Page 151 - Read Online
P. 151
Page 12 of 17 Li et al. J Cancer Metastasis Treat 2020;6:14 I http://dx.doi.org/10.20517/2394-4722.2020.27
Table 2. RET fusions and fusion partners in solid tumors other than lung cancer
Tumor histology RET fusion detection rate (%) Fusion partners
PTC 6% (Kondo et al. [112] 2006, Stransky et al. [121] 2014) AKAP13, FKBP15, HOOK3, PCM1,
PRKAR1A, SPECC1L, TBL1XR1,
TRIM24, TRIM27, CCDC6, ERC1,
KIF5B, NCOA4, GOLGA5, KTN1,
RFG9
CRC 0.2%-0.4% (Stransky et al. [121] 2014, Le Rolle et al. [122] 2015) CCDC6, NCOA4
BC 0.1% (Stransky et al. [121] 2014) ERC1
Spitz tumors 3% (Wiesner et al. [45] 2014) GOLGA5, KIF5B
PTC: Papillary thyroid cancer; CRC: colorectal cancer; BC: breast cancer; RET: rearranged during transfection
with three tissue-agnostic cancer drugs approved and more than a dozen in various stages of development,
the tissue-agnostic approach is becoming a viable route for demonstrating efficacy of a targeted agent in
multitude of tumor types with shared molecular aberration or target as the common denominator. This
approach is especially attractive for those cancers with rare or ultra-rare patient populations. At the same
time, it is important to acknowledge that there are still many challenges and limitations in this emerging
area of research and development.
The first challenge is to determine, at the target and biology levels, whether same aberrations in different
histologies have similar biological, functional, and pathological significance. The preclinical data and
clinical experience in targeting NTRK fusions clearly confirmed that NTRK fusions are the single dominant
oncogenic driver in fusion positive cancers, independent of tissue origin of the cancer [131] . Therefore,
NTRK fusions represent an ideal tissue-agnostic target. On the other hand, one of the prominent failures
during early days of tissue-agnostic exploration involved BRAF targeting in different tumors including
melanoma, thyroid carcinoma, and colorectal cancer [132] . Whereas vemurafenib was efficacious in BRAF
V600E melanoma [133] and thyroid carcinomas [134] , it failed to halt colorectal cancer with the same BRAF
mutation [135] , partly due to a tissue-specific feedback activation of EGFR pathway in CRC patients [136] . This
exemplifies the role of histological context plays in certain cancers that influence the drug-target response.
It is unclear what level of influence the tissue context has on the oncogenic fusions. Will the oncogenic
fusions of ALK, ROS1, FGFR, and RET behave similarly to NTRK fusions upon treatment? For example,
[79]
it has been shown that different ROS1 fusions exhibited different subcellular localizations , which could
lead to varied levels of activation and pathway involvement. Whether differential subcellular localization
is a more general feature regulating oncogenesis across different oncoprotein fusions remains unclear.
Therefore, extensive translational research efforts need to be an integral part of these trials to guide patient
selection strategy.
The clinical development path for tissue-agnostic indication can be challenging. For instance, how is the
sample size determined for each of the tumor types? What are the common endpoints, considering each
tumor type is likely to have distinct natural history, standard of care option(s) and treatment algorithm
(line of therapy), reference response rates and duration of response, and survival end points? Particularly,
response assessment criteria would require cross-tumor harmonization, since these can differ depending
on tumor type. There is no standard design of basket trials, especially for the very rare and ultra-rare
patient populations. For instance, larotrectinib was conditionally approved based on a 55-patient trial that
spanned 12 distinct tumor types, some of which were represented by just one patient. Will this happen to a
future trial and still get approved? It is obvious that in these trials the statistical analyses are different from
well-established practices and innovative approach will be needed to support drug development decisions.
Operationally, basket trials require well-coordinated effort from different specialists and their teams of the
respective departments, which are typically organized by organ site. This holds particularly true for the
collection and processing of the patients’ biological material for molecular diagnostics.