Next-Generation RET Inhibitor Achieves Preliminary Activity in RET-Driven Cancers

TPX-0046, a next-generation RET inhibitor demonstrated preliminary clinical activity in patients with RET-driven cancers who were treated in the phase 1/2 SWORD-1 clinical trial.

RET cancer with Alexander Drilon

Alexander Drilon, MD

TPX-0046, a next-generation RET inhibitor demonstrated preliminary clinical activity in patients with RET-driven cancers who were treated in the phase 1/2 SWORD-1 clinical trial (NCT04161391), according to initial results announced in a press release by Turning Point Therapeutics.

The activity observed with TPX-0046 in the study included objective responses and a tolerable safety profile, which are 2 of the co-primary end points explored in the study. The third end point is finding the recommended phase 2 dose (RP2D) of the agent for the treatment of patients with RET-positive cancer. Evaluation of patients to determine the RP2D of TPX-0046 is ongoing in the study. The protocol of the study will be altered to include phase 1 expansion cohorts who will be dosed with the RP2D of TPX-0046. Up to 75 patients with RET-altered cancers will be enrolled before the company has an end-of-phase 1 meeting with the FDA.

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,” said Alexander Drilon, MD, chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, in a statement. “While we continue to evaluate TPX-0046, the initial preliminary data are encouraging, with a generally tolerable safety profile and early signals of activity.”

A total of 21 patients in the study SWORD-1 were treated with the investigational RET inhibitor between December 2019 and March 10, 2021, 10 of whom have non–small cell lung cancer (NSCLC), and 11 of whom have medullary thyroid carcinoma (MTC). Three of the patients in the NSCLC cohort were naïve to treatment with a RET tyrosine kinase inhibitor (TKI) but they had received prior platinum-based chemotherapy and immunotherapy, and 7 patients in the cohort were previously treated with a RET TKI. In addition, 2 patients with MTC had never received a RET TKI, and 9 had.

Of the patients who had received prior RET inhibition, 56% had received more than 1 prior TKI. At baseline, 91% of patients had an ECOG performance status of 1, and the majority had received 3 or more prior therapies.

Fourteen patients from the study were evaluated for efficacy. The evaluable patients had measurable disease at baseline along with at least 1 post-baseline assessment per RECIST v1.1. The group included 3 patients with NSCLC who were TKI-naïve, 3 with MTC who were TKI-naïve, 4 with NSCLC who were pretreated with a TKI, and 6 patients with MTC who were pretreated with a TKI.

Four of the TKI-naïve patients had tumor regressions of –42%, –37%, –23%, and –3%. Notably, 2 patients showed a tumor regression with the 30 mg once daily dose of TPX-0046 and achieved a partial response lasting 5.6 and 5.8+ months. Three of the patients who experienced a tumor regression remained on TPX-0046 awaiting their next scan, according to the press release.

Tumor regressions of –44%, –27%, and –17% were also observed in 3 of the 9 patients who were previously treated with a TKI. All of the patients in the group remained on treatment while awaiting their next scan.

Overall, 50% of the evaluable population remained on treatment. The median duration of treatment ranged from 5.1 weeks to more than 51 weeks.

Dosing of the investigational RET inhibitor started at 10 mg once daily and went up to 30 mg once daily. The drug was mainly well tolerated, and grade 1/2 dizziness was the most common treatment-emergent adverse event (TEAE). The maximum tolerated dose of TPX-0046 was not determined and dose-limiting toxicity of grade 2 gait disturbance was observed in a patient who received the 30 mg once-daily dose of the agent.

Overall, TEAEs occurred in more than 20% of patients. The most common TEAEs observed included dizziness (43%) and fatigue (38%). Other TEAEs seen in patients treated with TPX-0046 were alkaline phosphatase increase, constipation, decreased appetite, dry mouth, hyperphosphataemia, lipase increase (29% each); and alanine aminotransferase (ALT) increase, dehydration, and muscular weakness (24% each).

Few dose reductions and treatment discontinuations occurred in the study.

In terms of treatment-related AEs (TRAEs), the majority were either grade 1 or 2, and none were grade 4 or 5. Additionally, no treatment-related grade 3 or higher ALT or aspartate aminotransferase elevations, any-grade hypertension, hemorrhagic events, or QT prolongation events were observed. There was also no interstitial lung disease or pneumonitis.

Available pharmacokinetic data of TPX-0046 showed that exposure to the drug increases in a dose-dependent manner.

“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, MD, executive vice president, and chief medical officer of Turning Point Therapeutics, in the 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 7, 2021. Accessed April 7, 2021.

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