TP Therapeutics Announces Updated Interim Phase 1/2 Clinical Trial Data of Repotrectinib (TPX-0005) in ROS1 Fusion-Positive Non-Small-Cell Lung Cancer Patients at 19th World Conference on Lung Cancer

Ongoing Antitumor Activity and Durable Responses Observed across Multiple Dose Cohorts in both TKI-naïve and TKI-pretreated ROS1 Positive NSCLC Patients

Overall Response Rate, Based on Blinded Central Review, is 80 Percent in TKI-naïve ROS1+ Patients and 23 Percent in Patients Treated with 1 Prior TKI

TP Therapeutics, a privately held, clinical-stage biopharmaceutical company developing oncology therapies with a focus on addressing drug resistance, announced today updated interim data as of July 13, 2018 from its ongoing Phase 1/2 TRIDENT-1 study of Repotrectinib (TPX-0005) in ROS1 fusion-positive non-small-cell lung cancer (NSCLC) patients.

“Additional follow-up of patients treated with Repotrectinib continues to demonstrate a meaningful and durable clinical benefit, with potency against difficult mutations that often drive resistance to this class of therapeutics,” said Alice Tsang Shaw, MD, PhD, Professor of Medicine, Harvard Medical School; Director of Thoracic Oncology, Massachusetts General Hospital; and an Investigator in the TRIDENT-1 study. “These early data, now supported by Blinded Independent Central Review, are encouraging in both TKI-naïve and TKI-pretreated NSCLC patients with the ROS1 fusion oncogene.”

Repotrectinib is an investigational next-generation tyrosine kinase inhibitor (TKI) designed to effectively target ROS1, TRKA-C and ALK kinases, and also clinical resistance kinase domain mutations. ROS1 rearrangement is an oncogenic driver of tumors in up to 2.6 percent of U.S. NSCLC patients.

As of the July 13, 2018 data cut-off, the study findings showed:

• A total of 72 patients (31 ALK+; 33 ROS1+; and 8 NTRK+ by local test) with advanced cancers had been treated across 6 dose levels (40 mg QD; 80 mg QD; 160 mg QD; 240 mg QD; 160 mg BID; and 200 mg BID), which comprises the safety population for the current dataset
• A total of 30 patients treated across the first 5 dose escalation cohorts with ROS1+ NSCLC were in the efficacy evaluable population, of which 27 were evaluable by Blinded Independent Central Review (BICR)
• Within the efficacy evaluable population of ROS1+ NSCLC, the median age was 52 years (range 30 – 75), with 53% of patients having CNS metastases at baseline; the median number of prior TKI therapies (majority of which were crizotinib) was 1 (range 0 to 3).

Preliminary Safety Analysis (n=72)

• Repotrectinib was generally well tolerated, with the most frequent treatment-related adverse events (TRAEs >15%) including dizziness (50%); dysgeusia (45.8%); paraesthesia (29.2%); constipation (19.4%); and fatigue (18.1%); the majority of TRAEs are Grade 1-2, and the Grade 3 TRAEs include 2.8% dizziness and 4.2% anemia
• The vast majority (31/36 cases, 86%) of dizziness were Grade 1 and there have been no cases of dizziness that have led to treatment discontinuation
• As of the data cut-off date, there have been no Grade 4 TRAEs
• Four dose-limiting toxicities (DLTs) were observed: Grade 2 or 3 dizziness (n=3: 2 at 160 mg BID; 1 at 240 mg QD) that resolved upon dose reduction; and Grade 3 dyspnea/hypoxia (n=1 at 160 mg BID) that resolved after study drug discontinuation
• Neither the maximum tolerated dose (MTD) nor the recommended Phase 2 dose (RP2D) has been reached

Preliminary Efficacy Analysis (n=27)

• As of the data cutoff, 27 ROS1+ NSCLC patients were evaluable for tumor response by BICR
• Of the 27 patients, 10 were TKI-naïve and 17 were previously treated with at least one ROS1 TKI therapy
• Fifteen of 27 patients (56%) remained on treatment
• The primary reason for treatment discontinuation was progression (radiologic or clinical, n=9), with 1 patient each discontinuing for withdraw of consent, investigator decision, and adverse event (DLT of Grade 3 dyspnea/hypoxia at 160 mg BID)

TKI-Naïve Efficacy Analysis (n=10)

• A confirmed overall response (ORR) by BICR analysis based on RECIST v1.1 was achieved in 8 of 10 patients (80%; CI 44-97), with a median time to response of 1.6 months (1.4-3.3). Confirmed responses were achieved across all 5 doses tested to date within dose escalation
• The Intracranial ORR was 100 percent with 3 of 3 patients with measurable CNS disease achieving a confirmed response (CI 29-100). All 3 patients who achieved an intracranial response also achieved an extracranial response
• The overall clinical benefit rate was 100 percent, with all 10 patients achieving stable disease for at least two cycles or a confirmed partial response
• Of the 8 patients who achieved a confirmed response, 5 continue to maintain their response (3.7+ - 11.1+ months)

TKI-Pretreated Efficacy Analysis (n=17)

• Across 5 dose escalation cohorts, a confirmed ORR was achieved in 3 patients (3/17, 18%; CI 4-44), with a median time to response of 1.6 months (1.5-1.8) with 2 of 3 responses occurring at the 160 mg QD dose level
• All 3 responses were achieved in patients treated with 1 prior TKI (3/13, 23%) and duration of the responses were 11.1+ months; 7.4 months; and 1 patient who was censored at the time of their last tumor assessment as they withdrew consent while remaining in response
• Intracranial ORR was achieved in 1 of 4 patients (25%)
• Of importance, the overall clinical benefit rate was 76 percent (95% CI: 56-97) with 13 of 17 patients achieving stable disease for at least 2 cycles or a confirmed partial response
• With respect to baseline plasma cell-free DNA (cfDNA), 16 of 17 TKI-pretreated patients had plasma samples evaluated at baseline
  • Four crizotinib-pretreated patients were identified as having a ROS1 solvent front G2032R mutation at baseline. All 4 patients had tumor regressions on Repotrectinib including 1 confirmed partial response of 7.4 months achieved at the 160 mg QD dose level. This patient remained on treatment for 11+ months at the time of the data cut-off.

“We are very pleased with the updated Phase 1 preliminary data, which continue to demonstrate the strong activity of Repotrectinib in both TKI-naïve and TKI-pretreated patients with ROS1+ NSCLC since our initial data presentation in June,” said Athena Countouriotis, M.D., Executive Vice President and Chief Medical Officer of TP Therapeutics. “We continue to enroll patients in additional dosing cohorts, and look forward to determining the recommended Phase 2 dose and discussing our path to registration with health authorities. We plan to begin the Phase 2 portion of the TRIDENT-1 study as soon as a RP2D is identified with the goal of bringing a potential new treatment option to patients in this area of high unmet need.”

The data were presented earlier today by Jessica J. Lin, M.D., Massachusetts General Hospital Cancer Center, in an oral presentation at the International Association for the Study of Lung Cancer (IASLC) 19th World Conference on Lung Cancer in Toronto.

Initial preliminary data from the ongoing Phase 1 portion of the TRIDENT-1 study were presented in June 2018 at the annual meeting of the American Society of Clinical Oncology (ASCO). In addition, the preclinical and clinical proof-of-concept data for Repotrectinib were recently published in the journal Cancer Discovery (The Cancer Discovery article may be found online at: http://cancerdiscovery.aacrjournals.org/content/early/2018/08/09/2159-8290.CD-18-0484?papetoc=).

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 ALK, ROS1, or NTRK1-3 rearrangements TRIDENT-1 study (www.clinicaltrial.gov number NCT03093116). Interested patients and physicians can also contact the TP Therapeutics Oncology Clinical Trial Hotline at 1-858-276-0005 or email clinical@tptherapeutics.com.

¹Note: TPX-0005 had an initial generic name of “ropotrectinib,” which was later changed to repotrectinib and is now the accepted name by USAN and WHO INN.

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 www.tptherapeutics.com.

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TP Therapeutics, Inc.
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Y. Peter Li, Ph.D., M.B.A.
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peter.li@tptherapeutics.com

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