Liquid Biopsy, Radiological Response Predict Posttreatment Outcomes in BRAF-Mutated Melanoma

A new study of patients who discontinued BRAF-targeted therapy for melanoma due to cumulative toxicity after sustained response found those who achieved complete response (CR) and tested negative for circulating tumor DNA (ctDNA) had improved postdiscontinuation progression-free survival (PFS) vs those with radiological residual disease or ctDNA positivity.

BRAF inhibition as monotherapy or in combination with a MEK inhibitor is standard of care for metastatic melanoma patients with BRAF-V600E/K mutations. Treatment until disease progression or unacceptable cumulative toxicity is recommended for these patients because it is unknown whether it is safe to stop targeted therapy after tumor response. The study, published in The Oncologist, points to ctDNA and achievement of CR as promising prognostic biomarkers for melanoma patients discontinuing BRAF and/or MEK inhibitor therapy.

The retrospective analysis included 24 patients treated with a BRAF inhibitor either alone or in combination with MEK inhibition for BRAF-mutated metastatic melanoma between June 1, 2011, and January 1, 2020. All of the patients discontinued treatment due to cumulative toxicity after CR or more than 12 months of partial response (PR). The median treatment duration was 59.4 months (95% CI, 55.4-63.4). Overall, 71% of patients experienced CR, with the remaining 29% showing PR.

The primary outcome was postdiscontinuation PFS at 12 and 24 months, and the median follow-up was 37.8 months (95% CI, 33.7-41.9) after treatment discontinuation. Liquid biopsies were done at the time of discontinuation and at each radiological evaluation after discontinuation until confirmed disease progression. All patients were alive at the time of analysis, and 45.8% experienced disease progression. The median time to disease progression after discontinuation was 10.4 months (95% CI, 6.9-13.8).

The postdiscontinuation PFS rate was 70.8% (95% CI, 54.8%-91.6%) at 12 months and 58.3% (95% CI, 41.6%-81.8%) at 24 months. Neither tumor characteristics nor treatment duration influenced disease progression risk, but time to best response was associated with postdiscontinuation PFS at univariate analysis.

Positive ctDNA at treatment discontinuation was associated with a significantly lower postdiscontinuation PFS rate vs negative ctDNA (63.6% [95% CI, 40.7%-99.5%] vs 85.7% [95% CI, 63.3%-100.0%] respectively.

The authors noted that the study’s small sample size prevents a formal demonstration of the effect that best response has on postdiscontinuation progression, but that 6 of 17 (35%) patients achieving CR eventually experienced disease progression during the study period compared with 5 out of 7 (71%) patients who had a PR during treatment.

None of the patients who experienced CR and tested negative for ctDNA at treatment discontinuation experienced disease progression post treatment over the course of the study. Patients who had residual disease detected by either radiological scans or ctDNA had a 12-month postdiscontinuation PFS rate of 53.8% (95% CI, 32.6%-89.1%).

One potential drawback of liquid biopsy is the sensitivity of testing. The authors note that low ctDNA levels or the presence of nonshedding tumors, like central nervous system metastases, might generate false negative results and impact treatment decisions. In patients with a sustained response to combination BRAF/MEK inhibitors, the impact of a false negative that leads to treatment discontinuation would be significant.

The authors do not recommend translating the study results into daily clinical practice given the need for development of clinical-grade ctDNA monitoring in liquid biopsies. They note, however, that prospective trials to hone the role of liquid biopsy in clinical decision-making for patients who respond to BRAF and MEK inhibitors are needed.

“The risk of progression is high even in patients with sustained sensitivity to BRAF/MEK inhibitors,” they wrote. “Integration of liquid biopsy in clinical trials investigating the optimal management of patients with sustained sensitivity to BRAF/MEK inhibitors is warranted.”

Reference

Di Guardo L, Randon G, Corti F, et al. Liquid biopsy and radiological response predict outcomes following discontinuation of targeted therapy in patients with BRAF mutated melanoma. Oncologist. Published online August 6, 2021. doi:10.1002/onco.13926