Abstract 1931P
Background
MAPK inhibition may impart immune stimulatory effects and enhance expression of putative tumor antigens in differentiated thyroid cancer (DTC). We hypothesize combined MAPK inhibitors and ICI will increase immunogenic cell death over ICI alone. We report results of a phase 2 study of either trametinib [TRM] or dabrafenib [DAB] plus anti-programmed death-1 (PD-1) antibody PDR001 in patients (pts) with radioiodine-refractory (RAIR) DTC.
Methods
This is an open-label, single center study. Pts with RECIST v1.1 measurable, DTC were enrolled: Cohort (Co.) A for tumors lacking BRAFV600E- mutation (mut), Co. B for BRAFV600E- tumors after progression on BRAF-directed therapy. Co. A received TRM 2 mg QD and Co. B received DAB 150 mg BID, each with PDR001 400mg IV Q4W. Primary endpoint was overall response rate (ORR). ≥ 4 responses among 15 pts in a Co. would be considered promising.
Results
Between 10/2020-2/2023, 12 pts enrolled in Co. A and 7 pts into Co. B. One pt in Co. A came off study before imaging due to TRM-related retinopathy. Histologies included 9 papillary, 2 high grade differentiated carcinoma, 3 poorly differentiated thyroid carcinoma (PDTC), 4 PDTC with oncocytic phenotype, and 1 oncocytic carcinoma. 11/12 Co. A pts had tumors with a putative driver mut: N/H/K-RAS (7), NF1 (3), and GNAS (1). ORR of PDR001+TRM was 33% (4 partial responses (PRs)/12). PRs occurred in pts with PDTC with oncocytic phenotype (2), oncocytic carcinoma (1), and high grade differentiated carcinoma (1). Two PRs occurred in tumors with mut burden >10 mut/MB. ORR of PDR001+DAB was 0% (0/7); 1 patient had an unconfirmed PR. 7/12 pts in Co. A and 7/7 pts in Co. B had stable disease (SD) as best response. 84% (16/19) had regression of any degree. Two pts were treated beyond progression with 1 pt remaining on treatment with SD >10 months after progression. Six pts (4 in Co. A, 2 in Co. B) remain on treatment.
Conclusions
PDR001+TRM showed efficacy in RAIR DTC lacking BRAFV600E- mut, meeting prespecified threshold for efficacy. PDR001+DAB had promising efficacy in BRAFV600E DTC, but evaluation was limited due to enrollment of just 7 pts at study completion. Further evaluation of this combination is warranted.
Clinical trial identification
NCT04544111.
Editorial acknowledgement
Legal entity responsible for the study
A. L. Ho.
Funding
Novartis.
Disclosure
W. Wong: Financial Interests, Institutional, Coordinating PI: Hookipa Pharma; Financial Interests, Institutional, Local PI: Bioatla. E.J. Sherman: Financial Interests, Personal, Advisory Board: AffyImmune, Eli Lilly, Eisai, Novartis; Financial Interests, Institutional, Coordinating PI: Fore Therapeutics. L. Michel: Financial Interests, Personal, Other, Consulting Agreement.: Kisoji Biotechnology. T.K.W. Hung: Financial Interests, Personal, Advisory Board: Regeneron. L. Dunn: Financial Interests, Personal, Advisory Board: Regeneron, Replimune, Merck; Non-Financial Interests, Institutional, Funding: Regeneron, IMVAQ, Replimune, Seagen. D. Pfister: Financial Interests, Institutional, Local PI: Akeso Biopharma, Hookipa Biotech. A.L. Ho: Financial Interests, Personal, Invited Speaker, discussed head and neck cancer therapies: Chinese American Hematologist and Oncologist Network; Financial Interests, Personal, Invited Speaker, Discussed salivary cancer therapies: Lurie Cancer Center (Northwestern); Financial Interests, Personal, Invited Speaker, discussed thyroid cancer therapies: Physician Education Resource; Financial Interests, Personal, Invited Speaker, Discussed thyroid cancer therapies: Endocrine Society; Financial Interests, Personal, Invited Speaker, Discussed head and neck cancer therapies: University of Pittsburgh Medical Center; Financial Interests, Personal, Invited Speaker, Discussed thyroid cancer therapeutics: New York University; Financial Interests, Personal, Advisory Board, Serve on DSMC: Affyimmune; Financial Interests, Personal, Other, Serve on the NCI Head and Neck Steering Committee: National Cancer Institute; Financial Interests, Personal, Advisory Board, Member of advisory board: Exelixis, Remix Therapeutics, Elevar Therapeutics, Prelude Therapeutics, Eisai, Ayala, Kura Oncology; Financial Interests, Personal, Other, Member of Safety Monitoring Committee: Kura Oncology; Financial Interests, Personal, Advisory Board, Member of advisory board.: Merck; Financial Interests, Personal, Other, Consultant: ExpertConnect; Financial Interests, Personal, Advisory Board, Member of advisory board and consulting.: Rgenta; Financial Interests, Personal, Advisory Board, Advisory Board: Coherus; Financial Interests, Personal, Advisory Board: Nested Therapeutics; Financial Interests, Personal, Full or part-time Employment: Memorial Sloan Kettering Cancer Center; Financial Interests, Institutional, Other, Listed as inventor for: Memorial Sloan Kettering Cancer Center; Financial Interests, Institutional, Coordinating PI, Serve as PI. also served on paid advisory board: Ayala; Financial Interests, Institutional, Coordinating PI, Serve as trial PI, also serve on paid SMC/advisory board: Kura Oncology; Financial Interests, Institutional, Local PI, Trial PI and served on an advisory board: Elevar Therapuetics; Financial Interests, Institutional, Coordinating PI, PI of IIT: Novartis, Merck, Bristol Meyer Squibb; Financial Interests, Institutional, Coordinating PI, PI of several IIT trials: Bayer; Financial Interests, Institutional, Coordinating PI, PI of trial: Bioatla, TILT Biotherapeutics, Genentech Roche, Astellas, Celldex; Financial Interests, Institutional, Local PI, PI of trial: OncC4; Financial Interests, Institutional, Coordinating PI, PI of several IITs: AstraZeneca; Financial Interests, Institutional, Coordinating PI, PI of trial and was part of paid advisory board: Eisai; Financial Interests, Institutional, Local PI, co-PI of trial: Poseida Therapuetics; Financial Interests, Institutional, Local PI: Hookipa; Financial Interests, Institutional, Coordinating PI, PI of IST clinical trial: Verastem; Financial Interests, Institutional, Coordinating PI, PI of Remix sponsored trial: Remix Therapeutics; Non-Financial Interests, Advisory Role: Cellestia, Inxmed; Non-Financial Interests, Member of Board of Directors: International Thyroid Oncology Group; Non-Financial Interests, Leadership Role: International Rare Cancer Initiative; Non-Financial Interests, Leadership Role, for the head and neck working group: Alliance for Clinical Trials in Oncology. All other authors have declared no conflicts of interest.
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