In the 11 years since it was approved for the treatment of melanoma, pembrolizumab (Keytruda) has become the go-to for adjuvant or neoadjuvant therapy for advanced melanoma, despite the potential for side effects, which can be severe and occur in more than half of all patients. Oncologists need to weigh the risk of those side effects against the strong evidence supporting the effectiveness of pembrolizumab to improve survival. More often than not, those scales tip toward using the drug to treat advanced melanoma, experts say.
Evidence has accumulated about which types of patients may be more susceptible to drug-related toxicities, how oncologists and other providers in the multidisciplinary team can manage those toxicities, and which treatment protocols may be most effective.
Today, pembrolizumab is indicated for the treatment of about 20 types of cancer, but the first indication for which the US Food and Drug Administration (FDA) approved it was advanced or unresectable melanoma in people who had already tried ipilimumab and a BRAF inhibitor if their tumors had a BRAF mutation. It was the first immune checkpoint inhibitor (ICI) targeting programmed cell death 1 (PD-1) approved by the FDA.
While it has been shown to extend life expectancy in melanoma and other types of cancers compared with ipilimumab, an anti–cytotoxic T lymphocyte antigen 4 (CTLA-4), and other older treatments, the side effects of pembrolizumab have been well-documented, particularly higher-grade toxicities (grades 3-5).
Researchers who have studied the drug told Medscape Medical News that years of experience have demonstrated pembrolizumab is safe to use in just about any patient with advanced melanoma.
The approval for pembrolizumab for advanced melanoma was based on the phase 3 KEYNOTE-006 trial, which found that the overall survival rate at 33 months was 50% vs 39% in patients on pembrolizumab vs ipilimumab. The rate of grade 3-5 adverse events (AEs) in the trial was 13%-16% for those on pembrolizumab and 20% for those on ipilimumab. A 10-year follow-up of the KEYNOTE-006 trial reported an overall survival rate of 34% for those on pembrolizumab and 23.6% for those on ipilimumab.
Who Can Be on Pembrolizumab?
“I think you can consider trying it in any patient,” Omid Hamid, MD, chief of Research and IM/Oncology at Cedars-Sinai The Angeles Clinic and Research Institute, Los Angeles, and co-author of a safety evaluation published last year of almost 9000 patients in 31 clinical trials of pembrolizumab, said.
Exceptions may be reinitiating pembrolizumab in a patient who had to halt treatment after a life-threatening AE or any patient with connective tissue disease or who has had a transplant, Hamid said.
The 2024 safety evaluation included patients with advanced melanoma in the pivotal phase 3 KEYNOTE-006 trial. The study also identified other patient conditions that may give oncologists pause before using pembrolizumab: Anemia, pneumonia, hematologic malignancies, myocarditis, and gastric bleeding and myositis.
“The myocarditis, the myositis that comes with the myasthenia has a significant mortality associated with it, about 20%, so we need to understand that,” Hamid said.
Sapna Patel, MD, a professor of oncology at the University of Colorado Anschutz Medical Campus in Aurora, Colorado, led a phase 2 trial, known as SWOG S1801, that randomly assigned patients with surgically resectable stage IIIB-IVC melanoma to two pembrolizumab regimens: One with three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) and the second with surgery followed by 200 mg pembrolizumab every 3 weeks for 18 doses for about 1 year or until disease recurrence or unacceptable toxic events developed (adjuvant-only group). Event-free survival at 2 years was 72% in the former group vs 49% in the latter.
Neoadjuvant-adjuvant pembrolizumab is indicated for patients with melanoma involving lymph nodes, particularly when the lymph nodes are readily measured on cross-sectional imaging or palpable on clinical exam, Patel said.
“We’re currently investigating whether this can be expanded to other stages of melanoma,” she said. “It is also approved to be given entirely postoperatively in the adjuvant setting, as well as for metastatic melanoma that has spread to distant parts of the body.”
Patel called SWOG S1801 “a practice-changing trial” that showed that using the standard regimen of 18 doses of pembrolizumab before and after the surgery instead of giving all the doses after surgery can yield superior results, Patel told Medscape Medical News.
Who May Not Be Good Candidates for Adjuvant Pembrolizumab?
Patients with concurrent autoimmune conditions and those of advanced age who may not derive a long-term benefit in reducing recurrence risk may not be good candidates for adjuvant pembrolizumab, said Jason Luke, MD, director of the Immunotherapy and Drug Development Center at the University of Pittsburgh, Pittsburgh. Luke led the long-term follow-up of the pivotal KEYNOTE-716 trial of patients on adjuvant pembrolizumab with resected stage IIB/IIC melanoma, which found that recurrence-free survival at 48 months was 71.3% for pembrolizumab and 58.3% for placebo. The trial did not reveal any new safety signals.
“Patients with active autoimmune disease requiring treatment or organ transplant recipients may not be optimal candidates for this type of treatment,” Patel added. Similarly, she said, patients on chronic immune suppression would not likely benefit from treatment with an ICI.
Even when side effects occur, oncologists should consider whether to discontinue pembrolizumab treatment carefully, Hamid said. “There are times where you might think to discontinue it, but in scenarios where this is a life-threatening disease or you have other options that limit their lifespan and there may be an imminent cause of mortality, pembrolizumab would be indicated despite the potential side effects,” he said.
Safety Profile
The safety evaluation Hamid co-authored found that more than half of all patients had an any-cause grade 3-5 AE, and about 1 in 8 discontinued treatment. However, 6% of toxicities were immune-mediated, which he described as “very low.”
This year a real-world study from Northern Ireland found that even low-grade immune-related AE (irAE) toxicities in patients on adjuvant pembrolizumab for stage III melanoma could have a significant impact. Up to one third of them had to stop treatment. In this study, 70% of patients had a treatment-related toxicity, with 51% of all patients having a grade 1-2 toxicity.
Among patients with only low-grade toxicity, 15% required hospitalized and 33% required immunosuppression with oral corticosteroids treatment. But steroid treatment comes with its own challenges, the study authors noted.
“Steroid tapering should be gradual as premature discontinuation may lead to relapse,” they wrote. However, long-term steroid use carries a risk for bone loss, particularly in patients aged 50 years or older. “The risk of bone loss may be observed even at low doses and within the first month of treatment,” they wrote.
Some patients may not respond to steroids for irAEs as shown in a different study, where 6.2% of patients with melanoma treated with checkpoint inhibitors did not respond to steroids.
In patients with grade 2 toxicities who discontinue therapy, the Northern Ireland researchers wrote, “these real-world data suggest that clinicians may be cautious” when resuming therapy.
An analysis of the FDA AE database focused on cardiac AEs linked to pembrolizumab. The study looked at 6719 ICI-related cardiac AEs, more than one third (34.3%) of which were fatal. The analysis found that 17.3% of all pembrolizumab-associated AEs were cardiac in nature. Pembrolizumab was found to be more often reported with myocarditis, pericardial disease, heart failure, and atrial fibrillation than other drugs in the FDA database, with myocarditis being the most significant. However, the study did not specify cancer types or stages.
In melanoma, the safety profile of pembrolizumab is comparable to that of other checkpoint inhibitors. The pivotal CheckMate 067 trial, which evaluated the combination of nivolumab, an anti–PD-1 agent like pembrolizumab, and ipilimumab against either drug alone in patients with melanoma, reported grade 3 or higher treatment-related AEs in approximately 59% of patients on combination therapy, with nearly 10% having to stop treatment.
Survival Outcomes and AEs
In the phase 2 SWOG S1801 trial, the incidence of AEs of grade 3 or higher was similar in both neoadjuvant-adjuvant and adjuvant-only treatment groups (12% and 14%, respectively), and significantly lower than other studies have found, study leader Patel said. The study did not specify irAEs.
Hamid said that most pembrolizumab-related AEs “are manageable and can get back to baseline.” Symptoms of irAEs can occur at 10 weeks into therapy or later, he said. Adrenal insufficiency, for example, occurred within about 6 months. The most commonly reported irAEs were hypothyroidism, pneumonitis, hyperthyroidism, colitis, and severe skin reactions, Hamid said.
“Any symptom needs to be looked at and considered in the setting of an immune-mediated toxicity,” Hamid said.
Alternative to Pembrolizumab
When pembrolizumab may not be optimal for treating melanoma, the use of first-line immunotherapy with alternative treatments and regimens might be. Hamid noted the phase 2 SECOMBIT trial showed that first-line immunotherapy followed by combination BRAF and MEK inhibition provided a survival benefit in patients with untreated BRAFV600-metastatic melanoma.
SECOMBIT included a treatment arm in which patients received 8 weeks of the BRAF inhibitor encorafenib with the MEK inhibitor binimetinib, followed by the combination of nivolumab with ipilimumab until PD — a regimen the study termed the “sandwich” arm. That arm had a 4-year total progression survival rate of 54% vs 29% for the arm taking encorafenib plus binimetinib until PD followed by ipilimumab and nivolumab, and 55% for the arm that started with ipilimumab and nivolumab until PD then switched to encorafenib and binimetinib.
“It’s the fact that immunotherapy takes time to work, so patients with aggressive high-tumor fraction growth may want to initially involve some form of priming dose,” Hamid said. “For those who are BRAF-mutated, a lead-in with BRAF inhibition, with BRAF and MEK combination therapy as per the SECOMBIT trial, may be indicated.”
Another option is what Patel called “flipped dosing,” which involves nivolumab plus ipilimumab for two doses. Another alternative to pembrolizumab in advanced melanoma is nivolumab plus relatlimab, a checkpoint inhibitor that targets the lymphocyte-activation gene 3, Patel said.
“Treatment for melanoma has dramatically changed over the past 10-15 years, moving from a general lack of treatment options to now a plethora of options,” Luke said. He noted the multitude of options, besides the ICIs such as pembrolizumab and nivolumab, include combinations of anti–PD-1 with anti-CTLA4 and anti-LAG3 agents, BRAF and MEK inhibition as targeted therapy, adoptive cell transfer of tumor-infiltrating lymphocytes, oncolytic viruses, and CD3-bispecific therapies.
The choices can be “daunting” for patients, according to Luke.
While there are several treatment options, overall, there is strong evidence supporting the life-extending effects of pembrolizumab despite the drug’s potential side effects.
Hamid disclosed having financial relationships with Alkermes, Amgen, Bactonix, BeiGene, BioAtla, Bristol Myers Squibb, Eisai Biotech, Roche/Genentech, Georgiamune, GigaGen, Grit Bio, GSK, Idera, Immunocore, Incyte, Instil Bio, IO Biotech, Iovance, Janssen, KSQ, Merck, Moderna, NGM Bio, Novartis, Obsidian, Pfizer, Regeneron, Sanofi, Seattle Genetics, Tempus, Vial Health Tech, and Zelluna.
Luke disclosed having financial relationships with AbbVie, Agenus, AstraZeneca, Bayer, Bristol Myers Squibb, Clasp, Curadev, Eisai, EMD Serono, Geneos, Gilead, HotSpot, Krystal, Janssen, Ikena, Immatics, Incyte, IO Biotech, iTeos, LegoChem, Lyvgen, Merck, Mersana, Novartis, Pfizer, Pioneering Medicines, Regeneron, Replimune, Storm, Sumitomo, Synlogic, and Teva.
Patel disclosed having financial relationships with Bristol Myers Squibb, Cardinal Health, Ideaya, IO Biotech, Merck Sharpe and Dohme, Natera, Novartis, OncoSec, Pfizer, Replimune, Scancell, TriSalus, Veda Trials, Foghorn Therapeutics, InxMed, Lyvgen, Provectus Biopharmaceuticals, Seagen, Syntrix Bio, and TriSalus Life Sciences.
No funding details were reported by the authors of the Northern Island study. One author of that paper disclosed receiving honoraria from DePuy companies and having other ties with various organizations. Another author reported having a consulting or advisory role with Bristol Myers Squibb UK.
Richard Mark Kirkner is a medical journalist based in Philadelphia.