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[16]
or anatomical site of origin . Recently, drugs that target these common features, for example microsatellite
[17]
instability-high (MSI-H)/mismatch repair deficient (dMMR) and tropomyosin receptor kinase (TRK)
[18]
fusions , across multiple tumor types have been approved by the FDA as the first wave of tissue-agnostic
therapies (one target, all/many tumor types).

This review summarizes the current status of the tissue-agnostic approach and proposes additional
molecular alterations, with the emphasis on oncogenic fusions, that are potential targets for drug discovery
and development.

FIRST TISSUE-AGNOSTIC APPROVALS
The FDA and its international counterparts traditionally approve cancer drugs on the basis of clinical
studies in patients of a particular tumor type. Even for biomarker-driven approvals such as erlotinib and
crizotinib, these drugs have generally been approved for a specific tumor type that harbors the target of
interest.

In 2017, however, a significant paradigm shift took place, when the FDA granted accelerated approval of
pembrolizumab, an anti-programmed cell death protein 1 (PD-1) therapy, in adult and pediatric patients
with locally advanced or metastatic solid tumors of any tumor type (hence, tissue agnostic) that are dMMR
or MSI-H, who have progressed after prior treatment, and who have no satisfactory alternative treatment
[17]
options . This approval was based on collective data from several clinical trials. In the Phase II study
code-named KEYNOTE-016 in patients (n = 58) with progressive metastatic carcinoma, high somatic
mutation burden was associated with significant prolonged progression-free survival (PFS). In addition,
two separate studies (KEYNOTE-158, n = 19; KEYNOTE-164, n = 61) specifically enrolled solid tumor
patients with MSI-H or dMMR. Additional data from KEYNOTE-12 (n =6) and KEYNOTE-28 (n = 5)
were included in the dataset after retrospective analysis of MSI and MMR status. By tumor type, among
149 patients with MSI-H and/or dMMR cancers across the five trials, the majority (n = 90) had colorectal
cancer (CRC), while 14 other distinct tumor types accounted for the remaining 59 patients. Collectively, the
ORR was 39.6%, which included 11 complete responses (CR) and 48 partial responses (PR). The response
rate for patients with colorectal cancer and those with other cancers were similar.

About a year later in November 2018, the second tissue-agnostic cancer therapy, larotrectinib, won
accelerated approval by the FDA for the treatment of adult and pediatric patients with solid tumors that
have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance
mutation, that are either metastatic or where surgical resection is likely to result in severe morbidity, and
who have no satisfactory alternative treatments or whose cancer has progressed following treatment .
[19]
It is the second tissue-agnostic FDA approval for the treatment of cancer, and the first small molecule
TKI that gained the tissue-agnostic status. The approval was based on clinical outcome in 55 patients
with unresectable or metastatic, NTRK-fusion-positive solid tumors from three multicenter, open-label,
single-arm clinical trials: LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE
(NCT02576431). The identification of positive NTRK gene fusion status was prospectively determined in
local laboratories using NGS or fluorescence in situ hybridization (FISH). The ORR was 75%, including
22% CR and 53% PR across 12 cancer types, with the most common being salivary gland tumors (22%), soft
tissue sarcoma (20%), infantile fibrosarcoma (13%), and thyroid cancer (9%), as well as lung, melanoma,
gastrointestinal stromal tumor (GIST), and colon cancer.

Soon after, the TRK/ROS1 inhibitor, entrectinib, was also granted accelerated approval by the FDA for the
treatment of adults and pediatric patients 12 years of age and older with solid tumors that have a NTRK
gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection
is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory