 receptors (B7-1Rs).

Current approvals. Atezolizumab is approved for non-small cell lung cancer,[1,2,3,4,5] small-cell lung cancer,[6] hepatocellular carcinoma,[7] melanoma,[8] and alveolar soft part sarcoma.[9]

Supporting study. Atezolizumab was evaluated in a phase IIa, multibasket, MyPathway study. The preplanned primary end point was objective response rate in patients with TMB-H (≥16 mut/Mb) tumors by FoundationOne TMB testing.[10]

Study population. This study included 120 patients with advanced solid tumors with TMB ≥10 mut/Mb by any Clinical Laboratory Improvement Amendments (CLIA)-certified assay. Among patients with local or central FoundationOne TMB testing results, 42 had TMB ≥16 mut/Mb tumors, comprising the primary efficacy population, and 49 had TMB ≥10 and <16 mut/Mb tumors, of whom 48 were efficacy evaluable.[10]

Efficacy. In the primary analysis population of 42 patients with TMB ≥16 mut/Mb tumors, the confirmed objective response rate was 38.1% (95% confidence interval [CI], 23.6%–54.4%) and the disease-control rate (the best response of complete response, partial response, or stable disease >4 months) was 61.9% (95% CI, 45.6%–76.4%), with a median follow-up of 9.9 months.[10][Level of evidence C3]

References:

1. Felip E, Altorki N, Zhou C, et al.: Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet 398 (10308): 1344-1357, 2021.
2. Herbst RS, Giaccone G, de Marinis F, et al.: Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med 383 (14): 1328-1339, 2020.
3. Socinski MA, Jotte RM, Cappuzzo F, et al.: Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med 378 (24): 2288-2301, 2018.
4. West H, McCleod M, Hussein M, et al.: Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 20 (7): 924-937, 2019.
5. Rittmeyer A, Barlesi F, Waterkamp D, et al.: Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389 (10066): 255-265, 2017.
6. Horn L, Mansfield AS, Szczęsna A, et al.: First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med 379 (23): 2220-2229, 2018.
7. Finn RS, Qin S, Ikeda M, et al.: Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med 382 (20): 1894-1905, 2020.
8. Ascierto PA, Stroyakovskiy D, Gogas H, et al.: Overall survival with first-line atezolizumab in combination with vemurafenib and cobimetinib in BRAFV600 mutation-positive advanced melanoma (IMspire150): second interim analysis of a multicentre, randomised, phase 3 study. Lancet Oncol 24 (1): 33-44, 2023.
9. Chen AP, Sharon E, O'Sullivan-Coyne G, et al.: Atezolizumab for Advanced Alveolar Soft Part Sarcoma. N Engl J Med 389 (10): 911-921, 2023.
10. Friedman CF, Hainsworth JD, Kurzrock R, et al.: Atezolizumab Treatment of Tumors with High Tumor Mutational Burden from MyPathway, a Multicenter, Open-Label, Phase IIa Multiple Basket Study. Cancer Discov 12 (3): 654-669, 2022.

Latest Updates to This Summary (02 / 12 / 2025)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Introduction

Revised the list of U.S. Food and Drug Administration–approved tissue-agnostic therapies to include repotrectinib.

NTRK Gene Fusion–Positive Solid Tumors

Added Repotrectinib as a new subsection.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about tissue-agnostic therapy for cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewer for Agnostic Cancer Therapies is:

• Jacob Adashek, DO (Johns Hopkins University)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."

The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Agnostic Cancer Therapies. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/types/agnostic-cancer-therapies-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 38771926]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us.

Last Revised: 2025-02-12