BRAF plus MEK inhibition shows meaningful activity and outcome in patients with advanced melanoma resistant to anti-PD-1-based immunotherapy

July 30, 2022

Abstract

Objectives:
Forty to sixty percent of patients with advanced melanoma show primary resistance to PD-1-based immunotherapy, 30–40% of initial responders also progress. Here, we evaluated the outcome of second-line targeted therapy (TT) after progression on PD-1-based immune checkpoint inhibition (ICI) in BRAFV600-mutated melanoma. In addition, we report data on the activity of re-exposure with PD-1-based regimes.

Methods:
Patients with advanced (non-resectable stage III or IV, AJCC 2017, 8th edition) melanoma progressing on PD-1-based ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line BRAF plus MEK inhibition were identified from the prospective multicenter skin cancer registry ADOREG.

Results:
We identified 108 patients with unresectable stage III or stage IV melanoma progressing on first-line ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line combined BRAF/MEK inhibition. Seventy-three percent of the cohort presented with primary PD-1 resistant disease. Median progression-free survival (PFS) on ICI was 2.6 (95% CI 2.2–2.9) months. Median PFS on subsequent TT was 6.6 (95% CI 5.4–7.8) months. Median OS from start of second-line TT was 16.0 (95% CI 11.2–20.8) months. The 3-year PFS and OS rates on second-line TT were 16% and 30%. The objective response rate (ORR) and disease control rate (DCR) to TT were 42.6% and 55.6%. In patients with brain metastases, the ORR and DCR were 31.4% and 43.1%. Patients without brain metastases showed an ORR and DCR of 52.6% and 66.7%, respectively. Response to first-line ICI was associated with a numerically higher ORR and DCR to second-line TT and improved OS on TT. Twenty-three patients received third-line ICI of whom two patients showed an objective response.

Conclusions:
BRAF plus MEK inhibition shows meaningful activity and outcome in patients with advanced melanoma resistant to anti-PD-1-based immunotherapy. Rates of long-term benefit and survival in our study were similar to those reported for treatment-naïve patients receiving first-line MAPKi.

Source:

Kreft, S., Glutsch, V., Zaremba, A., Schummer, P., Mohr, P., Grimmelmann, I., Gutzmer, R., Meier, F., Pföhler, C., Sachse, M. M., Meiss, F., Forschner, A., Haferkamp, S., Welzel, J., Terheyden, P., Herbst, R., Utikal, J., Kaatz, M., Weishaupt, C., … Schilling, B. (2022). MAPKINASE inhibition after failure of immune checkpoint blockade in patients with advanced melanoma – an evaluation of the Multicenter Prospective Skin Cancer Registry Adoreg. European Journal of Cancer, 167, 32–41. https://doi.org/10.1016/j.ejca...

https://www.ejcancer.com/article/S0959-8049(22)00121-6/fulltext