Tian Zhang, MD, MHS

Expert oncologists offer closing thoughts on emerging therapeutic strategies, unmet needs, and the future of kidney cancer treatment.

Future Outlook of Kidney Cancer Treatment

How I envision kidney cancer in the future is, that kidney cancer, if you think about it, is a cancer that starts in the kidney. But everybody diagnosed with kidney cancer has a unique kidney cancer, even though it's called clear cell. The analogy I use to show you the heterogeneity or how variable kidney cancer is this; we all know about COVID-19. COVID-19 is a virus that goes into the air, goes into our lungs, and there are different variants.

So the original variant and the alpha,…the beta, and the delta. Each variant is different from the first one. So, everybody diagnosed with kidney cancer, cancer started in their own body. Based upon the DNA of the kidney there was transformation into a cancer stage. So everybody with kidney cancer, everybody [with] clear cell kidney cancer has a unique variant. So, we need to get better … at [coming up] with a personalized treatment. If 70,000 to 80,000 people get diagnosed with kidney cancer in America, that's 70,000 to 80,000 different variants of kidney cancer.

How do I envision going forward? There are some really good provocative studies where you check the biopsy of the kidney cancer and they do genetic signatures, whether it is DNA of each person’s specific cancer DNA in the kidney cancer or the mRNA. Which is what the messenger RNA is. Which is something that kidney cancer becomes, it becomes a protein. And they're actually checking that to see what would be the best treatment for that specific patient.

For instance, we were talking about some patients that we give immunotherapy [IO], i.e., nivolumab and ipilimumab. For some patients I give lenvatinib and pembrolizumab, others I give cabozantinib and nivolumab, and then for others I give pembrolizumab and malaita, or axitinib. So in the future, what they're doing is this study right now, Dr Brian I. Rini [, MD,] is leading and it's called the OPTOC RCC [NCT05361720]. They're actually checking the mRNA of these person-specific cancers and they're trying to figure out which treatment is best based on that person's unique, clear-cell kidney cancer.

That's where it's going. It's going towards precision treatment, personalized treatment, where instead of having 4 different FDA [the United States Food and Drug Administration]-approved treatments, now we'll know which of those 4, is the best. Based upon that person's unique mRNA signature based on their clear-cell kidney cancer.

The other thing is, and this is very promising,[in] 2019, you know, the Nobel Prize [in Physiology or Medicine] was awarded to, a group of scientists, most notably from Dana-Farber. And what they found is a gene called the Von Hippel-Lindau gene. They found out the pathway that led to clear-cell kidney cancer, so patients tend to have this Von Hippel-Lindau mutation, and if they do, they're at a higher risk of developing kidney cancer. By going through this pathway, they found that the mechanism or the path is kind of blocked by an area called the HIF-2 alpha transcription factor.

So we have medications that are in clinical studies right now. They're called HIF-2 alpha transcription factor inhibitors, [such as] busudanulfan. And the studies look very promising. So this treatment is going to go up the line of treatment. In fact, we had this clinical study in many centers as well, where you have pembrolizumab and lenvatinib and we also had this third medication called busudanulfan, this HIF-2 alpha transcription factor. And that's going to be emerging for another treatment for kidney cancer.

The other thing that's moving forward in terms of kidney cancer is going to be the imaging. For instance, we have different types of imaging for cancers. We're very familiar with something called a PET scan. When we do a PET scan, it's called positron emission tomography. They inject a positron-emitting medication called FDG [fludeoxyglucose] into the blood, which binds to areas that are very active, i.e., cancer cells. So we use FTG PET for lung cancer and lymphoma. Recently we have something called PSMA PET. PSMA is also a PET scan. But instead of FTG, they use PSMA and PSMA stands for prosthetic specific membrane antigen, so specific for prostate cancer. So in the future, they're going to have a PET scan specifically for kidney cancer. And there was some emerging data at the ASCO [the American Society of Clinical Oncology yearly meeting] recently here in 2023.

In the future, we will be able to pick up cancer of the kidney much faster. You might ask, well, when do we need that? Our patients, who had kidney cancer, had the cancer removed with radical nephrectomy or total nephrectomy. They take everything out. So we have an FDA medication called pembrolizumab. And pembrolizumab is used for adjuvant treatment. That means after you get the cancer out, you give immunotherapy [IO] for up to 1 year and try to prevent the cancer from coming back. The problem with IO is that some of these patients might already be cured and we might be over treating these patients. In fact, studies have shown up to 10%, 1 out of 10 people that we give IO, can create a permanent side effect, such as a thyroid condition. I've had patients diagnosed with diabetes. I've had patients diagnosed with adrenal insufficiency. So in the future, what's going to happen is they're going to have this PET scan specifically for kidney cancer after they have surgery, and this will be able to pick up cancer to see if they truly need IO after surgery.

I think some of the unmet needs that remain are now that we have effective treatment strategies in advanced or metastatic kidney cancer, how do we optimally sequence these therapies? So we are finding good candidates for each combination and giving patients combinations in a sequence of each treatment is life-extending.

But how can we sequence so that we're finding different treatment resistance mechanisms and also trying to tailor our sequential therapies to conquer those treatment resistance paradigms? Are there other emerging agent treatment strategies? Absolutely. There are many agents, an early clinical investigation includes cellular therapies like CAR T cells [chimeric antigen receptor T cells], as well as novel IO targets like LAG3 [lymphocyte activation gene 3] and TIGIT [T-cell immunoreceptor with immunoglobulin and ITIM domain]. So a lot more to come, I think, for kidney cancer. And then finally, there is a whole HIF-2⍺ agent called busudanulfan, which is right around the corner in terms of its approval for advanced stages of kidney cancer. It's currently approved purely for patients with Von Hippel-Lindau syndrome. We're about to see a very large trial report out showing benefit in the refractory kidney cancer cohorts so I'm excited about that and about where it will bring busudanulfan in other stages of kidney cancer.

Thank you for joining me to learn about advanced kidney cancer. We hope you found this educated patient 

Transcript is AI-generated and edited for clarity and readability.

Videos

Tian Zhang, MD, MHS, provides an overview of the treatment of patients with non–clear cell renal cell carcinoma.

Treating Patients With Non–Clear Cell Renal Cell Carcinoma

Tian Zhang, MD, MHS: There are many different types of non–clear cell [NCC] kidney cancer, so often we're bucketing them together. They come in several different histology, the most common type of NCC is a type that we call papillary kidney cancer, which has now actually been separated into Met-driven or a second type called fumarate hydrated loss, or FH loss, papillary kidney cancer. These are very different in their presentations. They tend not to metastasize so much, but they can certainly metastasize in certain situations. There are also subtypes called chromophobe, collecting duct, and medullary subtypes as well as translocation. So all of these are different subtypes of NCC kidney cancer that we really do need to study more in depth.

For a long time, our trials for therapeutics were run as basket trials in which we looked at papillary chromophobe and collecting duct all together and we saw the signals for VEGF [vascular endothelial growth factor] blockade. Sunitinib and imatinib but we also saw a particular subset of patients with chromophobe, for example, respond to everolimus-based treatments. In the most or more recent era, we've seen more trials that are very specifically focused on papillary kidney cancer. There was the SAVOIR [NCT03091192], in France thinking about savolitinib targeting the Met amplification part of papillary kidney cancer vs sunitinib that found in effect for savolitinib. That has now generated another trial called SAMETA [NCT05043090] and that is adding durvalumab in immune therapy on top of savolitinib.

In the United States, we also ran a papillary kidney cancer trial from my colleague Dr [Sumanta] Pal [, MD,] and his colleagues and the SWOG [the Southwest Oncology Group] cooperative group called PAPMET [NCTNCT02761057]. This was initially a 4-cohort study. It became a 2-cohort study and ultimately found an effect of cabozantinib given for metastatic papillary cancer. Now, that has also set up a trial further for PAPMET called PAPMET2 [NCT05411081], where patients are randomized between cabozantinib vs cabozantinib with atezolizumab. And then finally, recently, we've had a couple of trials report out. There was a basket trial for NCC kidney cancer that was treated with lenvatinib and pembrolizumab. We did see some effects in both papillary chromophobe and unclassified as well as translocation. There were some partial responses [of approximately] 50% in each of these subtypes. So we are starting to come to a place where we have more and more options for each of these subtypes of NCC kidney cancer.

An overview of the treatment protocol for patients with advanced RCC who are receiving IO/TKI or IO/IO combination therapy.

Combination Immunotherapy for Treating Advanced Renal Cell Carcinoma

 The last combination immunotherapy [IO] is nivolumab and ipilimumab together. This can be a very tough regimen. And the reason is with the other combinations, you only had one IO. With this medication, you have a nivolumab, which is a PD, ie, an IO checkpoint inhibitor. Then you add a second checkpoint inhibitor called ipilimumab, which is a CTLA-4. Now, what's the problem and what's the benefit of this combination? The benefit is, of all 4 different combinations t we have right now, this tends to have the highest duration of response. Duration of response means that you give the treatment a year from now, maybe 2 years from now.

They did a 5-year update. If the patients respond, are they going to continue to respond? Some of the updated data have shown up to 25% to 30% of the patients who respond tend to respond. But the question is, at what price? Using an analogy, I played baseball when I was younger, in high school and middle school. And as a baseball player, you could always try to hit and get a home run. But if you try to home run every time your strikeout rate goes up. Some baseball players, choke up…and try to get singles and doubles and they have a higher average and more of a contact. So using that analogy, if you used nivolumab and ipilimumab, you have a higher chance of a homerun, i.e. complete response [CR], ie, duration of response. But the problem is if you strike out because if you do IO, it either works or it doesn't work. If the IO doesn't work, that means it could be 3 months of not receiving any treatment. If the patient doesn't receive any treatment for 3 months, the cancer can spread. So that's what I think about for my patients.

If I patient in front of me is very symptomatic and doesn't make it through the IO, they might not get the second treatment, so that's what I look at. Now, in terms of the complete response and the response rate, the response rate was around 40%, which is a little bit on the lower side. The progressive disease was 18% to 20%, which means 1 out of 5 people when they get this medication 3 months from now, the cancer is going to spread as opposed to cabozantinib-nivolumab, which was about 5% to 6%. And pembrolizumab-lenvatinib, which was also 5% to 6%. So those are the high-level overviews.

Now, what about the adverse effects of this dual checkpoint inhibitor, since you're really revving up the engine, and really revving up the IO in your body, you tend to have more IO adverse effects. So what are the IO adverse effects? The IO adverse effects tend to be more thyroid conditions, patients can end up with low thyroid. So we check the thyroid levels more often, maybe every 6 weeks. We had this condition called adrenal insufficiency. Adrenal insufficiency means right about our kidneys, we have these hormones called adrenal glands, and the adrenal glands release hormones such as cortisol to keep our blood pressure up and so on. More of these patients can have this adrenal insufficiency because the cortisol level is low.

As a physician, we have to put our thinking caps on. With low cortisol levels you look at the potassium level, is the blood pressure low, and whether the patient’s performance status is weaker. If I check a 9 am cortisol level and it’s low, I put them on hydrocortisone. So those at the high level for all of the different trials, there are benefits of the combination and there's also downsides of the combination. To recap, if I use the IO and a tyrosine kinase inhibitor [TKI], you have a much higher response rate, ie, 70%, for instance, for the lenvatinib, and pembrolizumab, 70% to 71% of the patients respond. If you use the nivolumab and ipilimumab, only 40% respond. But if they respond, they can have a long-term duration of response.

In terms of the adverse effects of nivolumab and ipilimumab, they tend to be harder at the beginning of the treatment. You have to look for thyroid conditions, diarrhea, fatigue, coughing, and adrenal insufficiency. In terms of the TKI and the IO combination, you have to think more about high blood pressure, diarrhea, and hand-foot disease, where their hands are feet are red. So that's how I customize which patients get which treatment.

 This is a great question for patients receiving treatments and how they are logistically delivered in our cancer center. For ipilimumab-nivolumab, this combination is a pure IO combination that's given IV [intravenously] once every 3 weeks over the course of 4 cycles. Followed by nivolumab on its own every 4 weeks or so, based on the patient and all of those are IV infusions. When we add in the anti-VEGF [vascular endothelial growth factor] component, these are often given in pill form. So these are oral administration that patients take at home. If it's axitinib, it's actually given twice a day. Cabozantinib and lenvatinib, are agents given once a day. But these are oral pills that patients would take at home.

On the management of toxicities, when we're thinking about these treatment effects and if patients experience adverse events, if it's a pure IO combination, we often will start with either topical steroids for rashes or oral steroids if it's diarrhea or elevated liver function or something else that's related all to the immune activation. If it's on the anti-VEGF treatments and more likely associated with the pills, we will often hold the pills to start. And then also try to treat the adverse effects.

If it's something like hypertension, for example, we will often be increasing the blood pressure medications or adding another blood pressure medications for patients that are already on them, and then also hoping to treat through some of those toxicities by continuing the anti-VEGF blockade. If it's something like really bad diarrhea, then holding the VEGF therapy while we get a clearer picture. Figuring out if it is from the VEGF therapy or the IO with a very low threshold to add systemic steroids to calm down the immune system. We've seen over these large trials that adding the steroids for treatment of the immune activation and the toxicities do not affect the overall efficacy of the treatments themselves so I think patients should feel that as we're managing and treating the toxicities, their cancer is still being treated. And [they should] not be afraid if they have toxicity to mention those to their doctors so that the care team can really help them manage the very severe toxicities that they're having.

Genitourinary oncologists discuss the safety and efficacy of IO/TKI and IO/IO combination therapies in advanced renal cell carcinoma.

Advanced RCC: Safety and Efficacy of IO/TKI Combination Therapies

In terms of front-line therapies, as we just mentioned, there are multiple immunotherapy [IO] combinations. When we look at ipilimumab-nivolumab, this is the pure immunotherapy accommodation from an efficacy standpoint; it does prolong overall survival [OS] when compared with sunitinib in the metastatic setting.

Our longest follow-up data for this combination comes from CheckMate 214 [NCT02231749], which was a phase 3 trial with a five-year follow-up now showing improved survival outcomes. The VEGF [anti-vascular endothelial growth factor] IO combinations also have shown improvements in OS and of note improvements in early progression-free survival [PFS] compared with sunitinib. We recently had data from ASCO [the American Society of Clinical Oncology Annual Meeting] 2023 from KEYNOTE-426 [NCT02853331], which was the axitinib with pembrolizumab combination, showing improved OS as well as improved PFS.

Then in the CLEAR trial [NCT02811861], from lenvatinib with pembrolizumab, we also saw both improved OS as well as improved PFS compared with sunitinib. And then finally, the cabozantinib and nivolumab combination also has shown both OS and PFS compared with sunitinib. When we talk about side effects, we absolutely have to think about the toxicities of these treatments when we’re deciding on the right combination to use.

And when we talk about these treatments, I often tell our patients that immunotherapy activates the immune system wherever [it is] active in the patient’s body. So on the skin, it can cause a rash; in the GI [gastrointestinal] tract, it can cause colitis or diarrhea; and then rarely would it cause inflammation of the liver, lungs, or kidney themselves. And finally, endocrinology, so toxicities affect the endocrine organs. The most common of [these] is thyroiditis or the toxicity of the thyroid, either high levels or low levels of thyroid hormone, and then also toxicities involving the pituitary-adrenal glands and pancreas.

We watch all of those hormone factors very carefully during the course of treatment. Now, when we add in the anti–blood vessel blockade, and our anti-VEGF therapies, these treatments often affect the cardiovascular system in particular. About 50% of patients will develop some elevated blood pressure, hypertension over baseline, and then also hand-foot syndrome or a painful rash on the palms of the hands in the soles of the feet. Mouth ulcers or taste changes are also pretty particular for the anti-VEGF component of these combinations. There are some overlapping toxicities, such as the diarrhea and the elevated liver function that we also keep an eye on and try to tease apart whether they’re due to the anti-VEGF blockade or if they’re due to the immunotherapy.

There are four landmark studies that I’m going to go into with detail. One was called the CLEAR study. The CLEAR study was a Phase 3 randomized study where patients [had] advanced renal cell and Stage 4 kidney cancer, and the medications were lenvatinib, which is a TKI [tyrosine kinase inhibitor] we talked about. And the dance partner was known as pembrolizumab, which is immunotherapy. The patients were randomized to either that treatment or the comparison arm, [which was] was sunitinib. There was a third arm of lenvatinib and everolimus. But, for the sake of the conversation, all of the trials used sunitinib as the comparison arm, so we’re just going to talk about sunitinib vs lenvatinib and pembrolizumab.

It was very striking…as a cancer doctor, the thing I look for is, how does the cancer respond? What is the response rate? If we have 100 people, how many of those patients are going to respond to treatment? The second thing I look at is, if I start them on medication three months from now, because typically that’s when we do a scan, what is the chance that the cancer is going to shrink, i.e., respond, or is cancer going to get worse? And the last thing is, are there any spots remaining? Let’s call it a complete response. A complete response means if you have some spots on the CT scan, you undergo treatment, and then on future CT scans, there are no spots. The CT scan is how we look for cancer.

In the CLEAR study, it had the highest response rate. Close to 70 to 71 out of 100 people responded to this medication, which is phenomenal in terms of a complete response; 17 out of 100 people had a complete response, which is striking. What’s the chance of cancer three months from now after you start this treatment? Are you going to have to give bad news to the patient? That is called progressive disease. Progressive disease means that you start a treatment and later on, three months from now, when you do the CAT scan, what’s the chance that you’re going to end up giving that patient bad news? That’s called progressive disease. In the CLEAR study, progressive disease was only 5%, which means three months from now, if you do this regimen, 19 out of 20 people that are on this regimen will either have cancer remaining the same size, getting smaller, or disappearing. So that really moved the needle for me.

Now, the problem with the CLEAR study and the lenvatinib and the pembrolizumab is at what price? This is where the kidney doctors and cancer doctors like myself really have to roll up our sleeves and keep an eye on things, because even though you might get a better response, you also have more toxicity. One of the things that I look for is high blood pressure. I always talk to my patients about high blood pressure on this medication, and make sure they have blood pressure cuffs at home. [Another one] is diarrhea. We have to know about any diarrhea. We have to treat the diarrhea. And we can also do a lower dose for the diarrhea. And then thyroid conditions are something I think about. So that’s the CLEAR study. It’s got the highest CR [complete response], the highest response rates and the lowest progressive disease. But you have to think about the toxicities because the patients, if you don’t treat them in a good fashion, you could end up with a lot of side effects.

The second study is called the KEYNOTE-426. The KEYNOTE-426 also uses the backbone of TKI with an immunotherapy. The TKI they used in this study was axitinib. The medication for the immunotherapy was called pembrolizumab. In this study, in the KEYNOTE-426, the response rate was very high. It was [about] 60%. The CR was in the 11% to 12% range. Progressive disease was in the 10% to 15% [range]. But the one thing about this combination is axitinib has the shortest half-life. So for our patients, it tends to be if you have any side effects of the medication, it’s much easier to control because if you hold that medication for three days and it’s caused by the TKI pill, the side effects would go away. So it’s much easier to control, but you do lose some of that CR and so on. Now it’s hard to compare studies, so I’ll just look at the terms of each study and not really compare.

In terms of the third combination called the CheckMate-9ER [NCT03141177]. The CheckMate-9ER is also composed of two treatments, one TKI, which is cabozantinib, and the second is nivolumab, which is a checkpoint inhibitor. Now, cabozantinib is like the Swiss Army knife of all the different TKIs. It is used for a lot of different diseases. It’s got a great response. In many of the studies, cabozantinib is treated at 60 milligrams per kilogram for kidney cancer, but in this study was 40 mg and nivolumab was every two to four weeks, depending upon the dosing of 240 and 480. In terms of the CR, it was in the 11% to 12% range. So, very respectable. In terms of progressive disease, it was [about] 67%. So that’s very low. In terms of response rate, it was in the 57% to 58% range.

Now, the one thing that I look at in terms of this combination for my patients is they have some really good data. It’s called the health quality of life data, reporting how our patients do with medication, fatigue, whether it is a hand-foot condition, where your hands are red or your feet are red. So the health-related quality of life of this combination is very impressive. This is something I think about for our patients when I’m thinking about the health-related quality of life.

Tian Zhang, MD, MHS

Future Outlook of Kidney Cancer Treatment

Treating Patients With Non–Clear Cell Renal Cell Carcinoma

Combination Immunotherapy for Treating Advanced Renal Cell Carcinoma

Advanced RCC: Safety and Efficacy of IO/TKI Combination Therapies

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