Histology Agnostic Drug Development: An Updated Review
Simple Summary
Abstract
1. Introduction
2. Promises and Pitfalls of Histology-Agnostic Therapy
- I.
- Approval of pembrolizumab in patients with unresectable or metastatic dMMR/MSI-H cancers (May 2017)
- II.
- Approval of larotrectinib in patients with unresectable or metastatic NTRK gene fusion-positive cancers (November 2018)
- III.
- Approval of entrectinib in patients with unresectable or metastatic NTRK gene fusion-positive cancers (August 2019)
- IV. Approval of pembrolizumab approved for patients with unresectable or metastatic TMB-H cancers (16 June 2020)
- V. Approval of dostarlimab in patients with unresectable or metastatic dMMR cancers (August 2021)
- VI.
- Approval of dabrafenib plus trametinib approved for patients with unresectable or metastatic BRAFV600E positive cancers (June 2022)
- VII.
- Approval of selpercatinib in patients with unresectable or metastatic RET-positive cancers in patients ≥ 12 years (September 2022)
- VIII.
- Approval of trastuzumab deruxtecan approved for patients with unresectable or metastatic HER2-positive cancers (April 2024)
- IX. Approval of repotrectinib approved for NTRK-positive tumors (June 2024)
3. Challenges, Remaining Questions and Future Directions
- (a)
- Does one size fit all?
- (b) Are there any diagnostic challenges?
- (c) Does the tumor microenvironment (TME) play a role?
- (d) Does tumor neoantigen burden (TNB) predict immunotherapy outcomes?
- (e) What agnostic therapies are on the horizon?
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
Declaration of Generative AI and AI-Assisted Technologies in the Writing Process
References
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Drug Name (s) | Approval Date (MM/DD/YYYY) | Indication | Clinical Trial (s) | Cohort (n) | Outcome Measures Used for Approval | Ref |
---|---|---|---|---|---|---|
Pembrolizumab | 05/23/2017 | MSI-H/dMMR solid tumors for adult and pediatric population | KEYNOTE-016,-164, -012, -028, and -158 | 149 | ORR = 39.6% (95% CI: 31.7, 47.9), CR = 11, PR = 48, 78% with DOR ≥ 6 months | [3] |
Larotrectinib | 11/26/2018 | NTRK fusion-positive solid tumors for adult and pediatric population | LOXO-TRK-1400, NAVIGATE, SCOUT | 55 | ORR = 75% (95% CI: 61, 85), CR = 22%, PR = 53%, mDOR = NR, 73% with DOR ≥ 6 months, 63% with DOR ≥ 9 months, 39% with DOR ≥ 12 months | [4] |
Entrectinib | 08/15/2019 | NTRK fusion-positive solid tumors for adult and pediatric population (12 years or older) | ALKA, STARTRK-1, STARTRK02 | 54 | ORR = 57% (95% CI: 43, 71), 68% with DOR ≥ 6 months, 45% with DOR ≥ 12 months | [5] |
Pembrolizumab | 06/15/2020 | TMB-H (≥10 mut/mb) solid tumors for adult and pediatric population | KEYNOTE-158 | 102 | ORR = 29% (95% CI: 21, 39), CR = 4%, PR = 25%, mDOR = NR, 57% with DOR ≥ 12 months. 50% with DOR ≥ 24 months | [6] |
Dostarlimab | 08/17/2021 | MSI-H/dMMR solid tumors for adult population | GARNET | 209 | ORR = 41.6% (95% CI: 34.9, 48.6), CR = 9.1%, PR = 32.5%, mDOR = 34.7 (2.6 to 35.8+) months, 95.4% with DOR ≥ 6 months | [7] |
Dabrafenib plus trametinib | 06/22/2022 | BRAF V600E solid tumors * for patients 6 years or older | BRF117019, NCI-MATCH, CTMT212X2101 | Adults: 131 Children: 36 | Adults: ORR = 41% (95% CI: 33, 50) Children: ORR = 25% (95% CI: 12, 42), 78% with DOR ≥ 6 months, 44% with DOR ≥ 24 months | [8] |
Selpercatinib | 09/21/2022 | RET fusion-positive solid tumors for adult population | LIBRETTO-001 | 41 | ORR = 44% (95% CI: 28, 60), mDOR = 24.5 months (95% CI: 9.2, NE), 67% with DOR ≥ 6 months | [9] |
Trastuzumab Deruxtecan | 04/05/2024 | HER2-positive (IHC3+) solid tumors for adult population | 1. DESTINY-PanTumor02 2. DESTINY-Lung01, 3. DESTINY-CRC02 | 192 | 1. ORR = 51.4% (95% CI: 41.7, 61.0), mDOR = 19.4 (1.3 to 27.9+) months 2. ORR = 52.9% (95% CI: 27.8, 77.0), mDOR = 6.9 (4.0 to 11.7+) months 3. ORR = 46.9% (95% CI: 34.3, 59.8), mDOR = 5.5 (1.3+ to 9.7+) months | [10] |
Reprotrectinib | 06/13/2024 | NTRK gene fusion-positive solid tumors for adult and pediatric patients 12 years or older | TRIDENT-1 | 88 | TKI naïve: ORR = 58% (95% CI: 41,73), mDOR = not estimable (NE) TKI-pretreated: 50% (95% CI: 35,65), mDOR = 9.9 (7.3, 13.0) months | [11] |
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Nguyen, K.; Fama, K.; Mercado, G.; Myat, Y.; Thein, K. Histology Agnostic Drug Development: An Updated Review. Cancers 2024, 16, 3642. https://doi.org/10.3390/cancers16213642
Nguyen K, Fama K, Mercado G, Myat Y, Thein K. Histology Agnostic Drug Development: An Updated Review. Cancers. 2024; 16(21):3642. https://doi.org/10.3390/cancers16213642
Chicago/Turabian StyleNguyen, Kevin, Karina Fama, Guadalupe Mercado, Yin Myat, and Kyaw Thein. 2024. "Histology Agnostic Drug Development: An Updated Review" Cancers 16, no. 21: 3642. https://doi.org/10.3390/cancers16213642