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Meeting the Challenges of Immunotherapy-Related Toxicities


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In 2011, the U.S. Food and Drug Administration (FDA) approved ipilimumab (Yervoy), an anticytotoxic T-lymphocyte– associated antigen 4 (CTLA-4), the first checkpoint inhibitor for the treatment of advanced melanoma.1 Since then, several more checkpoint inhibitors directed at both the programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) pathways have been approved by the FDA for the treatment of many cancers. Some of them include the anti– PD-1 therapies nivolumab (Opdivo) and pembrolizumab (Keytruda) for the treatment of advanced melanoma, non–small cell lung cancer (NSCLC), Hodgkin lymphoma, and urothelial cancer. Pembrolizumab has also been approved by the FDA in the treatment of renal cell carcinoma, head and neck cancer, Merkel cell carcinoma, and tumors of any organ with high microsatellite instability. 

Most recently, the FDA approved ipilimumab in combination with nivolumab for patients aged 12 and older with microsatellite instability–high or mismatch repair–deficient metastatic cancers, certain patients with renal cell carcinoma, and pembrolizumab for patients with recurrent or metastatic cervical cancer, among others.2 Some FDA-approved anti–PD-L1 drugs include avelumab (Bavencio) for the treatment of adolescents and older patients with metastatic Merkel cell carcinoma and atezolizumab (Tecentriq) and durvalumab (Imfinzi) for the treatment of advanced NSCLC after chemoradiation. 

Although immunotherapies can be effective in boosting the body’s natural defense against cancer in some patients, providing durable remissions in a small percentage of cases, they can also result in myriad immune-related adverse events due to misdirected stimulation of the immune system. Although overall anti–PD-1/PD-L1 drugs are less toxic than traditional chemotherapy agents, they are not without serious side effects, which can involve multiple body organs and include conditions such as immune-related colitis, hepatitis, pneumonitis, and thyroiditis. 

Sandip P. Patel, MD

Sandip P. Patel, MD

The ASCO Post talked with Sandip P. Patel, MD, Associate Professor of Medicine; Co-Leader of Experimental Therapeutics; and Deputy Director of the San Diego Center for Precision Immunotherapy at the University of California, about overcoming the treatment challenges of immunotherapy in the palliative care setting, assessing the risk factors for immunotherapy side effects, and managing patients’ unrealistic expectations. 

Bridging the Divide Between Immunotherapy and Palliative Care 

Please talk about the treatment challenges of immunotherapy in the palliative care setting. 

We don’t often do a great job of bridging the divide, either clinically or logistically, between treatment with immunotherapy and palliative care, because often we try immunotherapy as the last line of therapy in patients with advanced cancer. In this setting, the next step is usually palliative care for symptom management of their advanced cancer or hospice care if the immunotherapy is ineffective. 

And just as cancer requires a multidisciplinary team ranging from surgeons and radiation oncologists to medical oncologists to care for patients’ treatment needs, we now have to have an even wider group of physicians, including gastroenterologists, endocrinologists, pulmonologists, and many others to manage the side effects patients receiving immunotherapy may experience both during and after treatment. 

“Home palliative care offers many of the same benefits patients receive in the clinic, but it helps them avoid long commutes to the cancer center while allowing them to continue on systemic therapy if they so desire.”
— Sandip P. Patel, MD

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When we talk about cancer and immunotherapy, there are two major types of potential challenges we face. Most of us who treat patients with advanced cancer have found transformative efficacy from immunotherapy for some patients. When these therapies are effective, patients can live a long time— even years—with advanced metastatic disease, which is remarkable. Unfortunately, not all patients respond to immunotherapy. In fact, only a small percentage of patients—between 15% and 20%—receive some benefit from checkpoint inhibitors that target CTLA-4 or the PD-1 and PD-L1 pathways for the majority of tumor types. And although these drugs can stimulate the immune system to fight cancer, they can also cause immune-related adverse events in which the immune system starts attacking normal tissue the way we hope the therapy will attack the cancerous tissue, and some patients experience the side effects and none of the benefit. 

Currently, immunotherapy is often a patient’s last systemic line of treatment after chemotherapy for many solid tumor types, and the question is, what can we do to ease the side effect burden of that patient and manage his or her expectation that the therapy will work after chemotherapy has failed? This is one of the central challenges I face in my clinic. In my talks with patients, I quote the statistics of the likelihood the therapy will be effective based on the patient’s cancer type, stage of disease, and overall physical condition. Fundamentally, however, population-level statistics are less helpful in decision-making to an individual patient, who either responds or does not. I also discuss potential options if the last line of therapy doesn’t work, such as trying another immunotherapy either as standard therapy or as part of a clinical trial, or considering hospice care. And these options are very different. 

Jamie H. Von Roenn, MD, FASCO

Jamie H. Von Roenn, MD, FASCO

What I’ve done in my practice is to try to help bridge the divide between treatment and palliative care, and ultimately hospice care at the end of life for many unfortunately, is to offer patients home palliative care to ease a potential transition to hospice and to try to maximize their quality of life as the symptoms of their cancer may be at their most severe.

GUEST EDITOR

Addressing the evolving needs of cancer survivors at various stages of their illness and care, Palliative Care in Oncology is guest edited by Jamie H. Von Roenn, MD, FASCO. Dr. Von Roenn is ASCO’s Vice President of Education, Science, and Professional Development.

To begin, I assure my patients that home palliative care is different from hospice care and that palliative care can be essential for pain and symptom management. Home palliative care offers many of the same benefits patients receive in the clinic, but it helps them avoid long commutes to the cancer center while allowing them to continue on systemic therapy if they so desire. 

Another reason I like home palliative care is because often it is managed by the same organizations that offer home hospice care, and that can be beneficial if the immunotherapy the patient is taking isn’t working and there are no other good treatment options available and the patient needs to transition to hospice care. I have found the transition from home palliative care to home hospice care to be much smoother for my patients than referring them directly to hospice care and consider this a valuable option for patients who want to proceed with systemic therapy such as immunotherapy but are increasingly symptomatic. 

Prognosticating Risk for Immune-Related Adverse Events 

Can you tell in advance which patients may be at greater risk for immune-related adverse events? 

Currently, we do not have a clinical phenotype or blood test to tell us which patient is more or less likely to have immune-related toxicities, which are independent of age, gender, and in many cases their prior therapy. Patients with prior autoimmune conditions are more likely to have immune-related toxicities, either directly related to their autoimmune condition or sometimes unrelated to that condition as well, on immune checkpoint blockade. I want to emphasize that overall clinically meaningful (requiring systemic steroid therapy) immune-related adverse events are relatively rare events for patients receiving anti–PD-1/ PD-L1 monotherapy, which makes them more difficult to manage when they do occur, because of their delayed nature and lack of distinguishing characteristics from other side effects of cancer and its treatment. 

“The flip side of the benefit of immunotherapy, which is a long-term response against the cancer, is that toxicities can happen at the beginning of treatment or long after their last dose.”
— Sandip P. Patel, MD

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With chemotherapy, we can predict with near certainty the toxicities the majority of patients will experience. With immunotherapy, the side effects do not develop with the same kinetics as with chemotherapy, meaning a patient could develop an immune-related adverse event, such as colitis or hepatitis, after his or her first dose of therapy or after the twelfth dose. In contrast, we know the general neutropenic nadir for most chemotherapy regimens. The flip side of the benefit of immunotherapy, which is a long-term response against the cancer, is that toxicities can happen at the beginning of treatment or long after their last dose. Although palliative care is a crucial part of managing distress symptoms, physical symptoms, such as diarrhea and colitis, are best managed by the prescribing oncologist in close collaboration with the palliative care team to make sure patients aren’t receiving conflicting medications that do not address the underlying pathophysiology. 

For example, although high-dose corticosteroids may help patients with colitis, bowel obstruction, or bone pain, depending on the dose of the steroids used, they could interfere with the effectiveness of immunotherapy. Low-dose steroids (prednisone < 10 mg daily or equivalent) are often compatible with immune checkpoint blockades, but higher-dose steroids could have antitreatment effects, so maintaining good communication with palliative care colleagues is important. 

In addition, immune-related adverse events require constant vigilance. For example, diarrhea can be a sign of serious autoimmune colitis and needs assessment; cough with a fever may be a serious autoimmune pneumonitis; and fatigue may be a routine side effect or an indication of autoimmune hypophysitis, thyroiditis, or adrenalitis. Intervening early in the development of these conditions is critical because they may result in permanent organ damage and morbidity. 

Assessing Risk Factors for Immunotherapy Toxicity 

What are the mechanisms of immunotherapy that determine the level of toxicities patients may experience? 

The determining factor comes down to the combination of the drug itself and the patient’s immune system. The one clinical criterion that may influence the onset of an adverse event is the condition of the patient’s immune system before he or she undergoes immunotherapy. 

For example, if a patient has Crohn’s disease or ulcerative colitis and receives an immune checkpoint inhibitor, he or she is much more likely to suffer colitis than a patient without these conditions or who has a different immune-related adverse event. And then you have to have a conversation with the patient as well as the palliative care team about the risk/benefit of proceeding with the treatment and how best to manage the side effects. 

This past June, ASCO and the National Comprehensive Cancer Network® published guidelines to help oncologists understand and manage immunotherapy side effects.3,4 Hopefully, these resources will also be helpful in educating patients about their risk for side effects and prepare them for the possibility that such side effects can manifest soon after immunotherapy begins or long after treatment is completed, because there is no predictable timeline. 

Managing Patients’ Unrealistic Expectations 

How do you caution patients that they may not benefit from the therapy and manage unrealistic expectations? 

I start from the premise that all patients deserve to have the most accurate medical information available, which is often informed by biomarkers. However, if you tell a patient that he or she has a 15% chance of a 5-year survival on an immunotherapy, that isn’t as helpful. An individual patient is either going to respond to the therapy or is not. I explain what the data show for a general population of patients and then we often proceed with a philosophy of “hope for the best but prepare for the worst.” And preparing for the worst involves incorporating palliative care into the patients’ medical care, so they have the supportive care they need if the therapy isn’t effective and/or they experience immune-related adverse events. I’ve found that talking about palliative care, either in the clinic or home setting, offers a natural segue to making sure that we take good care of patients holistically rather than just during a particular treatment course. 

“I explain what the data show for a general population of patients, and then we often proceed with a philosophy of ‘hope for the best but prepare for the worst.’”
— Sandip P. Patel, MD

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One potential complicating aspect of immunotherapy that is often discussed is the development of pseudoprogression, in which the computed tomography scan shows that the malignant lesions are growing, but, in fact, the patient continues to have a clinical benefit. We also want to be cognizant that outside of that rare setting, the development of pseudoprogression is rare. If a patient experiences clinical decline, including losing weight and becoming physically inactive, he or she is actually having disease progression and should be treated with an alternative therapy or palliative care, or hospice care should be considered. 

For the vast majority of patients, “pseudo-pseudoprogression,” as I like to call it, which differs from treatment beyond radiographic disease progression, is where the patient and physician want to continue immunotherapy despite clear cancer growth on imaging scans and, more importantly, a decline in clinical status. This is a much bigger problem in oncology than pseudoprogression, which tends to be relatively rare (pseudoprogression, outside of melanoma, likely occurs in 2%–5% of patients, at most). There are many clinical scenarios in which you just aren’t sure whether patients are benefiting from the treatment, but given the relatively low toxicity profile of immunotherapies, particularly for anti–PD-1 monotherapy, for most patients, it may be reasonable to continue therapy if they desire. And it is in these scenarios as well that I have found home palliative care to be particularly beneficial to patients as a bridge to support them during their immunotherapy and a gentle transition if immunotherapy does not provide a benefit. ■

DISCLOSURE: Dr. Patel reported no conflicts of interest. 

REFERENCES 

1. Alexander W: The checkpoint immunotherapy revolution. PT 41:185-191, 2016

2. U.S. Food and Drug Administration: Hematology/Oncology (Cancer) Approvals & Safety Notifications. Available at www.fda.gov. Accessed July 18, 2018. 

3. Brahmer JR, Lacchetti C, Schneider BJ, et al: Management of immune-related adverse events in patients treated with immune checkpoint therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 36:1714-1768, 2018

4. Management of Immunotherapy-Related Toxicities. Available at www.nccn.org. Accessed July 16, 2018


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