We’ve had a robust discussion, we’ve covered a lot of information. In our remaining time, let’s talk about the final question we always have to ask. As far as your patients in your practice and the signs that we see, what do you think is the unmet need? What do you believe are the future perspectives in renal cell cancer?

 That’s a great question. I alluded to some of these things when we talked about the clinical trial needs. As we discussed appropriate second-line therapies, what happens when we introduce triplet therapy up front? When is it appropriate to discontinue our therapies for these patients?

The other thing would be: What’s the ideal adjuvant therapy for high-risk renal cell carcinoma [RCC]? Should we incorporate neoadjuvant therapy into that setting? There’s the PROSPER RCC trial right now with neoadjuvant nivolumab, so all these things are evolving. But the ideal would be to have a patient on an excellent frontline therapy, and maybe triplet therapy will be that frontline therapy that creates long-term durable responses with high CR [complete response] rates. It may cure a proportion of patients, like you saw in the cytokine era in terms of the tail of the curve. Those are the unmet needs as far as I can tell.

The other thing would be biomarkers. You hear a lot about this at the academic conferences. What biomarkers can we use to select patients who might do well with IO [immunotherapy] or TKI [tyrosine kinase inhibitor] monotherapy? Can we use it as a measure to see who can discontinue therapy and who can’t? Can we use it as a measure similar to the Signatera [assay] data in bladder cancer where you can select patients who would require adjuvant therapy? Those are all things that we should be striving for, and a lot of research is being done in that area.

I’d love to add something, but you hit every point that I’d add. The triplet therapy biomarker question will be interesting too. Can we utilize the biomarkers and predict? Triplet therapy starts off and you end up with things like combination therapy. But starting with anti-HIF-alpha inhibitors, at what point do we utilize that as a single agent when we find small renal tumors? These are amazing questions. The science is there, and I marvel at the scientists who are asking these questions.

To that end, I want to thank Dr Diamond for this very insightful discussion. To our viewing audience, thank you for joining us. We hope you found this 

 program to be useful and valuable to the treatment of your patients with RCC. Thank you.

Videos

Drs Alter and Diamond muse about the unmet needs in advanced RCC treatment.

Unmet Needs in the Management of Advanced RCC

Earlier, I mentioned why I use cabozantinib-nivolumab. We had to utilize an IO [immunotherapy]/TKI [tyrosine kinase inhibitor], as Elan mentioned before. At what point do you realize you have to bring out more aggressive therapies? IO/IO would’ve been well tolerated in someone with brain metastases, so that would have been fine. I felt that he was having more symptomatic disease and that we had to become a lot more cognizant of symptom improvement in a shorter period of time. Of the 3 IO/TKI regimens that we commonly use, we believe it has an impact in improvement in function and performance status about 3 weeks quicker than IO/IO. But I definitely believe that when you have to utilize symptom relief much faster in someone who’s eligible to receive a TKI therapy, that’s something we have to be aware of. Despite the fact that we have many options, we have to come up with our core foundation about the solution.

With bone metastases, we always think that cabozantinib is the right drug, although it isn’t perfect with everyone with bone metastases. Ten years ago, a drug called XL184, which was being studied for prostate cancer, made bone lesions disappear. That was cabozantinib in its infancy. It isn’t FDA approved for prostate cancer, but this is something we’ve always felt that the bone lesions can respond well to. What are your thoughts on cabozantinib-nivolumab? You must have used it. How do you find the tolerability? Where do you find the ideal patient in your settings?

 I agree with you 100%. I select patients with bone and brain metastases to treat with cabozantinib-nivolumab. In my experience, it’s a fairly well-tolerated regimen. It’s a little better tolerated than lenvatinib-pembrolizumab. The adverse reactions are fairly similar but less severe. But if you look at the CheckMate 9ER data, 56% of patients required dose reductions in that study. But I’d use it in the exact same way you have.

As you had in your first case, your patient was on maintenance therapy before he had to come off, and I have my gentleman on maintenance therapy at this point. I don’t know which drug to stop. Is it wrong to stop any of them? The patient has been enduring therapy well. I can’t tell you which drug made the most success. He’s tolerating the combination well. At this juncture, my approach isn’t to stop his therapy. He hasn’t had a clear toxicity to [either drug] that makes me feel we have to [stop].

All of our patients present differently when it comes down to it. You have to have these conversations with the patients. There are patients who come in and hear what they think they hear. Let’s say you give them IO/IO, 4 cycles of ipilimumab-nivolumab. You say, “We’ll do the scan afterward.” You do the scan, and they say “OK, am I done?” You say, “No, now we have more,” but they don’t hear everything. You have to always discuss the goals of care and the plan with your patients. The reinforcement helps them a little. Some patients get it and some patients can’t wait.

Then we have to have a conversation with some patients who wish to stop therapy. Do you stop one drug? Which drug do you stop? I don’t have enough experience to tell you that it’s easy to stop one. If they have TKI toxicity, that’s very easy. I’d stop that. If you have any concerns that they’re living far away and can’t come in as often, then stopping the IV [intravenous] therapy may be beneficial. But we’re going to see this over the course of many years, and we have to talk to our patients about how we have to adjust our therapies, our management.

 I agree 100%. Maybe the best guidance with this would be the pembrolizumab-axitinib data from KEYNOTE-426 where they continued the pembrolizumab for 2 years and then stopped it and just continued the TKI. They had a lot of patients with sustained response who did well after that. That’s the best level 1 evidence that I’m aware of regarding what to stop. But you’re correct, these are major clinical problems that need to be answered.

A discussion on the role of the cabozantinib and nivolumab regimen in the treatment of advanced RCC.

Cabozantinib + Nivolumab Regimen in the Treatment of Advanced RCC

 I’m going to go to the third case, and we’ll get a little more detailed about it. Maybe we’ll use a different regimen that we haven’t seen before. I had a 56-year-old gentleman. In his medical history you see hypertension, hyperlipidemia, and gastritis. Past surgeries included cholecystectomy, right knee replacement, and cataracts. Medications at home [were Percocet, Norvasc, Lipitor, and senna]. This person was social and had 2 children. He had a 30 pack-year history of smoking, and stopped smoking 6 months earlier. He was a plumber with exposures to the fumes and toxins that a plumber is exposed to. He denied alcohol use and had a family history significant for a paternal grandfather who had gastric cancer.

He presented in March 2021. He had a 2-month complaint of right side back and hip pain. He was limping when he presented. Initially, he went to his chiropractor, who did manipulations for 2 weeks. The chiropractor was unsuccessful, but he swore by his chiropractor. [He went to] the ED [emergency department], and you see his laboratory parameters there. He was a little anemic. His white blood cell count was a little up. His platelets were fine. He was hypercalcemic, so we were given a sense that he was defining his risk categorization.

He had a CT [computed tomography] scan that revealed a 12-by-9.8-by-12-cm mass that pretty much encompassed his entire left kidney and extended locally to the posterior abdominal wall with infiltration and fluid in the posterior perinephric space. He had a 10-by-6.5-cm right iliac bone lesion, which explained the limp, and extraosseous extension into the gluteus musculature. A chest x-ray revealed bilobar pulmonary masses measuring just under an inch. An MRI [magnetic resonance imaging] of the abdomen confirmed the renal mass, 13.4 cm, endophytically extending into the left renal sinus collecting system. As a staging workup in an asymptomatic patient, we did an MRI of the brain and saw several lesions there. There was nominal edema but localized metastases.

Completing the bone workup, his bone scan showed lytic destruction in the right iliac bones. It was surprising that that was his only lesion. That was the area where we biopsied the right iliac bone, which was positive for clear cell renal cell carcinoma. You see the IHC [immunohistochemistry] stains there [positive for EMA, PAX-8, vimentin, CAM5.2]. Then we started to focus on symptom management first. He wasn’t having hematuria. We were cognizant of his symptoms of bone pain. He had asymptomatic brain metastases, so we put out the fire a little first. We made his symptomatic limp become asymptomatic. He went to rehabilitation afterward and did extraordinarily well. He received SBRT [stereotactic body radiation therapy] for his lesions. We put him on Zometa monthly a year ago. We felt that we were taking care of the periphery of his disease, but we had to take care of his central core.

We decided to give him cabozantinib-nivolumab. At this juncture last year, lenvatinib wasn’t FDA approved, though we did have some experience using lenvatinib as a combination therapy in the first line. It still wasn’t FDA approved at that point. We did have data looking at single-agent nivolumab for brain metastases. We had data on cabozantinib for brain metastases. We waited the appropriate time between the initiation of cabozantinib after completion of SBRT. We waited maybe 6 weeks before we started cabozantinib after he finished SBRT. I’m not going to go into detail, but you see the left renal mass initially had shrinkage. It was up to 13 cm, and after 2 months of therapy, it went down to 9.6 cm. Two months later, it went down to 7.9 cm, and he had decrease in the size of the pulmonary lesions.

Now it was November. He’d been on therapy for 7 months. His renal lesion appeared to be stagnant. It was present but not growing. His pulmonary lesions still appeared to be decreasing mildly. His functional performance status had improved significantly. He was very independent and driving himself. Previously, he was coming in a wheelchair. The question we had to address is: Are we tapped out with therapy? Are we doing the best that we can, or should we try a little more?

Rather than adding more drugs, we decided to do a cytoreductive nephrectomy. We took out the renal lesion, which measured 7.5 cm and was grade 2. We don’t have a renal biopsy from before. I can’t tell you if we downgraded the disease. We definitely shrunk the disease. It’s clear cell renal cell carcinoma with extensive necrosis. It still reinvaded the renal sinus and abutted the peritoneal fat. The margins were negative. There was no vascular invasion, and we didn’t suspect any on his initial presentation. He’s had an unremarkable postoperative course.

He still has his pulmonary lesions. His bone lesions seem to be inactive. He had a bone scan that showed no new lesions and faint activity on previous lesions. His right iliac bone isn’t active anymore. We changed his nivolumab to every 4 weeks compared with every 2 weeks, the initial dosage. He still has some toxicity from cabozantinib. We haven’t required dose reductions. We keep him at 40 mg/m2. We’re utilizing urea cream for his grade 1 hand-foot syndrome. He was in the office 2 weeks ago. He’s about to propose to his girlfriend, so hopefully she’s not hearing this.

Robert Alter, MD, presents the patient profile of a 56-year-old man with clear cell renal cell carcinoma presenting with hip and leg pain.

Patient Profile Presentation: A 56-Year-Old Man with Clear Cell RCC

 You’re in a hub that’s a major referral center. You receive patients from urologists, which is extraordinary. Are community oncologists referring patients to you? Do they feel as if they know what’s going on, and there’s enough going on through NCCN [National Comprehensive Cancer Network], that they have a sense that they can take care of this? Or do they still realize the value of an expert like yourself who sees this and can treat these patients better?

 Community oncologists do refer patients, and we co-manage patients very often. I’m fairly impressed with the penetration in the community that the data regarding these combination therapies have had. But these are very challenging regimens. The best way to know how to manage these, especially immune-related toxicities, is by experience. When you see these patients and toxicities over and over again, you develop a facile way of managing them. That’s very important. That would be an indication—especially if you have fairly limited experience—to refer patients [to], or at least for co-management with, an academic center or an organization like ours, New Jersey Urology.

The other important thing is to refer patients for clinical trials because there’s a major unmet need in renal cell carcinoma, especially in the second-line setting, as Dr Alter alluded to. We have a plethora of wonderful first-line therapies. But when we come to the second line, we don’t have a good sense of what to do. Cabozantinib in the METEOR trial [NCT01865747] has been effective. At ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] this year, there was a real-world study of cabozantinib post I/O [immuno-oncology]–I/O or post I/O–TKI [tyrosine kinase inhibitor] called CABOSEQ, which should show reasonable response rates. But these need to be evaluated in prospective randomized phase 3 clinical trials, and the only way we can do that is if we have patients for it.

We also need to answer the questions that Dr Alter posed. What do you do after adjuvant pembrolizumab? What’s the ideal adjuvant therapy? If you have patients with renal cell carcinoma, I strongly urge you to refer them for appropriate clinical trials.

 Right. Speaking of which, our next dilemma isn’t going to be which combination therapy we should put our patients on. When they present the COSMIC-313 [NCT03937219] data, which is probably going to be presented at ESMO [European Society for Medical Oncology Congress], the question will be: What do you do with triple therapy?

You’re treating patients with ipilimumab-nivolumab and cabozantinib as a first-line therapy. I don’t have any inside track [but] I suspect it’s going to be impressive data, taking 2 significant active regimens and combining them. They’re asking the next question. When you take belzutifan, which we see is going to be active in second line, what happens when you combine it with first-line therapy? There’s an ongoing study looking at lenvatinib-pembrolizumab with belzutifan or quavonlimab, which is a CTLA-4 inhibitor, and then vs lenvatinib-pembrolizumab. We now have more ingredients to play with and we’re going to ask the next question, so we’re probably going to have 3 drugs up front as therapy. What do we use as second-line therapy? What happens when you need to take 4 drugs years later?

It’s great for patients. You have to be able to recognize it’s about the tolerability of the regimen. You have to still think the way we did archaically 5 years ago. It’s about sequencing therapy. You can’t get more excited about using as many drugs [as possible]. It’s not about that first mile. It’s about the duration of the patient’s therapy.

Elan Diamond, MD, describes when and how often community oncologists refer patients with suspected advanced renal cell carcinoma to his practice.

Advanced RCC Patient Referrals from Community Oncologists

 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?

 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.

 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?

 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.

 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.

Oncologists review the IO/IO combination regimens available for treatment of advanced RCC and discuss patient selection for treatment with nivolumab and ipilimumab.

Nivolumab + Ipilimumab Combination Regimen for Advanced RCC

 Let’s go to our second case. That was a great discussion. Thank you, Elan. This is your case. Take it from here.

 All right, thank you so much. This is a 70-year-old man with very good performance status and a history of hypertension and hyperlipidemia. He’s a never smoker and denied occupational exposures. The patient had a rather odd presentation, with left testicular swelling. He had a physical examination that revealed scrotal edema. Laboratory evaluation at that time showed anemia and mild hypercalcemia. He had an elevated ANC [absolute neutrophil count] and platelet count. The patient underwent a CT urogram. The left kidney is diffusely infiltrated by tumor, which they measured 9 x 9.6 x 11 cm. There was a filling defect in the left renal vein. There was a mass that was inseparable from the left adrenal gland measuring 3.9 x 5.2 x 8.8 cm. He had left para-aortic lymphadenopathy and a smaller left para-aortic lymph node measuring 2.3 cm. You can see the image on the right.

The patient underwent a CT scan of his chest. This is 2 different views of that CT scan showing extensive mediastinal and hilar lymphadenopathy. The patient also had an amorphous 3.8-cm mass in the right upper lobe, which you can appreciate on the images on the right. Before I got involved in this case, the patient underwent a CT-guided biopsy of his renal mass, which showed that it was morphologically and immunohistochemically compatible with clear cell renal cell carcinoma [RCC], and the patient had tumor necrosis present. The diagnosis here is stage IV clear cell renal cell carcinoma. He’s IMDC [International Metastatic RCC Database Consortium] poor risk on the basis of his presentation with metastatic disease and his laboratory parameters as noted before.

I sat with the patient and went over his treatment options. They were what Dr Alter mentioned. In addition, the patient could have been treated with ipilimumab and nivolumab. The patient ultimately chose to be started on lenvatinib and pembrolizumab. That was after reviewing the response rates and CR [complete response] rates. That was very attractive to the patient.

Several weeks after starting therapy, the patient presented to the emergency department with gross hematuria. I was consulted. Knowing that lenvatinib can cause bleeding as a potential adverse effect, I held the lenvatinib for 2 weeks, and then I dose reduced him. The patient continued on therapy and then had a 3-month restaging CT and bone scan, showing a very nice response. You can see on these images to the right that his lung findings essentially disappeared, including that right upper lobe lesion, and then his mediastinal adenopathy also essentially resolved. On the abdominal portion, you can see that the renal mass is significantly smaller and has almost disappeared. The only residual disease is that small renal mass in the lower pole, and a small adrenal metastasis. The patient had a great response.

At cycle 7 of lenvatinib and pembrolizumab, the patient developed hemoptysis and watery diarrhea. I held his lenvatinib again, and this turned out to be a permanent discontinuation. I’ll explain why. But the patient’s diarrhea and hemoptysis resolved. Imaging of the chest after cycle 7 didn’t show any recurrence of his pulmonary finding, so there’s no lesion to explain the development of hemoptysis.

While off of lenvatinib, the patient then developed jaundice and was noted to have a total bilirubin of 17.94 mg/dL. His alkaline phosphatase was 2423 IU/L [international units per liter]. His AST [aspartate aminotransferase] and ALT [alanine aminotransferase] were elevated. The patient had imaging, including an MRCP [magnetic resonance cholangiopancreatography], which showed echogenic liver architecture and no evidence of biliary ductal dilatation. I consulted hepatology and GI [gastroenterology specialists]. Pembrolizumab was discontinued. After discussion with our consultants, we believed that this was a grade 4 toxicity from immunotherapy, and the patient was started on prednisone 2 mg/kg per day. He didn’t improve after 3 days and therefore was started on CellCept 1000 mg [twice a day]. After 4 months of therapy—this patient required prolonged immunosuppressive therapy—his liver function test normalized. The patient remains with a very good partial response off of therapy several months later

 Wow, yes. That’s exactly what we see with our patients. They come off therapy, and we just hope that the toxicity, which isn’t technically a biomarker, can predict a better response. As they come off therapy, can they sustain that response? It’s toxic, but remarkable.

Dr Elan Diamond presents the patient profile of a 70-year-old man with stage IV clear cell renal cell carcinoma.

Patient Profile Presentation: A 70-Year-Old Man with Stage 4 Clear Cell RCC

 The bigger question that we always think about is sequencing therapy. We always think about what we have next for our patients. When we had I/O [immuno-oncology] therapy, the sequencing was easy. We gave them a TKI [tyrosine kinase inhibitor]. In the old days, when we had only TKIs, our limited choices were that when you failed a TKI, you went on an mTOR [inhibitor]. If you failed on an mTOR, you went on a TKI. Then you bring in a new mechanism of I/O therapy.

The purists would always say that I/O–I/O was good. Now when we’ve treated with up-front I/O–TKI therapy, the question I always get asked is, “What do you treat when they progress?” It’s so hard to know. There aren’t any first-line data that have good evidence at this point. Level 1 evidence has yet to be proven. But if you progress after receiving first-line lenvatinib-pembrolizumab, you’re probably going to receive Cabometyx [cabozantinib] at this point. I wouldn’t use single-agent mTOR therapy. It’s interesting, because I’ve always used lenvatinib-everolimus as a second- or third-line measure on patients who failed a TKI. I don’t think we have that opportunity. If you fail lenvatinib-pembrolizumab, we can’t use lenvatinib-everolimus as your next therapy. It’s going to be a sequence of therapies.

Eventually, we’re going to have to incorporate tivozanib into this conversation. Tivozanib is a regimen we’re going to have to start playing with. Belzutifan is another regimen coming. It’s FDA approved in patients who have 

 mutations, but soon we’re going to have enough data. Michael Atkins presented data at ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] 2 years ago, and that’s going to result in more approval. That’s the question. If you use a great regimen up front with an I/O–TKI, what do you use in the second line? Now that we have KEYNOTE-564 data presented that look at adjuvant immunotherapy, what happens to our patients if they progress at that point? What do you think? How would you take care of those patients?

 The answer is unknown at this point because this is uncharted territory. These are data that came out very recently. We haven’t had the chance to have clinical experience or conduct clinical trials in this disease space. When I imagine what I’d do in that setting, it would depend on when the patient progressed following treatment with pembrolizumab.

For example, I have a patient I’m treating with adjuvant pembrolizumab. He had T3 N1 clear cell renal cell carcinoma, got a couple of cycles of pembrolizumab, and then developed omental metastatic disease. This is a patient who clearly is refractory to the I/O mechanism. This is someone whom I focus on TKI-based therapy, with either cabozantinib or lenvatinib-everolimus. But then you may have a patient who has recurred 2 or 3 years later, and the question is whether you can rechallenge them with an I/O–I/O or an I/O–TKI combination. That’s unknown at this point, but it’s very tempting based on a priori reasoning. That’s probably what I’d do in that situation.

Experts discuss how they sequence I/O–TKI treatments for advanced renal cell carcinoma.

Sequencing Therapies for Advanced RCC

 Elan, what toxicity did you see with the I/O [immuno-oncology]–TKIs [tyrosine kinase inhibitors]? What do you commonly see? How do you manage them?

 Toxicities are quite common. For example, in the CLEAR trial, there was a 70% discontinuation rate due to toxicities. The major challenge with toxicities with I/O–TKI combinations is that it’s often hard to discern what’s being caused by the TKI and what’s being caused by the immunotherapy. A guide would be that TKI adverse effects are usually earlier in the treatment course and tend to be a little more low grade. The I/O adverse effects after several weeks tend to be a little more fulminant and can cause systemic symptoms. But the potential adverse effects can include diarrhea, constipation, nausea, vomiting, and stomatitis.

In the CLEAR trial, the diarrhea took about 28 weeks to develop. That was in a later analysis. It can cause fatigue, weight loss, dysphonia, rash on the hands and the feet, hypothyroidism, and hypertension. There were also severe adverse reactions, like cardiac dysfunction, severe hypertension, osteonecrosis of the jaw, and fistula formation. There’s quite a bit to think about as a practicing oncologist using these agents. In general, if the patients have grade 2 or 3 toxicity from TKIs, I’ll discontinue until resolution of those symptoms. If it’s grade 1, I’ll restart at a dose reduction. If I think the adverse reaction is being caused by the immunotherapy, it depends on the grade. There was an excellent guide in the NCCN [National Comprehensive Cancer Network] Guidelines under the supportive care section on managing immune-related adverse events. We’ll talk more about that later in the discussion.

 With this patient, I followed the guidelines. Based on the clinical trial, I went from 20 mg down to 14 mg. He did well but still has grade 1 fatigue. The diarrhea pretty much resolved but still requires Lomotil. I’m not interested in dose escalating. We have him at a good place.

After a while, the toxicities can be very much a deterrent to the patient benefiting from therapy or having to hold or discontinue therapy, physically and mentally. A lot of times, they come into a better dosing schedule with better tolerability. The durability and positive reinforcement about less toxicity gives the patient a lot more desire to remain on therapy. We believe that sometimes efficacy is driven by potency, so we should be trying to give as much of the drug as possible and that we’d see better efficacy. But when you see many clinical trials, maintaining patients on therapy is better than having patients come off therapy. The efficacy is driven by durability rather than trying to push toxicity.

Brian Rini had great data using axitinib and dose escalating based on hypertension, which was proven to be a biomarker. But that’s the only time I’d recommend dose escalation short of reintroducing the therapy back to the patient. We should be more cognizant of the patient and not necessarily the dosing. Then there’s the question of what to do. Do I keep them on therapy? Do I discontinue the TKI and possibly improve his quality of life? Is it the TKI that got him the benefit? Is it the maintenance of immunotherapy? These are questions we don’t know the answers to.

The studies had patients receive pembrolizumab for 2 years. I’ll probably follow suit on that trial. As long as he doesn’t have TKI toxicities, we’ll probably maintain him at 14-mg doses of lenvatinib. The result being what it is, he’s in no rush to change his regimen. It’s proven to be successful. I won’t even call it superstition. I call it data. He has data that prove the benefit of what he’s having. But there’s that big concern about chronic TKI toxicity. Every I/O–TKI study that we talked about talks about health-related quality-of-life factors, when it comes down to it. Dr [Robert] Motzer presented something at ASCO [American Society of Clinical Oncology Annual Meeting] in June 2021. Do you want to talk about that?

 Absolutely. The presentation by Dr Motzer was an analysis of the secondary end point of the CLEAR trial, which was a study of lenvatinib-pembrolizumab or lenvatinib-everolimus vs sunitinib in the frontline setting for metastatic clear cell renal cell carcinoma. In this analysis, they used 3 measures of quality of life in longitudinal analysis and in analysis of time to deterioration. They found that for lenvatinib-pembrolizumab vs sunitinib, scores were very similar or there was an improvement from baseline, and this was in physical functioning dyspnea or constipation. There was also an improvement in median time to deterioration for patients who were treated with lenvatinib-pembrolizumab vs sunitinib.

The same thing wasn’t true for lenvatinib-everolimus vs sunitinib. The scores were better for sunitinib, which isn’t surprising for people who use that regimen, especially in the second-line setting. The question is how to apply this in our practice. It reassures me that lenvatinib-pembrolizumab is going to be a fairly tolerated regimen in general. The thing to understand is that this was compared with sunitinib, which is a fairly toxic drug in and of itself that we don’t really use anymore. We also have to take into account our clinical experience. In my experience, and I’m sure yours as well, lenvatinib has its toxicities and challenges in terms of management. But in general, it’s something that we can safely give our patients.

 Right. That’s exactly what you have to think. I always tell my patients, “It’s not about the first mile. It’s about the whole marathon.”

Elan Diamond, MD, explains toxicities commonly seen with I/O–TKI combination regimens, how to manage them, and how to discuss toxicities with patients with advanced renal cell carcinoma.

Toxicities with IO-TKI Combination Regimens for Advanced RCC and Their Management

 We’re going to start by discussing the therapy options that I thought about using. We’re blessed to have several options of first-line systemic therapy utilizing an I/O [immuno-oncology]–TKI [tyrosine kinase inhibitor] regimen. As far as risk categorizations, it’s approved and favorable in intermediate- and poor-risk [disease], so one doesn’t stand out more than the other. With the opportunity of using lenvatinib and pembrolizumab, our options of using axitinib and pembrolizumab or cabozantinib and nivolumab have all been discussed with the patient, as I discuss with all my patients.

When you look at the data, there’s a very good line in regard to efficacy. The response rates range from 55% to 71%, and the CR [complete response] rates range from 11% to 16%. They’re durable, and the tolerability seems to be relatively equal. We see 2 separate TKI toxicities that we’ve learned to manage, and then the I/O toxicities that we manage. But when we have these opportunities to give these patients systemic therapy, it depends on the patient and habit forming. We have the benefit of using 3 good options of I/O-TKI therapy.

Elan, what factors do you consider when you choose among these 3 regimens?

 Thank you for that question. There are multiple factors that we look at when choosing initial therapy for metastatic clear cell renal cell carcinoma [RCC]. First, I consider the IMDC [International Metastatic RCC Database Consortium] risk criteria. For patients who have intermediate or high risk, I tend to choose agents such as lenvatinib and pembrolizumab or cabozantinib and nivolumab. Another option would be I/O–I/O combination, with nivolumab and ipilimumab. For favorable-risk disease, I’d shy away from the I/O–I/O combination because that showed limited efficacy in this patient population. Also, pembrolizumab-axitinib in the 5-year follow-up data from KEYNOTE-426 showed fairly limited efficacy in patients with favorable-risk disease. If I have patients in that category, I’ll choose a single-agent TKI or lenvatinib-pembrolizumab or cabozantinib-nivolumab.

The other things that I think about are disease burden and need for immediate response. The response rates for lenvatinib-pembrolizumab and nivolumab-cabozantinib are quite high, and patients achieve a fairly rapid response. If you have a patient who is symptomatic and has a high disease burden, these would be fairly good choices, especially over something like an I/O-I/O combination. In this case, Dr Alter was looking for a response and appropriately chose lenvatinib and pembrolizumab.

There are other factors that are important to consider, including performance status and medical comorbidities. If you have a patient with poor performance status, you may want to be thinking about using a single-agent I/O. There were very impressive data from the phase 2 trial HCRN GU16-260, which showed that nivolumab in the front line had very impressive response rates. You may also want to consider pembrolizumab and axitinib. Although axitinib has similar toxicity to the other TKIs, it has a rather short half-life, so if you need to discontinue therapy, those symptoms related to the TKI will likely respond very quickly.

The other thing I think about is medical comorbidities. If patients have poorly controlled autoimmune disease, renal transplantation, or any other organ transplantation for that matter, it may make me think twice about using an immunotherapy drug in those patients. For the TKI, patients with uncontrolled hypertension, prior osteonecrosis of the jaw, bleeding disorders, or history of venous thromboembolism would also make me think twice. There are a number of other factors, but that’s a good start.

 That’s a great start. I’ll jump exactly on what you said. My conclusion was exactly what you said. This patient had a need to go on a therapy that would give an immediate response. Having used lenvatinib in the past, I’ve seen that patients use lenvatinib in combination with an mTOR, and we can talk about that at a later time. I definitely felt his performance status was good. I chose between either the cabozantinib-nivolumab or the lenvatinib-pembrolizumab. I felt as if his ability to tolerate a TKI was going to be an important factor in what I decide, and I needed an immediate response. The concern was the contralateral kidney, or the solitary kidney, which we wanted to avoid a potential concern for dialysis. He tolerated it well.

When you talk about dosing, the CLEAR trial looked at patients receiving lenvatinib at 20 mg daily and pembrolizumab at standard dose compared with sunitinib 50 mg daily for 28 days on and 14 days off. There was a question of whether this is an appropriate way of starting lenvatinib in regard to a dose of 20 mg, when we were very familiar with how to use it when it was combined with everolimus, where lenvatinib was started at an 18-mg dose. Even on that clinical trial, they saw toxicity that required dose reduction. I chose to use 20 mg. It’s the way the clinical trial was written, and my approach has always been that data are data. The patient required dose reductions, which was common. Approximately 65% or 67% of the patients required dose reductions on that lenvatinib clinical trial. We have to pace ourselves with our patients. We can’t believe we have to make them as toxic as they might be. But I did require response in him, and he tolerated the medicines well.

A review of the first-line I/O-TKI combination regimens available for advanced RCC and selecting the right patients and dose for treatment with lenvatinib and pembrolizumab.

Front-Line Lenvatinib + Pembrolizumab Combination Regimens for Advanced RCC: Selecting Patients and Dose

 program titled “Improving Outcomes in Advanced RCC: Translating Evidence to Clinical Practice.” I’m Robert Alter, the co-division chief of the division of the genitourinary oncology at the John Theurer Cancer Center, HMH [Hackensack Meridian Health], at Hackensack University Medical Center in Hackensack, New Jersey. I’m joined by my colleague and friend Dr Elan Diamond. I’m going to ask Elan to introduce himself.

 My name is Elan Diamond. I’m the medical director of urologic oncology for New Jersey Urology, a Summit Health affiliate.

 Elan, welcome, and thank you for joining me. We’re going to discuss recent advances in the treatment of advanced RCC [renal cell carcinoma] and their impact on clinical practice. We’ll present 3 real-world patient cases and discuss our treatment approaches to illustrate how we incorporate recent data in our practice. Let’s get started on our first topic.

The first case I’m going to present is of a patient we actively see. This is a 56-year-old gentleman. Borderline hypertension is his only past medical history. Diverticulitis in the past required 1 hospitalization, but he never had a recurrence. He had anal fistula repair, which was incidental. He takes Rapaflo at home. He has a good social history, with 3 children. He’s married and is a high school principal not far from our center. He drinks alcohol socially and denies cigarette use. We see a remote family history: his mother had a smoking history and lung cancer.

In September 2017, he had an episode of painless gross hematuria, initially pinkish, and wasn’t quite sure what it was. It turned red the following day, and he presented himself to his primary care physician. He immediately underwent a CT scan of the abdomen and pelvis, which revealed a right lower pole renal mass extending into the central sinus fat and involving the right renal pelvis, extended exophytically to the right perinephric space, and infiltration of the right perinephric fat measuring 9 by 8.6 by 6.8 cm. He was met by the urologist and underwent a robot-assisted right radical nephrectomy 9 days later, with pathology revealing an 8.5-cm clear cell renal cell carcinoma, Fuhrman nuclear grade 3—this goes back to the Fuhrman grades—with tumor involving the right renal sinus fat, right renal pelvis, and no evidence of lymphovascular invasion or a perinephric fat invasion, all negative margins. By size and extension, this is a T3 disease.

He was seen by me the following month. Based on his age and the aggressiveness of the disease, we discussed the S-TRAC data of adjuvant Sutent, which is FDA approved. The patient was hesitant after having a lengthy conversation about toxicities, and my hesitation was the efficacy, long-term data, and overall survival, so we both chose not to do it. My approach is always to educate patients about opportunities that exist. We both agreed that this wasn’t the right therapy for them. The following month, we did a formal staging, and he had pulmonary micronodules with the right hilar lymph node measuring 1.5 by 0.9 cm in size. The patient was totally asymptomatic. We continued scans. Those nodules and the lymph node were unchanged in size over the course of the next year and a half. Then because of COVID-19 and his limitations of accessibility, he was lost to follow-up.

Three and a half years later, he presented to his primary care physician complaining of left flank pain, a 15-lb weight loss, mild anorexia, and mild dyspnea on exertion. Outpatient CT scan revealed a 1.7-by-1.1-cm right hilar lymph node and a 2.5-cm exophytically enhancing lesion in the left interpolar kidney, which is now the contralateral side. The MRI confirmed a 2.7-by-2.5-cm solid lesion, partially exophytic, from the posterior medial interpolar kidney. However, this region extends to involve the renal pelvis with a vascular invasion extending into the IVC [inferior vena cava].

The patient was subsequently seen by his urologist with the hopes of having the patient go for partial nephrectomy and thrombectomy. No guarantees were offered, with the potential complication of more extensive resection leading to a radical nephrectomy or a decrease in kidney function with the possibility of needing to go for hemodialysis. The patient re-presented to myself, and options of therapy were discussed. I recommended that if we were going to initiate therapy, [our best option was] the recent FDA approval of the pembrolizumab-lenvatinib data. We discussed and applied the patient to receive lenvatinib at 20 mg/m2 as well as pembrolizumab 200 mg IV [intravenously] every 3 weeks as based on the CLEAR clinical trial.

Scans performed 2 months after initiation of therapy showed the left renal mass decreasing in size. It went from 2.7 cm to 1.8 cm. Vascular invasion was unchanged. The right hilar adenopathy resolved. He had toxicities of grade 2 to 3 diarrhea, which was controlled by Lomotil. He had mild fatigue. Because of the toxicity, lenvatinib was held for 1 week and then reduced to 14 mg daily, and the patient had much better tolerance and continued system therapy.

We’re going to go through the scans of the next few studies. In November 2021, the 2.7-cm lesion that went to 1.8 cm was down to 0.6 cm. Vascular extension has resolved, and scans performed 3 weeks ago revealed no evidence of disease. The renal mass has resolved as well. Not listed is that we scanned the chest again and the hilar adenopathy has resolved, so the patient has achieved a complete remission. As of last week, he received his 13th dose of pembrolizumab. He maintains himself on lenvatinib at 14 mg. Grade 1 fatigue is still being monitored. The patient is fully functional at work and still wearing a mask.

Robert Alter, MD, presents the patient profile of a 56-year-old man with metastatic clear cell renal cell carcinoma presenting with chromaturia.

Elan Diamond, MD

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