Clinical trialPhase 2Thyroid cancer

Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer

J Clin Oncol · 201816 evaluable patients with anaplastic thyroid cancer in the initial report (safety population: 100 patients with seven rare histologies); 36 patients in the 2022 updated analysis

Subbiah V, Kreitman RJ, Wainberg ZA, et al. J Clin Oncol. 2018. 36:7-13

A newer report of this study has been published: Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study (2022)

Study type: Clinical trial
Study name: ROAR (BRF117019) – ATC
Phase: Phase 2
Design: Open-label, non-randomised, single-arm basket trial in rare cancers with a BRAF V600E mutation (the ROAR study); report of the anaplastic thyroid cancer cohort
Sample size: 16 evaluable patients with anaplastic thyroid cancer in the initial report (safety population: 100 patients with seven rare histologies); 36 patients in the 2022 updated analysis
Source: J Clin Oncol · 2018
Trial registration: NCT02034110

In plain words

Anaplastic thyroid cancer is the rarest and most aggressive type of thyroid cancer, and before this study there was no effective drug treatment for it. In some of these patients, the tumour has a mutation called BRAF V600E. In this study, a combination of two targeted tablets (dabrafenib and trametinib) shrank the tumour in more than half of patients, and about half of patients were alive after one year, which is a big step forward for this disease. For this reason, testing for the BRAF mutation should be done as soon as possible after anaplastic cancer is diagnosed.

Key results

69% (11 of 16 patients)

Confirmed overall response rate (initial report)

95% CI 41%–89%; seven ongoing responses

90%, 79% and 80%

12-month estimates of duration of response, progression-free survival and overall survival (initial report)

Medians not reached because of too few events; median follow-up 47 weeks

56% (including 3 complete responses)

Overall response rate (updated analysis, 36 patients)

Updated analysis (Subbiah et al., Ann Oncol 2022; DOI: 10.1016/j.annonc.2021.12.014; whole cohort of 36 patients, data cut-off 14 September 2020, median follow-up 11.1 months); 95% CI 38.1%–72.1%; 12-month duration of response rate 50%

6.7 months and 14.5 months

Median progression-free survival and overall survival (updated analysis)

51.7% and 31.5%

12- and 24-month overall survival (updated analysis)

Updated analysis (Subbiah et al., Ann Oncol 2022; DOI: 10.1016/j.annonc.2021.12.014; whole cohort of 36 patients, data cut-off 14 September 2020, median follow-up 11.1 months)

Dose and schedule cards

Dabrafenib + trametinib (ROAR)

Locally advanced or metastatic BRAF V600E-mutant anaplastic thyroid cancer with no satisfactory locoregional treatment optionsCycle length: ContinuousOn the page “Thyroid cancer” · Anaplastic thyroid cancer: targeted therapy and chemotherapy

Locally advanced or metastatic BRAF V600E-mutant anaplastic thyroid cancer with no satisfactory locoregional treatment options

Drug	Dose	Route	Schedule
Dabrafenib	150 mg	Oral, 1 hour before or 2 hours after a meal	Twice daily
Trametinib	2 mg	Oral	Once daily

Cycle length: Continuous
Duration: Until disease progression or unacceptable toxicity

Sources: FDA labels; ROAR. Fever is common: for a fever of 38 to 40 °C, withhold dabrafenib until the fever resolves, then resume at the same or a lower dose; LVEF before starting and periodically.

On the page “Thyroid cancer” · Anaplastic thyroid cancer: targeted therapy and chemotherapy

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Dabrafenib + trametinib

Dabrafenib orally 150 mg twice daily (12 hours apart) with trametinib orally 2 mg once daily (together with the morning dose of dabrafenib), both on an empty stomach (1 hour before or 2 hours after a meal) with about 200 mL of water, continuously in 28-day cycles, until unacceptable toxicity, disease progression or death. Tumour assessment every 8 weeks.

Source of the regimen details: Full text of the JCO 2018 paper in PMC (PMC5791845) and ClinicalTrials.gov NCT02034110 (fasting administration, 12-hour interval, 28-day cycle); the adult dose of dabrafenib in the FDA label (TAFINLAR) is also 150 mg twice daily. Updated analysis: Ann Oncol 2022 (PMC9338780).

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 18 years and older with locally advanced (unresectable) or metastatic anaplastic thyroid cancer with a BRAF V600E mutation, with no standard treatment option available (in the judgement of the treating physician), with measurable disease per RECIST 1.1, sufficient tumour tissue to confirm the mutation, ECOG 0 to 2, ability to swallow the drugs and adequate organ function. Exclusion criteria: previous treatment with a BRAF or MEK inhibitor, radiotherapy within 7 days before enrolment, unresolved toxicity of previous treatment, disease curable by surgery alone, not having received previous standard treatment, and lymphoma, sarcoma or metastasis from another site. All patients had previously received radiotherapy and/or surgery, and six had received previous systemic therapy.

Endpoints

Primary endpoint: investigator-assessed overall response rate. Secondary endpoints: duration of response, progression-free survival, overall survival and safety.

Safety and side effects

The safety population comprised 100 patients with seven rare histologies: 93% had an adverse event of any kind and 42% a grade 3 or 4 adverse event; adverse events leading to dose reduction, temporary interruption/delay and permanent discontinuation occurred in 30%, 38% and 8%, respectively. Common adverse events: fatigue (38%), pyrexia (37%) and nausea (35%); most common grade 3 and 4 adverse events: fatigue, anaemia and neutropenia (5% each). In the anaplastic thyroid cancer cohort, the most common adverse events were fatigue (44%), pyrexia (31%) and nausea (31%), and the most common grade 3 and 4 adverse event was anaemia (13%); three patients had serious treatment-related adverse events (acute kidney injury and rhabdomyolysis, pyrexia, hyponatraemia). No new safety signal was seen; in the 2022 updated analysis, with longer follow-up, no new safety signal was identified either.

Clinical significance and place in guidelines

Based on this study (ROAR/BRF117019; overall response rate 61% in 23 evaluable patients at the time of the FDA review), the US Food and Drug Administration (FDA) approved dabrafenib with trametinib on 4 May 2018 for patients with locally advanced or metastatic anaplastic thyroid cancer with a BRAF V600E mutation and no satisfactory locoregional treatment options; this was the first drug treatment approved for this disease. The 2022 updated analysis with 36 patients confirmed the clinical benefit and long-term survival.

Limitations

The study was non-randomised and single-arm, and the number of patients was very small (16 patients in the initial report, 36 patients in the updated analysis). Because of the short follow-up, the figures in the initial report were more optimistic than in the updated analysis (for example a response rate of 69% versus 56%). The results apply only to patients with a BRAF V600E mutation.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.