Skip to main content

Tumor-Agnostic Treatment for Cancer: When How is Better than Where

Clinical Drug Investigation volume 40, pages 519–527 (2020)Cite this article

Abstract

In the evolving landscape of precision oncology, genomic characterization of tumor has become crucial in order to move toward a molecular-based therapy for the vast majority of cancers. Recently, translational research has offered new perspectives in systemic cancer treatment thanks to the identification of novel oncogenic targets and the development of new targeted therapies, followed by the latest applications of genomic sequencing. Simultaneously, next-generation sequencing (NGS) has expanded its accessibility, being incorporated into clinical studies at the time of the initial screening, disease progression, and often in longitudinal monitoring of molecular changes. Consequently, new potentially targetable molecular alterations have been identified in several different types of tumors, leading to the development of tumor-agnostic treatments. Being highly selective for specific molecular alterations, these drugs are active against different subtypes of oncogene-addicted cancers. Three of these drugs—pembrolizumab [an anti-programmed death 1 (PD-1) monoclonal antibody (MAb)], larotrectinib [a pan-tropomyosin receptor tyrosine kinase (TRK) inhibitor], and entrectinib [a pan-TRK, anaplastic lymphoma kinase (ALK) and ROS-1 inhibitor]—received US FDA approval in 2017, 2018, and 2019, respectively. In this article, we critically review the clinical studies responsible for FDA approval and the most recently updated results. We then discuss the benefits and limitations of these new methodological approaches, paying particular attention to the largest precision medicine master protocol, NCI-MATCH. Among the benefits, there are the increased chances of offering targeted therapies for patients with specific alterations identified in different types of tumors. Among the limitations, we highlight that the same driver mutation may require different therapeutic strategies in different types of cancers. Additionally, the complex study design undeniably requires a dynamic strategy to enroll patients with considerable economic and managerial efforts.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 49.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

References

  1. Sanchez-Vega F, Mina M, Armenia J, et al. Oncogenic signaling pathways in the cancer genome Atlas. Cell. 2018;173(2):321–337.e10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kandoth C, McLellan MD, Vandin F, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502:333–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Goodwin S, McPherson JD, McCombie WR. Coming of age: ten years of next-generation sequencing technologies. Nat Rev Genet. 2016;17(6):333–51.

    Article  CAS  PubMed  Google Scholar 

  4. Zhang H, Liu R, Yan C, et al. Advantage of next-generation sequencing in dynamic monitoring of circulating tumor DNA over droplet digital PCR in cetuximab treated colorectal cancer patients. Transl Oncol. 2019;12(3):426–31.

    Article  PubMed  Google Scholar 

  5. Renfro LA, Sargent DJ. Statistical controversies in clinical research: basket trials, umbrella trials, and other master protocols: a review and examples. Ann Oncol. 2017;28(1):34–433.

    Article  CAS  PubMed  Google Scholar 

  6. Garber K. Tissue-agnostic cancer drug pipeline grows, despite doubts. Nat Rev Drug Discov. 2018;17(4):227–9.

    Article  CAS  PubMed  Google Scholar 

  7. Lemery S, Keegan P, Pazdur R. First FDA approval agnostic of cancer site: when a biomarker defines the indication. N Engl J Med. 2017;377:1409–12.

    Article  PubMed  Google Scholar 

  8. Vitrakvi (larotrectinib) capsules prescribing information, Loxo Oncology, November 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211710s000lbl.pdf. Accessed 27 Dec 2019.

  9. Rozlytrek (entrectinib) capsules prescribing information, Genentech, August 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212725s000lbl.pdf. Accessed 27 Dec 2019.

  10. Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov. 2015;5(1):25–34.

    Article  CAS  PubMed  Google Scholar 

  11. Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15:731–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Demetri GD, Paz-Ares L, Farago AF et al. Efficacy and safety of entrectinib in patients with NTRK fusion-positive tumors: pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372–001 [abstract no. LBA17]. Presented at the 2018 ESMO Congress; 19–23 October 2018; Munich.

  14. 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. 2017;7(4):400–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Robinson GW, Gajjar AJ, Gauvain KM, et al. Phase 1/1B trial to assess the activity of entrectinib in children and adolescents with recurrent or refractory solid tumors including central nervous system (CNS) tumors. J Clin Oncol. 2019;37(15 Suppl):10009.

    Article  Google Scholar 

  16. Cortes-Ciriano I, Lee S, Park WY, et al. A molecular portrait of microsatellite instability across multiple cancers. Nat Commun. 2017;8:15180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bonneville R, Krook MA, Kautto EA, et al. Landscape of microsatellite instability across 39 cancer types. JCO Precis Oncol. 2017. https://doi.org/10.1200/PO.17.00073..

    Article  PubMed  PubMed Central  Google Scholar 

  18. Latham A, Srinivasan P, Kemel Y, et al. Microsatellite instability is associated with the presence of lynch syndrome pan-cancer. J Clin Oncol. 2019;37(4):286–95.

    Article  CAS  PubMed  Google Scholar 

  19. Dolcetti R, Viel A, Doglioni C, et al. High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability. Am J Pathol. 1999;154:1805–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lee V, Murphy A, Le DT, et al. Mismatch repair deficiency and response to immune checkpoint blockade. Oncologist. 2016;21(10):1200–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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. 2020;38(1):11–9.

    Article  PubMed  Google Scholar 

  24. 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. 2020;38(1):11–9.

    Article  Google Scholar 

  25. Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36(8):773–9.

    Article  CAS  PubMed  Google Scholar 

  26. McNeil C. NCI-MATCH launch highlights new trial design in precision-medicine era. J Natl Cancer Inst. 2015;107(7):193.

    Article  Google Scholar 

  27. Azad NS, Gray RJ, Overman MJ, et al. Nivolumab is effective in mismatch repair-deficient noncolorectal cancers: results from arm Z1D-A subprotocol of the NCI-MATCH (EAY131) study. J Clin Oncol. 2020;38(3):214–22.

    Article  PubMed  Google Scholar 

  28. Chae YK, Vaklavas C, Cheng HH, et al. Molecular analysis for therapy choice (MATCH) arm W: phase II study of AZD4547 in patients with tumors with aberrations in the FGFR pathway. J Clin Oncol. 2018;15:2503.

    Article  Google Scholar 

  29. Kalinsky K, Hong F, McCourt CK et al. AZD5363 in patients (Pts) with tumors with AKT mutations: NCI-MATCH subprotocol EAY131-Y, a trial of the ECOG-ACRIN cancer research group (EAY131-Y). Presented at the 30th EORTC-NCI-AACR Symposium;13–16 Nov 2019: Dublin

  30. Jhaveri KL, Wang XV, Makker V, et al. Ado-trastuzumab emtansine (T-DM1) in patients with HER2-amplified tumors excluding breast and gastric/gastroesophageal junction (GEJ) adenocarcinomas: results from the NCI-MATCH trial (EAY131) subprotocol Q. Ann Oncol. 2019;30(11):1821–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Krop IE, Jegede O, Grilley-Olson JE, et al. Results from molecular analysis for therapy choice (MATCH) arm I: Taselisib for PIK3CA-mutated tumors. J Clin Oncol. 2018;36(Suppl 15):101.

    Article  Google Scholar 

  32. Janku F, Jegede O, Puhalla SL, et al. NCI-MATCH Arms N & P: phase II study of PI3K beta inhibitor GSK2636771 in patients (pts) with cancers (ca) with PTEN mutation/deletion (mut/del). Ann Oncol. 2018;29(Suppl 8):133–48.

    Google Scholar 

  33. Bedard PL, Li S, Wisinski KB, et al. NCI Molecular Analysis for Therapy Choice (NCI-MATCH EAY131) arm B: phase II study of afatinib in patients (pts) with HER2 (ERBB2) activating mutations. Cancer Res. 2019;79(13):139.

    Google Scholar 

  34. Clark AS, Llewellyn C, Shahmanesh M, et al. Molecular analysis for therapy choice (NCI-MATCH, EAY131) arm Z1B: phase II trial of palbociclib for CCND1, 2 or 3 amplified tumors. Cancer Res. 2019;79(13):10.

    Google Scholar 

  35. Kummar S, Li S, Reiss K, et al. NCI-MATCH EAY131-Z1I: phase II study of AZD1775, a wee-1 kinase inhibitor, in patients with tumors containing BRCA1 and BRCA2 mutations. Cancer Res. 2019;79(13):138.

    Google Scholar 

  36. Salama AKS, Li S, Macrae ER, et al. Dabrafenib and trametinib in patients with tumors with BRAF V600E/K mutations: results from the molecular analysis for therapy choice (MATCH) Arm H. J Clin Oncol. 2019;37(15 Suppl):3002.

    Article  Google Scholar 

  37. Jonsson P, Bandlamudi C, Cheng ML, et al. Tumour lineage shapes BRCA-mediated phenotypes. Nature. 2019;571(7766):576–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Choi BD, Curry WT. IDH mutational status and the immune system in gliomas: a tale of two tumors? Transl Cancer Res. 2017;6(Suppl 7):S1253–S12561256.

    Article  CAS  PubMed  Google Scholar 

  39. Helsten T, Elkin S, Arthur E, et al. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res. 2016;22(1):259–67.

    Article  CAS  PubMed  Google Scholar 

  40. Clovis Oncology, Inc. A study to evaluate rucaparib in patients with solid tumors and with deleterious mutations in HRR genes (LODESTAR). ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT04171700. Accessed 27 Dec 2019.

  41. Idience Co., Ltd. Basket trial of IDX-1197, a PARP inhibitor, in patients with HRR mutated solid tumors (VASTUS). ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT04174716. Accessed 27 Dec 2019.

  42. Yonsei University. K-BASKET, TAS-117, PI3K/AKT gene aberration. ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT03017521. Accessed 27 Dec 2019.

  43. Canadian Cancer Trials Group. Canadian profiling and targeted agent utilization trial (CAPTUR). ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT03297606. Accessed 27 Dec 2019.

  44. Debiopharm International SA. Basket trial in solid tumors harboring a fusion of FGFR1, FGFR2 or FGFR3 (FUZE Clinical Trial). ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT03834220. Accessed 27 Dec 2019.

  45. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20):1877–88.

    Article  PubMed  CAS  Google Scholar 

  47. Kopetz S, Desai J, Chan E, et al. Phase II pilot study of vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J Clin Oncol. 2015;33(34):4032–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Prahallad A, Sun C, Huang S, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012;483:100–3.

    Article  CAS  PubMed  Google Scholar 

  49. Atreya CE, Van Cutsem E, Bendell JC et al. Updated efficacy of the MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E mutated (BRAFm) metastatic colorectal cancer (mCRC) [abstract no. 103]. J Clin Oncol. 2015;33(Suppl).

    Article  Google Scholar 

  50. Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med. 2019;381(17):1632–43.

    Article  CAS  PubMed  Google Scholar 

  51. Kopetz S, McDonough SL, Morris VK et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406) [abstract no. 3505]. J Clin Oncol. 2017;35(Suppl).

  52. Khan SS, Chen AP, Takebe N. Impact of NCI-MATCH: a nationwide oncology precision medicine trial. Expert Rev Precis Med Drug Dev. 2019;4(4):251–8.

    Article  Google Scholar 

  53. Hirakawa A, Asano J, Sato H, et al. Master protocol trials in oncology: review and new trial designs. Contemp Clin Trials Commun. 2018;12:1–8.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medical Oncology, Careggi University Hospital, Florence, Italy

    Daniele Lavacchi

  2. Department of Health Sciences, University of Florence, Florence, Italy

    Giandomenico Roviello

  3. Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY, UK

    Alberto D’Angelo

Authors
  1. Daniele Lavacchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giandomenico Roviello
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alberto D’Angelo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniele Lavacchi.

Ethics declarations

Funding

No financial support was received for the preparation of this review.

Conflict of interest

Daniele Lavacchi, Giandomenico Roviello, and Alberto D’Angelo declare they have no conflicts of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lavacchi, D., Roviello, G. & D’Angelo, A. Tumor-Agnostic Treatment for Cancer: When How is Better than Where. Clin Drug Investig 40, 519–527 (2020). https://doi.org/10.1007/s40261-020-00915-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40261-020-00915-5