43O - A dose-escalation study of TNO155 (TN) in combination with spartalizumab (SPA) or ribociclib (RIB) in adults with advanced solid tumors

Background

NCT03114319 is an ongoing open-label phase I dose escalation/expansion trial of TN, an allosteric inhibitor of SHP2, in combination with the anti-PD-1 antibody, SPA, or the CDK4/6 inhibitor RIB in adults with advanced solid tumors.

Methods

Eligible patients (pts) were treated with either A) TN (5-50 mg BID, 20 or 60 mg QD) on a 2 weeks on/1 week off (2w/1w) schedule with SPA 300 mg once every 3 weeks (Q3W) or B) TN (20-60 mg QD, 20-40 mg BID), 2w/1w or 3w/1w with RIB (150-200 mg QD) continuously, 2w/1w, or 3w/1w (excludes data from Japan-specific escalation). A Bayesian hierarchical model was used to guide dose escalation. The primary objective was to characterize safety and tolerability; secondary objectives were pharmacokinetics (PK) and antitumor activity.

Results

As of March 23, 2023, 57 pts were enrolled in arm A (5 pts ongoing) and as of May 5, 2023, 46 pts were enrolled in arm B (2 pts ongoing). Preliminary PK analysis did not show evidence of any drug interaction in either arm. In Arm A, dose-limiting toxicities (DLTs) were reported with TN 20 mg QD, 20 mg BID, 60 mg QD, 40 mg BID, and 50 mg BID. In Arm B, DLTs were reported with TN 40 mg QD 2w/1w + RIB 200 mg QD, TN 60 mg QD 2w/1w + RIB 200 mg QD, TN 40 mg QD 3w/1w + RIB 150 mg QD 3w/1w, TN 30 mg BID 3w/1w + RIB 200 mg QD 3w/1w, TN 40 mg BID 3w/1w + RIB 200 mg QD 3w/1w, and TN 40 mg QD 2w/1w + RIB 200 mg QD 2w/1w. The most common treatment-emergent adverse events were increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), and blood creatine phosphokinase (CPK) in arm A, and thrombocytopenia, anemia, and increased AST, ALT, and blood CPK in arm B. Declared recommended doses (RDs) were TN 60 mg QD 2w/1w + SPA 300 mg Q3W and TN 40 mg QD 2w/1w + RIB 200 mg QD 2w/1w. Per RECIST 1.1, best overall response in Arm A was partial response in 1 pt (head and neck squamous cell carcinoma), stable disease (SD) in 13 pts, progressive disease (PD) in 28 pts, and was not evaluable (NE) in 15 pts, and in Arm B, best overall response was SD in 6 pts, PD in 31 pts, and was NE in 9 pts. Change in tumor DUSP6 expression after treatment will be presented.

Conclusions

TN + SPA and TN + RIB appeared well-tolerated at the RDs. Safety profiles of the combinations were consistent with those observed with each single agent.

Clinical trial identification

NCT03114319.

Editorial acknowledgement

Medical editorial assistance was provided by Amrita Dutta, PhD of Novartis Healthcare Pvt. Ltd., India.

Legal entity responsible for the study

Novartis Pharmaceuticals.

Funding

Novartis Pharmaceuticals.

Disclosure

J. Machiels: Financial Interests, Personal, Advisory Board: Pfizer, Roche, Bayer, Merck Serono, Boehringer Ingelheim, BMS, Novartis, Incyte, Cue Biopharma, ALX Oncology, iTEOS, eTheRNA, NEKTAR, F-Star, Seagen, Genmab, Astellas, CureVac, MSD, GSK, Merus; Financial Interests, Personal, Other, Travel: BMS, Amgen, Pfizer, MSD, Gilead, Sanofi; Financial Interests, Personal, Other, Data Safety Monitoring Board with Honoraria: Psioxus; Financial Interests, Personal, Principal Investigator: EORTC. R.A. Soo: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, BMS, Lily, Merck, Novartis, Pfizer, Roche, Taiho, Takeda, Yuhan, Janssen, Merck Serono, Puma Biotech, Thermo Fisher; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: AstraZeneca, Boehringer Ingelheim. B.B.Y. Ma: Financial Interests, Personal, Invited Speaker, Advisory Board/Consultancy: Novartis, BMS, MSD; Financial Interests, Personal, Advisory Board, Consultancy: Y-biologics, Boehringer Ingelheim, Merck Serono; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board, Ad board and consultancy: Viracta Therapeutics; Financial Interests, Personal, Other, Consultancy: Alentis; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, Merck Serono; Financial Interests, Institutional, Research Grant, Research Grant Preclinical: Novartis; Non-Financial Interests, Personal, Principal Investigator, NRG oncology study PI: NRG Oncology. T. Zander: Financial Interests, Personal, Advisory Board: Novartis, BMS, Roche, MSD, Lily. Y. Wang: Non-Financial Interests, Personal, Principal Investigator: Shanghai Pharmaceuticals Holding Co., Hengrui Pharmaceuticals Holding Co., Janssen Pharmaceutical Ltd., AstraZeneca. J.J. Lin: Financial Interests, Personal, Other, Consulting: Turning Point Therapeutics, Nuvalent, Elevation Oncology, C4 Therapeutics, Bayer, Novartis, Mirati Therapeutics, Regeneron, CLaiM Therapeutics; Financial Interests, Personal, Advisory Board, Consulting: Blueprint Medicines, Genentech; Financial Interests, Personal, Other, Honorarium, travel: Pfizer; Financial Interests, Institutional, Invited Speaker: Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche/Genentech, Novartis, Hengrui Therapeutics, Pfizer, Nuvalent. V. Gambardella: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Institutional, Other, Research: Research Funding: Bayer, Boehringer Ingelheim, Roche; Financial Interests, Institutional, Other, Institutional: Institutional Funding: Genentech, Merck, Roche, Bayer, Lilly, Novartis, Takeda, AstraZeneca, BM. J. Zhao, K. Nakhla, S. Yang, D. Kodack: Financial Interests, Personal, Full or part-time Employment: Novartis. S. Moody: Financial Interests, Personal, Full or part-time Employment: Novartis; Financial Interests, Personal, Stocks/Shares: Novartis. N. Yamamoto: Financial Interests, Personal, Invited Speaker: ONO, Chugai, Daiichi-Sankyo, Eisai; Financial Interests, Personal, Advisory Board: Eisai, Takeda, Boehringer Ingelheim, Cimic, Chugai, Healios; Financial Interests, Institutional, Invited Speaker, Principal Investigator in industry sponsored trial: Astellas, Chugai, Eisai, Taiho, BMS, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi Sankyo, Bayer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Takeda, Ono, Janssen Pharma, MSD, Merck, GSK, Sumitomo Dainippon, Chiome Bioscience, Otsuka; Financial Interests, Institutional, Invited Speaker, Principal investigator in industry sponsored trial: Carna Biosciences, Genmab, Shionogi, Toray; Financial Interests, Institutional, Research Grant, Principal investigator in industry sponsored trial: Rakuten Medical, InventisBio Co., Ltd. All other authors have declared no conflicts of interest.