Tumor-Agnostic Treatments: A Bold Frontier in Oncology Drug Development
                     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. 
Tumor–agnostic 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
 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 R&D and regulatory challenges, connect  with seasoned IEB 
healthcare experts through email [email protected].
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