'Big Deal': NCCN Guide for Immunotherapy Adverse Events

Nick Mulcahy

March 29, 2018

ORLANDO, Florida — The National Comprehensive Cancer Network (NCCN) has introduced a new guideline on immunotherapy adverse events.

Immunotherapy with checkpoint inhibitors has had a huge impact on the treatment of many different types of cancer during the past 7 years, since the first of these products was approved by the US Food and Drug Administration. That was ipilimumab (Keytruda, Merck & Co) for melanoma, but a volley of checkpoint inhibitors have since been approved for a variety of cancers, including lung, kidney, and bladder cancer.

However, "this good news has come with some not-so-good news," commented John Thompson, MD, of the Fred Hutchison Cancer Research Center in Seattle, Washington. Thompson, who is a melanoma specialist, was chair of the panel that authored the new guideline.

The good news is that immune checkpoint inhibition has shown remarkable efficacy in melanoma, as well as lesser efficacy in many other cancers. The bad news concerns important immune-related adverse events, some of which have been fatal.

Driven by these new drugs, the immune system not only attacks cancers but may also attack normal tissues, Thompson summarized.

The new guide, which was developed jointly with the American Society of Clinical Oncology, was published February 14 in the Journal of Clinical Oncology and online at NCCN.org, as reported by Medscape Medical News.

At the National Comprehensive Cancer Network 23rd Annual Conference, oncologists got a more personal introduction to the flow-diagram guidance, and some reacted immediately.

The new guideline is "a big deal," said Randall Oyer, MD, clinical director, Ann Barshinger Cancer Institute at Lancaster General Health in Pennsylvania.

"This is a new class of drugs that no medical oncologist who is practicing now was trained to use. This is a whole new body of knowledge," Oyer told Medscape Medical News during an interview at the meeting.

This is a whole new body of knowledge. Dr Randall Oyer

"Some of these side effects can sneak up on you and can become profoundly dangerous quickly," he added. "You need to know how to jump on that."

Oyer said that Thompson's presentation about the new guideline was one of the most valuable sessions of the whole meeting.

He said that he was planning to create collaborative agreements with cardiologists, hepatologists, and endocrinologists at his institution to address immunotherapy-specific side effects, such as myocarditis, immune-related hepatitis, and diabetic ketoacidosis, which can be severe and potentially life threatening.

The agreements will expedite specialists' scheduling and advising cancer patients about immunotherapies.

No agreements are necessary with pulmonologists and gastroenterologists, said Oyer. The long-standing use of chemotherapy has made oncologists and their colleagues "accustomed to looking for and managing the related lung and GI [gastrointestinal] problems."

Oyer also followed Thompson's suggestion to download an immunotherapy adverse events card from the Oncology Nursing Society's website. The cards are intended for patients to carry and show to nononcology medical staff, especially in emergency departments, as previously reported by Medscape Medical News.

Oyer also intends to create a standard reporting system for adverse events at his cancer center, through which events will be tagged as mild, moderate, severe, or life threatening.

The grade of an adverse event is a key to management, according to the guidance.

Generally, immunotherapy can be continued with close monitoring for grade 1 toxicities, with the exception of neurologic and some hematologic toxicities.

Immunotherapy should be halted for most grade 2 toxicities and held until symptoms or laboratory values revert to those associated with effects of grade 0 or 1. Corticosteroids (initial dose of 0.5 to 1 mg/kg/day of prednisone or equivalent) may be administered.

The checkpoint inhibitors should be stopped for grade 3 toxicities, and high-dose corticosteroids (prednisone 1-2 mg/kg/day or methylprednisolone IV 1-2 mg/kg/day) should be initiated. Corticosteroids should be tapered over a period of at least 4 to 6 weeks; if symptoms do not improve after 48 to 72 hours of treatment with high-dose corticosteroids, infliximab may be offered for some toxicities.

When symptoms or laboratory values revert to those of grade 0 or 1, a treatment rechallenge may be offered, although caution is advised, especially for patients who experience adverse events early in therapy. Dose adjustments are not recommended.

Grade 4 toxicities will generally warrant permanent discontinuation of the drug, except for endocrinopathies that have been controlled by hormone replacement.

The guidelines also provide highly detailed recommendations for managing specific toxicities that have been observed in various systems of the body.

In general, the CTLA-4 agents have been more toxic than the PD-1 and PD-L1 agents, both in overall toxicity and in serious toxicities of grades 3 to 5, said Thompson.

The time of onset of toxicities ranges from almost immediate (skin and GI toxicities) to up to 4.5 years after start of therapy (skin toxicities).

Stopping Therapy and Patient Concerns

When patients are advised that immunotherapy should be stopped, they may disagree, said Thompson. "They don't want to lose any antitumor effect. They are desperately afraid of their cancer continuing to grow," he said.

Thompson presented data that would be reassuring to such patients. He showed a slide depicting outcomes of a clinical trial among melanoma patients who had been treated with ipilimumab plus nivolumab and who experienced adverse events. The patients either discontinued therapy (during the induction phase) or continued treatment.

There was no significant difference in overall survival at 2 years between the two groups (J Clin Oncol. 2017;35:3807).

Thompson's advice was to accentuate the positive: "We have some reassurance that we can counsel our patients that if we have to stop therapy due to serious toxicity, that as far as we can tell, we are not jeopardizing anticancer effect."

Dr Thompson serves as a scientific advisor to Calithera and Celldex. Dr Oyer has disclosed no relevant financial relationships.

National Comprehensive Cancer Network (NCCN) 23rd Annual Conference. Presented March 24, 2018.

Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick

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