On April 6, 2021 Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a precision oncology company developing next-generation therapies that target genetic drivers of cancer, reported initial clinical data from the ongoing Phase 1/2 SWORD-1 study of its RET inhibitor drug candidate, TPX-0046 (Press release, Turning Point Therapeutics, APR 6, 2021, View Source [SID1234577625]).
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The initial data from the Phase 1 dose finding portion of the study showed preliminary clinical activity, including objective responses and a generally well-tolerated safety profile. Turning Point continues to evaluate doses and schedules to determine a recommended Phase 2 dose, and plans to revise the study protocol to include Phase 1 expansion cohorts at the recommended Phase 2 dose.
"RET-driven cancers affect nearly 10,000 patients annually in the U.S. and E.U., and patients who progress following treatment with a selective RET inhibitor remain particularly underserved," said Alexander Drilon, M.D., chief, Early Drug Development Service, Memorial Sloan Kettering Cancer Center. "While we continue to evaluate TPX-0046, the initial preliminary data are encouraging, with a generally tolerable safety profile and early signals of activity."
TPX-0046 Initial Clinical Data
Twenty-one patients enrolled in the study including 10 with non-small cell lung cancer (NSCLC) and 11 with medullary thyroid carcinoma (MTC) who were treated from December 2019 to the data cut-off date of March 10, 2021. Patients included those with RET-altered TKI-naïve NSCLC (n=3; all previously treated with platinum-based chemotherapy and immunotherapy) and MTC (n=2), and TKI-pretreated NSCLC (n=7) and MTC (n=9).
All 16 TKI-pretreated patients were previously treated with a selective RET TKI and 9 patients (56%) were treated with more than 1 prior TKI. Ninety-one percent of patients (19/21) had a baseline ECOG performance score of 1, and nearly half (10/21) received 3 or more prior therapies.
Preliminary efficacy data by investigator assessment was available for 14 evaluable patients with baseline measurable disease and at least one post-baseline assessment per RECIST v1.1, including TKI-naïve NSCLC (n=3) and MTC (n=2), and TKI-pretreated NSCLC (n=4) and MTC (n=5).
As of the March 10, 2021 data cut-off date:
Preliminary Safety and Pharmacokinetic Results
A total of 21 patients with RET-altered NSCLC or MTC were treated with TPX-0046 across multiple doses and schedules from 10mg once daily (QD) to 30mg QD
TPX-0046 was generally well tolerated, with the most frequent treatment emergent adverse event (TEAE) being Grade 1 or 2 dizziness
The maximum tolerated dose had not been determined, with 1 dose-limiting toxicity of treatment-related Grade 2 gait disturbance at 30 mg QD
TEAEs reported in greater than 20 percent of patients were dizziness (43%); fatigue (38%); alkaline phosphatase increase, constipation, decreased appetite, dry mouth, hyperphosphataemia, lipase increase (29% each); and alanine aminotransferase increase, dehydration, and muscular weakness (24% each)
There were infrequent dose reductions or drug discontinuations due to TEAEs
The majority of treatment related adverse events (TRAEs) were Grade 1 or 2 and there were no Grade 4 or 5 TRAEs
There were no treatment related Grade 3 or greater ALT/AST elevations, any grade of hypertension, hemorrhagic events or QT prolongation, and no interstitial lung disease or pneumonitis
Preliminary pharmacokinetic data indicates exposure increases in a dose dependent manner
Preliminary Efficacy Results
Of 5 RET TKI-naïve patients, 4 showed tumor regressions of -42%, -37%, -23%, and -3%, including 2 patients dosed at 30 mg QD who achieved confirmed partial responses with duration of responses of 5.6 and 5.8+ months, respectively. Three of the 4 patients with regressions remained on treatment awaiting their next scan
Of 9 TKI-pretreated patients, 3 patients (2 treated with only 1 prior selective RET TKI) achieved tumor regressions of -44%, -27% and -17%. All 3 patients remained on treatment awaiting their next scan
Of the 14 evaluable patients, 7 (50%) remained on treatment with duration of treatment ranging from 5.1 to 51+ weeks
"Given the encouraging data we have seen, we plan to modify the SWORD-1 study to include a dose expansion portion utilizing additional clinical sites," said Mohammad Hirmand, M.D., executive vice president and chief medical officer of Turning Point Therapeutics. "We look forward to advancing our development of TPX-0046 in both the RET-positive TKI-naïve and less heavily pretreated TKI-pretreated settings."
After determination of the recommended Phase 2 dose, Turning Point plans to study TPX-0046 in multiple Phase 1 dose expansion cohorts in up to 75 patients with RET-altered malignancies prior to an end of Phase 1 meeting with the Food and Drug Administration.
Webcast and Conference Call
Turning Point will host a webcast and conference call accompanied by a slide presentation to discuss the results at 4:30 p.m. ET today. Athena Countouriotis, M.D., president and chief executive officer, will host the call, which will also include Dr. Hirmand.
The discussion will be accessible through the "Investors" section of tptherapeutics.com or by dialing (877) 388-2118 (in the United States) or (470) 495-9489 (outside the U.S.) using conference ID 9939858. A replay will be available through the "Investors" section of www.tptherapeutics.com.