While much progress has been made since interleukin-2 was used to treat melanoma, physicians are still weighing the advantages and disadvantages of monotherapy versus combination therapies.
The addition of immune checkpoint inhibitors to the treatment armamentarium for metastatic cancer has meant a significant advance in terms of prolonging survival, but the optimal utility of the agents has yet to be revealed.
"The response rates (of PD1 checkpoint inhibitors) were spectacular," says Bartosz Chmielowski M.D., Ph.D., assistant clinical professor, Melanoma Program, Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, Calif. "As monotherapies, nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruday, Merck) resulted in response rates of 30 to 35%."
The role of immune checkpoint inhibitors was discussed during the 10th Canadian Melanoma Conference (Whistler, British Columbia, Canada, February 2016).
Much progress has been made since interleukin-2 was used to treat melanoma. While it was shown to be effective, it produced a low response rate and was very toxic, according to Dr. Chmielowski.
"The use of IL-2 marked the beginning of immunotherapy," says Dr. Chmielowski. "It was followed by research on vaccines, but the response rate was low and we had no approved vaccines until talimogene laherparepvec (IMLYGIC, Amgen)."
It was greater understanding of immunobiology that resulted in the identification of CTLA-4 as a natural blocker of the immune system and created a therapeutic target. "It functions like the brakes on your car," Dr. Chmielowski explains. "CTLA-4 is like a brake on the immune system."
Anti CTLA-4 monoclonal antibodies such as ipilimumab (Yervoy, Bristol-Myers Squibb) and tremelimumab (CP-675,206, AstraZeneca) were designed to block CTLA-4 signaling and produced significantly better outcomes than IL-2 agents. Ipilimumab was approved based on the results of the randomized trial showing improvement in overall survival, Dr. Chmielowski notes.
The discovery of specific checkpoints and the ligands of checkpoints, respectively PD1 and PDL1, on tumors resulted in new therapeutic targets, according to Dr. Chmielowski. "They (PD1 and PDL1) create a situation where cancer can use natural inhibitory mechanisms to evade the immune system," he explains.
Two key immune checkpoint inhibitors, nivolumab and pembrolizumab, produced impressive response rates, proving them to be even more effective than ipilimumab, Dr. Chmielowski notes. There has not been a significant difference between nivolumab and pembrolizumab as monotherapy in terms of outcomes like progression-free survival, he explains.
"The efficacy of these drugs is almost identical," he says.
The next step in the development of immunotherapy was the introduction of the combination of PD-1 and CTLA-4-blocking antibodies. The major disadvantage of combining therapies like nivolumab and pembrolizumab with ipilimumab is a significantly increased risk of serious toxicities: Nearly 40% of patients discontinued the treatment because of side effects.
"The overall result is better with combination than with monotherapy, but the additional benefit over nivolumab alone is smaller," Dr. Chmielowski says. "The question is whether we use a single agent anti-PD1 antibody alone because it is much less toxic or do we use the combination treatment because of the additional benefit in progression-free survival. No one knows the answer to the question, but this question may be answered after we have the overall survival data."
In clinical practice, Dr. Chmielowski suggests that combination therapy be initiated for advanced melanoma as a rule, but put forth that patient characteristics, such as the presence of existing co-morbidities, be considered in the treatment algorithm.
"I try to use the combination in almost every patient," Dr. Chmielowski says. "If they have co-morbidities such as a history of auto-immune diseases, then combination therapy is not the right way to go. If they have a history of ulcerative colitis or Crohn's disease, for example, then you would use a PD1 immune checkpoint inhibitor alone."
Dr. Chmielowski underlines that age is not a consideration in opting for combination therapy to treat advanced melanoma.
"Age is not a contraindication (to combination therapy)," he says. "Younger or older age does not change the risk of the development of side effects."
In addition, age is not a factor that influences the efficacy of immune checkpoint inhibitors. A recent meta-analysis that included randomized, controlled trials of ipilimumab, tremelimumab, nivolumab, and pembrolizumab looked at outocmes like progression-free survival and overall survival and found a consistent benefit in both younger and older groups of patients. The cut-off was 65 to 70 years of age.1
Patients develop dermatological side effects such as pruritus and dermatitis with the administration of immune checkpoint inhibitors like nivolumab and pembrolizumab. Topical steroids are generally sufficient to treat these skin side effects.
"We try not to give systemic steroids unless the toxicity is significant because they might decrease the magnitude of response," Dr. Chmielowski says.
Other immune checkpoint inhibitors and new combinations of checkpoint inhibitors are expected to emerge in the future as treatments in the oncology setting, Dr. Chmielowski says.
Disclosure: Dr. Chmielowski has been investigator for Bristol Myers Squibb and Merck as well as has participated in advisory boards for Bristol Myers Squibb and Merck.
1 Nishijima TF, Muss HB, Shachar SS, Moschos SJ. Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: A systematic review and meta-analysis. Cancer Treat Rev. 2016;45:30-37.