Toni K. Choueiri, MD

Toni K. Choueiri, MD, medical director, International Strategic Initiatives, director, Lank Center for Genitourinary Oncology, director, Kidney Cancer Center, senior physician, at Dana-Farber Cancer Institute and the Jerome and Nancy Kohlberg chair and professor of Medicine, Harvard Medical School, discusses a key next step for using pembrolizumab (Keytruda) in the treatment of renal cell carcinoma (RCC).

In the KEYNOTE-564 clinical trial (NCT03142334), sustained clinical benefit was demonstrated with the use of adjuvant pembrolizumab in patients with post nephrectomy RCC.

Whereas pembrolizumab was used as an experimental agent in KEYNOTE-564, the phase 3 trial LITESPARK-022 (NCT05239728) trial will now use pembrolizumab in the control arm of LITESPARK-022. Patients will then be administered an experimental agent, belzutifan (Welireg).

For future work, we are using pembrolizumab as control. It is called LITESPARK-022. Pembrolizumab, which was used in the experimental of KEYNOTE-564 will be used in the control arm of LITESPARK-022. Then, we are adding an experimental agent called belzutifan, which is a HIF-2α inhibitor that showed efficacy in metastatic disease.

We're adding it to pembrolizumab in the adjuvant setting to see if we can improve on pembrolizumab efficacy because despite the benefit over placebo, there will be patients who will not respond to pembrolizumab. Also, despite adjuvant pembrolizumab, patients will experience cancer that will come back.

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Toni K. Choueiri, MD, discusses a key next step for using pembrolizumab in the treatment of renal cell carcinoma.


Next Steps for Treatment With Pembrolizumab in RCC

Toni K. Choueiri, MD, medical director of International Strategic Initiatives, director of the Lank Center for Genitourinary Oncology, senior physician and director of the Kidney Cancer Center at Dana-Farber Cancer Institute, and the Jerome and Nancy Kohlberg chair and professor of medicine at Harvard Medical School, discusses results from the KEYNOTE-564 (NCT03142334) efficacy analysis of adjuvant pembrolizumab (Keytruda) in renal cell carcinoma (RCC).

The double-blind phase 3 KEYNOTE-564 trial randomly assigned 994 patients with clear cell RCC to receive either pembrolizumab or placebo every 3 weeks following nephrectomy for up to 17 cycles. The primary end point was disease-free survival (DFS), which was reported at 24 months with a hazard ratio (HR) of 0.68 favoring pembrolizumab (95% CI, 0.53-0.87; 

Choueiri presented the results of key secondary end points at the 2022 American Society of Clinical Oncology Annual Meeting: time to first subsequent therapy (TFST), distant metastasis-free survival (DMFS), and time to second disease progression (PFS2). Overall survival data are not yet mature.

At 30.1-month median follow-up, there was an HR for DMFS of 0.63 favoring pembrolizumab (95% CI, 0.49-0.82). The TFST also favored pembrolizumab significantly, with a HR of 0.67 (95% CI, 0.50-0.90). The HR for PFS2 was 0.57 (95% CI, 0.39-0.85), showing longer time to disease progression after receiving subsequent therapy. The median was not reached for these end points, but they are consistent with the benefit to DFS.

 For DMFS, there were 140 events for placebo and 95 for pembrolizumab. There was a difference of 9% absolute difference in the metastases with an HR of 0.63, a 37% decrease in that specific risk. The TFST, in terms of drug therapy, radiation therapy, surgery, no matter what you look at, the events were higher in placebo-treated patients. The hazard ratio was 0.67, so [there was] a 33% decrease in the risk. And the time to second disease progression, also called PFS2, is the time from randomization to progression on next-line therapy or any cause of death; here also in addition the HR was 0.57, so [there was] a 43% decrease in their risk of having time to second disease progression [with pembrolizumab].

Toni K. Choueiri, MD, discusses results from the KEYNOTE-564 efficacy analysis of adjuvant pembrolizumab in renal cell carcinoma.

Adjuvant Pembrolizumab Improves Secondary Efficacy End Points in RCC

Toni Choueiri, MD, medical director, International Strategic Initiatives, director, Lank Center for Genitourinary Oncology, director, Kidney Cancer Center and senior physician at Dana-Farber Cancer Institute as well as the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School, discusses the phase 3 LITESPARK-022 (NCT05239728) study design.

 A Multicenter, Double-blind, Randomized Phase 3 Study to Compare the Efficacy and Safety of Belzutifan (MK-6482) Plus Pembrolizumab (MK-3475) Versus Placebo Plus Pembrolizumab, in the Adjuvant Treatment of Clear Cell Renal Cell Carcinoma (ccRCC) Post Nephrectomy (MK-6482-022) 

LITESPARK-022 follows the phase 3 KEYNOTE-564 clinical trial (NCT03142334), in which adjuvant pembrolizumab (Keytruda) or placebo was administered to patients with clear cell renal cell carcinoma (ccRCC). Results from the study showed that pembrolizumab significantly improved disease-free survival compared with placebo. The findings led the FDA to grant approval to pembrolizumab for the treatment of patients with RCC at intermediate-high or high risk for recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions.

Even with the success of pembrolizumab monotherapy, patients with risk of recurrence after definitive surgery require more effective treatment options. According to Choueiri, the addition of belzutifan (Welireg) to pembrolizumab will being tested in LITESPARK-022 based on its prior activity and tolerability in patients with ccRCC at risk for recurrence after definitive surgery.

Choueiri will be presenting the study design in full during the 2022 ASCO Annual Meeting.

 This is a large trial of around 1,600 patients with resected renal cell cancer. So, it follows the same structure N1 and M1 NED. It’s within 2 years, that's the difference [from] KEYNOTE-564, [it was] twice a year [and] we include also microscopic positive margin.

 Patients will be randomized to pembrolizumab for a year or pembrolizumab plus belzutifan, and also for the year the primary endpoint is disease-free survival with overall survival and safety as secondary endpoints. The study is going to be international open in multiple sites. The study already opened in a few sites. So, we're looking forward to improving the outcome of patients with kidney cancer with this study.

Choueiri TK, Bedke J, Karam JA, et al. LITESPARK-022: A phase 3 study of pembrolizumab + belzutifan as adjuvant treatment of clear cell renal cell carcinoma (ccRCC). 

. 2022;40 (suppl 16; abstr TPS4602). doi: 10.1200/JCO.2022.40.16_suppl.TPS4602

Articles

Toni K. Choueiri, MD, discusses the design of the phase 3 LITESPARK-022 study, which investigates adjuvant pembrolizumab in patients with clear cell renal cell carcinoma.

Adjuvant Pembrolizumab Plus Belzutifan in ccRCC

Toni Choueiri, MD, director Lank Center for Genitourinary Oncology, director, Kidney Cancer Center, and senior physician at Dana-Farber Cancer Institute as well as a Jerome and Nancy Kohlberg chair and professor of Medicine, Harvard Medical School, explains what led to the phase 3 COSMIC-313 clinical trial.

In COSMIC-313, the cabozantinib (Cabometyx; cabo) will be combined with the immunotherapy doublet nivolumab (Opdivo; nivo) and ipilimumab (Yervoy; ipi) to treat patients with previously untreated advanced or metastatic renal cell carcinoma.

The study is being conducted on 840 patients across 167 locations in North America, South America, Europe, Asia, and Oceania.

 First, the rationale of combining these 3 drugs ipilimumab the anti-CTLA 4 [agent] nivolumab, the PD-1 inhibitor and cabozantinib, the TKI that targets essentially VEGF receptor, but also targets other kinases involved in resistance, all of these drugs have approval in renal cell carcinoma. Cabozantinib [is approved] as a single agent in refractory disease, nivolumab as a single-agent in refractory disease, and cabozantinib as a first-line treatment in intermediate and poor risk [disease]. And ipilimumab’s role in renal cell cancer is first-line in combination with nivolumab. So naturally, you want to combine them all and there is some safety data that came from Dr. Apollo from the National Cancer Institute that showed that 3 of them could be combinable with cabozantinib at 40 milligrams a day.

 So, the rationale was to you know, look at the modern control arm and that will be nivolumab ipilimumab and cabozantinib. So, it's a phase 3 trial randomized to nivo/ipi/cabo versus nivo/ipi placebo with 1 to 1 randomization. The primary endpoint is progression-free survival and the usual suspects as secondary end points are response rate, safety, quality-of-life, and others.

Toni Choueiri, MD, explains what led to the phase 3 COSMIC-313 clinical trial.









Rationale for the Phase 3 COSMIC-313 Study in RCC

 Toni, you’re the leader of the COSMIC-313 study and also the belzutifan studies. Do you want to speak to those trials in terms of where they stand and what people should be watching for and anticipating with those studies? 

Thank you, Bob. COSMIC-313 is a study that asked the question, “Is 3 superior to 2?” We went through this lovely talk from 1 to 2, to perhaps a 3, where cabozantinib is going to be added to nivolumab and ipilimumab vs controlled nivolumab and ipilimumab and modern control finally, not sunitinib. The study just finished. Accrual about to wrap up was primary end point PFS [progression-free survival], secondary end point OS [overall survival] with over 800 patients. In intermediate and poor risk, it’s important to see if we can push survival more and push the CRs [complete responses] more. 

The second study you alluded to is a study with a totally new agent. Here, we’re not adding drugs that are already approved as single agent or combo. Belzutifan is an HIF2 inhibitor, and Tom in a very eloquent way discussed the biology of clear-cell RCC [renal cell carcinoma] initially. HIF2 is a transcription factor thought for a long time to be completely undruggable. HIF2 doesn’t have those small pockets where the drugs could go until recently, with elegant crystallographic work showing it could. We could have molecules and the second-generation molecule MK 6482 belzutifan showing a response rate and a refractory population of clear cell RCC of more than 50 patients. It’s mostly at 25% with quite tolerable adverse effects. You don’t have diarrhea, hypertension, and anemia, which is on target because you target downstream HIF2. 

Down regulating actually could be a pharmacodynamic biomarker with these drugs. Hypoxia was another, which is likely on target. Toxicity was HIF2 physiology. We’re taking this to a phase 3 trial post-VEGF inhibitor plus PD-1 inhibitor, belzutifan against everolimus later lines. And belzutifan is being introduced first line and second line with other studies that are being planned. The 1 thing about this treatment, as Tom mentioned, is that the time to respond seems to be not 2 to 3 months with single-agent TKI or less than 2 months with the combos, but it takes time—around 6, 6½ months with it. It doesn’t work quickly if you want an average. But it’s a nice set addition, and I hope this would be there. Data also in VHL [von Hippel–Lindau] syndrome associated clear-cell RCC, where we saw some image of blastoma is shrinking. Just yesterday or the day before, there was an FDA note about. VHL syndrome is scheduled, I believe in September. This is all good news for the renal cell cancer field.

This transcript has been edited for clarity.

Toni Choueiri, MD, closes with promising new studies that will impact metastatic clear-cell renal cell carcinoma therapeutics in the years to come. 

Promising Studies for the Future of Frontline mRCC

 I use both in my practice. I try to keep nivolumab-ipilimumab in the approved indication: intermediate and poor. I don’t use it in good risk. I don’t think it’s a mistake, because of the CR [complete response] rate, but I do not. That’s 1. In patients with sarcomatoid histology, it is the combo that should be the best standard because of the complete responses of 19% from CheckMate 214. That’s the second 1. The third 1, in patient with tumors that are not progressing rapidly, it was significant disease volume. Although we’ve seen responses with nivolumab-ipilimumab, I lean toward VEGF–TKI [tyrosine kinase inhibitor] rather than nivolumab-ipilimumab.

That’s an area where you’re going to get different opinions from all our friends and colleagues. I still think there’s an advantage. Especially with CRh [CR with partial hematologic recovery] and I/O [immuno-oncology] TKIs, the degree of shrinkage and the clinical benefit rates are excellent. You can always carve out patients that could be treated with just a single-agent TKI. I do have some of these patients in my practice, but the standard should be the default, should be I/O–TKI vs the other way around. Go into a favorable-risk situation if you made the decision to treat and not just monitor. The majority of people will make the decision to go forward with treatment that an I/O–TKI should be your default. Then you can carve out from them a smaller group that may benefit with just the TKI.

For instance, patients I just saw 2 types of patients today in clinic. One was an organ transplant patient. Obviously with a favorable-risk patient, you’re going to avoid your checkpoint inhibitor. Giving a single-agent TKI is reasonable. Another group that I’m leaning on, that we have the most data in the setting, is patients whose disease is predominantly in the remaining kidney. They’ve had a renal cell. They’ve lost a kidney from that. They have 1 kidney remaining, and it has tumors. And you’re channeling them like a patient with VHL [von Hippel–Lindau], and you’re trying to be careful and preserve kidney function. But sometimes we end up having to put them on a systemic therapy with the hope of making tumors they have smaller to allow a percutaneous intervention or just to stabilize things.

I’ve had patients on a single-agent VEGF TKI, and most of us are aware of the data coming out of Houston, Texas, in the past where that was somewhat instrumental. They’ve done a lot of that work on looking at the degree of shrinkage in the tumor from the TKIs. I’m sure I/O–TKIs do that at some level too. I’m just not as familiar with that degree of shrinkage. I’ll have those patients on a single agent. But that’s the minority. The default for me, mostly is I/O–TKI. If a select group seems to be ideally suited for just a single-agent VEGF inhibitor, then I would consider using traditional sunitinib or pazopanib.

I see a role for that, especially for the follow-up, and we understand the CLEAR data better. Right now, the agent with the longest follow-up and the most attractive 1 is the durability of the response that exists with the I/O–I/O. What drives that, the ipilimumab or not, no one knows. There are triplet studies planned that add ipilimumab into an I/O–TKI regimen. It will be interesting to see the benefits. I completely agree with Toni. I usually agree with Toni on most things. But the way he unpacked that is a reasonable approach, where you are using both. You can look at the way that the patient is presenting. Do they have time? The difference is the I/O–I/O combination is going to work in less people.

The clinical benefit rate is less. Do you have a patient who can afford to have I/O–I/O not work? As the volume of disease sets, it would allow that. If you have someone on the other end of the spectrum, where you really need to have an insured a rapid response, we see the data, and we didn’t talk about it at the time to response for lenvatinib-pembrolizumab. The cabozantinib-nivolumab is probably pretty quick. You can get these really symptomatic patients under control quickly.

The other thing that we also didn’t mention is expanding understanding about stopping it. How do you go about stopping an I/O–TKI vs the I/O–I/O? Some people would say it’s a disadvantage to be on an I/O–TKI and try to stop. Other people would say it’s an advantage because you could go off the I/O or the TKI and do it that way. There’s a lot that we have to understand about these drugs. If I was predicting that CLEAR study on the CheckMate 9ER trials to continue to evolve, where there’s evidence of durability of response, the more durable those responses are, the less I’d be inclined to use an I/O–I/O in those setting. But we don’t know that yet.

Both nivolumab + ipilimumab and lenvatinib + pembrolizumab TKI/IO combinations are discussed, with patient selection and appropriate use being the focus. 