Study Details Adverse Events in Pivotal Ipilimumab Trial

Jeffrey S. Weber, MD, PhD

Director, Donald A. Adam Comprehensive Melanoma Research Center, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL

Adverse events (AEs) associated with ipilimumab (Yevoy) for the treatment of metastatic melanoma are better understood after further analysis of clinical trial data that led to the FDA’s 2011 approval of the drug, including when those AEs are likely to manifest and the best methods of managing them.

The results of the analysis confirm that “careful follow-up and early intervention,” coupled with guidelines-based management of immune-related adverse events (irAEs), are vital components of treating patients with the immunotherapy agent, according to the analysis published in Cancer.¹ Concomitant medications were given frequently to patients treated during the study (Table).

Jeffrey S. Weber, MD, PhD, of the H. Lee Moffitt Cancer Center and Research Institute in Florida, and others set out to look at the pivotal clinical trial data once again to determine the patterns and development of these AEs.

Weber and colleagues used data from the phase III MDX010-20 trial, in which 676 previously treated patients with metastatic melanoma were randomized 3:1:1 to receive ipilimumab 3 mg/kg plus the glycoprotein 100 melanoma antigen vaccine (gp100), ipilimumab 3 mg/kg plus placebo, or the gp100 vaccine plus placebo.

In the entire clinical trial population, 14 deaths appear related to the study drugs, including seven deaths associated with irAEs. For ipilimumab monotherapy, the irAEs consisted of one case each of bowel perforation and liver failure. Among those treated with ipilimumab plus gp100, deaths related to irAEs included three patients with bowel perforation/inflammatory colitis, bowel perforation, or multiorgan failure/peritonitis; and one case each of colitis and septicemia, and Guillain-Barré syndrome.

The most frequently reported irAEs affected the skin and gastrointestinal (GI) tract, and most of the patients who died as a result of irAEs experienced GI events, notably colitis. However, Weber et al noted that, “There is no evidence that bowel involvement in patients with melanoma increases the likelihood that colitis, especially dose-limiting colitis, will occur after receiving ipilimumab.”

Table. Selected Concomitant Medications Used by ≥10% of Patients in MDX010-20 Trial¹

Percentage of Patients

Medication

Ipilimumab Alone

(n = 131)

Ipilimumab Plus gp100

(n = 380)

gp100

(n = 132)

Analgesics

68.7

72.4

78

Drugs for acid-related disorders

43.5

45.3

46.2

Psycholeptics

41.2

41.3

44.7

Antibacterial for systemic use

35.9

38.9

30.3

Antihistamines for systemic use

33.6

36.1

26.5

Anti-inflammatory and antirheumatic products

37.4

35.8

38.6

Corticosteroids for systemic use

35.1

34.5

25

Psychoanaleptics

29

28.7

27.3

Antithrombotic agents

33.6

25.8

36.4

Drugs for functional gastrointestinal disorders

23.7

22.1

27.3

Instead, they noted that patients with metastatic melanoma are predisposed to experience worse outcomes if colitis occurs. “The key to handling ipilimumab-associated colitis is rapid and timely intervention mediated by a high level of communication between staff and patients,” they wrote.

The researchers found that grade 2-5 irAEs tended to develop during the induction phase of treatment, which occurs between weeks 0 and 12 of treatment. Most of these irAEs, including those that were grade 3 or 4, were reversible, with grade 2 side effects generally being resolved in six weeks after induction and eight weeks for grade 3 and 4 side effects.

“The severe side effects resolve quickly, meaning the patients aren’t sick for weeks and weeks and weeks, but the technically appropriate assessment of resolution can take a fair amount of time,” Weber said in an interview.

Weber and colleagues developed a line curve that illustrates the severity of symptoms from onset to resolution. Skin and gastrointestinal adverse events would occur earlier, between week 3 and 4 of treatment, and resolve earlier, perhaps by approximately week 10 of treatment.

Endocrine and hepatic toxicities would occur between six and eight weeks of treatment, but, while hepatic toxicities would eventually subside by about week 14, the endocrine toxicity remains steady.

“Even though the symptoms go away with replacement hormones, you can have long-term side effects from the endocrine toxicity of ipilimumab that could potentially last one’s whole life,” Weber said. “That being said, those patients feel fine. I’ve had patients on hormone replacement for two, three, four, five years who went into remission or relapsed on ipilimumab in an adjuvant trial and are fine.”

Weber explained that patients experiencing endocrinologic side effects might present with fatigue, headache, or mental status changes, all of which could indicate hypophysitis, or inflammation of the pituitary gland. Additionally, older men with low testosterone levels can present with some of the same side effects. If these side effects are encountered in patients receiving ipilimumab, Weber said he usually prescribes a brief course of the corticosteroid prednisone for several weeks followed by hormone replacement therapy.

Weber also said that steroids could help these patients, despite the counterintuitive nature of prescribing an immunosuppressive molecule to someone who is also receiving a drug like ipilimumab designed to stimulate the immune system.

“In these clinical trials, it has been well shown that in patients who develop significant side effects requiring the use of steroids, giving the steroids doesn’t affect their ability to respond,” Weber said.

However, Weber stressed that clinicians should be confident that the patients receiving steroids truly need them to manage their side effects, and that the steroids won’t cancel out any beneficial properties of their treatment for melanoma.

While these AEs are something that clinicians should definitely keep in mind when prescribing ipilimumab, Weber said that the methods of treating these side effects are safe and effective for patients provided the clinicians follow established guidelines. “Virtually every single side effect will go away if appropriately managed,” Weber said.

Reference

1. Weber JS, Dummer R, de Pril V, et al. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab [published online ahead of print February 7, 2013]. Cancer. 2013;119(9):1675-1682.