Outcomes after progression of disease with anti-PD-1/PD-L1 therapy for patients with advanced melanoma

Abstract

Background: Greater than one-half of patients with melanoma who are treated with antibodies blocking programmed cell death protein 1 receptor (anti-PD-1) experience disease progression. The objective of the current study was to identify prognostic factors and outcomes in patients with metastatic melanoma that progressed while they were receiving anti-PD-1 therapy.

Methods: The authors evaluated 383 consecutively treated patients who received anti-PD-1 for advanced melanoma between 2009 and 2019. Patient and disease characteristics at baseline and at the time of progression, subsequent therapies, objective response rate (ORR), overall survival, and progression-free survival were assessed.

Results: Of 383 patients, 247 experienced disease progression. The median survival after progression was 6.8 months. There was no difference in survival noted after disease progression based on primary tumor subtype, receipt of prior therapy, or therapy type. However, significantly improved survival after disease progression correlated with clinical features at the time of progression, including normal lactate dehydrogenase, more favorable metastatic stage (American Joint Committee on Cancer eighth edition stage IV M1a vs M1b, M1c, or M1d), mutation status (NRAS or treatment-naive BRAF V600 vs BRAF/NRAS wild-type or treatment-experienced BRAF-mutant), decreasing tumor bulk, and progression at solely existing lesions. After progression, approximately 54.3% of patients received additional systemic therapy. A total of 41 patients received BRAF/MEK inhibition (ORR of 58.6%, including 70.4% for BRAF/MEK-naive patients), 30 patients received ipilimumab (ORR of 0%), and 11 patients received ipilimumab plus nivolumab (ORR of 27.3%).

Conclusions: The current study identified prognostic factors in advanced melanoma for patients who experienced disease progression while receiving anti-PD-1, including lactate dehydrogenase, stage of disease, site of disease progression, tumor size, and mutation status.

Keywords: immunotherapy; ipilimumab; melanoma; nivolumab; pembrolizumab; programmed cell death protein 1 (PD-1); progression.

Figure 1

A: Overall survival for full cohort (median 24.3 months). B: Survival after progression based on mutation status and prior BRAF/MEK inhibitor treatment. BRAF mutation with no prior BRAF/MEK inhibitor treatment 11.2 months, BRAF mutation with prior BRAF/MEK inhibitor treatment 3.4 months, NRAS mutation 10.4 months, other/WT/unknown 5.5 months (p=0.015). C: Survival after progression based on initial response to therapy. Median survival after progression for initial complete response or partial response (n=42), stable disease (n=31), or progressive disease (n=174); 21.3 vs. 14.2 vs. 3.8 months (p<0.001). D: Survival after progression based on metastatic stage at progression. Median survival by stage at progression: M1a 21.0 months, M1b 9.6 months, M1c 7.7 months, M1d 2.5 months (p<0.001). Missing data, n=8.

Figure 2

A: Survival after progression based LDH at progression. Normal 13.7 months, 1–2x ULN 7.2 months, 2–4x ULN 1.6 months, >4x ULN 0.8 months (p<0.0001). B: Survival after progression based location of lesion at progression. New and existing 5.5 months versus existing only 11.0 months or new only 10.8 months (p = 0.001). C: Survival after progression based on presence of symptoms at progression. Asymptomatic at progression 13.3 months, symptomatic 3.7 months (p<0.0001). D: Survival after progression based on size of largest lesion at progression. 0–2cm 18.3 months, >2–5cm 10.4 months, >5–8cm 8.6 months, >8cm 3.2 months (p<0.0001).