July 2015, Special ASCO Edition

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ABCs of Immunotherapy

Immunotherapy

With the surge in new immunotherapies becoming available for the treatment of melanoma, non–small cell lung cancer, bladder cancer, and other solid tumors, it is important to know how to assess response patterns that differ from those of chemotherapy, manage the unique side effects, and understand the mechanisms of action of these drugs.

These topics were covered at an education session on “The ABCs of Immunotherapy.”

Response Patterns

“Response patterns differ in patients who get immunotherapy. Sometimes it appears that the tumor is actually progressing, and then eventually the patient responds. We see this phenomenon of pseudoprogression in some patients,” F. Stephen Hodi, MD, Dana-Farber Cancer Institute, Boston, MA, told listeners.

Traditional criteria for response to chemotherapy, such as RECIST or World Health Organization (WHO) criteria, do not capture the patterns of response seen with immunotherapies. Immediate and delayed pseudoprogression can occur on immunotherapies.

“It can look like the disease is worsening, but the treatment works,” Hodi said. “Patients on immunotherapy can develop new lesions or the tumor can increase in size, but then the patients get better,” he continued.

Patterns of clinical activity with checkpoint blockade are novel. Immunotherapy has effects on the tumor and microenvironment.

A working group of oncologists, immunologists, and regulatory experts developed immune-related response criteria (irRC) based on WHO criteria in 2004 and 2005. These response criteria considered that confirmation of progressive disease might be needed and allowed for clinically insignificant progressive disease. They incorporated the idea that durable disease may represent clinical benefit.

“Now the field is moving fast, with nivolumab and pembrolizumab, so we have developed spider plots to assess response. We need irRC version 2.0,” he said.

Response criteria for immunotherapy now include conventional response, delayed response, overall tumor burden plus or minus new lesions, durable stable disease, and confirmation of disease progression, and they allow for the addition of new lesions. In the future, response patterns may differ for specific drugs and/or diseases.

“All of these response patterns are associated with favorable survival. Histologic investigations support the under-lying science. With all of the new therapies, it is complicated to assess response even when we use irRC. We are at a point in time where we have a tremendous opportunity to refine these criteria,” Hodi continued.

To develop new response criteria, prospective evaluation of patterns and confirmation of use of these patterns as a surrogate end point will be needed. Also, there is a need for biomarkers associated with these novel response patterns, he said.

The advent of newer immunotherapies requires clinicial discussions and education of patients. “You must make clinical judgments. A decline in performance status is unlikely to reflect late response,” Hodi noted.

Mechanisms

“Checkpoint inhibitors co-opt certain immune checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumor antigens,” explained Drew Pardoll, MD, Johns Hopkins School of Medicine, Baltimore, MD. “The immune system is an ideal anticancer agent.”

Now that the “brakes” or checkpoints of the immune system are better understood, releasing the brakes elicited by the immune system activates the patient’s endogenous immune response. Checkpoints such as cytotoxic T-lymphocyte antigen-4, programmed death-1 (PD-1), and PD-1 ligand 1 are the targets of current therapies such as ipilimumab, nivolumab, and pembrolizumab, respectively.

Vaccines are also being studied in melanoma and other cancers. These vaccines are engineered to educate the immune system.

There are 3 categories of cancer vaccines: conventional vaccines that express shared self-antigens upregulated in the tumor, “endogenous” vaccinations that turn a patient’s own tumor into a vaccine, and “personalized” vaccines created for each patient based on the tumor’s mutations.

Managing Side Effects

Although available immunotherapies improve progression-free survival, and combinations of them are now being studied, they have side effects. Studies show that grade 3/4 treatment-related side effects occur in 25% of patients treated with ipilimumab, 16.3% of those treated with nivolumab, and 55% treated with the combination of ipilimumab and nivolumab, explained Michael Andrew Postow, MD, Memorial Sloan Kettering Cancer Center, New York City.

Despite higher rates of grade 3/4 adverse events with the combination of ipilimumab and nivolumab, no treatment-related deaths have been reported in melanoma patients treated with this strategy.

Immunotherapy-related grade 3/4 adverse events occur most commonly in the skin. Gastrointestinal toxicities are also fairly common, with diarrhea and colitis the most frequent events. Hepatic adverse events also occur, typically asymp­tomatic elevations in liver enzymes. Immunotherapy-related endocrine effects include hypothyroidism, hyperthyroidism, and adrenal insufficiency.

The time line of immunotherapy-related adverse events differs from that of chemotherapy. “The main message is that these don’t occur immediately and usually take weeks to set in,” Postow said.

Effects on the skin are the earliest to appear, after about 5 weeks for nivolu­mab. These are followed by gastrointestinal, renal, and endocrine effects that typically occur 30 days later.

The good news is that with continuous treatment, the adverse events tend to resolve, at least with nivolumab and the combination of ipilimumab and nivolumab.

“Most patients on nivolumab or the combination have side effects in the first 3 months of therapy, but more time on therapy does not mean that side effects accumulate. This is different from chemotherapy,” Postow said.

The take-home message for management of immunotherapy-related adverse events is early recognition and immunosuppression with steroids. “Don’t be concerned about using steroids for immunotherapy-related adverse events,” he emphasized.

For ipilimumab-related adverse events, Postow suggested Googling “ipi­limumab management” to access risk evaluation mitigation strategy and management algorithms.

For rashes associated with PD-1 agents (nivolumab and pembrolizumab), systemic steroids may be required depending on the severity of the rash. Use topical agents first, orals next, Benadryl for pruritus, and systemic steroids if orals do not work, he advised.

Diarrhea and colitis can be severe and require steroid immunosuppression. Early treatment can mitigate other subsequent adverse events. For very severe diarrhea, consider infliximab (a drug used to treat rheumatoid arthritis).

Hypophysitis (pituitary gland inflammation) is an immunotherapy-related adverse event that can manifest as headache and fatigue. Imaging of the central nervous system is helpful in evaluating this event.

“It is controversial whether higher doses of steroids during acute hypophy­sitis can prevent long-term pituitary dysfunction, because there is a risk of adrenal crisis,” he noted.

Immunotherapy-related pneumonitis can be diagnosed by radiographic changes or shortness of breath. “These patients need chest imaging, because x-ray is not sensitive enough,” Postow said. “Be sure to exclude infection.”

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