Clinical Features of Acquired Resistance to Anti–PD-1 Therapy in Advanced Melanoma

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 vs. 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.

Acquired resistance to immunotherapy in MMR-D pancreatic cancer

“…A case series of acquired resistance to PD-1 axis inhibitors in 26 NSCLC patients found that a majority (89%) of these patients had recurrence limited to one or two sites of disease [ 7 ]. Isolated progression was also reported in the majority (78%) of 36 melanoma patients with acquired resistance to PD-1 blockade [ 29 ]. MMR-D patients under PD-1 blockade have been reported to develop acquired resistance, with tumors developing from occult sites such as the brain and the bone [ 1 ].…”

Cytoreduction and the Optimization Of Immune Checkpoint Inhibition with Radiation Therapy

“…In those patients who do respond to ICB, failure frequently occurs in sites of prior disease, with 60% of failures in anti-PD-1/PD-L1 treated NSCLC and 39% of failures in anti-PD-1 treated melanoma occurring in this way (Table 1). 42,43 Possible explanations include the importance of the activated T cell to tumor burden ratio in melanoma, 37 the existence of heterogeneous tumor-immune microenvironments in different metastatic lesions within a single patient, 44 and the presence of antigen loss variantsdcancer cells that have lost or mutated an antigen being targeted by cytotoxic T cellsdwithin bulk tumor populations. 45 Improved ICB response with decreased disease burden and failure in sites of gross disease point directly to the importance of effective ablation in this setting.…”

“…1). 37,64 The combination of preliminary clinical data that suggest a small clinical benefit of single-site radiation therapy plus ICB 52,53 and the predictable failure of ICB in sites of gross disease 42,43 with preclinical data by Zhang et al 66 that demonstrates local irradiation can lead to cytotoxic T cell mediated eradication of antigen loss variants leads directly to the theoretical importance of complete cytoreduction. However, the pivotal role of cytotoxic T cells and the importance of their ratio to tumor burden as outlined earlier highlight a potential limitation of this approach: if tumor-infiltrating lymphocytes are killed by irradiation, complete cytoreduction could amplify unwanted immunosuppressive effects.…”

Perspectives on Acquired Resistance to PD-1 Axis Inhibitors in Patients with Non–Small Cell Lung Cancer

“…As in the study by Gettinger et al, 10 isolated progression was noted in the majority (78%) of the 36 patients with melanoma and was amenable to local therapy. 15 This report from the melanoma literature suggests the possibility of shared biological mechanisms of acquired resistance across cancer types.…”