The features and management of acquired resistance to PD1-based therapy in metastatic melanoma
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Updated: Jul 10, 2025
Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
Adriana Hepner1, Judith M Versluis2, Roslyn Wallace3
1Melanoma Institute Australia, The University of Sydney, NSW, Australia; Instituto do Cancer do Estado de Sao Paulo, SP, Brazil.
Background:
Anti-PD-1 therapy (PD1) either alone or with anti-CTLA-4 (CTLA4), has high initial response rates, however 20% of patients (pts) with complete response (CR) and 30% with partial response (PR) within 12 months of treatment experience subsequent disease progression by 6 years. The nature and optimal management of this acquired resistance (AR) remains unknown.
Methods:
Pts from 16 centres who responded to PD1-based therapy and who later progressed were examined. Demographics, disease characteristics and subsequent treatments were evaluated.
Results:
299 melanoma pts were identified, median age 64y, 44% BRAFV600m. 172 (58%) received PD1 alone, 114 (38%) PD1/CTLA4 and 13 (4%) PD1 and an investigational drug. 90 (30%) pts had CR, 209 (70%) PR. Median time to AR was 12.6 mo (95% CI, 11.3, 14.2). Most (N = 193, 65%) progressed in a single organ site, and in a solitary lesion (N = 151, 51%). The most frequent sites were lymph nodes (38%) and brain (25%). Management at AR included systemic therapy (ST, 45%), local therapy (LT) +ST (31%), LT alone (21%), or observation (3%). There was no statistical difference in PFS2 or OS based on management, however, PFS2 was numerically superior for pts treated with ST alone who progressed off PD1 therapy than those who progressed on PD1 (2-year PFS2 42% versus 25%, p = 0.249). mOS from AR was 38.0 months (95% CI, 29.5-NR); longer in single-site versus multi-site progression (2-year OS 70% vs 54%, p < 0·001).
Conclusions:
Acquired resistance to PD1 therapy in melanoma is largely oligometastatic, and pts may have a favorable survival outcome following salvage treatment.
Insights
Acquired resistance to PD-1 therapy in melanoma often presents as limited, single-site disease. Patients with acquired resistance may achieve favorable survival outcomes with appropriate salvage treatment strategies.
Area of Science:
- Oncology
- Immunotherapy
- Melanoma Research
Background:
- Anti-PD-1 therapy (PD1) shows high initial response rates in melanoma but is followed by acquired resistance (AR) in a significant proportion of patients.
- Understanding the characteristics and optimal management of AR to PD1-based therapies remains a critical unmet need in melanoma treatment.
Purpose of the Study:
- To characterize the nature of acquired resistance to PD-1 based immunotherapy in melanoma patients.
- To evaluate the impact of different management strategies on outcomes in patients who develop acquired resistance.
Main Methods:
- A multicenter study examined 299 melanoma patients who responded to PD-1 based therapy and subsequently progressed.
- Data collected included demographics, disease characteristics, time to progression, sites of progression, and subsequent treatment interventions.
Main Results:
- Acquired resistance occurred at a median of 12.6 months, with most patients progressing in a single organ site (65%) and solitary lesion (51%).
- Common sites of progression were lymph nodes (38%) and brain (25%). Management strategies included systemic therapy, local therapy plus systemic therapy, local therapy alone, or observation.
- While no statistical difference in progression-free survival (PFS2) or overall survival (OS) was seen based on management, patients treated with systemic therapy alone who progressed off PD1 therapy showed numerically superior PFS2 compared to those progressing on PD1.
- Median overall survival from acquired resistance was 38.0 months, significantly longer in patients with single-site versus multi-site progression.
Conclusions:
- Acquired resistance to PD-1 therapy in melanoma is frequently oligometastatic, characterized by limited disease spread.
- Patients experiencing acquired resistance may have favorable survival outcomes following salvage treatment, particularly with single-site progression.
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