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Developing Drugs for Tissue-Agnostic Indications: A Paradigm Shift in Leveraging Cancer Biology for Precision Medicine.

ABSTRACT: Targeted therapies have reshaped the landscape of the development of cancer therapeutics. Recent biomarker-driven, tissue-agnostic clinical trials represent a significant paradigm shift in precision cancer medicine. Despite their growth in preclinical and clinical studies, to date only a few biomarker-driven, tissue-agnostic indications have seen approval by the US Food and Drug Administration (FDA). These approvals include pembrolizumab in microsatellite instability-high or mismatch repair deficient solid tumors, as well as both larotrectinib and entrectinib in NTRK fusion-positive tumors. Complex cancer biology, clinical trial design, and identification of resistance mechanisms represent some of the challenges that future tissue-agnostic therapies have to overcome. In this Review, we present a brief history of the development of tissue-agnostic therapies, comparing the similarities in the approval of pembrolizumab, larotrectinib, and entrectinib for tissue-agnostic indications. We also explore the future of tissue-agnostic cancer therapeutics while identifying important challenges for the future that drugs targeting tissue-agnostic indications will face.

SUBMITTER: Seligson ND

PROVIDER: S-EPMC7891377 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Developing Drugs for Tissue-Agnostic Indications: A Paradigm Shift in Leveraging Cancer Biology for Precision Medicine.

Seligson Nathan D ND Knepper Todd C TC Ragg Susanne S Walko Christine M CM

Clinical pharmacology and therapeutics 20200716 2

Targeted therapies have reshaped the landscape of the development of cancer therapeutics. Recent biomarker-driven, tissue-agnostic clinical trials represent a significant paradigm shift in precision cancer medicine. Despite their growth in preclinical and clinical studies, to date only a few biomarker-driven, tissue-agnostic indications have seen approval by the US Food and Drug Administration (FDA). These approvals include pembrolizumab in microsatellite instability-high or mismatch repair defi ...[more]

PMID: 32535906

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Project description:Precision medicine just witnessed two breakthroughs in oncology in 2017. Pembrolizumab (Keytruda), Merck's anti-programmed cell death-1 (PD-1) monoclonal antibody (mAb), received accelerated approval in May 2017 by the US Food and Drug Administration for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having microsatellite instability-high (MSI-H) or deficient DNA mismatch repair (dMMR). Shortly after, nivolumab (Opdivo), Bristol-Myers Squibb's anti-PD-1 mAb, gained an accelerated approval in August 2017 for adult and pediatric patients with MSI-H or dMMR metastatic colorectal cancer that has progressed after standard chemotherapy. These regulatory approvals marked an important milestone that a cancer treatment may be approved based on a common biomarker rather than the anatomic location in the body where the tumor originated, and therefore established a precedent for tumor type-agnostic therapy. In the 2017 American Society for Clinical Oncology annual meeting, larotrectinib (LOXO-101), Loxooncology's oral, potent, and selective inhibitor of tropomyosin receptor kinases (TRK), demonstrated unprecedented efficacy on unresectable or metastatic solid tumors with neurotrophic tropomyosin receptor kinase (NTRK)-fusion proteins in adult and pediatric patients. Both the anti-PD-1 mAbs and the TRK-targeting therapies share some basic features: (a) biomarker-based, well-defined rare patient population; (b) exceptionally high clinical efficacy, e.g., near 40% overall response rate (ORR) for pembrolizumab across 15 tumor types with MSI-H/dMMR and 75% ORR for larotrectinib across more than 12 tumor types with NTRK-fusion proteins; (c) durable responses lasting at least 6 months with complete responses observed; and (d) parallel development in adult and pediatric populations. With increasing accessibility to genetic analysis tools such as next-generation sequencing, tumor type-agnostic therapy has become a reality, both during clinical development and in clinical practice. Adjustments in our approaches to developing new anti-cancer drugs and to adopting these new cancer treatments in clinical practice need to occur in order to prepare ourselves for the new era of precision medicine.

Dataset Information

Developing Drugs for Tissue-Agnostic Indications: A Paradigm Shift in Leveraging Cancer Biology for Precision Medicine.

Publications

Developing Drugs for Tissue-Agnostic Indications: A Paradigm Shift in Leveraging Cancer Biology for Precision Medicine.

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