Dabrafenib and trametinib (D+T) in BRAFV600E differentiated thyroid cancer: A real-world experience in Italy

BackgroundLenvatinib is the first line for radioiodine resistant differentiated thyroid cancer (RAIR-DTC). However, side effects burden is not negligible. BRAFV600E mutation is the most common genomic alteration in papillary thyroid cancer (PTC), being present in about 50% of tumors. We present data from a series of BRAFV600E DTC patients treated with D+T, within a named-patient program.MethodsData from 8 Italian sites were retrospectively collected. D (150 mg twice daily) + T (2 mg daily) were administered until disease progression, toxicity, or patient's withdrawal of consent. Primary endpoint was investigator-assessed ORR per RECIST 1.1. Secondary endpoints were side effects (CTCAE v 5.0); progression-free survival (PFS) and overall survival (OS). Statistical analyses have been performed by the R software v4.2.2.ResultsFrom 2020 to 2022, 37 PTC patients were treated with D+T. M/F were 24/13 with a median age of 60 yrs (range, 28-84 yrs). 30 out of 37 received total thyroidectomy, 5 lobectomy and 2 were not operated on. 31 out of 37 received RAI, with a mean dosage of 332 mCi (range 100-1277 mCi). BRAF was assessed by IHC in 1, RT-PCR in 14 and NGS in 22 cases, respectively. 18 patients received D+T as 1st line, 13 as 2nd line and 6 as > 2 lines. Partial response was recorded in 18 patients (52.9%, 95% CI 35.1-70.2). ORR was 78.6% (95% CI 49.2-95.3) in 1st line and 36.8% (95% CI 16.3-61.6) in ≥ 2nd line. Toxicities ≥ G3 were recorded in 29% of patients (diarrhea in 4 cases, fever in 4 cases, myalgia in 1, hyperglicemia in 1, uveitis in 1, nausea in 2, CPK increase in 1, platelets decrease in 1). With a median follow up of 103.0 months (95% CI 59.0-168.0), median OS and PFS were 210 months (95% CI 131-NA [NA: cannot be estimated]) and NA (95% CI 15-NA) for 1st line patients; 159 months (95% CI 106-NA) and 10 months (95% CI 6-NA) for ≥ 2nd lines, respectively. BRAFV600E RAIR-DTC patients who received D+T ≥ 2nd lines have an increased risk of progression compared to those patients in 1st line (hazard ratio 5.2, 95% CI 1.1-25.0, p-value 0.04).ConclusionsD+T is active in 1st line and beyond. Toxicities profile is manageable with limited side effects ≥ G3. This combination has not been approved in EU for thyroid cancer, D+T repurposing should be urgently claimed.Legal entity responsible for the studyIstituti Clinici Scientifici Maugeri IRCCS.FundingHas not received any funding.DisclosureL.D. Locati: Financial Interests, Personal, Invited Speaker: Eisai, Ipsen, SunPharma, Bayer, Novartis, Seagen; Financial Interests, Personal, Advisory Board: MSD, Merck Serono, Eli Lilly, Roche; Financial Interests, Personal, Other, Scientific consultant: Istituto Gentili Srl; Financial Interests, Institutional, Local PI: Eisai; Financial Interests, Institutional, Funding: Pfizer; Non-Financial Interests, Leadership Role, Endocrine Tumor Group: EORTC; Non-Financial Interests, Advisory Board: AIOM (Italian Association of Medical Oncology), MSGS (Multidisciplinary Salivary Glands Society); Non-Financial Interests, Advisory Role: AIOCC (Associazione Italiana Oncologia Cervico Cefalica). L. Fugazzola: Financial Interests, Personal, Advisory Board: Eisai, Lilly, Ipsen. P. Bossi: Financial Interests, Personal, Advisory Board: Merck, MSD, Sanofi-Regeneron, GSK, Merus, Pfizer, SunPharma, Angelini. S. Zovato: Financial Interests, Personal, Advisory Board: Eisai, Lilly, Ipsen, MSD, Astra Zeneca. D. Salvatore: Financial Interests, Personal, Advisory Board: Eisai, Lilly; Financial Interests, Advisory Board: IBSA. R. Elisei: Financial Interests, Personal, Advisory Board: Eisai, Lilly, Bayer, Ipsen, Roche. C. Durante: Financial Interests, Personal, Advisory Board: Eisai, Lilly, Ipsen. All other authors have declared no conflicts of interest.