Pembrolizumab Plus Ipilimumab Following Anti-PD-1/L1 Failure in Melanoma

Daniel J. Olson, MD; Zeynep Eroglu, MD; Bruce Brockstein, MD; Andrew S. Poklepovic, MD; Madhuri Bajaj, MD; Sunil Babu, MD; Sigrun Hallmeyer, MD; Mario Velasco, MD; Jose Lutzky, MD; Emily Higgs, BS; Riyue Bao, PhD; Timothy C. Carll, MD; Brian Labadie, MD; Thomas Krausz, MD; Yuanyuan Zha, PhD; Theodore Karrison, PhD; Vernon K. Sondak, MD; Thomas F. Gajewski, MD, PhD; Nikhil I. Khushalani, MD; Jason J. Luke, MD


J Clin Oncol. 2021;39(24):2647-2655. 

In This Article

Abstract and Introduction


Purpose: Combination of antiprogrammed cell death protein-1 (PD-1) plus anti–cytotoxic T-cell lymphocyte-4 (anti-CTLA-4) immunotherapy shows greater response rates (RRs) than anti-PD-1 antibody alone in melanoma, but RR after initial anti-PD-1 and programmed death ligand-1 (PD-L1) antibody progression awaits robust investigation. Anti-CTLA-4 antibody alone after anti-PD-1/L1 antibody progression has a historical RR of 13%. We report the results of the first prospective clinical trial evaluating ipilimumab 1 mg/kg plus pembrolizumab following progression on anti-PD-1 immunotherapy.

Methods: Patients with advanced melanoma who had progressed on anti-PD-1/L1 antibody as immediate prior therapy (including non–anti-CTLA-4 antibody combinations) were eligible. Patients received pembrolizumab 200 mg plus ipilimumab 1 mg/kg once every 3 weeks for four doses, followed by pembrolizumab monotherapy. The primary end point was RR by irRECIST. After 35 patients, the trial met the primary end point and was expanded to enroll a total of 70 patients to better estimate the RR.

Results: Prior treatments included 60 on anti-PD-1 antibody alone and 10 on anti-PD-1/L1 antibody–based combinations. Thirteen patients had progressed in the adjuvant setting. The median length of prior treatment with anti-PD-1/L1 antibody was 4.8 months. Response assessments included five complete and 15 partial responses, making the irRECIST RR 29% among the entire trial population. The median progression-free survival was 5.0 months, and the median overall survival was 24.7 months. The median duration of response was 16.6 months. There was no difference in median time on prior anti-PD1/L1 or time to PD1 + CTLA4 initiation between responders and nonresponders. Grade 3–4 drug-related adverse events occurred in 27% of patients. Responses occurred in PD-L1–negative, non-T-cell–inflamed, and intermediate tumor phenotypes.

Conclusion: To our knowledge, this is the first prospective study in melanoma of pembrolizumab plus low-dose ipilimumab after anti-PD-1/L1 immunotherapy failure, demonstrating significant antitumor activity and tolerability.


For patients with advanced melanoma, the introduction of targeted and immune checkpoint inhibitor therapies has greatly improved systemic therapy outcomes.[1] With antibodies against the immune checkpoints cytotoxic T-lymphocyte–associated antigen 4 (anti–cytotoxic T-cell lymphocyte-4 [CTLA-4]; ipilimumab) and programmed cell death protein-1 (PD-1; pembrolizumab and nivolumab), some patients have achieved long-term disease control, with 5-year survival rates ranging from 34% to 52%.[2,3] Combination immunotherapy using both anti-PD-1 and anti-CTLA-4 antibodies demonstrates a numerically higher response rate (RR), progression-free survival (PFS), and overall survival (OS) relative to anti-PD-1 antibody monotherapy, but with a grade 3–4 toxicity rate of up to 59%.[4] This has prompted many treating oncologists to begin with single-agent anti-PD-1 therapy, with the prospect of using ipilimumab in the second line upon treatment failure.

However, in patients who have experienced tumor progression on anti-PD-1 and programmed death ligand-1 (PD-L1) antibody monotherapy, no prospective trials of ipilimumab or an anti-PD-1 plus anti-CTLA-4 antibody combination exist. Post hoc assessment of 97 patients who crossed over to ipilimumab directly after pembrolizumab in the randomized phase III KEYNOTE-006 trial demonstrated a 13% objective response rate (ORR).[5] Similarly, a retrospective review of treatment outcomes in 355 patients with progression on an anti-PD-1/L1 antibody demonstrated that those who subsequently received ipilimumab achieved an RR of 13% versus 32% in those who received ipilimumab of dose 3 mg/kg once every 3 weeks for four doses plus an anti-PD-1/L1 antibody. The OS also appeared to favor the combination group at 20.4 months versus 8.8 months, respectively.[6] These findings support the hypothesis that combined PD-1 and CTLA-4 inhibition can be effective after progression on a prior anti-PD-1/L1. The use of this combination in the second line might also theoretically spare the higher toxicity rate for patients who only required single-agent anti-PD-1 therapy for disease control.

Despite demonstrating the highest ORR, PFS, and OS, the combination of nivolumab plus ipilimumab at 3 mg/kg treatment is not uniformly used in advanced melanoma because of serious immune-related adverse events.[4] A strategy for mitigating toxicity with this combination immunotherapy is administration of low-dose ipilimumab, 1 mg/kg, in combination with an anti-PD-1 antibody. The randomized Checkmate-511 study compared nivolumab with ipilimumab at 1 mg/kg or 3 mg/kg, demonstrating that high-grade adverse events (grades 3–5) occurred in 34% versus 48% of patients, respectively, whereas exploratory efficacy outcomes were similar.[7] No prospective studies have yet described the utility of anti-PD-1 plus anti-CTLA-4 antibody therapy following progression on anti-PD-1/L1 monotherapy.

Multiple biomarkers of anti-PD-1 treatment response, such as PD-L1 immunohistochemistry and gene expression profiling centered on interferon-associated transcripts, have been identified to stratify immunotherapy treatment outcomes. T-cell–inflamed gene expression, which more broadly describes the tumor microenvironment than PD-L1 staining alone, perhaps has the strongest predictive association with response in melanoma.[8] Immunotherapy biomarkers have been predominately explored in the treatment-naïve setting, and it remains unclear what relationship these biomarkers have with response after failure on an anti-PD-1/L1 antibody.

Herein, we report outcomes from a phase II clinical trial for the combination of pembrolizumab plus low-dose ipilimumab following progression on an anti-PD-1/L1 antibody in advanced melanoma. We also report baseline tumor biomarkers of clinical response to this combination immunotherapy regimen.