Kidney Cancer Coverage from Every Angle

Nivolumab + Ipilimumab (Renal Cell Carcinoma)

Posted: Wednesday, March 6, 2019

Melanoma and Renal Cell Carcinoma: Highly Immunogenic Tumors

Both melanoma and renal cell carcinoma have long been characterized as highly immunogenic malignancies.1 As such, these tumor types have historically been considered resistant to chemotherapy.2,3 When tyrosine kinase inhibitors emerged as an anticancer therapeutic class, several agents were tested, with moderate success in kidney cancer.4 However, immunotherapy emerged as the treatment modality of choice in melanoma.5

Checkpoint Inhibitors, Singly and in Combination

Building on the efficacy of single checkpoint inhibitors in melanoma, investigators next explored the potential of immunotherapy combinations.6,7 Likewise, kidney cancer researchers, who had already begun using single-agent nivolumab in previously treated patients based on findings from CheckMate 025,8 decided that a similar combinatorial approach might yield benefit for patients with renal cell carcinoma. The phase III CheckMate 214 study—which compared nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma—was initiated and reported encouraging results, including a 9% complete response (CR) rate for nivolumab plus ipilimumab in intermediate- and poor-risk patients.9 The combination was approved in the spring of 2018 for treatment of patients with intermediate- or poor-risk, previously untreated advanced renal cell carcinoma.10

Nivolumab Plus Ipilimumab in Kidney Cancer

Nivolumab is a fully human immunoglobulin (Ig)G4 antibody that selectively blocks the interaction between programmed cell death receptor 1 (PD-1) and its ligands PD-L1 and PD-L2.11 Ipilimumab is a cytotoxic T lymphocyte antigen 4 (CTLA-4)–blocking antibody.12 Of note, although PD-L1 levels appear to influence tumor responsiveness or at least the degree of responsiveness to checkpoint inhibitors in other tumor types, such as non–small cell lung cancer,13 PD-L1 testing in renal cell carcinoma was not found to be useful.

For the CheckMate 214 trial in kidney cancer, the investigators reduced the dose of ipilimumab in the combination. As a result, they noted a slightly lower incidence of adverse effects, compared with melanoma trial data, without affecting the clinical benefit. 

Every patient who receives nivolumab plus ipilimumab or even nivolumab alone has a chance of developing a severe autoimmune complication, and clinicians need to know how to manage these events.

Elizabeth R. Plimack, MD, MS, Chief of the Division of Genitourinary Medical Oncology and Associate Professor at Fox Chase Cancer Center in Philadelphia, told JNCCN 360, “although dosing for the nivolumab/ipilimumab regimen differs somewhat when used in renal cell carcinoma—and therefore the percentage of patients who need corticosteroids might be different—in general, management of patients is similar to what clinicians may already be familiar with from the melanoma setting.” She emphasized that “every patient who receives nivolumab plus ipilimumab or even nivolumab alone has a chance of developing a severe autoimmune complication, and clinicians need to know how to manage these events.”

Favorable-Risk Versus Intermediate- or Poor-Risk Renal Cell Carcinoma

One of the findings reported by researchers was that checkpoint inhibitors were more effective than tyrosine kinase inhibitors in patients with intermediate- and poor-risk renal cell carcinoma,14 but those with favorable-risk disease obtained the greatest benefit from sunitinib.9 Therefore, the combination of nivolumab plus ipilimumab is not recommended as a preferred first-line regimen for patients with favorable-risk renal cell carcinoma.15 When the investigators analyzed each risk group by PD-L1 expression, they observed that those in the favorable-risk group had the lowest PD-L1 levels. 

“PD-L1 testing is not included in the NCCN Guidelines for treatment of renal cell carcinoma,”15 Dr. Plimack asserted, “because it is not useful. That said, there are many biologic variables we are still learning about, and they may explain why the patients in the favorable-risk group seemed to have the lowest PD-L1 expression compared with those in the intermediate- and poor-risk groups.”

Identifying Patients at Risk for Serious Immune-Mediated Toxicity

Now that immunotherapy has become a mainstay of treatment for many tumor types, some in the community may consider it a relatively “easy” therapy to administer and for patients to tolerate, observed Zita D. Lim, PA-C, of the GU Medical Oncology Department at The University of Texas MD Anderson Cancer Center in Houston. “Granted, for the majority of patients who do not experience serious immune-related adverse events, it is ‘easy’ to administer. But, there are patients who develop severe toxicities. The ability to identify those individuals in advance would help us spare those patients the development of serious morbidities,” she said.

Advanced practice clinicians are often on the front lines of identifying and managing toxicities. As such, Ms. Lim pointed out that they need to remain vigilant, “before treatment is initiated—during the initial history—and when patients reach out because of symptoms. After having participated in these clinical trials,” she told JNCCN 360, “I’ve grown to respect these agents even more than I initially did. The potential for cure in a percentage of patients is exciting, and most patients tolerate these drugs quite well. However, there are a few patients who are subject to some serious toxicities that may not have been observed in the trials. In my current experience, about 25% to 30% of our hospitalized patients are here as a result of immune-mediated toxicities. It’s all about a careful history and maintaining a vigilant index of suspicion.”

Administration: Nivolumab + Ipilimumab

According to Ms. Lim, the use of premedications is not standard when the combination of nivolumab and ipilimumab is administered. Supportive medications are offered during infusion on an as-needed basis. At MD Anderson, she noted, they include acetaminophen, diphenhydramine, and meperidine. The protocol used also includes instructions for infusion nurses in the case of hypersensitivity reaction. 

Quality of Life

Of note, Motzer et al9 stated that patient-reported quality-of-life instruments (Functional Assessment of Cancer Therapy Kidney Symptom Index-19 [FKSI-19], Functional Assessment of Cancer Therapy–General [FACT–G], and EuroQol 5-dimensional 3-level [EQ-5D-3L]) administered at baseline and during treatment showed that the nivolumab-plus-ipilimumab combination was favored by patients with intermediate- and poor-risk disease compared with sunitinib.16

The difference in quality of life between the immunotherapy combination regimen and sunitinib may be explained, Dr. Plimack suggested, by the fact that “patients on the checkpoint inhibitor combination who develop severe or serious adverse effects discontinue treatment and come off study.” Those who continue treatment generally do well and have few mild or no side effects. In contrast, patients who receive the tyrosine kinase inhibitor are on chronic treatment, sometimes with chronic adverse effects, which can be mild to severe. “Almost everyone on a tyrosine kinase inhibitor has side effects,” she said. “Even when the side effects are not severe, patients still have to deal with them on a daily basis, often over the long term. At each visit,” she explained, “we discuss the benefit of cancer control versus the impact of drug-related side effects on quality of life. Is treatment worth the benefit?”

In addition, Ms. Lim pointed out that of the available tyrosine kinase inhibitors, sunitinib is one of the more poorly tolerated drugs. In the COMPARZ trial, pazopanib, for example, was better tolerated than sunitinib.17 Another explanation is that the CheckMate 214 trial was conducted primarily in large academic cancer centers. “Thanks to our experience with these drugs in other settings,” Ms. Lim cautioned, “we were fairly successful at preventing and/or identifying immune-mediated adverse effects and intervening aggressively before they became grade 3 or 4.” However, in the community setting, “we may find that the incidence of severe toxicities associated with the combination of checkpoint inhibitors is higher than that reported in the trial.”

Ms. Lim described how potential immune-related adverse effects are approached at MD Anderson Cancer Center. “If a patient complains of slight shortness of breath or a new cough, I will hold immunotherapy rather than simply waiting to see whether a fever develops or perhaps prescribing a cough medication. We may order a chest x-ray, perhaps computed tomography imaging, to see whether there is evidence of ground-glass opacities. We will compare current pulmonary function testing with baseline and perform a 6-minute walk, measuring oxygen desaturation. We may decide to intervene with corticosteroids, rather than waiting for the patient’s condition to deteriorate.”

Challenging Toxicities

The neurologic toxicities potentially associated with nivolumab plus ipilimumab—such as myasthenia gravis, nerve palsies, and Guillain Barré syndrome—are the most challenging from a management perspective, Dr. Plimack, who is also Director of Genitourinary Clinical Research at Fox Chase Cancer Center, noted.

Ms. Lim concurred. “Now that we as clinicians have enough experience with these types of immune-oncology agents, the more common immune-related adverse effects, such as endocrinopathies, pneumonitis, and colitis, can be managed effectively. We know what to look for, we can address them early, and often we can avoid hospitalization,” she said. Adverse effects such as myositis, myasthenia gravis, and myocarditis are difficult to treat, according to Ms. Lim, and are associated with high levels of morbidity and mortality.

“These patients are very sick,” Ms. Lim said, noting that they are hospitalized for a long time and that their care must be coordinated with multiple services. Identifying these toxicities early is crucial. “I am learning not to dismiss even minor comments about fatigue or weakness, for example, made during clinic visits. Even something like dysphagia can be the first hint of myasthenia gravis,” she told JNCCN 360.

Because they practice at an academic cancer center, the experts at MD Anderson Cancer Center are often consulted about patients who are treated in the community. “I’ve noticed that certain early symptoms may not be identified early or are undertreated,” Ms. Lim observed. For instance, a practitioner may prescribe a “short course of methylprednisolone believing it will be sufficient. Or a community provider may believe that adding diphenoxylate and atropine to loperamide will effectively control diarrhea. In fact, intervention should be initiated more rapidly and more aggressively. I’ve seen patients who had full-blown colitis by the time they presented at our clinic. They needed to be hospitalized to achieve control,” she stated. This point—namely that the same symptoms signify different risks when they appear after chemotherapy versus immunotherapy—is critical and needs to be emphasized at every level, including among nursing staff who may be the first to hear about symptoms from patients.

Unpredictability of Toxicities

One of the most challenging aspects of using these agents and regimens is the unpredictability—at this time—of the appearance of toxicities. It is clear that a thorough history is essential in terms of identifying any autoimmune issues or a history of myasthenia. “Ideally, it would be great to develop tests that would allow us to flag which patients might be prone to developing toxicities with checkpoint inhibitors. Perhaps there’s a predisposition to autoimmune processes in some patients, and these agents act as a trigger?” Ms. Lim speculated. “It’s similar to any other beneficial intervention: millions of patients receive flu shots without any untoward effects, but every once in a while, there’s an incident of myasthenia gravis or some other side effect,” she told JNCCN 360. A screening tool that could be administered before therapy even starts would be immensely helpful.

“That said, these decisions are highly individual ones. A patient with a history of eczema should not (or may not want to) be excluded from the opportunity to forestall (or even cure) her cancer,” Ms. Lim said. On the other hand, “a patient with a history of Guillain Barré syndrome is probably not a good candidate for immunotherapy.” If we remain aware of some of the bigger pitfalls associated with immune therapies, she advised, “we can guide our patients through treatment successfully.”

Duration of Nivolumab Maintenance

With regard to the duration of nivolumab maintenance, “we do not have data yet to make recommendations about how long to treat or when to stop treatment,” Dr. Plimack told JNCCN 360. “We are still treating patients who started on the original nivolumab study18 5 years ago.”

Because of toxicities, some patients may not complete the full four doses of combination treatment. “It’s important to recognize that we don’t know the ideal duration of therapy for these regimens and that benefit may still be provided with fewer than the full four combination doses.” Even if the decision is made to discontinue therapy, the patient may still derive substantial benefit—even a complete response, Ms. Lim pointed out.

At MD Anderson, if a patient experiences a complete response (without toxicities or contraindications), “we generally continue nivolumab for 2 years and then stop treatment,” Ms. Lim said. “However, the jury is out on whether that’s the best plan. I’m eager to see evolving data, both in renal cell carcinoma and in other tumor types.”

Complete Response and Long-Term Treatment-Free Survival

One of the most exciting findings from the CheckMate 214 trial was an almost 10% complete response rate. “Complete response is a ‘Response Evaluation Criteria in Solid Tumors’ (RECIST) construct, where there is no tumor visible on imaging,” Dr. Plimack explained. Some patients might have what is termed a partial response, “but really, they don’t have disease,” she said. Imaging may show a scar or a treated cancer that can be measured, but the disease appears to be in remission.

According to Dr. Plimack, some patients with metastatic disease experience sustained disease control off treatment after immunotherapy. “We monitor these patients with scans and are always on the lookout for the development of new metastases,” she continued. Classically, oncologists are taught that once disease has become metastatic, “it usually comes back.”

Most patients who are off treatment and have stable disease have a complete response by RECIST criteria, but not all of them do,” she continued. An analysis of the treatment-free interval was presented at the European Society for Medical Oncology (ESMO) 2018 Congress.19 According to that presentation, there is a subset of patients who receive nivolumab plus ipilimumab who can discontinue therapy and experience disease control.

“Whether they qualify as a ‘complete response’ or not,” Dr. Plimack said, “their cancer doesn’t grow. In other cases, the cancer grows very slowly.” Clinically, “complete response and treatment-free survival overlap a great deal,” Dr. Plimack noted, “but they are not exactly the same thing. We all have patients for whom the cancer has not yet returned. With immunotherapy, only time will tell whether treatment-free survival can be maintained long term—we certainly hope that is the case.”

With regard to a treatment-free interval versus remission, Ms. Lim commented that “you can’t biopsy everything.” Therefore, questions about how to characterize what is seen on imaging remain. “Is it necrotic tissue? Is the tumor still there but dormant? We’ve been watching a number of patients like that, namely individuals who appear on imaging still to have a tumor but who are stable and symptom-free. Should we call those outcomes ‘near-complete response?’” Moreover, Ms. Lim pointed out that if an adrenal or lymph node had been involved, even with a response to treatment in the node, there will be some residual tissue. How is that calculated? “For the patient who is symptom-free and off treatment, each scan offers more confidence that durable disease control has been achieved,” she reported.



Elizabeth R. Plimack, MD, MS, has served as a scientific advisor for BMS, Genentech, Incyte, Janssen, and Merck. She has participated in data safety monitoring for AstraZeneca and Pfizer and has received clinical research grants from Astellas, AstraZeneca, BMS, Genentech, Merck, Peloton, and Pfizer. She has also participated as faculty or reviewer in CME programs for the American Urological Association, Clinical Care Options, Fox Chase Cancer Center, Medscape, the NCCN, Omniprex, PriME Oncology, and Research to Practice.

Zita D. Lim, PA-C, has served on the speakers’ bureau for Exelexis.



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