RAF inhibitor re-challenge therapy in BRAF-aberrant pan-cancers: the RE-RAFFLE study

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• RAF pathway alterations are common in various cancers, including melanoma.
• BRAF inhibitors are standard treatment but acquired resistance limits efficacy.
• Rechallenging RAF pathway with subsequent inhibitors may overcome resistance.

Purpose of the Study:

• To evaluate the efficacy and clinical benefit of rechallenging patients with RAF inhibitors after prior BRAF inhibitor therapy.
• To assess response rates, clinical benefit rates, progression-free survival, and overall survival in a rechallenge setting.

Main Methods:

• Retrospective observational study of 44 patients with RAF-altered tumors.
• Patients received a second RAF inhibitor (monotherapy or combination) after first-line RAF inhibitor treatment.
• Tumor types included melanoma, thyroid, ovarian, cholangiocarcinoma, and anaplastic astrocytoma.

Main Results:

• Overall response rate (ORR) was 18.1%, with partial responses (PR) observed across multiple tumor types.
• Clinical benefit rate (CBR) was 54.5%, with over 30% achieving durable responses (PR/SD > 6 months).
• Median progression-free survival (PFS) on second RAF inhibitor was 2.7 months, but median PFS-2 for responders improved to 12.8 months. Median overall survival (OS) from retreatment was 15.5 months.

Conclusions:

• RAF inhibitor rechallenge demonstrates clinical activity and benefit in patients with RAF-altered cancers previously treated with BRAF inhibitors.
• Durable responses suggest potential for long-term disease control in a subset of patients.
• Further prospective studies are warranted to confirm these findings and explore optimal combination strategies.