During a Targeted Oncology case-based roundtable event, Brian Rini, MD, discussed the choice of treatment options including dual immunotherapy and tyrosine kinase inhibitors plus immunotherapy for a patient with stage IV clear cell renal cell carcinoma.
Targeted OncologyTM: Would you discuss the use of immunotherapy (IO) doublets for patients with RCC?
RINI: I guess our answers [to the polling question] were all of the preferred regimens for intermediate- or poor-risk [patients]. And the IO [immunotherapy] doublets [are also] category 1 [National Comprehensive Cancer Network (NCCN) recommendations].1 I don’t use much of the NCCN guidelines in my practice per se because [the guidelines give] you 5 options. So that doesn’t necessarily help you narrow it down. I think what we want to do is dig into the data and talk about how you might choose a given regimen. Having said that, I think understanding your regimen and its nuances, and knowing when to dose reduce and hold drugs, as with any cancer regimen, may be more important than which one you pick. [I believe] that patients should get immune-based therapy upfront because that’s the only curative therapy. But aside from that, I think any of the 4 doublets are good choices.
There are 4 immune-based doublets [available in the frontline setting]: CheckMate 214’s [NCT02231749] ipilimumab [Yervoy]/nivolumab [Opdivo]2,3; then the 3 IO/tyrosine kinase inhibitor [TKI] doublets: axitinib [Inlyta]/pembrolizumab [Keytruda],4,5 cabozantinib [Cabometyx]/nivolumab,6,7 and lenvatinib [Lenvima]/pembrolizumab.8-10 The IMDC [International Metastatic RCC Database Consortium] risk breakdown [among] the trials is similar but not identical. Median follow-ups are obviously different, with ipilimumab/ nivolumab now having 5-year follow-up with the most recent publication, axitinib/pembrolizumab [as the] IO/TKI [with the longest follow-up], and then the others at 2 to 3 years.
There is consistent survival effect [with these doublets]. CheckMate 9ER [NCT03141177] has not been updated. When that’s updated I’m almost sure that [the hazard ratio for overall survival (OS)] will be [approximately] 0.76,7 but [that there will be] a remarkably consistent survival or relative survival advantage to the IO doublets vs sunitinib [Sutent], which was the control arm in all these trials.2-10
As we look at the most mature data, we see a median OS that’s creeping up on 6 years for the ipilimumab/nivolumab-treated patients and I think it will be broadly similar for the other regimens.2,3 I use this number in practice when I’m sitting with a new patient. They say, “How long am I going to live?” and with the normal caveats I say, “The longest follow-up data for our current regimen say that the average survival is nearly 5 years, and there are some patients who are cured,” and we’ll talk about that or at least about very long-term disease control. That 5-year update had 30% of patients who were progression free at 5 years.2 I tend to use those numbers because I think [they give hope] to patients. There’s a lot of misinformation about kidney cancer out there, and if you’re looking at old data, [they are] quite obviously not this hopeful. So I do use some of these numbers in practice.
I don’t know that [the landmarks] are that critical just looking across studies, and these are early landmarks, of course. Then you see the PFS [progression-free survival] advantages that have gotten better as the regimens have had data presented.2-10
One thing to note is we don’t have median PFS here, but it was in the 15-month range for axitinib/pembrolizumab4,5; I think 16, 17 months for cabozantinib/nivolumab.6,7 It was almost 2 years…for lenvatinib/pembrolizumab.8-10 And you see some of that reflected in the response rates, 55%, 60% vs 70%. Lenvatinib/pembrolizumab appears to have higher numbers, and whether that’s an actual difference in the regimen or just the vagaries of different trials, we don’t know. CR [complete response] rates are approximately 10% across regimens. Again, lenvatinib/pembrolizumab seems to stand out, and it’s unclear why. We’ll dig more into the cabozantinib/nivolumab and lenvatinib/pembrolizumab data. Last year, there were 2 regimens approved, cabozantinib/nivolumab and lenvatinib/pembrolizumab.11,12
Would you discuss the details of the CLEAR trial (NCT02811861)?
This patient [received] lenvatinib/pembrolizumab as part of a trial. Obviously it wasn’t approved in late 2019. [The CLEAR trial is] different from the other trials in that they had a lenvatinib/everolimus arm and I don’t know how many use that regimen in a refractory setting. I don’t use it much because of its toxicity, but the reason this happened to be included is it was a postmarketing requirement from the FDA. It was approved on the basis of a randomized phase 2 study [NCT01136733]. The FDA made them include it in this phase 3 [trial]. It doesn’t turn out to be that important in this trial, so we’ll mostly focus on the lenvatinib/pembrolizumab arm and the old standard of care, sunitinib.
All the trials that we’ll talk about are pretty darn similar. Upfront, clear-cell kidney cancer stratified by [location]—I guess this was MSKCC [Memorial Sloan Kettering Cancer Center] and the others are IMDC—and geographic region, and they’re all 600-, 800-patient trials.8 So they’re all broadly similar groups, comparing across trials.
In the PFS curves, you see a very impressive hazard ratio, the lowest on the board, 0.39 [95% CI, 0.32-0.49; P < .001], with a median of almost 2 years of PFS for lenvatinib/pembrolizumab.8
If I’m going to choose an IO/TKI regimen…which of the 3 would I choose? I was giving a lot of axitinib/pembrolizumab and still am. It’s very easy to give and has good data. When cabozantinib/nivolumab came along, I didn’t switch much. I think the efficacy data are similar. Then when lenvatinib/ pembrolizumab came along, I started to shift my practice a little bit and give lenvatinib/pembrolizumab. We’ll talk about toxicity, but it’s a more toxic regimen, in my opinion. I’m not sure it’s applicable to every patient but I have started to use this regimen a little more. You see lenvatinib/everolimus in the middle here. I don’t think [we] are using this as a frontline regimen. That’s why I’m sort of ignoring those results and those curves.
I think [investigators] wildly overinterpret forest plots. I usually just look at it and say yes, there’s a pretty consistent effect across subgroups here. There’s nothing that jumps out where it’s more or less effective in a subgroup.
There are some other prespecified analyses.8,13 There’s nothing here to me that jumps off the page. I don’t look at these and say, “I’m going to give it to this group or not to that group.” It’s a consistent effect, and to me that’s what you want and that’s why you do these analyses. Although again, [doctors] tend to pick their favorite one, and there are some hazard ratios crossing 1 and then they get all excited about it, but I think that’s not the right thing to do.
Do you believe there is an effect with this combination for sarcomatoid features?
[The population with sarcomatoid features] is so small. All of these trials allowed, but didn’t mandate, sarcomatoid features. You have a smattering. You also have to remember, to my knowledge none of this was centrally reviewed. A data coordinator checked the sarcomatoid box because a local pathologist thought they saw some, so I’m not sure it’s an accurate reflection of true sarcomatoid, but I think the numbers are too small.
What were the findings of the CLEAR trial?
This is the OS, and the median follow-up, I think, at this point was in the 24-month range. So I wouldn’t pay too much attention to the censored data at the end here, but you see a clean split in survival.8,10 This was the initial hazard ratio on the table [HR, 0.66; 95% CI, 0.49-0.88; P = .3].8 I presented the updated HR, which was 0.72 [95% CI, 0.55-0.93].10 Obviously the median has not been reached yet, but [there is] a pretty strong survival signal as was seen in the other trials. It was presented at a small kidney cancer meeting [in fall 2021].
[Regarding] the response rate numbers, 71% is the highest we’ve seen in any phase 3 trial in kidney cancer, same with the CR rate of 16%.8,9 I think the other thing about IO/TKI regimens in general, and especially with this regimen, is the rate of primary progression as well. It’s 1 out of 20 patients who gets put on this regimen and at the first scan are worse.
[Some] have interpreted this, as I do, to say if you have a patient with higher tumor burden, more critical symptomatic disease, then an IO/TKI regimen is probably better to start with than ipilimumab/nivolumab. [With] ipilimumab/nivolumab, it’s [approximately 20% of] patients who have progression as their primary response; it’s [approximately] 5% with the IO/TKI regimen. I think it’s generally accepted, even if [physicians] tend to choose different regimens, that the criteria [from] which you choose a regimen is reasonably valid.
What is the safety profile like with this regimen?
I mentioned lenvatinib/pembrolizumab as being a bit of a more toxic regimen. You can see 80% of patients with a grade 3 adverse event.8 These are treatment emergent, not necessarily treatment related. Most patients are going to have dose reductions, so 70%. Dosing of lenvatinib was 20 mg in this study, which is on the higher end, and many [patients] needed to be dose reduced. You can see some of the other numbers here but [they are] pretty typical for these regimens, although these numbers are on the higher end.
I like [the tornado plot] way of presenting toxicity more than a table. I think it’s visually more appealing and you can see the balance of toxicity of one regimen vs the other. I don’t think there are any surprises in terms of the type of toxicity. It’s pretty typical TKI/IO stuff. Clearly there’s more with the combination than with sunitinib, especially diarrhea, hypertension, thyroid disorders—which are probably immune-mediated, although both drugs can cause them—and grade 3 events. There’s definitely more toxicity on the lenvatinib/ pembrolizumab side and I think it’s one of the most toxic, albeit perhaps the most effective, IO/TKI regimens.
Can you discuss treatment of RCC with cabozantinib and nivolumab?
Let’s talk about cabozantinib/nivolumab now [from the CheckMate 9ER trial], the other regimen approved [approximately] a year ago.11 [It is] pretty similar to lenvatinib/ pembrolizumab. It’s a smaller trial, 650 patients. Obviously it had just the 2 arms, not the 3, but pretty similar stratification and end points.6,14
PFS curves show 16.6 months.6,15 Hazard ratio was 0.51 [95% CI, 0.41-0.64; P < .001]. I guess there was a follow-up with consistent results, 17 months and a hazard ratio of 0.52 [95% CI, 0.43-0.64]. This was from ASCO GU [2021 American Society of Clinical Oncology Genitourinary Cancers Symposium] and was pretty typical for the IO/TKI regimens. They separate at the first scan and stay split. One of the things we don’t know: I mentioned that for ipilimumab/ nivolumab at 5 years, 30% of patients are progression free. The IO/TKI data are too immature. I think it’s [approximately] 18.6 months follow-up. You can see still most patients are progression free, but we don’t know if these curves are going to go to zero or where they’re going to plateau, and I think that is an important consideration in choosing a regimen. We just don’t have mature data for the IO/TKI regimens yet.
Again, I think [there are] no great surprises [in the forest plot].6,14 I think they’re relatively consistent; in fact, I wouldn’t overinterpret some of these. All of these are overlapping in my opinion. I don’t view this as being very different.
This is survival, so again [let’s look] at the updated data from ASCO GU last year.6,15 Hazard ratio of 0.66 [95% CI, 0.50-0.97; P = .003]; again, I think this will get updated and this [hazard ratio] will probably be 0.7 like the other regimens. There’s a clear survival advantage to immune-based combos vs TKI monotherapy in upfront kidney cancer. That’s a consistent theme.
The response rate data, I think, are axitinib/pembrolizumab-like, so it doesn’t look as good as lenvatinib/pembrolizumab. We can argue why that is spurious or real, but not quite a 60% response rate [95% CI, 50.1%-61.2%], CR rate of 8%.14,15 Some of the updated numbers show a CR rate of 9.3%, pretty similar to the other regimens within the confidence interval. Median time to response was basically 12 weeks, which is when they did the first scan.
The duration of response for the IO/TKI regimens tended to be [approximately] 2 years.14,15 That doesn’t tell you everything. It doesn’t tell you the tail of the curve, it just tells you the median; but it tends to be [approximately] 2 years, for all these regimens.
How does the safety profile for cabozantinib/ nivolumab compare with that of lenvatinib/pembrolizumab?
Dose reductions are a little less [common with] the lenvatinib/pembrolizumab.14,15 I should have pointed this out; cabozantinib in the study was 40 mg, not 60 mg. Single-agent cabozantinib is 60 mg; in combination it was 40 mg. It could be that that lower dose of cabozantinib accounts for the lower response rate compared with lenvatinib/pembrolizumab. Maybe some of the TKI-responsive patients were underdosed. That’s just my hypothesis, but it allowed the regimen to be more tolerable. You can see the 56% dose reduction and the other numbers, and sunitinib was typical.
The tornado plot was balanced.14 This looks a little more balanced than what we saw with lenvatinib/pembrolizumab, with the notable exception of diarrhea, and some of the other numbers just a little bit worse for cabozantinib/nivolumab, including the grade 3 AEs. But it looks a little more balanced to me than lenvatinib/pembrolizumab. I’ve certainly given this regimen. I think it’s reasonably well tolerated especially because of the lower-dose cabozantinib.
1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 4.2022. Accessed March 24, 2022. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf
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. Albiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020;5(6):e001079. doi:10.1136/esmoopen-2020-001079
4. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): results from 42-month follow-up of KEYNOTE-426. J Clin Oncol. 2021;39(suppl 15):4500. doi:10.1200/JCO.2021.39.15_suppl.4500
5. Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020;21(12):1563-1573. doi:10.1016/S1470-2045(20)30436-8
6. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982
7. Apolo AB, Powles T, Burotto M, et al. Nivolumab plus cabozantinib (N+C) versus sunitinib (S) for advanced renal cell carcinoma (aRCC): outcomes by baseline disease characteristics in the phase 3 CheckMate 9ER trial. J Clin Oncol. 2021;39(suppl 15): 4553. doi:10.1200/JCO.2021.39.15_suppl.4553
8. 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
9. Grünwald V, Powles T, Kopyltsov E, et al. Analysis of the CLEAR study in patients (pts) with advanced renal cell carcinoma (RCC): depth of response and efficacy for selected subgroups in the lenvatinib (LEN) + pembrolizumab (PEMBRO) and sunitinib (SUN) treatment arms. J Clin Oncol. 2021;39(suppl 15):4560. doi:10.1200/JCO.2021.39.15_suppl.4560
10. Choueiri TK, Powles T, Porta C, et al. A phase 3 trial of lenvatinib plus pembrolizumab versus sunitinib as a first-line treatment for patients with advanced renal cell carcinoma: overall survival follow-up analysis (the CLEAR study). Abstract presented at: Kidney Cancer Research Summit; October 7-8, 2021; Philadelphia, PA.
11. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. FDA. January 22, 2021. Accessed March 24, 2022. https://bit.ly/3rIKriw
12. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. FDA. Updated August 11, 2021. Accessed March 24, 2022. https://bit.ly/3qNOVFB
13. Choueiri TK, Eto M, Kopyltsov E, et al. Phase III CLEAR trial in advanced renal cell carcinoma (aRCC): outcomes in subgroups and toxicity update. Ann Oncol. 2021;32(suppl 5):S678-S724. doi:10.1016/annonc/annonc675
14. Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase III CheckMate 9ER trial. Ann Oncol. 2020;31(suppl 4):S1142-S1215. doi:10.1016/annonc/annonc325
15. Motzer RJ, Choueiri TK, Powles T, et al. Nivolumab + cabozantinib (NIVO+CABO) versus sunitinib (SUN) for advanced renal cell carcinoma (aRCC): outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER. J Clin Oncol. 2021;39(suppl 6):308. doi:10.1200/JCO.2021.39.6_suppl.308