KEY TAKEAWAYS
- The phase I trial aimed to assess TN’s safety and efficacy combined with SPA or RIB in advanced solid tumor patients.
- The results demonstrated that TN combined with SPA or RIB was well-tolerated at recommended doses, with safety profiles consistent with individual agents.
Omar Saavedra Santa Gadea and the team spearheaded the study that aimed to assess the safety and efficacy of TNO155 (TN), an allosteric SHP2 inhibitor, combined with spartalizumab (SPA) or ribociclib (RIB), in adults with advanced solid tumors in an open-label phase I trial.
The study enrolled eligible patients who received treatment regimens were TN administered at doses ranging from 5 to 50 mg twice daily or 20 or 60 mg once daily on a 2-week on/1 week off schedule, along with SPA given at 300 mg once every 3 weeks, or TN administered at doses ranging from 20 to 60 mg once daily or 20 to 40 mg twice daily, on either a 2 weeks on/1 week off or 3 weeks on/1 week off schedule, in combination with RIB given at doses ranging from 150 to 200 mg once daily, either on a 2 weeks on/1 week off or 3 weeks on/1 week off schedule (excluding data from Japan-specific escalation).
A Bayesian hierarchical model guided dose escalation was used. The primary objective was to characterize safety and tolerability, while secondary objectives included pharmacokinetics (PK) and antitumor activity assessment.
About 57 patients were enrolled (with 5 patients ongoing), and as of May 5, 2023, 46 patients were enrolled in Arm B (with 2 patients ongoing). Preliminary PK analysis revealed no evidence of drug interaction in either arm. Dose-limiting toxicities (DLTs) were observed in Arm A with TN doses of 20 mg once daily (QD), 20 mg twice daily (BID), 60 mg QD, 40 mg BID, and 50 mg BID.
In Arm B, DLTs occurred with TN doses of 40 mg QD for 2 weeks followed by 1 week + RIB 200 mg QD, TN 60 mg QD for 2 weeks followed by 1 week + RIB 200 mg QD, TN 40 mg QD for 3 weeks followed by 1 week + RIB 150 mg QD for 3 weeks followed by 1 week, TN 30 mg BID for 3 weeks followed by 1 week + RIB 200 mg QD for 3 weeks followed by 1 week, TN 40 mg BID for 3 weeks followed by 1 week + RIB 200 mg QD for 3 weeks followed by 1 week. TN 40 mg QD for 2 weeks followed by 1 week + RIB 200 mg QD for 2 weeks followed by 1 week.
The most frequently reported treatment-emergent adverse events (TEAEs) included increased levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and blood creatine phosphokinase (CPK) in Arm A, and thrombocytopenia, anemia, increased AST, ALT, and blood CPK in Arm B.
The recommended doses (RDs) were declared as TN 60 mg once daily (QD) for 2 weeks followed by 1 week + SPA 300 mg every 3 weeks, and TN 40 mg QD for 2 weeks followed by 1 week + RIB 200 mg QD for 2 weeks followed by 1 week.
According to RECIST 1.1 criteria, the best overall response (OR) in Arm A included a partial response (PR) in 1 patient (with head and neck squamous cell carcinoma), stable disease (SD) in 13 patients, progressive disease (PD) in 28 patients, and not evaluable (NE) in 15 patients. In Arm B, the best OR consisted of SD in 6 patients, PD in 31 patients, and NE in 9 patients. Changes in tumor DUSP6 expression post-treatment will be presented.
The study concluded that the combinations of TN + SPA and TN + RIB were well-tolerated at the RDs. The safety profiles of these combinations remained consistent with those observed with each single agent. Research was funded by Novartis Pharmaceuticals.
Source: https://cslide.ctimeetingtech.com/tat2024/attendee/confcal/show/session/5
Clinical Trials: https://clinicaltrials.gov/study/NCT03114319
https://clinicaltrials.gov/study/NCT04000529
Saavedra Santa Gadea O, Machiels JP, Soo RA, et al. (2024) ‘’A dose-escalation study of TNO155 (TN) in combination with spartalizumab (SPA) or ribociclib (RIB) in adults with advanced solid tumors.’’ Presented at ESMO-TAT 2024 (43O).
