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

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–approved test.

Evidence. 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.[11,22][Level of evidence C3]

Efficacy. A total of 102 patients (13%) had tumors identified as TMB-H (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.[11] The median follow-up was 13.4 months.[22]

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 mutation; 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 trials evaluated 54 adult patients who received entrectinib at various doses and schedules and two trials evaluated 33 pediatric patients.[11,22][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%), with a median follow-up of 15 months.[11] 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.[22]

Identification of biomarker. Identification of positive NTRK gene fusion status was determined in local laboratories or a central laboratory using nucleic acid-based tests prior to enrollment. There are patients with NTRK gene mutations that are not gene fusions, and there is no evidence of clinical efficacy of entrectinib for these patients.

Larotrectinib

Indication. Larotrectinib is indicated for adult and pediatric patients with solid tumors and an NTRK gene fusion without a known acquired resistance mutation; 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. Approval was based on data from three multicenter, open-label, single-arm clinical trials: LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431).[33,44][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.[33,55]

Identification of biomarker. NTRK gene fusion status was prospectively determined in local laboratories using next-generation sequencing or fluorescence in situ hybridization. There are patients with NTRK gene mutations that are not gene fusions, and there is no evidence of clinical efficacy of larotrectinib for these patients.

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 onlineAvailable online. Last accessed April 3, 2024.

BRAF V600E Mutation–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 mutation. 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 approval was based on data from the following populations:[11,22,33,44,55][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).[11,22,33]
• One trial included 36 pediatric patients: CTMT212X2101 (NCT02124772) (median follow-up, not defined).[44]

The approval was also supported by results from COMBI-d (NCT01072175), COMBI-v (NCT01597908), and BRF113928 (NCT01336634).[66]

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%).[55]

Identification of biomarker. Biomarker status was determined in 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 onlineAvailable online. Last accessed April 3, 2024.
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 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).[11,22][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.[11,22]

Identification of biomarker. Clinical Laboratory Improvement Amendments (CLIA) or CLIA-equivalent locally obtained molecular testing was performed in 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).[11,22][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.[11,22]

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.[11] 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:[22,33,44][Level of evidence C3]

• DESTINY-PanTumor02 (NCT04482309).[22]
• DESTINY-Lung01 (NCT03505710).[33]
• DESTINY-CRC02 (NCT04744831).[44]

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 onlineAvailable online. Last accessed April 15, 2024.
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,[11,22,33,44,55] small-cell lung cancer,[66] hepatocellular carcinoma,[77] melanoma,[88] and alveolar soft part sarcoma.[99]

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.[1010]

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.[1010]

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.[1010][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 (05 / 13 / 2024)

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.

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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.

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Last Revised: 2024-05-13