Title: Tumor-Agnostic Treatments: A Bold Frontier in Oncology Drug Development
1Tumor-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
2- 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
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