Investigational RET Inhibitor TPX-0046 Show Preliminary Clinical Activity in NSCLC, MTC

In a dose-finding trial, TPX-0046 elicited responses in patients with non–small cell lung cancer and medullary thyroid cancer who were naïve to prior tyrosine kinase inhibitors and whose tumors harbored alterations in RET.

Results of the dose-finding portion of the phase 1 SWORD-1 trial examining the investigational RET inhibitor TPX-0046 showed antitumor activity in patients with non–small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC) as well as safety of the regimen, announced Turning Point Therapeutics who is responsible for developing the agent.

The investigators are evaluating different dosages and schedules of the agent to determine the recommended phase 2 dose for revision of the dose-expansion portion of the trial.

RET-driven cancers affect nearly 10,000 patients annually in the [United States and European Union], and patients who progress following treatment with a selective RET inhibitor remain particularly underserved,” Alexander Drilon, MD, chief, Early Drug Development Service, Memorial Sloan Kettering Cancer Center, said in a press release. “While we continue to evaluate TPX-0046, the initial preliminary data are encouraging, with a generally tolerable safety profile and early signals of activity.”

Of the 21 patients evaluated, 3 had RET-altered NSCLC, were naïve to therapy with a tyrosine kinase inhibitor (TKI), and had received prior chemoimmunotherapy; 2 had RET-altered, TKI-naïve MTC; 7 had TKI-pretreated NSCLC; and 9 had TKI-pretreated MTC. Of the 16 patients with prior TKI therapy, all had received a selective RET inhibitor and 9 (56%) had experience with more than 1 TKI. Nineteen patients (91%) had an ECOG performance status of 1 and 10 (48%) had received 3 or more prior lines of therapy. All patients were treated with doses ranging from 10 mg once daily to 30 mg once daily.

There were 14 patients available for response assessment, which required baseline measurable disease and at least 1 post-baseline assessment by RECIST 1.1. The response-evaluable group was comprised of 3 patients with TKI-naïve and 4 with TKI-pretreated NSCLC plus 2 patients with TKI-naïve and 5 with TKI-pretreated MTC.

In patients without prior RET TKI, 4 out of 5 had tumor regression of 42%, 37%, 23%, and 3%, 3 of whom remained on therapy. Two had confirmed partial responses, with durations of response of 5.6 and 5.8+ months. In TKI-pretreated disease, 3 out of 9 had tumor regression of 44%, 27%, and 17%, with all patients remaining on therapy.

The most frequently reported treatment-emergent adverse event (TEAE) was grade 1 or 2 dizziness. One dose-limiting toxicity of grade 2 treatment-related gait disturbance was reported. TEAEs reported in more than 20% of patients included dizziness (43%); fatigue (38%); alkaline phosphatase increase, constipation, decreased appetite, dry mouth, hyperphosphatasemia, lipase increase (29% each); and alanine aminotransferase increase, dehydration, and muscular weakness (24% each). The maximum tolerated dose was not reached and TEAEs infrequently led to dose reductions or discontinuations. There were no grade 4 or 5 treatment-related AEs.

Preliminary pharmacokinetic data suggest that drug exposure is dose dependent. After the phase 2 dose is determined, the dose-expansion portion of the trial will enroll up to 75 patients with RET-altered tumors.

“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,” Mohammad Hirmand, MD, executive vice president and chief medical officer of Turning Point Therapeutics, said in a press release. “We look forward to advancing our development of TPX-0046 in both the RET-positive, TKI-naïve and less heavily pretreated TKI-pretreated settings.”


Turning Point Therapeutics Announces Initial Clinical Data From Phase 1/2 SWORD-1 Study of RET Inhibitor TPX-0046. News release. Turning Point Therapeutics. April 5, 2021. Accessed April 6, 2021.