Responses to Pembrolizumab and Ipilimumab After Anti–PD-1/L1 Failure in Advanced Melanoma

Get Permission

Despite new and effective treatments for melanoma with checkpoint inhibitors and targeted therapies, patients with metastatic melanoma who progress on frontline treatment generally do very poorly. “We really need to make sure we give these patients access to drugs that we know have some efficacy,” Jason J. Luke, MD, said in an interview with The ASCO Post. Dr. Luke is corresponding author of a study finding that nearly 30% of patients with advanced melanoma refractory to an anti–PD-1/L1 antibody responded to pembrolizumab plus low-dose ipilimumab, with a median duration of response of 16.6 months.

“Our idea was, would we enhance the benefit of CTLA-4 by continuing anti–PD-1 antibody in the second line, but reduce the toxicity by using a lower dose of ipilimumab?”
— Jason J. Luke, MD

Tweet this quote

“This study demonstrated long-term responses, suggesting that durable survival—a hallmark of immunotherapy activity—may be possible even after failure of an anti–PD-1/L1 antibody,” the study authors wrote in the Journal of Clinical Oncology.1

Dr. Luke noted that novel combinations of anti–PD-1 antibodies being tested by others were yielding response rates of around 20%. “But now we show the response rate is close to 30% using the drugs we already have. That is probably better than anything else you are going to give on a clinical trial,” he said. “This treatment can generate long-term survival in some patients.” Dr. Luke is Director of the Cancer Immunotherapeutics Center and Associate Professor of Medicine at UPMC Hillman Cancer Center in Pittsburgh.

Maintaining Efficacy

At the time the study was being designed, an incremental increase in response rate was being reported for ipilimumab and nivolumab compared to nivolumab alone in patients with advanced melanoma, but with “a substantial toxicity profile” for the combination, Dr. Luke noted. “There was a big debate about whether (upfront combination) was the right thing to do. Also at that time, there was this idea in the field that we might be able to find other PD-1 combination partners, which would have similar efficacy but lower toxicity relative to ipilimumab/nivolumab.” Delaying exposure to ipilimumab until the second line would reduce toxicity but it was unclear whether efficacy would be maintained.

“Anti–CTLA-4 antibody alone after anti–PD-1/L1 antibody progression has a historical response rate of 13%,” according to the study authors. “So, the question for the trial,” Dr. Luke said, was, “Can you increase that, given that you are going to continue the anti–PD-1? Would CTLA-4 blockade drive T cells to the tumor and, in the absence of PD-1 blockade, would some of them get exhausted or dysfunctional? If we continue anti–PD-1, will we actually enhance [the response rate]? And that is what we saw.”

No Gap in Immunotherapy

The open-label, single-arm phase II trial involved 70 patients recruited from 7 medical centers across the United States. To be eligible for the study, patients had to have unresectable or metastatic melanoma with known BRAF mutation status and measurable disease. The most common subtype was cutaneous melanoma, and uveal melanoma was excluded. The median age of the patients was 64 years old, with a range of 27 to 87, and 67% were male.

“All patients must have experienced disease progression during treatment with an anti–PD-1/L1 antibody immediately before accrual to this study or disease progression within 6 months of adjuvant anti–PD-1 antibody without intercurrent therapy,” the authors noted.

The trial was specifically designed so that there would be no gap in immunotherapy, to avoid a bias from intervening therapy. “At the time, it was somewhat controversial because BRAF inhibitors are associated with overall survival,” Dr. Luke reflected. In fact, some researchers contacted about participating in the trial “told us they would not be willing to do the trial because it would be withholding therapy,” he said.

Nowadays, however, in the academic setting, physicians “will tend to use multiple lines of immunotherapy before they use targeted therapy and it is because, even in later lines of immunotherapy, we all individually have patients who have functionally been cured,” Dr. Luke noted, even with third-line immunotherapy. “We know that with BRAF inhibitors, we are not going to cure anybody. So, we tend to save that. We’ll give patients immunotherapy and then if they are progressing really rapidly, we’ll give them BRAF inhibitors to try to get the disease back under control. Then we will try to transition the patients to a clinical trial at some point.”

Dosing Strategy

Patients received pembrolizumab at 200 mg intravenously plus low-dose ipilimumab at 1 mg/kg intravenously once every 3 weeks for four doses, followed by pembrolizumab intravenously at 200 mg once every 3 weeks for up to 2 years. Treatment continued until confirmed radiographic disease progression, intolerable toxicity, patient withdrawal of consent, investigator decision, or completion of therapy.

“We used a dosing strategy of low-dose anti–PD-1 antibody with low-dose ipilimumab, which is now the standard of therapy for a lot of tumor types, but at the time we did it, that was somewhat controversial. Our idea was, would we enhance the benefit of anti–CTLA-4 antibody by continuing anti–PD-1 antibody in the second line, but reduce the toxicity by using a lower dose of ipilimumab? And it seems like that was true,” Dr. Luke stated.”

Adverse Effects

“Although high rates of toxicity have previously limited safe delivery of anti–PD-1 plus anti–CTLA-4 combinations, the 27% grade 3-4 adverse event rate observed with pembrolizumab plus low-dose ipilimumab reflects a comparatively manageable side effect profile,” the authors noted. Overall, adverse effects occurred in 87%, “with the most frequent events being pruritis, rash, diarrhea, fatigue, nausea, and transaminase elevations.”

The rates of adverse effects “are not that much higher than we see in clinical practice for monotherapy PD-1,” Dr. Luke said. “The primary endpoint concerned increasing the efficacy,” he pointed out. “The improvement in toxicity is a positive, but frankly it is not the important feature here because I think people have become much more comfortable in managing the toxicities.”

There were 8 nonevaluable patients, including 1 patient who withdrew after experiencing grade 3 immune-related hepatitis after 1 dose of study therapy.

No dose reductions of pembrolizumab or ipilimumab were permitted, consistent with standard practice use of immune-checkpoint inhibitors.

“Our study was augmented by a large retrospective study by the Melanoma Institute in Australia demonstrating similar outcomes,” Dr. Luke said. “It was an international aggregated series of around 300 patients, with about a 30% response rate with the same treatment, given off label.2 In conjunction with our study, this has essentially changed the perspective in the field so that it is no longer reasonable to give ipilimumab monotherapy. We now always give it as a combination with anti–PD-1.”

Responses Across Subgroups

“Most responses were observed among patients who progressed on a prior anti–PD-1/L1 antibody within 6 months” and “occurred predominantly among patients with intermediate to non–T cell–inflamed and PD-L1–negative tumors,” the researchers reported. This “is contrary to what has been observed in the anti–PD-1/L1 antibody–naive setting, where biomarkers of T cell inflammation and PD-L1 expression enrich for response.”

“The important point is that this shows we can still salvage some of these patients who don’t have a tumor with an immune phenotype that we think is advantageous,” Dr. Luke noted. “The patients that are PD-L1–positive are more likely to respond to immunotherapy. But even when patients progress, if the tumors are low or non–T cell inflamed, with this treatment we can still get long-term responders. That is a hopeful thing because, if it was the case that PD-L1 status was still driving the response, then you would assume that in the nonresponder population of our trial—people who progressed already on frontline—the response would be pretty low. But we didn’t see that.”

Homing in on Drug Development Targets

“The durable responses observed with pembrolizumab plus low-dose ipilimumab suggest that this benefit may carry forward when using an anti–PD-1 plus anti–CTLA-4 antibody combination after anti–PD-1 antibody failure,” the authors wrote. “These findings may be particularly informative for future drug development after failure of an anti–PD-1/L1 antibody by setting an important benchmark for therapies in this space.”

“We are going to become better about homing in on which tumors we should really be focusing immunotherapy development on,” Dr. Luke said. “Broadly speaking, I have advocated that we should be profiling patients’ tumors for the number of mutations and for the T cell–inflamed gene expression scores in the microenvironment because, independently, those two are both very strong biomarkers of response. When we think about selecting patients for new drug therapy trials, we should be selecting those patients because that is where it is probably going to work.” Dr. Luke said.

“For people who have low mutational burden and low interferon response, we need to think about what we could do that would enhance immune response to these tumors, because low tumor mutational burden means the number of antigens there is not going to be really robust. That said, there is a whole field of research to suggest that if we use the right approaches, even in those low tumor mutational burden tumors, we can still turn them from cold to hot.” 

DISCLOSURE: Dr. Luke holds stock or other ownership interests in Actym Therapeutics, Alphamab Oncology, Arch Oncology, Kanaph Therapeutics, Mavu Pharmaceutical, Onc.AI, Pyxis, and Tempest Therapeutics; has served in a consulting or advisory role for 7 Hills Pharma, AbbVie, Alnylam, Alphamab Oncology, Astellas Pharma, Bayer, Bristol Myers Squibb, Checkmate Pharmaceuticals, Crown Bioscience, CStone Pharmaceuticals, Eisai, EMD Serono, Flame Biosciences, Genentech, Immunocore, Incyte, Inzen, Janssen, Kadmon, KSQ Therapeutics, Merck, Mersana, Nektar, Novartis, Partner Therapeutics, Pfizer, Reflexion Medical, Regeneron, Ribon Therapeutics, Rubius, Silicon Therapeutics, Spring Bank, Synlogic, Tempest Therapeutics, Tesaro, TRex Bio, Werewolf, Xencor, and Xilio; has received research funding from Agios, Array BioPharma, Astellas Pharma, BioNTech AG, EMD Serono, Fstar, Genmab, Ikena Oncology, Immatics, Kadmon, KAHR Medical, Moderna Therapeutics, Nektar, Numab, Replimmune, Rubius Therapeutics, Scholar Rock, Spring Bank, Synlogic, Takeda, Tizona Therapeutics Inc, and Trishula Therapeutics; has received institutional research funding from AbbVie, Bristol Myers Squibb, Corvus Pharmaceuticals, Incyte, Macrogenics, Merck, and Xencor; holds intellectual property in “Serial #15/612,657 (Cancer Immunotherapy)” and “Serial #PCT?US18/36052 (Microbiome biomarkers for anti-PD-1/PD-L1 responsiveness: Diagnostic, prognostic, and therapeutic uses thereof)”; and has been reimbursed for travel, accommodations, and expenses by Array BioPharma, Bristol Myers Squibb, EMD Serono, Janssen, Merck, Mersana, Novartis, Pyxis, Reflexion Medical, and Xilio.


1. Olson DJ, Eroglu Z, Brockstein B, et al: Pembrolizumab plus ipilimumab following anti-PD-1/L1 failure in melanoma. J Clin Oncol. May 4, 2021 (early release online).

2. Pires da Silva I, Ahmed T, Reijers, ILM, et al: Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: A multicentre, retrospective, cohort study. Lancet Oncol 22:836-847, 2021.

Related Articles

A Shift in the Treatment of Advanced Melanoma

Answers to questions about first-line treatment of metastatic melanoma are “going to be shifting,” Jason J. Luke, MD, told The ASCO Post, with the change coming on the heels of the phase III RELATIVITY-047 trial reported at the 2021 ASCO Annual Meeting.1

That abstract reported that using two...