Cancer Discovery Highlights Potent Effects of TP Therapeutics’ Novel, Lead Investigational Compound Repotrectinib in Tumors Harboring ROS1, TRK or ALK Fusions with Solvent Front Mutations

Findings in the ongoing Phase 1/2 TRIDENT-1 Clinical Study Illustrate
Potential to Overcome Drug Resistance

SAN DIEGO–(BUSINESS WIRE)–TP Therapeutics, a privately held, clinical-stage biopharmaceutical
company developing oncology therapies with a focus on addressing drug
resistance, today announced the publication in Cancer Discovery
of preclinical and clinical proof-of-concept data for its lead
investigational compound, Repotrectinib (TPX-0005), a next-generation
tyrosine kinase inhibitor (TKI) designed to effectively target ROS1,
TRKA-C and ALK fusion proteins, and overcome clinical resistance due to
secondary kinase domain mutations.

The preclinical data show that repotrectinib can potently inhibit the
wildtype fusion kinases and their solvent front mutations involving ROS1
(ROS proto-oncogene 1 receptor tyrosine kinase), TRKA-C (tropomyosin
receptor kinases A, B, and C), and ALK (anaplastic lymphoma kinase).
Proof-of-concept clinical data from the ongoing Phase 1/2 TRIDENT-1
study (
number NCT03093116) highlighted two patients with ROS1 or TRKC
fusion-positive cancers who achieved confirmed partial responses after
previously relapsing on earlier generation TKIs due to solvent front
mutation-mediated resistance. One of the patients had brain metastases,
which responded to treatment with repotrectinib.

“Targeted therapies have demonstrated remarkable efficacy in the
treatment of various oncogene-driven solid tumors, yet patients
invariably develop resistance which leads to clinical progression,” said
Alice Tsang Shaw, MD, PhD, Professor of Medicine, Harvard Medical
School; Attending Physician, Chief of Thoracic Oncology, Massachusetts
General Hospital; and corresponding author of the Cancer Discovery
publication. “What is unique about the preclinical and early clinical
data with repotrectinib is the drug’s potency against the mutations that
often drive clinical resistance. These early data are encouraging and
suggest that repotrectinib could represent an effective treatment for
patients with ROS1-, NTRK, or ALK-rearranged
malignancies who have progressed on earlier generation TKIs.”

“Repotrectinib was intentionally designed with the goal to more
effectively target and overcome solvent front mutations that ultimately
hinder long-term effectiveness of other TKI therapies,” said Dr. J. Jean
Cui, founder, President, and Chief Scientific Officer of TP
Therapeutics. “With each patient our investigators treat, we learn more
about Repotrectinib’s safety and efficacy profile and become more
encouraged by its potential to ultimately help a broad range of cancer

The Cancer Discovery article may be found online at:

Preliminary data from the ongoing Phase 1 portion of the TRIDENT-1
clinical trial were previously presented in June 2018 at the annual
meeting of the American Society of Clinical Oncology (ASCO).

Highlights of the findings published in Cancer Discovery include:

  • In Ba/F3 models harboring wild type ROS1 fusion proteins,
    Repotrectinib was more potent (IC50 <0.2 nM) compared to all known or potential ROS1 inhibitors: crizotinib, ceritinib, brigatinib, ensartinib, cabozantinib, and lorlatinib.
  • Repotrectinib was more potent than lorlatinib against the most common
    clinically acquired resistance mutation ROS1 G2032R with an IC50
    of 3.3 nM, compared to an IC50 of 160.7 nM for lorlatinib.
  • In Ba/F3 models harboring wild type TRKA-C fusion proteins,
    Repotrectinib was more potent (IC50 <0.2 nM) compared to larotrectinib and entrectinib, two TRK inhibitors in late stage clinical development.
  • In Ba/F3 models, Repotrectinib retained potent activity against TRKA
    G595R (IC50 0.4 nM), TRKB G639R (IC50 0.6 nM),
    TRKC G623R (IC50 0.2 nM) and TRKC G623E (IC50
    1.4 nM), whereas solvent front mutations (TRKA G595R, TRKC G623R) have
    been identified in patients who are resistant to larotrectinib and
  • Repotrectinib treatment demonstrated a rapid, dramatic and durable
    confirmed partial response in a patient with an ETV6-TRKC G623E+
    mammary analogue secretory carcinoma (MASC) within the
    first few days of administration who was previously treated with
    multiple TKIs.
  • Repotrectinib treatment demonstrated a confirmed partial response and
    a response within metastases of the brain in a patient with CD74-ROS1
    G2032R+ non-small cell lung cancer (NSCLC) previously treated with
    crizotinib who had progressed.

About repotrectinib (TPX-0005)

Repotrectinib (TPX-0005) is a potent and orally bioavailable
investigational small molecule kinase inhibitor for ALK, ROS1, and TRK
family. The clinical benefits of targeting ALK, ROS1, or TRK fusion
kinase have been demonstrated with multiple kinase inhibitors already
approved for the treatment of ALK+ non-small cell lung
cancer (NSCLC), in addition to crizotinib for ROS1+ NSCLC,
and larotrectinib and entrectinib in clinical studies for TRK+
cancers. The successes of these therapies are overshadowed by the
development of acquired resistance. The acquired solvent front mutations
including ALK G1202R, ROS1 G2032R, TRKA G595R and TRKC G623R render a
common clinical resistance to the current ALK, ROS1, and TRK inhibitors.

Repotrectinib has demonstrated potency against wildtype and mutated ALK,
ROS1 and TRK family kinases, especially the clinically significant
solvent front mutations, gatekeeper mutations, and emerging compound
mutations after multiple line treatments. Repotrectinib may provide a
new opportunity to inhibit the abnormal signaling of ALK, ROS1, or TRK
family in solid malignancies, and overcome multiple resistance
mechanisms seen in refractory patients. Repotrectinib is currently being
evaluated in a Phase 1/2, open-label, multi-center, first-in-human study
of the safety, tolerability, pharmacokinetics and anti-tumor activity in
patients with advanced solid tumors harboring ALKROS1,
or NTRK1-3 rearrangements (TRIDENT-1, NCT03093116).
For additional information about the repotrectinib trial, please refer
Interested patients and physicians can also contact the TP Therapeutics
Oncology Clinical Trial Hotline at 1-858-276-0005 or email

Note: TPX-0005 had an initial generic name of “ropotrectinib,” which was
later changed to repotrectinib and is now the accepted name by USAN and

About TP Therapeutics, Inc.

TP Therapeutics, Inc. (TP) is a clinical-stage structure-based oncology
drug design company founded in October 2013 by Dr. J. Jean Cui, the lead
inventor of Pfizer’s oncology drug crizotinib and lorlatinib. The TP
team is focused on the design and development of novel chemical entities
within oncology for established oncogene drivers with high incidence of
secondary resistance mutations; newly identified disease-driven targets;
and potential targets regulating the tumor microenvironment and tumor
immunity. For more information, please visit us at


Investor and Media Contact:
For TP Therapeutics
Peter Li,