Clinical trialPhase 2Thyroid cancer

Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study

Annals of Oncology · 202236 patients

Subbiah V, Kreitman R, Wainberg Z, Cho J, Schellens J, Soria J, et al. Annals of Oncology. 2022. 33:406-415

Study type: Clinical trial
Study name: ROAR
Phase: Phase 2
Design: Phase 2, open-label, non-randomised, single-group basket study; updated analysis of the anaplastic thyroid cancer (ATC) cohort
Sample size: 36 patients
Source: Annals of Oncology · 2022
Trial registration: NCT02034110

In plain words

Anaplastic thyroid cancer is a rare and very aggressive cancer. In this study, 36 patients whose tumour had the BRAF V600E gene mutation took two targeted tablets, dabrafenib and trametinib. About half of the patients (56%) responded to treatment, and more than half of them (51.7%) were alive a year later. The side effects were in line with what was already known about these drugs, and nothing new was seen.

Key results

56%

Investigator-assessed objective response rate (ORR)

95% CI 38.1%–72.1%; including three complete responses

50%

Duration of response rate at 12 months

6.7 months

Median progression-free survival (PFS)

12-month PFS rate: 43.2%

14.5 months

Median overall survival (OS)

12-month OS rate: 51.7%

31.5%

Overall survival rate at 24 months

11.1 months

Median follow-up

Range 0.9 to 76.6 months; data cutoff: 14 September 2020

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 plus trametinib (ATC cohort, single group)

Dabrafenib 150 mg twice daily with trametinib 2 mg once daily, both orally and continuously in 28-day cycles (fasting: 1 hour before or 2 hours after a meal; dabrafenib 12 hours apart and trametinib with the morning dabrafenib dose), until disease progression, intolerable toxicity or death; dose modification to manage toxicity was allowed per protocol. Disease assessment every 8 weeks. Mean daily dose received: dabrafenib 252.7 mg (target 300 mg) and trametinib 1.7 mg (target 2 mg).

Source of the regimen details: Full text of the paper (Ann Oncol 2022, PMC9338780) and ClinicalTrials.gov NCT02034110 (fasting administration and 28-day cycle)

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

36 patients aged 18 and older with unresectable or metastatic anaplastic thyroid cancer (ATC) with a BRAF V600E mutation (determined by local testing and retrospective central review with the THxID-BRAF kit), with at least one measurable lesion by RECIST 1.1, no standard treatment option, ECOG 2 or less, ability to swallow tablets and recovery from toxicities of prior treatments. All patients had to have received prior surgery and/or external-beam radiotherapy to the primary tumour (small resected primary tumours without radiotherapy, or metastatic disease without surgery/radiotherapy, were also allowed). Prior treatment with a BRAF and/or MEK inhibitor and radiotherapy within 7 days before enrolment were not allowed; thyroid lymphoma and sarcoma, metastases from another site and ATC with squamoid differentiation were excluded. Median age 71 years; ECOG 1 in 86%; stage IVC in 97%; 42% had prior chemotherapy.

Endpoints

Primary endpoint: investigator-assessed objective response rate (ORR) by RECIST version 1.1. Secondary endpoints: duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety.

Safety and side effects

All 36 patients had at least one adverse event (75% treatment-related), and grade 3 or 4 events occurred in 58%. Most common events: pyrexia 47% (no grade 3/4), anaemia 36% (grade 3/4: 19%), decreased appetite 33%, fatigue 33% (grade 3/4: 8%) and nausea 33%; pneumonia 25% (grade 3/4: 19%) and hyponatraemia 22% (grade 3/4: 17%). Serious adverse events in 56% (treatment-related 19%); 3 deaths due to adverse events occurred, none treatment-related. Dose reduction due to adverse events in 47%, interruption in 50% and permanent discontinuation in 17% (mostly within the first 6 months); pyrexia was the most common reason for dose reduction (17%) and interruption (14%). With longer follow-up, no new safety signal was identified.

Clinical significance and place in guidelines

Based on the earlier interim analysis of this cohort, dabrafenib plus trametinib had been approved in several countries for BRAF V600E-mutant ATC. This updated analysis with longer follow-up confirms the clinical benefit and manageable toxicity and shows the combination to be a meaningful option for this rare and aggressive disease. These findings underline the importance of BRAF V600E mutation testing in patients with ATC. The exact status of drug approval and guideline recommendations should be checked separately.

Limitations

The study was open-label and non-randomised, without a control group. The sample size was small (36 patients), and the primary endpoint was investigator-assessed. Median follow-up was 11.1 months with a wide range (0.9 to 76.6 months). Direct comparison with other treatments is therefore not possible from these data.

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.