Role of Risk Stratification in Treatment Planning for mRCC

Transcript: Daniel J. George, MD: For the non-clear cell, they saw similar or even higher response rates with papillae, which suggest that pembrolizumab alone has some real activity in this frontline setting. Those 2 studies there, to me, sort of support the rationale for somebody who’s maybe a little bit frail and maybe has other issues we’re concerned about in terms of long-term tolerance of combination therapy—what do you think about starting with monotherapy and then adding in additional treatment as needed?

Chung-Han Lee, MD, PhD: Yes, I think that’s very reasonable for the favorable-risk people; they do quite well. And because they do quite well, I think what we really want to take into consideration is how much toxicity are we planning on giving them, and we really have to balance that. All of us know that these are not medications without potential adverse effects, and when we add more drugs we often do add more adverse effects related to this.

Nizar M. Tannir, MD, FACP: And cost.

Chung-Han Lee, MD, PhD: And cost, yeah, of course.

Nizar M. Tannir, MD, FACP: The other scenario, you mentioned the patient who has contraindication to receiving a TKI, but there are patients who have contraindication to receiving an immune checkpoint inhibitor—somebody with a history of Guillain-Barré syndrome in the past or who has a neuromuscular disorder or an autoimmune disorder—if they have favorable risk, I would be very comfortable in treating them with just a TKI. I think those are the scenarios where I don’t think we should completely eliminate the role of monotherapy in favorable-risk patients in first line.

Robert S. Alter, MD: Right. I actually had a patient who presented a few weeks ago. A patient who actually has a favorable risk with sarcomatoid variant. Around 90% of his tumor is sarcomatoid.

Yet he met all criteria for favorable risk, and we had been very disappointed with our therapies with favorable risk. Brian Rini, MD, presented an abstract at the American Society of Clinical Oncology 2019 Genitourinary Cancers Symposium that’s looking at the Keytruda, actually the KEYNOTE-426 clinical trial, which looks at patients with sarcomatoid variants. And again to that endpoint, they also met, and compared again was pembrolizumab and axitinib versus sunitinib. Those patients actually meeting their primary endpoints of overall survival and progression-free survival with a very strong hazard ratio of 0.52 and 0.58 again, utilizing the combination in favorable-risk patients, but sarcomatoid variants.

I think this is an area in which we are evolving. I think we’re going to see these patients, unfortunately, but if we see them early enough and we have the ability to give them aggressive therapy in combination therapy, I think we may have difficulty abiding by the guidelines of the NCCN [National Comprehensive Cancer Network].

Daniel J. George, MD: The thing to know about this risk stratification is that it’s not a perfect system. I mean, it’s going to give us a general idea of favorable, intermediate, and poor, but there are factors outside those independent prognostic factors that could also influence outcome. And sarcomatoid is 1 of them. Nizar, what’s your take on that? You have some additional data on this and other factors.

Nizar M. Tannir, MD, FACP: Sure. I was going to mention that in addition to the KEYNOTE-426 that Brian Rini presented about the sarcomatoid, we looked at it in CheckMate 214 as well, and it was also impressive. We looked at it because the vast majority of patients whose sarcomatoid have usually intermediate risk or poor risk rather than favorable risk.

In that 1096-patient phase III trial, CheckMate 214, we identified retrospectively 60 patients treated with nivolumab-ipilimumab who had intermediate risk and poor risk who also had sarcomatoid in their pathology. Either the primary tumor from nephrectomy specimen or a biopsy. And the CR [complete response] rate was 18%.

Daniel J. George, MD: The CR rate.

Nizar M. Tannir, MD, FACP: The CR rate was 18%, and an objective response rate of 57% versus 0% with sunitinib, and a 19% objective response rate with sunitinib in that cohort. The median overall survival was 31 months with nivolumab-ipilimumab, versus 13 months with sunitinib. I think results that are really impressive.

Now I looked at the abstract we’ll see tomorrow in the presentation, on the KEYNOTE-426 and the sarcomatoid cohort, but the CR rate was 10% with pembrolizumab-axitinib in the sarcomatoid, and it was 18% with nivolumab-ipilimumab. I think there is something to the biology that patients with intermediate risk and poor risk who have these aggressive histologies, the high-grade sarcomatoid, rhabdoid, have this phenotype that really responds well to the immune chain. These are the inflamed tumors, if you will, that respond really well to the immune checkpoint inhibitors.

And so, again, it was a small number of patients, but of the 60 who had sarcomatoid intermediate risk and poor risk, about 30% had PD-L1 [programmed death-ligand 1]—positive as well. The response rate was 70%, and the CR rate was 30% in that small cohort of poor risk [and] intermediate risk, with sarcomatoid and PD-L1–positive tumors. Seventy percent response rate, 30% CR rate. I mean, that’s really impressive. I think there is value to look at the tumor type, and then that obviously influences my selection of first-line therapy for these patients.

Daniel J. George, MD: I think that’s right. We were going to not necessarily use PD-L1 status routinely on everybody, but there will be certain context where I think it could be helpful in saying, how aggressive do you want to be with that patient if they’ve got even a greater likelihood of this really durable affect, in this time off therapy as a goal? These are the kinds of patients who might be on the fence, who you might push toward trying a regimen like that because of this additional information. They’re good things to consider in addition to your risk stratification.

Transcript Edited for Clarity