Endocrinopathies Common With Checkpoint Immunotherapy for Cancer

Miriam E Tucker

May 09, 2017

AUSTIN, Texas — Cancer patients receiving treatment with recently approved immune checkpoint inhibitors are increasingly developing endocrine disorders that are mostly mild, but in some cases can be serious, new research suggests.

These agents — the first of which was approved in 2011 — generate immune responses to tumors, causing them to be rejected, and break tumor-induced immune tolerance.

They have been hailed as breakthrough treatments for advanced neoplasias, including metastatic melanoma, non–small-cell lung cancer, and advanced renal-cell carcinoma. However, their mechanism of action can lead to a variety of inflammatory toxicities, including those involving the thyroid, adrenal, and other glands, attendees were told here at the American Association of Clinical Endocrinologists (AACE)  2017 Annual Scientific & Clinical Congress.

Single-center data presented on May 6 showed that not only are these endocrine disorders quite common — occurring in about one in three patients receiving the agents — but some are serious and life-threatening.

Moreover, the timing of their occurrence suggests that monitoring should be more frequent and of longer duration than has recently been proposed, endocrinology fellow Lauren Clarine, DO, said in presenting chart review findings from Scripps Health in San Diego.

"These drugs are showing a lot of promise, and more and more are being developed," Dr Clarine told Medscape Medical News, so, as endocrinologists, "if you haven't already seen one of these disorders, you probably will," she noted.

And previous research suggests that the patients who develop adverse events from immune checkpoint inhibitors are the ones whose cancers are most likely to respond to them.

So "it's important to maintain a high degree of suspicion and treat early so patients don't have to discontinue cancer treatment because of an endocrine disorder that we should be able to manage," Dr Clarine noted. 

Greater Coordination of Care Needed Between Specialties

The phenomenon calls for greater coordination of care between specialists, session moderator David Lieb, MD, associate professor of internal medicine and program director of the endocrinology fellowship program at Eastern Virginia Medical School, Norfolk, Virginia, told Medscape Medical News.

"I think the key things are education for endocrinologists and oncologists and collaborating together. We need to follow these patients long term to get a good understanding of what types of endocrinopathies they develop and when. We're still at an early stage....It's not a small niche thing."

Thyroid dysfunction was the most common endocrinopathy reported by Dr Clarine's group, followed by inflammation of the pituitary gland (hypophysitis).

Speaking with Medscape Medical News prior to the AACE meeting, oncologist Jonathan Powell, MD, PhD, associate director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University, Baltimore, Maryland, said he and his colleagues have become "very much attuned to" this phenomenon, and that "the good news is that a lot of times we can inhibit the autoimmune response."

But when that's not possible they refer patients to the relevant specialists — at Johns Hopkins, both endocrinologists and rheumatologists are beginning to specialize in the autoimmune consequences of the new cancer therapies.

"We have people at Hopkins who had seen a couple of cases, so now we send them all our cases." 

Dr Powell, who is also professor of oncology and of pharmacology and molecular sciences at Hopkins, added: "Coming from my end, the percentage of patients who have suffered these problems is relatively low. Given that cancer is going to kill them, I think the risk is well worth it."

Of course, Dr Lieb pointed out, untreated adrenal insufficiency and thyroid dysfunction can also be life-threatening.  

A Variety of Endocrinopathies Seen

Dr Clarine and colleagues identified a total of 117 Scripps patients — 66% men and 34% women — who had received immune checkpoint inhibitors from January 2015 through December 2016. Of those, 26 had received the anti-CTLA4 antibody ipilimumab (Yervoy, Bristol-Myers Squibb), 83 were treated with the anti-PD1 antibody nivolimumab (Opdivo, Bristol-Myers Squibb) or pembrolizumab (Keytruda, Merck), while the other eight patients had received a combination of the two inhibitor types.

Of the 26 receiving ipilimumab, seven (27%) developed hypophysitis, four (16%) hypothyroidism, and one thyroiditis. Of those with hypophysitis, six had central adrenal insufficiency and two had central hypothyroidism.

Among those receiving nivolimumab or pembrolizumab, 21 (25%) became hypothyroid and two (4%) developed type 1 diabetes (both of whom were on nivolimumab).

And of the eight on combination immune checkpoint inhibitor treatment, one developed hypophysitis — with both central adrenal insufficiency and central hypothyroidism — while another developed thyroiditis.

Gender did not appear to be a factor, as 32% of the women and 27% of the men receiving the immune checkpoint inhibitors developed an endocrinopathy. And, in contrast to previous reports, the incidence of hypophysitis was not associated with higher ipilimumab doses, Dr Clarine noted.

The patients who developed hypophysitis and type 1 diabetes were hospitalized and immunotherapy eventually discontinued. At 9 months, none of the seven hypophysitis patients with central adrenal insufficiency had recovery of function despite high-dose glucocorticoid therapy.

Moreover, three of three cases of central hypothyroidism in the hypophysitis patients had not resolved completely, although the thyroid-hormone–replacement dose requirement decreased significantly in one.

"While other hormone axes may recover, development of central adrenal insufficiency is likely to be permanent," Dr Clarine commented.

How Should These Cases Be Screened and Managed?

Even at their single institution, Dr Clarine and colleagues found a great deal of variability in obtaining baseline and subsequent thyroid-function and pituitary-hormone testing.

One published protocol, from Joshi et al in Clinical Endocrinology, suggests baseline biochemistry prior to the start of immune checkpoint treatment, checking for clinical features prior to each treatment cycle, and further screening bloodwork at weeks 8 and 16. If normal, no further testing is advised.

However, the current findings suggest that more laboratory testing than that is necessary, given that most of the endocrinologic adverse events occurred between the second and fifth infusion, with one occurring after the first infusion and another after 14 infusions.

The average number of doses of immunotherapy given prior to the development of the endocrinopathy was 3 for hypophysitis, 5.5 for hypothyroidism, and 2 for thyroiditis.  

"It is important to monitor closely for development of immune-related adverse events throughout therapy given the variable onset," Dr Clarine observed, adding that the current recommendation to stop at 16 weeks "could be problematic," because it could lead to some of these conditions being missed.

Instead, she suggests monthly thyroid-function testing during treatment and continuation of testing beyond the recommended 16 weeks.

Dr Lieb noted that the thyroid disorders associated with these agents can take the form of thyroiditis, primary hypothyroidism, or Graves' hyperthyroidism, and in the setting of thyrotoxicosis "treatment might be symptomatic control with a beta-blocker and then watching them over time.

"The key thing is going to be following them. Understanding the types of thyroid conditions that arise is going to be very important."

Dr Clarine and Dr Lieb have no relevant financial relationships. Dr Powell is founder of Dracen Pharmaceuticals and consultant for/shareholder in Corvus.

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American Association of Clinical Endocrinologists (AACE) 2017 Annual Scientific & Clinical Congress. May 6, 2017; Austin, Texas. Abstract 716.

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