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Clinical Features of Acquired Resistance to Anti-PD-1 Therapy in Advanced Melanoma
Daniel Y Wang1, Zeynep Eroglu2, Alpaslan Ozgun2
1Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Abstract:
Anti-PD-1 therapy has improved clinical outcomes in advanced melanoma, but most patients experience intrinsic resistance. Responding patients can develop acquired resistance to anti-PD-1. We retrospectively reviewed 488 patients treated with anti-PD-1 from three academic centers and identified 36 patients with acquired resistance, defined as disease progression following objective response. The incidence, timing, disease sites, post-progression survival (PPS), and outcomes were evaluated descriptively. The acquired resistance cohort consisted of 67% with more than 1 feature of poor prognosis (stage M1c, elevated LDH, or brain metastasis), and 67% had previously received ipilimumab. Partial and complete responses were achieved in 89% (n = 32) and 11% (n = 4) of patients, respectively, and median time to resistance (progression-free survival; PFS) was 11.1 months (range 4.3-32.8 months). Most progression was isolated (78% of patients, n = 28) and occurred while receiving therapy (78%, n = 28). The median PPS was 12.8 months (range 0.1-51.8 months), and the median overall survival was 33.7 months. Among isolated progressors, 15 received localized therapy (12 with surgery, 3 with radiation). Patients with isolated versus systemic progression exhibited a trend for improved PPS (P = 0.081), and patients with an initial PFS ≥ 15 months showed significant PPS improvement (P = 0.036). Two patients experienced subsequent responses to anti-PD-1 resumption. In conclusion, acquired resistance to anti-PD-1 was frequently associated with excellent clinical outcomes and often presented as isolated progression amenable to localized therapy (surgery or radiation) or systemic progression sensitive to therapy resumption. Cancer Immunol Res; 5(5); 357-62. ©2017 AACR.
Insights
Patients developing acquired resistance to anti-PD-1 therapy for advanced melanoma often have good outcomes. Resistance can present as isolated progression treatable with localized therapy or systemic progression responsive to re-treatment.
Area of Science:
- Oncology
- Immunotherapy
- Melanoma Research
Background:
- Anti-programmed cell death protein 1 (anti-PD-1) therapy has significantly improved outcomes in advanced melanoma.
- However, both intrinsic and acquired resistance to anti-PD-1 therapy remain significant clinical challenges.
Purpose of the Study:
- To investigate the incidence, characteristics, and outcomes of patients who develop acquired resistance to anti-PD-1 therapy in advanced melanoma.
- To evaluate the impact of isolated versus systemic progression and initial progression-free survival on post-progression survival.
Main Methods:
- Retrospective review of 488 patients treated with anti-PD-1 therapy across three academic centers.
- Identification and descriptive analysis of 36 patients with acquired resistance, defined as disease progression after an objective response.
Main Results:
- Acquired resistance occurred in a subset of patients, with a median time to resistance (progression-free survival) of 11.1 months.
- Most progressions were isolated (78%) and occurred during therapy (78%).
- Patients with isolated progression or an initial progression-free survival of ≥15 months showed trends toward improved post-progression survival.
Conclusions:
- Acquired resistance to anti-PD-1 therapy in melanoma is often associated with favorable clinical outcomes.
- Isolated progression may be amenable to localized treatments (surgery, radiation), and systemic progression can respond to re-initiation of anti-PD-1 therapy.