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3618 Dabrafenib, Alone or in Combination with Trametinib, in Pediatric Patients with BRAF V600 Mutation-Positive Langerhans Cell HistiocytosisClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Clinical Trials, Non-Biological therapies, Workforce, Diseases, Pediatric, Therapies, Myeloid Malignancies, Study Population
Monday, December 13, 2021, 6:00 PM-8:00 PM

James A. Whitlock, MD1, Birgit Geoerger, MD, PhD2*, Michael Roughton, MSc3*, Jeea Choi, PhD4*, Lisa Osterloh, Dr. rer. nat.5*, Mark Russo, MD, PhD6* and Darren Hargrave, MD7*

1Division of Haematology/Oncology, The Hospital For Sick Children, Toronto, ON, Canada
2Department of Childhood and Adolescent Oncology, Gustave Roussy Cancer Center, Villejuif, France
3Novartis Pharma AG, Basel, Switzerland
4Global Drug Development, Novartis Pharmaceuticals, East Hanover, NJ
5Novartis Oncology, Novartis Farmacéutica S.A., Barcelona, Spain
6Novartis Oncology, Novartis Pharmaceuticals, East Hanover, NJ
7Paediatric Oncology, University College London - Great Ormond Street Institute of Child Health, London, United Kingdom

Introduction: Langerhans cell histiocytosis (LCH) is a rare proliferative disorder associated with varied clinical presentations. Patients (pts) with advanced disease have frequent recurrences despite standard chemotherapy and a significant proportion experience long-term complications, including orthopaedic, endocrine, auditory, or neurodegenerative complications. BRAF V600 mutations have been reported in over 50% of LCH cases. The BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib is approved for BRAF V600-mutation positive melanoma, NSCLC, and anaplastic thyroid cancer. Here we describe the pooled analysis of pts with LCH from two open-label phase I/II studies in pediatric pts with recurrent/refractory malignancies, treated with dabrafenib monotherapy (CDRB436A2102; NCT01677741) or dabrafenib plus trametinib (CTMT212X2101; NCT02124772).

Results: At the data cut-off date of January 19, 2021, 13 pts with LCH had received dabrafenib monotherapy (n=2, escalation; n=11, expansion). Median age was 3 years (range, 1-11) and all pts had received prior chemotherapy (100%); one patient received prior immunoglobulin and prior anti-CD52 monoclonal antibody (8%). Median duration of exposure to dabrafenib was 51 months (range, 7-65); 7 pts continued treatment on a rollover study and 6 discontinued, due to adverse events (AE; n=2), investigator decision (n=3), or switch to combination therapy via compassionate use (n=1). All pts experienced AEs, regardless of relationship to treatment; 11 pts (85%) had grade ≥3 AEs. All pts experienced AEs, suspected to be related to treatment, most commonly vomiting (46%), increased creatinine (38%), dry skin, rash, and melanocytic naevus (each 30%). AEs led to treatment discontinuation in 2 pts (increased blood creatinine; Epstein-Barr virus associated lymphoma, not related to treatment); there were no on-treatment deaths. The overall response rate (ORR) was 77% (6 complete response [CR]; 4 regressive disease [RD]); median duration of response (DOR) was not reached (NR), the estimated 24-month DOR rate was 90% (95% CI, 40-100). Median PFS was NR; the estimated 24-month PFS rate was 90% (95% CI, 50-100).

At the data cut-off date of February 10, 2021, 12 pts with LCH had received dabrafenib + trametinib combination (2, escalation; 10, expansion). Median age was 4 years (range, 2-13) and all pts had received prior chemotherapy (100%). Median duration of exposure to treatment was 22 months (range 1.8-35.9); 8 patients continued therapy on a rollover study and 4 discontinued, due to AEs (n=2), lack of efficacy (n=1), or long term CR (n=1). All pts experienced AEs; 9 pts (75%) had grade ≥3 AEs. All pts experienced AEs, suspected to be related to treatment, most commonly pyrexia (58%), diarrhoea, dry skin, decreased neutrophil count, and vomiting (each 42%). AEs led to treatment discontinuation in 2 pts (AST increased; ALT increased); there were no on-treatment deaths. The ORR was 58% (4 CR; 3 RD); median DOR was NR, the estimated 24-month DOR rate was 100% (95% CI, NR-NR). Median PFS was NR; the estimated 24-month PFS rate was 100% (95% CI, NR-NR).

Conclusions: Dabrafenib, with or without trametinib, demonstrated durable efficacy in pediatric pts with relapsed/refractory BRAF V600E mutation-positive LCH, with 90-100% of responses ongoing at 24 months. Treatment was associated with acceptable tolerability and manageable toxicities; the safety profile was consistent with what has been seen in other pediatric indications and in adult studies.

Disclosures: Whitlock: Sobi Pharmaceuticals: Consultancy; Novartis: Research Funding; Amgen; Jazz Pharmaceuticals: Honoraria. Roughton: Novartis Pharma AG: Current Employment. Choi: Novartis Pharmaceuticals: Current Employment. Osterloh: Novartis Farmacéutica S.A. Spain: Current Employment. Russo: Novartis: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Hargrave: AstraZeneca; Bayer; DayOne; Janssen; Novartis; Roche: Consultancy; AstraZeneca: Research Funding; AstraZeneca; Bayer; Novartis; Roche: Honoraria; Bayer: Speakers Bureau.

OffLabel Disclosure: Trametinib in combination with dabrafenib is approved for the treatment of unresectable/metastatic melanoma with BRAF V600E or V600K mutations; adjuvant treatment for melanoma with BRAF V600E or V600K mutations; metastatic non-small cell lung cancer with BRAF V600E mutation; locally advanced/metastatic anaplastic thyroid cancer with BRAF V600E mutation.

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