Phase I/II trial of concurrent extracranial palliative radiation therapy with Dabrafenib and Trametinib in metastatic BRAF V600E/K mutation-positive cutaneous Melanoma

Wei Wang; Jessica Louise Smith; Matteo Salvatore Carlino; Bryan Burmeister; Mark Blayne Pinkham; Gerald Blaise Fogarty; David Robert Harry Christie; Vanessa Estall; Mark Shackleton; Arthur Clements; Rory Wolfe; Le Thi Phuong Thao; Elizabeth Jane Paton; Victoria Steel; Narelle Catherine Williams

doi:10.1016/j.ctro.2021.08.006

Phase I/II trial of concurrent extracranial palliative radiation therapy with Dabrafenib and Trametinib in metastatic BRAF V600E/K mutation-positive cutaneous Melanoma

Clin Transl Radiat Oncol. 2021 Aug 14:30:95-99. doi: 10.1016/j.ctro.2021.08.006. eCollection 2021 Sep.

Authors

Wei Wang^{1

2}, Jessica Louise Smith¹, Matteo Salvatore Carlino^{1

2}, Bryan Burmeister³, Mark Blayne Pinkham^{4

5}, Gerald Blaise Fogarty⁶, David Robert Harry Christie^{7

8}, Vanessa Estall⁹, Mark Shackleton^{10

11}, Arthur Clements¹², Rory Wolfe¹³, Le Thi Phuong Thao¹³, Elizabeth Jane Paton¹⁴, Victoria Steel¹⁴, Narelle Catherine Williams¹⁴

Affiliations

¹ Department of Radiation Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, NSW 2145, Australia.
² Sydney Medical School, The University of Sydney, Camperdown, NSW 2006, Australia.
³ GenesisCare, Fraser Coast, QLD 4655, Australia.
⁴ Department Radiation Oncology, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia.
⁵ Queensland University of Technology, Brisbane City, QLD 4000, Australia.
⁶ Mater Genesis Care Radiotherapy Centre, 25 Rocklands RD, Crows Nest, NSW 2065, Australia.
⁷ Genesiscare, Tugun, QLD 4224, Australia.
⁸ Bond University, Robina, QLD 4226, Australia.
⁹ Liverpool Cancer Therapy Centre, Liverpool, NSW 2170, Australia.
¹⁰ Department of Oncology, Alfred Health, Melbourne, VIC 3004, Australia.
¹¹ Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.
¹² SAN Integrated Cancer Centre, Wahroonga, NSW 2076, Australia.
¹³ School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC 3004, Australia.
¹⁴ Melanoma and Skin Cancer Trials, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC 3004, Australia.

Abstract

Background: Concurrent treatment with BRAF inhibitors and palliative radiation therapy (RT) could be associated with increased toxicity, especially skin toxicity. Current Eastern Cooperative Oncology Group (ECOG) consensus guideline recommend ceasing BRAF inhibitors during RT. There is a lack of data regarding concurrent RT with combined BRAF and MEK inhibitors. This single-arm phase I/II trial was designed to assess the safety and tolerability of palliative RT with concurrent Dabrafenib and Trametinib in patients with BRAF-mutant metastatic melanoma.

Materials and methods: Patients received Dabrafenib and Trametinib before and during palliative RT to soft tissue, nodal or bony metastases. The RT dose was escalated stepwise during the study period. Toxicity data including clinical photographs of the irradiated area was collected for up to 12 months following completion of RT.

Results: Between June 2016 to October 2019, ten patients were enrolled before the study was stopped early due to low accrual rate. Six patients were treated at level 1 (20 Gy in 5 fractions, any location) and 4 patients at level 2a (30 Gy in 10 fractions with no abdominal viscera exposed). All alive patients completed one year of post-RT follow-up. Of the 82 adverse events (AEs) documented, the majority (90%) were grade 1 and 2. Eight grade 3 events (10%) occurred in five patients, only one was treatment-related (grade 3 fever due to Dabrafenib and Trametinib). No patients experienced grade 3 or 4 RT related toxicities, including skin toxicities. One serious AE was documented in relation to a grade 3 fever due to Dabrafenib and Trametinib requiring hospitalisation.

Conclusions: The lack of grade 3 and 4 RT-related toxicities in our study suggests that Dabrafenib and Trametinib may be continued concurrently during fractionated non-visceral palliative RT to extracranial sites.

Keywords: BRAF inhibitors; Dabrafenib; MEK inhibitors; Melanoma; Radiation therapy; Skin toxicity; Trametinib.