The RET inhibitor TPX-0046 demonstrated encouraging preliminary activity, which included objective responses, and an acceptable toxicity profile when used in patients with RET-driven advanced solid tumors.
The RET inhibitor TPX-0046 demonstrated encouraging preliminary activity, which included objective responses, and an acceptable toxicity profile when used in patients with RET-driven advanced solid tumors, according to data from the phase 1/2 SWORD-1 trial (NCT04161391).1
Results indicated that of 5 patients who never received RET TKIs, 4 experienced tumor regressions with TPX-0046; 1 patient experienced a 42% reduction, another experienced a 37% reduction, the third had a 23% reduction, and the fourth had a 3% reduction.
Notably, this included 2 patients who received the RET inhibitor at a daily dose of 30 mg who experienced confirmed partial responses and had duration of responses of 5.6 months and 5.8+ months. Three of the 4 patients who experienced tumor regression continued to receive treatment awaiting their next scan.
Of 9 patients who were pretreated with TKIs, 3 patients experienced tumor regressions of 44%, 27%, and 17%. Two of the 3 patients were previously treated with only 1 selective RET TKI. All of these patients are still receiving treatment and are awaiting their next scan.
Additionally, of the 14 evaluable patients, 50% (n = 7) continued to receive treatment with TPX-0046 and. the median duration of treatment ranged from 5.1 weeks to 51+ weeks.
“RET-driven cancers affect nearly 10,000 patients annually in the United States and the European Union, and patients who progress following treatment with a selective RET inhibitor remain particularly underserved,” Alexander Drilon, MD, chief of Early Drug Development Service at Memorial Sloan Kettering Cancer Center, stated 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.”
A total of 21 patients were enrolled to the study; of these patients, 10 had non–small cell lung cancer (NSCLC) and 11 had medullary thyroid carcinoma (MTC). Participants received treatment from December 2019 to March 10, 2021, which was the data cutoff date.
Three participants had RET-altered, TKI-naïve NSCLC, all of whom had prior platinum-based chemotherapy and immunotherapy, and 2 patients had RET-altered, TKI-naïve MTC. Additionally, 7 patients had TKI-pretreated NSCLC and 9 patients had TKI-pretreated MTC.
Notably, all 16 patients who had been pretreated with TKIs had received a selective RET TKI, while 56% (n = 9) had previously received more than 1 TKI. Moreover, 91% of the 21 patients had an ECOG performance status of 1 at baseline and 10 patients had previously received 3 or more treatments.
Fourteen evaluable patients had baseline measurable disease and at least 1 post-baseline assessment per RECIST v1.1 criteria. Of these patients, 3 had TKI-naïve NSCLC, 2 had TKI-naïve MTC, 4 had TKI-pretreated NSCLC and 5 had TKI-pretreated MTC.
Twenty-one patients with RET-altered NSCLC or MTC received TPX-0046 across several doses and schedules, ranging from a once-daily dose of 10 mg to a once-daily dose of 30 mg.
Additional pharmacokinetic data revealed exposure increases in a dose-dependent manner.
The agent was also found to be well tolerated, and the most common treatment-emergent toxicity reported was dizziness that was just grade 1 or 2 in severity. The maximum-tolerated dose of the RET inhibitor has not yet been identified, although 1 dose-limiting toxicity was observed, and it was determined to be associated with treatment. Grade 2 gait disturbance was reported in a patient who had received the agent at a once-daily dose of 30 mg.
Treatment-emergent adverse effects (TEAEs) that were observed with the drug in more than 20% of participants included dizziness (43%), fatigue (38%), increased alkaline phosphatase (29%), constipation (29%), reduced appetite (29%), dry mouth (29%), hyperphosphatemia (29%), increased lipase (29%), increased alanine aminotransferase (24%), dehydration (24%), and muscular weakness (24%).
Dose reductions and treatment discontinuations because of TEAEs were infrequent.
Additionally, most of the AEs determined to be associated with TPX-0046 were grade 1 or 2 in severity. Notably, no grade 4 or 5 treatment-related toxicities were noted. Additionally, no grade 3 or higher treatment-related elevated liver transaminase levels, any-grade hypertension, hemorrhagic effects, or QT prolongation were reported, nor was interstitial lung disease or pneumonitis.
“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, added in the 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.”
Once the recommended phase 2 dose of the RET inhibitor is established, the pharmaceutical company shared that they will then study the agent in several phase 1 dose-expansion cohorts of up to 75 patients with RET-altered malignancies.