Immunotherapies such as PD-1 inhibitors have improved survival for many patients with cancer. However, these therapies are associated with adverse events that, if not properly managed, impair quality of life and may lead to treatment interruptions or discontinuation. Pruritus is one of the most common immune-related adverse events, and while many cases may be managed with conventional therapy, some patients do not respond. Shawn Kwatra, MD and colleagues reported on a case of an 88-year-old woman receiving pembrolizumab, a PD-1 inhibitor, for metastatic lung adenocarcinoma who developed severe pruritus refractory to standard treatment. Dr. Kwatra and colleagues found that intravenous naloxone, an opioid antagonist, resulted in a reduction in pruritus severity from 10 to 1 (on a scale of 0 to 10) within 1 hour. i3 Health spoke with Dr. Kwatra, Assistant Professor of Dermatology at Johns Hopkins University School of Medicine, about his findings and the challenges, potential advances, and role of multidisciplinary care in the management of dermatologic immune-related adverse events.
What is the most challenging aspect of managing immune-related adverse events?
Shawn G. Kwatra, MD: The most difficult aspect of managing adverse events related to therapy is that you don't want to stop the therapy because, oftentimes, patients who have adverse effects, at least in respect to the skin, are having a good response to therapy. What we're trying to do is manage patient symptoms while not taking them off of therapy.
Oftentimes, when a patient has a drug reaction, the drug is stopped and then things get better but, with a PD-1 inhibitor, what you want to do is keep them on the drug if it is effective in fighting their underlying malignancy and find a way to make them a little bit more comfortable. Often, patients who have skin eruptions—rashes, itch, even vitiligo—are responding well to the drug.
How do you counsel your patients through those adverse events?
Dr. Kwatra: PD-1 inhibitors are very new, so one of the main hurdles is knowing if the adverse event is actually related to the PD-1 inhibitor because there are many different reaction patterns. There are lichenoid, eczematous, psoriasiform, lupus-like, and other drug reactions. It is important to tie in what's going on with these patients and explain that we want to manage their symptoms because the cancer is the most important thing that we're dealing with.
The main thing is making sure we do not limit their anticancer therapy. It is a situation where dermatologists have an important role in doing everything they can to make sure therapy isn't stopped. There are many patients whose oncology team held therapy because of the significant skin side effects and diminishment of quality of life. It becomes an important management issue.
What is the role of multidisciplinary care in the management of immune-related adverse events?
Dr. Kwatra: A multidisciplinary team is definitely needed. Oncology treats the tumor, but if patients have a skin reaction pattern, you need a dermatologist involved. You need a rheumatologist if they have joint pain or a variety of other autoimmune phenomenon. There is also a role for many other specialists such as pulmonologists and ophthalmologists. It really is important that you have practitioners of different specialties that have knowledge of these kinds of effects.
I recently had a patient whose immunotherapy was held for a rash that the patient had because there was concern that the rash would be more progressive. Dermatologists can help with the management of these patients because they can say when they think the eruption will be stable or progress more rapidly.
Often, involvement of the mucus membranes is a negative sign. If patients have a rash, but they don't have mucus membrane involvement, that usually is a signal that you may be able to continue cancer therapy. It is a team-based approach because we don't want these patients off therapy.
What is the current standard for treating pruritus?
Dr. Kwatra: There is not an FDA-approved agent specifically designed to treat pruritus although many agents are in development. Thus, treatment is often empiric. Oftentimes, nonspecific therapies are utilized such as antihistamines or corticosteroids. Systemic steroids are an incredibly nonspecific therapy, but currently, they are one of the frontline agents per national guidelines for managing immunotherapy-related toxicity and adverse reactions. They're a global anti-inflammatory, immunosuppressive medicine that have very significant side effects like weight gain, glaucoma, cataracts, and bone thinning. I try to stay away from systemic steroids as much as possible because I don't want patients to be exposed to those side effects.
For this reason, I am always looking for novel anti-itch therapies that have a better side effect profile. In this case, naloxone's side effect profile and its targeted mechanism of action make it an appealing option. More studies are needed to evaluate this medication further in patients with immunotherapy-related pruritus.
I use naltrexone in my clinic off-label for conditions such as prurigo nodularis, atopic dermatitis, and chronic itch. The continuous infusion of the intravenous formulation definitely has the most powerful effect. I've seen it work for many different types of itch.
Can you speak more about what led you to use naloxone in the treatment of PD-1 blockade-induced pruritus?
Dr. Kwatra: The opioid system has a prominent role in both pain and itch. Morphine, classically, reduces pain but can also induce itch. Anesthesiologists have known about that for many years. Recently, we've used other types of opioids, off-label, and some of them can provide relief. We found that naltrexone can help in chronic itch by reducing mu-opioid tone. In chronic itch there tends to be more mu-opioid activity and less kappa-opioid activity, which is one of the reasons there are now several pharmaceutical companies entering the arena with either kappa-opioid agonists or combination kappa-opioid and mu-opioid antagonists for the treatment of chronic itch. Naloxone is one of the oldest, common, acceptable therapies.
We had a patient that had this itch that didn't respond to first-line systemic steroids and antihistamines. Drug eruption-related pruritus in many situations does not respond to anti-histamines. We had the suspicion that naloxone could be effective but were most surprised that the results were nearly immediate. When the medication was started, the itch nearly completely abated and when it was stopped, the itch came back, so there's a very clear relationship between the medicine and the relief the patient felt. I continued to follow the patient for several months afterwards, and I could see how much she improved as we switched to the oral formulation.
The important thing is that naloxone is available in all hospitals around the country. When these patients come in, sometimes unable to sit still because of such a terrible skin eruption and intractable itch, doctors who are aware of naloxone have something they can pull out of their tool bag. I've searched the literature and couldn't find many additional cases. In some cases, it had been used in liver-related itch, but there wasn't a lot of information, especially on how to dose it. Regarding administration, the intravenous route is the fastest acting. Orals take a while to work, and they don't have as high potency, but the intravenous formulations can result in an almost immediate effect.
The hope is that this is something someone can read and try the next day if a patient is recalcitrant to conventional therapy. I want to make sure people are aware of different options. A lot of the agents in the pipeline are many years away, and they may not be accessible for all patients.
We're really in uncharted territory with managing adverse effects for immunotherapy. Immunotherapy is becoming increasingly used as a first-line therapy for cancer, so we have to come up with novel ways to deal with these skin eruptions and other adverse effects.
What advances in PD-1 blockade-induced pruritus do you expect to see?
Dr. Kwatra: One thing I would like to do is partner with some of these pharmaceutical companies producing immunotherapy agents in the future to see if they're open to having us do more studies involving these patients to see what types of signaling pathways are dysregulated. If these drugs are going to become increasingly common, we need to find ways to keep patients on them, and we can try to give them the most effective therapy. That's the direction I'd like to take it in. Hopefully, the companies making these important agents are interested in partnering together.
About Dr. Kwatra
Shawn G. Kwatra, MD is an Assistant Professor of Dermatology at Johns Hopkins University School of Medicine. His primary research interest is the pathogenesis and treatment of chronic pruritus. He is a member of American Academy of Dermatology and the Society for Investigative Dermatology.
For More Information:
Kwatra SG, Ständer SS & Kang H (2018). PD-1 blockade-induced pruritus treated with a mu-opioid receptor antagonist. N Engl J Med, 379(16):1578-1579. DOI:10.1056/nejmc1805637
Transcript edited for clarity