PD-1 Agents Vie for Frontline Spot in Melanoma Immunotherapy

Jason J. Luke, MD, FACP

New checkpoint blockade agents that target the PD-1 pathway are moving forward quickly in the melanoma treatment paradigm and likely will become a frontline immunotherapy choice for patients with advanced or metastatic disease, according to Jason J. Luke, MD, FACP, a leading researcher in the field.

Pembrolizumab (Keytruda) and nivolumab (Opdivo), which are both PD-1 inhibitors, gained FDA approval last year as therapies for patients with unresectable or metastatic melanoma whose disease has progressed after treatment with ipilimumab (Yervoy), and who are not candidates for drugs targeted at BRAF V600 mutations.

Ipilimumab, which targets CTLA-4 to enhance T-cell activation, became the first monoclonal antibody to employ the immune checkpoint blockade strategy when the FDA approved the drug in 2011.

In January, the National Comprehensive Cancer Network (NCCN) revised its melanoma treatment guidelines to include pembrolizumab and nivolumab along with ipilimumab among the preferred systemic options for patients with advanced or metastatic disease.¹ Ipilimumab is the only one of the three checkpoint agents with a category 1 recommendation. However, the NCCN panel noted that both PD-1 agents have “higher response rates and less toxicity compared to ipilimumab, and that both drugs should be included as options for first-line treatment.”

“It was not an explicit recommendation, but NCCN said that it would not be unreasonable either,” said Luke, who is an assistant professor of Medicine in the Melanoma and Developmental Therapeutics Clinic at the University of Chicago. “The days of anti-PD-1 inhibitors as second-line therapy are going to be limited. I think we are all very confident that anti-PD-1 inhibitors will soon become frontline care.”

Although the clinical benefit of pembrolizumab and nivolumab has not been followed for as long as it has been with ipilimumab, nonetheless, Luke said, “We’ve seen durable tumor response.”

“The follow-up data for survival from the phase I [nivolumab] study presented at ASCO 2014 suggested that 80% of patients were alive at 2 years.² In the context of a disease where the median life expectancy was 9-12 months just a few years ago, that’s something outstanding,” said Luke.

The mechanisms of action of the two anti-PD-1 agents are similar, although the antibodies affect different epitopes on the PD-1 receptor, said Luke.

But the advent of newer immunotherapies in advanced melanoma has ushered in new immune-related toxicities that oncologists should keep in mind, noted Luke. With the immune system unchecked, there is the possibility that immune cells attack other parts of the body, causing serious problems in the intestines, liver, nerves, eyes, or other organs.

“Getting control of these immune side effects quickly is important because they get worse over time and become more difficult to manage,” said Luke. He recommends that practicing oncologists take any report seriously and facilitate conversation with the patient so the onset of toxicities can be monitored and treated quickly.

Side effects for the anti-PD-1 inhibitors are similar, but with a somewhat lower incidence, to those associated with ipilimumab, said Luke. He noted that the incidence of pneumonitis or lung inflammation appeared higher with anti-PD-1 agents, compared with ipilimumab, and in some cases resulted in death. “In our practice, we screen for any pulmonary symptoms—from shortness of breath to severe dyspnea, to even cough,” said Luke.

The NCCN panel noted that ipilimumab “has the potential for significant immune-mediated complications.” Patients must participate in a risk evaluation and mitigation strategy, and should be monitored closely, the panel said.

“The ideal ipilimumab patient is any patient with metastatic melanoma,” said Luke. “There are specific instances where the checkpoint inhibitor would not be appropriate—in patients who have rapidly progressing disease, in patients who have some form of autoimmunity, or in patients who have brain metastases.”

Luke has been exploring ipilimumab’s mechanism of action and recently published a case report detailing the antitumor responses and toxicities experienced by a 61-year-old woman with unresectable metastatic melanoma who underwent treatment. ³

The adverse events included high fevers, drenching sweats, facial asymmetry, vision changes, lymphadenopathy, and peripheral neuropathy. The tumor mass initially grew in size, but subsequently regressed.

Luke and colleagues concluded that the patient experienced “an active and effective granulomatous antimelanoma response as a result of ipilimumab treatment,” as opposed to granulomas previously associated with toxicities of the drug. Luke noted that a hypothesis has been advanced that ipilimumab may deplete regulatory T cells in the tumor microenvironment. “In our case report, however, we saw what appeared to be a granulomatous therapeutic response, which is not necessarily in keeping with the suggested mechanism of action. We also noted the identification of unusual immune-related adverse events with neuropathy and a putative cytokine storm,” said Luke. “These highlight the need for clinical observation of patients receiving the drug.”

References

1. NCCN Clinical Practice Guidelines Melanoma Version 2.2015. Published January 1, 2015. Accessed February 27, 2015.
2. Sznol M, Kluger HM, Callahan MK, et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). Presented at the Annual Meeting of ASCO, June 2, 2014. Abstract LBA9003.
3. Luke J, Lezcano C, Hodi FS, Murphy GF. Antitumor granuloma formation by CD4+ T cells in a patient with rapidly progressive melanoma experiencing spiking fevers, neuropathy, and other immune-related toxicity after treatment with ipilimumab [published online March 10, 2014]. J Clin Oncol. 2015;33(6):e32-35.