Nivolumab + Ipilimumab Combination Regimen for Advanced RCC

Robert Alter, MD: Let’s talk about IO [immunotherapy]/IO therapy. We talked a little about how this patient presented with volumes of disease and required something a little more. Who would be a good candidate for IO/IO therapy using ipilimumab-nivolumab? Which patient would be the ideal candidate?

Elan Diamond, MD: That’s a very good question. When I think about IO/IO combinations, I think about patients who have poor- or intermediate-risk renal cell carcinoma who don’t require an immediate response. Because we know that the overall response rates for IO/IO combination therapy are lower than they are for IO/TKI [tyrosine kinase inhibitor]-based therapy.

The other thing I discuss with the patient is duration of therapy and treatment-free survival. As you alluded to before, one of the attractive features of an IO/IO combination is that it has the promise of a prolonged treatment-free survival compared with IO/TKI combinations. There was a good meta-analysis recently published by Moshe Ornstein, [MD, MA,] et al that showed that of the patients treated with a dual immune checkpoint inhibitor therapy who discontinued therapy, at 12 months, 50% of them didn’t require additional treatment. That argues for that very prolonged response that you see with IO/IO combinations. That was compared with a 5% treatment-free survival for patients who had IO/TKI. I discuss that with my patients. I offer them that if they choose to be treated with an IO/IO combination.

Robert Alter, MD: Right. Then we talked about the toxicities of a TKI. You mentioned before Robert Motzer, [MD,] presenting the health-related quality-of-life data at ASCO [American Society of Clinical Oncology annual meeting] 2021 on patients receiving lenvatinib and pembrolizumab in the CLEAR clinical trial. …at ESMO [European Society for Medical Oncology Congress] a year and a half ago presented the health-related quality-of-life information as 42-month data on patients receiving ipilimumab and nivolumab in the CheckMate 214 clinical trial. The early data presented at 24 months were reaffirmed at 42 months. They looked at time to first deterioration and time to first clinical deterioration. They talked about different factors in regard to physical and psychological benefits.

There were much fewer treatment-related toxicities both physically and functionally. There was an emotional quality-of-life factor that wasn’t clinically beneficial for patients receiving IO/IO therapy. But it comes down to what benefit it offers our patients. We’re blessed to have options. We don’t take that for granted. There’s the durability of being on a maintenance IO therapy, a single agent. Our patients are in the office less. They aren’t reminded to take a pill every day. Without a TKI, there usually isn’t hand-foot syndrome, fatigue, hypertension, diarrhea, or potential toxicity. These patients are doing well. In your case, your patient is being sustained on surveillance with better quality of life and no toxicities.

The question is whether our patients who are receiving IO/IO, or eventually only maintenance IO, or even IO/TKI and maintenance TKI therapy, can have better quality of life and long-term durable responses and continued remissions. It’s on a patient-by-patient basis, but our patients should be treated to the best of our ability to have quality of life and survival. We talked about the benefits and toxicities of IO therapies. How are the toxicities different from IO/TKIs?

Elan Diamond, MD: There are pretty significant differences in my opinion. Whenever I talk about it with my patients, I divide the toxicities of immunotherapy into a couple different categories. First, I talk about the less threatening toxicities, like pruritus, rash, joint aches, and endocrinopathies. Patients often develop hypothyroidism, which is usually fairly easily managed by adding Synthroid, or levothyroxine. Patients can be referred to endocrinology for skin manifestations. Usually, they’re easily managed with topical steroids. Diarrhea can be a little trickier. We’ll talk about that later. But there are potentially serious toxicities that I counsel my patients about, like pneumonitis, hepatitis, nephritis, neuritis, and hypophysitis. These can potentially be life-threatening and require steroids or infliximab, hospitalization, or even result in death. I counsel my patients regarding that. It’s something that requires an in-depth discussion.

Robert Alter, MD: Yes. I put the onus on the health care providers, the physicians and staff. We have to know what to look for and determine the toxicity itself. We have to grade it. Identifying it is just part of it. Our patients have to be educated enough to contact us when they aren’t in the office about potential toxicities they’re experiencing. Then we have to make an assessment on it. Do we hold the therapy? Do we have to use steroids? Do we discontinue therapy, as you had to do with your patient based on the hepatic toxicities? What judgment call do we have? Then recognizing that there are significant guidelines that we think will be beneficial.

I thought your approach to your patient, initiating CellCept relatively early, was an excellent choice. We have to be aware of how fast we can expect to have reverse of toxicities when using prednisone. You gave the patient 2 mg/kg. When we see no improvement at all, initiating the next form of therapy is quite important. Based on our exposures, we’re going to see more of these cases, unfortunately. The onus is on the health care providers to recognize these when we can, but grade 1 would the best time to do so.

[Let’s] talk about what we do when your patients get brain metastases. A lot of these patients have their initial presentation. IO therapies are relatively safe. The first thing we should probably do is treat the brain metastases. We have to look to SBRT [stereotactic body radiation therapy] and sometimes resections. But you have to gain control of the threat first as the patients heal. There are data that were recently presented on utilizing Cabometyx, or cabozantinib, and immunotherapy, both as single agents and in combination. It may even be beneficial in the first line of therapy as well. We don’t always see these patients, but the availability to incorporate options of therapy based on recent data that were presented is quite important as well.

Transcript edited for clarity.