Second-Line Targeted Therapy Beneficial for PD-1 Resistant Melanoma

melanoma skin cancer woman shoulder
Macro shot of a big skin mole that should be inspected by a dermatologist.
The outcome of second-line targeted therapy after progression on PD-1-based immunotherapy in patients with BRAFV600-mutant melanoma is examined.

Patients with BRAFV600-mutant melanoma and resistance to PD-1-based immunotherapy may benefit from second-line BRAF plus MEK MAPK inhibition therapy, according to study data published in the European Journal of Cancer.

Investigators queried the ADOREG database, a prospective multicenter skin cancer registry, and identified patients with unresectable stage II or IV melanoma whose disease was progressing while being treated with first-line PD-1-based immune checkpoint inhibition (ICI) therapy: nivolumab, pembrolizumab, or ipilimumab plus nivolumab. The identified patients also were receiving second-line BRAF plus MEK MAPK-targeted inhibition therapy.

Of 108 patients identified, 54.6% were men, and 73% had primary PD-1 resistant disease.

The median progression-free survival was 2.6 months on ICI and 6.6 months on second-line BRAF/MEK therapy. The median overall survival (OS) was 23.9 months on ICI and 16 months on second-line therapy.

The objective response rate (ORR) and disease control rate (DCR)for second-line therapy were 42.6% and 55.6%, respectively. In patients with brain metastasis on second-line therapy, the ORR was 31.4% and the DCR was 43.1%. A multivariate Cox regression analysis showed a significant association between LDH level and second-line therapy OS and progression-free survival rate.  Response to first-line ICI was associated with a higher ORR and DCR to second-line therapy, and an improved OS on second-line therapy.

The study was limited by not incorporating adjuvant therapies into the analysis.

Addressing how to sequence ICI and second-line therapy in treatment-naïve BRAFV600-mutant melanoma patients, the study authors wrote that “upfront ICI treatment seems the superior sequence in patients with BRAF mutant melanoma.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Kreft S, Glutsch V, Zaremba A, et al. MAPKinase inhibition after failure of immune checkpoint blockade in patients with advanced melanoma – an evaluation of the multicenter prospective skin cancer registry. Eu J Cancer. 2022;167:32-41. doi:10.1016/j.ejca.2022.02.023