IO/IO Versus IO/TKI Frontline Therapy for Intermediate-Risk RCC


During a Targeted Oncology case-based roundtable event, Moshe Ornstein, MD, MA, discussed the factors influencing the choice of frontline therapy for a patient with stage IV clear cell renal cell carcinoma whose risk status was intermediate.

Moshe Ornstein, MD, MA (Moderator)

Genitourinary Medical Oncologist

Cleveland Clinic Taussig Cancer Center

Cleveland, OH

Moshe Ornstein, MD, MA (Moderator)

Genitourinary Medical Oncologist

Cleveland Clinic Taussig Cancer Center

Cleveland, OH


A 59-year-old African-American woman presented with a left renal mass​. She underwent left radical nephrectomy in December 2019 revealing clear cell renal cell carcinoma (RCC)​. Nine months later, she developed nodules in both lungs, with mediastinal (35 × 38 mm), and retroperitoneal lymph nodes​. Lung biopsy confirmed stage IV RCC with clear-cell histology​. Her Karnofsky performance status was 90%​. Hemoglobin was 11.1 g/dL and ​corrected calcium, neutrophils, platelets were within normal limits. She was considered to have an International Metastatic RCC Database Consortium (IMDC) intermediate risk status.

A decision was made to initiate systemic therapy. What frontline therapy are you most likely to choose for this patient?

Axitinib + pembrolizumab
Cabozantinib + nivolumab
Lenvatinib + pembrolizumab
Nivolumab + ipilimumab

ADRIANA ALVAREZ, MD: There is a higher rate of patients in the intermediate and poor [risk group] in the [CheckMate 214 trial; NCT02231749] of ipilimumab [Yervoy] plus nivolumab [Opdivo]. So even though the numbers look worse, I think that the population may be a bit different.1,2 If you look at the CLEAR trial [NCT02811861], the poor prognosis percentage is 9% against 17% in the [CheckMate 214 trial], so I [chose] ipilimumab/nivolumab.1,3 One of the other things that I take into consideration as a community oncologist is…how easy it is to give immunotherapy compared with adding a TKI [tyrosine kinase inhibitor] because the adverse events [AEs] are significant. Not always, but we need to do a lot of hand holding in terms of how we’re going to set the dose, and the timing of starting therapy because of pre-authorization process. I think that all the options are very valid, and I usually present all the options to the patients. But, in practicality, I like the idea of the ipilimumab/nivolumab and I’m more familiar with it, too.

MOSHE ORNSTEIN, MD, MA: I think that’s a great point. First of all, when you look at [the 4 frontline trials,] there are different breakdowns for the different IMDC risk populations within the trial. Interestingly, the patients who have intermediate and poor risk tend to do better in these trials. I think that having a lower percentage of poor-risk patients is a disadvantage to that regimen because the favorable-risk patients do well almost regardless of what you give them. But I think the second point is accurate. All these regimens are 100% appropriate, but to choose one based on the ease of administration is completely reasonable.

I think we’ve been giving ipilimumab/nivolumab for the longest time of all these regimens because it was approved first. It has the longest follow-up, and when you look at the 5-year follow-up, approximately 50% of patients are still alive and approximately 30% are still progression-free.2 We’re comfortable giving it. It doesn’t require a TKI and [so] I give it as well.

ASHIS CHAKRABARTI, MD: I voted for lenvatinib [Lenvima] and pembrolizumab [Keytruda]. The reason behind that is…patients like to see a little quicker response, so adding a TKI always give you a little quicker response than just IO [immunotherapy] plus IO. I have used all 4 regimens. I had a bad experience with axitinib [Inlyta] and pembrolizumab. The patient had a hypertensive crisis and was admitted to the hospital with seizures and delusions. We still do not know whether he had a posterior reversible encephalopathy versus just a hypertensive crisis. We had to discontinue axitinib and he is doing fine on pembrolizumab alone. Lately I've been using cabozantinib [Cabometyx] or lenvatinib/pembrolizumab, and I’m very comfortable with the combinations. I just have to do little dose adjustments. I’m in a community practice, so…I look at the risk factors but I’m not bound by the risk factors [for choosing which] combination I use. So far, I have not got pushback from the insurance companies. I have a few patients on lenvatinib/pembrolizumab and I’m very comfortable with that combination; they’re all doing very well.

ORNSTEIN: Great. It’s interesting to hear how much personal experience plays a role in decision making. If somebody has a bad experience with, let’s say, cabozantinib and nivolumab—in the context of having 3 other regimens approved, they’re not going back to it. So it’s interesting to hear that you have that experience with axitinib/pembrolizumab and you tried other regimens [and you were] comfortable with them.

LARISA SCHWARTZMAN, MD: I’ve used axitinib/pembrolizumab and ipilimumab/nivolumab in this patient population, and both of these regimens have significant potential AEs. I have had patients on ipilimumab/nivolumab with significant AEs where I have to drop immunotherapy or at least 1 of the drugs, which made me a little bit reluctant to give it to patients whom I thought will do OK on axitinib and pembrolizumab. Having said that, I had patients with significant AEs with axitinib and had to either drop it or significantly dose reduce it. I use both of these regimens with caution, and the risk factors…but also clinical judgment is key. I use both of the regimens with excellent results and with patients who’ve had significant AEs.

ORNSTEIN: Is there a reason you would use axitinib/pembrolizumab over lenvatinib/pembrolizumab or cabozantinib/nivolumab or is it just you have the experience with axitinib/pembrolizumab?

SCHWARTZMAN: I definitely have much more experience with axitinib and pembrolizumab. For that very reason I don’t think I’ve ever use lenvatinib and pembrolizumab in metastatic RCC because I’m so much more familiar with the other regimens. I’ve used lenvatinib in other cancers and that can be a challenging drug, too.

TARAL PATEL, MD: The lenvatinib/pembrolizumab looked like the best [drug] for progression-free survival, but…[the trial] had…very few patients with poor prognostic factors.3 I think comparing cross trial is not a good idea, in my opinion, because they do not have the same population enrolled. Personal experience is more important than this trial.

ORNSTEIN: I think the note that I would caution on is when you look at the subgroup analyses in these trials, the benefit is more significant in the patients who have intermediate and poor risk. So, one would expect that for a trial that has less than 10% of patients with poor risk, the outcomes would be a little bit worse than the other trials.

BRIAN MULHERIN, MD: I found lenvatinib the most difficult of these TKIs to manage out of all the TKIs that we have here. I have tended to use lenvatinib/pembrolizumab in patients who are very fit and very symptomatic since the objective response rate seems to be a bit higher.3

BAIDEHI MAITI, MD: I have more experience with axitinib because at the Cleveland Clinic, we had the trial published by Brian Rini, MD, and we adopted it pretty fast.4 But, if somebody is at high cardiovascular risk, where TKIs would be very high risk, I have gone towards the IO/IO combination.

ORNSTEIN: Because we had a good chunk of patients on the trial and Dr Rini was here, we shifted to axitinib/pembrolizumab quickly when it got approved. And now there’s more of a smattering of different agents being used now that we have more approvals.


1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126

2. Motzer RJ, Tannir NM, McDermott DF, et al. Conditional survival and 5-year follow-up in CheckMate 214: First-line nivolumab + ipilimumab (N+I) versus sunitinib (S) in advanced renal cell carcinoma (aRCC). Ann Oncol. 2021;32(suppl_5):S678-S724. doi: 10.1016/annonc/annonc675

3. Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716

4. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116-1127. doi:10.1056/NEJMoa1816714

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