Nivolumab (Opdivo)

In October 2015, the U.S. Food and Drug Administration (FDA) expanded approval¹ of nivolumab, an injectable immune checkpoint inhibitor, to second-line treatment of all metastatic non–small cell lung cancer (NSCLC, both squamous and nonsquamous) after disease progression on prior platinum-containing chemotherapy.

The approval of the first immune checkpoint inhibitors for treatment of PD-L1–expressing metastatic NSCLC^1–4 heralded a new strategy in lung cancer treatment.⁵ The incidence of lung cancer, which is mostly NSCLC, has been on the decline in both men and women as smoking rates decrease.⁶ Nevertheless, without a cohesive approach to screening and early detection, mortality from NSCLC is still high⁷; use of modalities such as surgery, radiation therapy, and chemotherapy represent strategies to improve outcomes, and recently, there have been impressive gains in small subpopulations of patients with targetable alterations, such as epidermal growth factor receptor (EGFR) mutations and rearrangements of the anaplastic lymphoma kinase (ALK) gene. The advent of immune checkpoint inhibitors, though, potentially encompasses many more patients with this all-too-common cancer and offers hope to those patients who derive a robust benefit from this treatment.

Nivolumab is one of three immune checkpoint inhibitors (the others are pembrolizumab and atezolizumab) with a category 1 recommendation as subsequent therapy in the NCCN Clinical Practice Guidelines in Oncology for NSCLC.⁸

JNCCN 360 was fortunate to chat with Hossein Borghaei, DO, MS, Chief, Division of Thoracic Medical Oncology and Associate Professor, Department of Hematology/Oncology at the Fox Chase Cancer Center in Philadelphia. He noted that practitioners’ questions about the clinical use of nivolumab typically fall into one of three broad categories: how to manage adverse events; how to recognize so-called pseudoprogression and what to do about it; and when and how to re-start treatment if management for adverse events has been effective. Asked to comment, Roy S. Herbst, MD, PhD, Ensign Professor of Medicine and Chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Connecticut, added, “These drugs have transformed the way we care for patients with cancer.”

Role of PD-L1 Testing

The current label for nivolumab in metastatic NSCLC does not include a specific PD-L1 expression level as an eligibility requirement for treatment. Therefore, although nivolumab is an immune checkpoint inhibitor that is thought to be generally more effective in patients whose tumors express higher levels of PD-L1,⁹ the role of such testing in practice may need clarification.

With regard to prescribing nivolumab, Dr. Borghaei said, “Until a few months ago, I might have said that we do not need the PD-L1 expression results when treating with nivolumab in the second-line setting. However, pembrolizumab has now been approved in the first line for patients with high PD-L1 expression.¹⁰ So, at this point, any patient with lung cancer with any histology who presents in our clinics is tested for PD-L1 expression. The standard of care has changed in the first line,” he explained, “so even though those results are not ‘needed’ in the second line, we will know the PD-L1 status for all of our lung cancer patients upfront.”

Talking With Patients About Likelihood of Benefit

How to frame those test results for patients represents an important challenge in communication. “When patients are known to have no PD-L1 or very low levels, we explain that the chance of benefit with nivolumab is lower and that we will perform a computed tomography (CT) scan in 6 to 8 weeks to make a preliminary assessment.” If there is a question about whether something on imaging represents pseudoprogression versus real disease progression, checking back to the PD-L1 levels at baseline will provide another clue about the likelihood of real response. “We try to paint as clear a picture as we can for the patient, with any new treatment. And we talk about what’s next if the therapy doesn’t work.”

In addition to transparency and a candid assessment of the likelihood of benefit, Dr. Herbst suggested that patients with little or no PD-L1 expression might consider a clinical trial exploring a combination of agents.

“You also need to make sure that the patient is a good candidate, that he or she doesn’t have any comorbidities or other condition that would preclude giving a treatment that activates the immune system,” Dr. Herbst cautioned.

Treatment to Achieve Disease Control

Patients with lung cancer often have symptoms, such as fatigue, cough, and weight loss. If they are switched from a first-line chemotherapy regimen to nivolumab because of disease progression, the oncologist has been following them closely and is familiar with their health status and comorbidities. To be eligible to participate, patients in the nivolumab clinical trials were required to have a good performance status of 0 or 1.¹¹ “In clinical practice, though,” Dr. Borghaei pointed out, “nivolumab might also be offered to some patients with a performance status of 2, if we think that performance status is declining because of disease progression. It might be necessary to get comorbid conditions under control—eg, pulmonary issues—before starting treatment. Many times, these issues are due to disease and the total tumor burden. Checkpoint inhibitors, such as nivolumab, are generally well tolerated, and most oncologists would not hesitate to offer treatment, with the hope of obtaining some disease control.”

Likewise, Dr. Herbst observed, “You don’t have to be as strict in practice as you would be in a clinical trial with regard to performance status.” Nevertheless, he said, “the patient should be at least ambulatory and able to recognize the risks associated with therapy. And, of course, any patient for whom a checkpoint inhibitor is being considered shouldn’t have any active immune-related processes, such as psoriasis, autoimmune endocrinopathies, etc.”

Adverse Events Versus Immune-Related Adverse Events

Although almost all medical therapies for cancer are associated with some level of toxicity, immunotherapy has a unique profile that may include what are termed “immune-related adverse effects (irAEs).”^12,13 Endocrinopathies, for instance, such as thyroid dysfunction, are more common in patients with NSCLC who receive immune checkpoint inhibitors, whereas those with melanoma may more commonly develop colitis.¹⁴ In addition, although well tolerated and generally easier for patients than chemotherapy, checkpoint inhibitors may be associated with adverse effects such as fatigue and rash.

“We tell patients that they can anticipate fatigue, which is associated with many anticancer therapies. And, when we talk about the rash, we make sure that the patient agrees to let us evaluate the rash to make sure it’s not getting out of control,” Dr. Borghaei said. The potential to develop any irAEs, such as pneumonitis; colitis; hepatitis; and/or thyroid, adrenal, pituitary, and other endocrine issues, should also be discussed.

“We explain that if pneumonitis or colitis develops, for instance, hospitalization might be required. It is difficult to manage severe reactions on an outpatient basis.”

Dr. Herbst recommended providing patients with a card or other type of document, “explaining that they are taking an immune-related agent, in case they are seen in a local hospital or an emergency department. The staff should be aware,” he explained, “that they are on a checkpoint inhibitor because it will affect how those hospital providers think about the differential diagnosis.”

Dr. Borghaei also pointed out that most of these irAEs are reversible by stopping the drug and starting steroids. He advised describing the consequences of high doses of steroids and the need to taper them. “Obviously, steroids can reduce the immunotherapy-related symptoms, but they come with their own adverse effects,” he cautioned.

The other issue that Dr. Borghaei emphasizes to these patients before they begin treatment with nivolumab is that some of the endocrinopathies are not reversible. “In other words,” he said, “if a patient has to take thyroid medication, he or she is probably looking at life-long thyroid supplementation.” From a quality-of-life perspective, these issues are important to address with patients upfront.

Rash

The dermatologic toxicity associated with these agents is different from that associated with EGFR inhibitors (eg, erlotinib, gefitinib), “but I’ve seen some severe skin rashes even with chemotherapy,” Dr. Borghaei observed. Although it is quite rare, “I just want to make sure the patient doesn’t develop something like a Stevens-Johnson type of reaction.” Explaining that it is difficult to rely on a patient’s description of a rash over the phone, he prefers to examine patients who develop a rash with a new drug. “We don’t have any algorithms for prevention or management right now, as there are with the EGFR inhibitors. And, because the rash is immune-related, I want to make sure it’s local and not something uncontrolled that might require oral steroid therapy.”

Many of the irAEs (eg, pneumonitis, colitis, severe skin rash) are reversible with steroids, but something like hypothyroidism is not. “I usually consult with my endocrinology colleagues to decide when to start a patient on thyroid supplementation. The endocrinopathies require support with whatever supplements are appropriate for the gland (thyroid, adrenals, pituitary, etc) that has become dysfunctional due to immune system effects.”

Restarting Treatment

Treatment for an irAE usually consists of high-dose steroids for about a month, after which the steroids are tapered very slowly. “If the steroids are tapered too quickly,” Dr. Herbst cautioned, “the reaction will usually recur.” After the steroids are tapered and the patient is off treatment, “you could consider restarting the checkpoint inhibitor, but it depends on where the patient is in the overall treatment plan. If he or she already had a good response to nivolumab and then developed a grade 3 or higher reaction, I might not even start again. I might just leave it alone. In contrast, if the patient was still early in the course of treatment and didn’t see any benefit yet, you might want to restart the nivolumab—especially if the reaction was lower grade—to see whether the patient could still derive benefit.”

Despite developing an irAE with treatment, “patients are usually eager to get back on the medicine that is going fight their cancer,” Dr. Herbst said, “but it’s up to us as clinicians to be judicious about restarting therapy. With these agents, we have no idea how much therapy someone needs. There have been reports of patients who had as little as one dose of a checkpoint inhibitor nevertheless having a long-lasting response.” He observed that assessments should be made on a case-by-case basis, considering factors such as the severity of the toxicity, whether it was life-threatening, how completely it resolved, and whether the patient is completely off steroids.

“I have a patient who was hospitalized for pneumonitis after a complete response on immunotherapy. Now that he is off drug, why would we start him again—if he has a complete response?” Dr. Herbst asked. “I would only start nivolumab again if there’s a reason.”

Pseudoprogression

The concept of pseudoprogression refers to a temporary increase in tumor size or the development of new lesions being prematurely or erroneously judged to be real disease progression. Because immunotherapy may be associated with delayed benefit or an unconventional pattern of benefit, clinicians have been cautioned not to immediately interpret signs of tumor growth on imaging as lack of response to treatment.

This is one of the areas that practitioners are concerned about. However, Dr. Borghaei commented that it is not generally difficult to distinguish pseudoprogression from real disease progression in patients with NSCLC.

“As I pointed out, by the time we are initiating second-line treatment, we are well acquainted with the patient. If he or she is clearly deriving clinical benefit, perhaps some measure of functionality has improved, cough seems to be less, he or she seems to be well, not losing weight—even if there are one or two lesions on a scan that seem to be a little larger—it makes sense to continue treatment and check again in 6 weeks,” he explained. In contrast, if the patient seems not to be well or is even worse than when he started treatment—for example, cough is bad, weight loss is more significant, night sweats are worse—and the CT scan shows that all areas of disease seem to be larger, “that’s a pretty strong sign that treatment is not working and the disease seems to be progressing.”

It is not just a matter of what can be seen on imaging. If a lesion seems to be objectively larger, the conclusion may be that disease is progressing. But, Dr. Borghaei explained, that assessment is out of context: one needs to see the patient. It is the responsibility of the clinician to make that judgment. “Look at the patient,” he said. “If he or she is not in distress and the treatment is well tolerated, we can give it another two or three rounds (treatment is every 2 weeks), and then re-image to see how things are going.” In contrast, if the patient is not doing well, is losing weight, and imaging shows that the disease is growing, “I would not call that pseudoprogression. I would stop the drug and consider switching to something else.”

Pseudoprogression can occur in lung cancer, but it is rare.¹⁵ “The last thing we want is for a patient to stay on a drug that is clearly not working because of the hope that what is seen on the scan is pseudoprogression,” Dr. Borghaei said. “Immunotherapy clearly is not effective in many patients, and we need to keep that in mind. We don’t want to treat patients with ineffective drugs and increase the risk of toxicities.”

Listen to the Patient

Distinguishing a disease-related symptom, such as cough, from a treatment-related adverse effect, which may also be cough, boils down to the clinician’s knowledge of the individual. “Certainly, a smoker who has chronic obstructive pulmonary disease and emphysema and who presents with lung cancer is going to have a cough,” Dr. Borghaei observed. The clinician needs to ask, ’Is the cough now different in any way from what you used to have?’”

In medical school, physicians are taught that, “if you listen to a patient long enough, he or she will tell you what’s wrong.” Most patients will be able to report whether a symptom is new or different from what they had before.

It is not generally difficult to distinguish pseudoprogression from real progression in patients with NSCLC…. If he or she is clearly deriving clinical benefit...it makes sense to continue treatment and check again in 6 weeks. In contrast, if the patient seems not to be well or is even worse than when he started treatment...and the CT scan shows that all areas of disease seem to be larger, that’s a pretty strong sign that treatment is not working and the disease seems to be progressing."

Dr. Borghaei suggested that when a patient is being examined and she coughs, the clinician might ask, “Is this new?” If the answer is, “no. I’ve had this cough for 10 years,” the symptom is not likely to be treatment related. “Again, it’s a matter of clinical judgment. If the patient does not seem to be in distress when she coughs, then you would be safe to assume that this cough is from the underlying disease. On the other hand, if her spouse reports “she’s been coughing her head off for 2 weeks,” and it is clearly something that is new, you need to investigate further.”

Dr. Herbst emphasized the importance of being attuned to potential adverse effects. “In my experience, you have to think about it to find it,” he said. For instance, “if a patient reports feeling tired, you have to think about adrenal toxicity—eg, adrenal cortical function or endocrine function. If a patient reports shortness of breath, is it related to pneumonitis or the heart?”

Community oncologists have done a great job of adopting and embracing these new treatments, Dr. Borghaei observed. “This is quite challenging,” he said, “because these novel therapies have the potential for adverse effects that we are not accustomed to. I’m fortunate because I work solely on lung cancer and so I have more opportunities to learn about and to use new drugs and new techniques. However, community practitioners treat patients with a variety of malignancies and have done a remarkable job of keeping up to date.”

Disclosures

Hossein Borghaei, DO, MS, has served as a scientific advisor for Bristol-Myers Squibb Company, Eli Lilly and Company, Boehringer Ingelheim GmbH, Pfizer Inc., Genentech, Inc., and Clovis Oncology; has served as a consultant for Bristol-Myers Squibb Company,  Eli Lilly and Company, and AstraZeneca; and has received research support from Millennium Pharmaceuticals, Inc.

Roy S. Herbst, MD, PhD, has served as a consultant for AstraZeneca, Eli Lilly, Genentech/Roche, Merck, and Pfizer and has received clinical trials support or grant support from Genentech and Merck.

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