Understanding the Treatment Options for PD-1–Refractory Melanoma

Get Permission

For the treatment of advanced melanoma that is refractory to anti–PD-1 antibodies, there is no standard approach. The various options, with a look to the future, were discussed by Melinda L. Yushak, MD, MPH, Assistant Professor of Hematology and Oncology at Emory University School of Medicine, at the 2023 Debates and Didactics in Hematology and Oncology conference, sponsored by Emory’s Winship Cancer Institute.1

“Over the past decade, we’ve seen an explosion in the number of therapies we can offer our patients with melanoma,” she said, referring to the checkpoint inhibitors; BRAF and MEK inhibitors; and, most recently, the oncolytic virus talimogene laherparepvec. “Most of these drugs have been approved either in the adjuvant setting or the [advanced disease] front-line setting, so that leaves clinicians with questions as to what to do in the second-line setting when patients have experienced disease progression on them.”

“Patients who have BRAF-mutated disease may achieve responses if they experience disease progression on a PD-1 inhibitor and are switched over to BRAF/MEK inhibitors.”
— Melinda L. Yushak, MD, MPH

Tweet this quote

Dr. Yushak presented two clinical scenarios that illustrate the increasingly common dilemmas surrounding the treatment of PD-1 refractoriness, which can be primary or acquired. One patient was a 52-year-old man with BRAF-mutated stage IIIC melanoma treated with adjuvant nivolumab, who presented for his tenth cycle with imaging that was concerning for new lung and liver lesions. A second patient was a 63-year-old woman with metastatic melanoma that progressed on pembrolizumab and is BRAF wild-type. Such typical patients represent a huge unmet treatment need, she said.

BRAF-Mutated Melanoma

Approximately 40% of all patients with melanoma will have a BRAF mutation, but rather than receive a BRAF inhibitor, they are often treated first with immunotherapy. The key data for patients with PD-1–refractory, BRAF-mutated disease come from a post hoc analysis of KEYNOTE-006,2 in which patients with unresectable stage III or IV melanoma received pembrolizumab at 10 mg/kg every 2 or 3 weeks, experienced disease progression, and received BRAF inhibitors with or without MEK inhibitors. The response rate for all comers was 30%, rising to 43% for patients naive to BRAF/MEK inhibitors. Median overall survival from the time of BRAF/MEK initiation was 16 months in patients without prior BRAF/MEK inhibition and 12 months for patients previously treated with these targeted agents.

Similarly, in the DREAMseq study, patients with BRAF-mutated disease progressing on ipilimumab plus nivolumab who subsequently received dabrafenib and trametinib had a response rate of 48%.3 “Some of these data, therefore, indicate patients who have BRAF-mutated disease may achieve responses if they experience disease progression on a PD-1 inhibitor and are switched over to BRAF/MEK inhibitors,” she said.

PD-1–Refractory Disease Without BRAF Mutations

Approximately 60% of the melanoma population lack a BRAF mutation. For these patients, three different regimens are now approved either in the adjuvant or metastatic setting: single-agent nivolumab and pembrolizumab, the combination of nivolumab plus ipilimumab, and the combination of nivolumab plus the anti–LAG-3 antibody relatlimab.

The addition of low-dose ipilimumab (1 mg/kg) to pembrolizumab, after disease progression on an anti–PD-1/L1 antibody, led to responses in 29% of patients (including some complete responses), a median duration of response of almost 17 months, a median progression-free survival of 5 months, and a median overall survival of almost 25 months.4 “It appears that by treating with a combination, we are able to rescue some of these patients,” Dr. Yushak noted.

“After patients experience disease progression on nivolumab and relatlimab, some are able to be rescued with. subsequent therapies.”
— Melinda L. Yushak, MD, MPH

Tweet this quote

“Another question arises for the patient who has experienced disease progression on single-agent anti–PD-1 therapy, and you are thinking of adding ipilimumab. Should you use ipilimumab by itself or combine it with nivolumab? SWOG 1616 tried to answer this question,” she said.

The study included 92 patients with unresectable or metastatic disease who had not responded to anti–PD-1 monotherapy and were randomly assigned to receive ipilimumab alone or with nivolumab.5 The response rates were 28% to the combination and 9% to single-agent ipilimumab; the 6-month progression-free survival rate was 34% vs 13% (hazard ratio [HR] = 0.63; P = .04), and the 12-month overall survival rate was 63% vs 57%, respectively.

“Essentially, because of the results of this and other trials, if a patient is experiencing disease progression on anti–PD-1 monotherapy, and you’re going to add ipilimumab, you need to use ipilimumab and nivolumab together, as opposed to ipilimumab alone,” she emphasized.

Nivolumab Plus Relatlimab

Relatlimab was approved in combination with nivolumab about 1 year ago as a first-line option for metastatic melanoma. Early-phase studies leading to the drug’s approval mostly
enrolled heavily pretreated patients. In a study in which 46% of patients had received at least three prior lines, treatment with relatlimab at 80 mg plus nivolumab at 240 mg every 2 weeks resulted in a response rate of 11% and a disease control rate of 49%.6 Subsequently, the pivotal RELATIVITY-020 trial of patients experiencing disease progression on an anti–PD-1 inhibitor or an anti–PD-1 inhibitor plus ipilimumab, a similar response rate of 12% was observed, and the 6-month progression-free survival rate was 20%.7

“After patients experience disease progression on nivolumab and relatlimab, some are able to be rescued with subsequent therapies,” Dr. Yushak continued. Retrospective pooled data showed that treatment with ipilimumab alone or with an anti–PD-1 antibody yields low response rates and limited progression-free survival.8 However, in RELATIVITY-047, where patients had received nivolumab plus relatlimab in the first-line metastatic setting (not later), subsequent treatment with nivolumab plus ipilimumab led to responses in 25%, about half of which were complete responses.9

Future Directions

Tumor-infiltrating lymphocyte (TIL) therapy is proving to be a promising approach in PD-1–refractory disease. In a recent phase III trial of patients experiencing disease progression on one prior therapy, median progression-free survival was 7 months vs 3 months with ipilimumab (HR = 0.50; P < .001).10 Median overall survival was 26 vs 19 months, and 49% vs 21% of patients achieved responses.

The manufacturing process of the TIL product has been a logistical drawback, but this has become simpler with the development of lifileucel, an autologous TIL that is centrally manufactured over 22 days. Patients typically receive a nonmyeloablative lymphodepleting regimen for 5 days and then one dose of lifileucel and interleukin-2 every 8 to 12 hours for up to six doses.

In a study of 66 patients with unresectable or metastatic melanoma, at least one resectable lesion, and prior disease progression on immunotherapy and, where applicable, BRAF and MEK inhibitors, the overall response rate was 24% (3% complete responses), and the disease control rate was 53%.11 Response rates were similar regardless of whether patients received nivolumab in the front-line setting or as subsequent therapy and whether they had primary vs acquired refractoriness to anti–PD-1 therapy. Lifileucel is expected to be approved soon, potentially making it a good option for some patients, stated Dr. Yushak.

“The treatment of PD-1–refractory melanoma is an area of ongoing clinical investigation. There’s a huge role for clinical trials and a need to identify patients who will benefit most from subsequent therapy. That said, for patients in our clinic, there are data suggesting that combination therapy—particularly ipilimumab and nivolumab—for patients who have received only single-agent anti–PD-1 or BRAF/MEK inhibitors if BRAF-mutated—may achieve a response. And there are exciting options on the horizon that, hopefully, we will hear more about in the next few months,” she concluded. 

DISCLOSURE: Dr. Yushak reported no conflicts of interest.


1. Yushak M: Treatment of PD-1–refractory melanoma. 2023 Debates and Didactics in Hematology and Oncology Conference. Presented July 21, 2023.

2. Long GV, Arance A, Mortier L, et al: Antitumor activity of ipilimumab or BRAF ± MEK inhibition after pembrolizumab treatment in patients with advanced melanoma: Analysis from KEYNOTE-006. Ann Oncol 33:204-215, 2022.

3. Atkins MB, Lee SJ, Chmielowski B, et al: Combination dabrafenib and trametinib versus combination nivolumab and ipilimumab for patients with advanced BRAF-mutant melanoma: The DREAMseq Trial–ECOG–ACRIN EA6134. J Clin Oncol 41:186-197, 2023.

4. Olson DJ, Eroglu Z, Brockstein B, et al: Pembrolizumab plus ipilimumab following anti–PD-1/L1 failure in melanoma. J Clin Oncol 39:2647-2655, 2021.

5. Vanderwalde AM, Moon J, Kendra K, et al: S1616: Ipilimumab plus nivolumab alone in patients with metastatic or unresectable melanoma that did not respond to anti–PD-1 therapy. AACR Annual Meeting 2022. Abstract CT013. Presented April 12, 2022.

6. Ascierto PA, Melero I, Bhatia S, et al: Initial efficacy of anti-lymphocyte activation gene-3 (anti–LAG-3; BMS-986016) in combination with nivolumab in pts with melanoma previously treated with anti–PD-1/PD-L1 therapy. 2017 ASCO Annual Meeting. Abstract 9520.

7. Ascierto PA, Lipson EJ, Dummer R, et al: Nivolumab and relatlimab in patients with advanced melanoma that had progressed on anti-programmed death-1/programmed death ligand 1 therapy: Results from the phase I/IIa RELATIVITY-020 trial. J Clin Oncol 41:2724-2735, 2023.

8. Menzies AM, Pires da Silva I, Trojaniello C, et al: CTLA-4 blockade resistance after relatlimab and nivolumab. N Engl J Med 386:1668-1669, 2022.

9. Tawbi HA, Hodi FS, Lipson EJ, et al: Nivolumab plus relatlimab vs nivolumab in previously untreated metastatic or unresectable melanoma: 2-year results from RELATIVITY-047. 2023 ASCO Annual Meeting. Abstract 9502.

10. Rohaan MW, Borch TH, van den Berg JH, et al: Tumor-infiltrating lymphocyte therapy or ipilimumab in advanced melanoma. N Engl J Med 387:2113-2125, 2022.

11. Chesney J, Lewis KD, Kluger H, et al: Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: Pooled analysis of consecutive cohorts of the C-144-01 study. J Immunother Cancer 10:e005755, 2022.