Tumor-Agnostic Treatments: A Bold Frontier in Oncology Drug Development

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Tumor-Agnostic Treatments A Bold Frontier in
Oncology Drug Development

• With the advent of personalized medicines, cancer
  treatment has been undergoing a radical
  transition in the therapeutic paradigm, shifting
  from location-specific (tissue/organ) to
  molecular-specific/ tumor-agnostic therapies.
  Tumoragnostic treatment represents a completely
  different approach to cancer treatment and is a
  genomically informed treatment strategy that
  seeks out novel targets regardless of
  histological origin.
• What makes Tumor-Agnostic Treatment a
  Breakthrough in Oncology?
• Since most cancer types are driven by more than
  one molecular aberration different sets of
  combination therapies, comprising chemotherapy,
  targeted therapy, and immunotherapy, have been
  investigated in order to enhance the efficacy of
  the single treatments and overcome possible
  resistances. However, the advantages obtained
  with combination therapies, if not guided by the
  identification of specific mutations, are not
  always clearly imputable to a synergic effect of
  the combined drugs. Such treatments could cover
  different subgroups responsive to different
  therapies, leading to a loss of precision and
  consequent overtreatment of some subgroups of
  patients.
• On the contrary, molecular-specific/tumor-agnostic
  treatments have emerged principally to meet two
  specific clinical needs
• Precisely identifying the molecular aberration
  associated with the tumor for which there was a
  targeted therapy already available for other
  tumor types.
• Locating rare mutations/aberrations, potentially
  druggable, across different tumor types,
  including rare and ultra-rare cancers.
• To identify the cancer-causing molecular
  alterations, genomic data is being assessed
  through next-generation sequencing. Based on the
  mutation, precision treatment for the tumor is
  being designed to help provide the right therapy
  to the right patient at the right time.
  Tsimberidou et al. found that advanced cancer
  patients who had received sequencing- matched
  therapy had a higher overall response rate (27
  vs. 5) and longer survival time (median of 13.4
  vs. 9.0 months) when compared to patients who did
  not receive the sequencing-matched therapy.
• Approved Tumor-Agnostic Treatments
• Since 2017, seven drugs have been investigated
  and approved with a molecular-
  specific/tumor-agnostic indication. Below is the
  list of approved tumor-agnostic drugs.
• 2017 pembrolizumab (Brand name KEYTRUDA) for
  patients with tumors deficient in mismatch
  repair (MMR) or with high microsatellite
  instability (MSI)
• 2018 larotrectinib (VITRAKVI) for patients with
  neurotrophic tyrosine receptor kinase (NTRK)
  fusions-positive tumors
• 2019 entrectinib (ROZLYTREKTM) in patients with
  NTRK fusions-positive tumors

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• 2020 pembrolizumab (KEYTRUDA) for patients
  affected by tumors with high tumor mutational
  burden (TMB), which is 10 mut/mb.
• 2021 dostarlimab-gxly (Jemperli) for patients
  with mismatch repair deficient tumors
• 2022 dabrafenib trametinib (Tafinlar and
  Mekinist) in patients with BRAF V600E mutated
  tumors
• 2022 selpercatinib (Retsevmo) in patients with
  REarranged during Transfection (RET)
  fusion-positive tumors
• Challenges of Tumor Agnostic Approvals
• Determining the link between aberrations and
  physiological changes
• One of the key challenges is to determine whether
  the same aberrations in different histologies
  are linked with similar biological, pathological,
  and functional changes. Preclinical and clinical
  data on NTRK fusions confirmed that NTRK fusions
  are the single dominant oncogenic driver in
  fusion-positive cancers, regardless of tissue
  origin. Thus, these fusions are considered an
  ideal tissue-agnostic target. Also, targeting
  oncogenic BRAF for various tumors, such as
  melanoma, thyroid carcinoma, and colorectal
  cancer, may lead to the early failures of
  tissue-agnostic exploration. Although
  vemurafenib was effective in BRAF V600E melanoma
  and thyroid carcinomas, it was ineffective in
  colorectal cancer patients with the same BRAF
  mutation, possibly due to tissue-specific
  feedback activation of the EGFR pathway. This
  exemplifies how histological context influences
  drug-target response in certain cancers. It is
  unknown how much influence the tissue context has
  on oncogenic fusions.
• Complex clinical trials for tumor-agnostic
  treatments
• The path to clinical development for tumor
  agnostics can be difficult. Because response
  assessment criteria differ depending on tumor
  type, cross-tumor harmonization would be
  required. Basket trials have no standard design,
  especially for very rare and ultra-rare patient
  populations.
• Regulatory challenges
• Regulatory agencies in various countries and
  geographic regions, such as the US/North
  America, the EU, Japan, and other Asia-Pacific
  countries, may accept the tissue-agnostic
  approach to varying degrees.
• Conclusion
• Despite the challenges in oncology, it is
  expected that tissue-agnostic approvals will
  expand the therapeutic options available to
  cancer patients. Compared to the traditional
  treatment plans, tumor-agnostic treatment
  represents a new way of thinking about how cancer
  is treated. In order to innovate diversified
  courses of treatment appropriate for various sub-
  groups of cancer patients along with addressing
  the RD and regulatory challenges, connect with
  seasoned IEB healthcare experts through email
  contact_at_iebrain.com.
• About Ingenious e-Brain

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