During a Targeted Oncology Case-Based Peer Perspective virtual event, Amir Mortazavi, MD andMoshe Ornstein, MD, MA discussed available treatment regimen for a patient with clear cell renal cell carcinoma and sarcomatoid features.
During a Targeted Oncology Case-Based Peer Perspective virtual event, Amir Mortazavi, MD, an associate Professor—Clinical, at The Ohio State University Comprehensive Cancer Center—Arthur G. James Cancer Hospital and Richard J. Solove Research Institute in Columbus, OH discussed available treatment regimen for a patient with clear cell renal cell carcinoma (RCC) and sarcomatoid features.
Mortazavi is joined by Moshe Ornstein, MD, MA, a Genitourinary medical oncologist at the Taussig Cancer Institute of Cleveland Clinic in Cleveland, OH in the discussion.
Targeted OncologyTM: How do you assess patient risk, and does the risk status influence your treatment decision?
MORTAZAVI: We may not document [the risk status], but I think it’s important when that’s truly involved in your decision-making for different reasons.
There is a software available [to assess International Metastatic RCC Database Consortium (IMDC) risk that’s] basically calculation, and then you plug in [the risk factors]. Obviously, when there [are] none, then it’s good risk. If it’s 1 or 2 [factors], that’s intermediate risk. Three or more [factors] make it poor risk, which helps us decide, at least based on the evidence, which treatment to pick. But there are always other factors playing into that decision-making.
When a patient comes in with advanced disease, like in this case, what additional work-up would you do for the patient?
MORTAZAVI: Technically, if you go by the guidelines—guidelines are made by us, of course, mostly based on the data—the bone scan is indicated if you’re suspicious for bone mass either [due to] hypercalcemia, elevated alkaline phosphatase with your bone pain, or MRI or CT findings suggestive of bone mass. Then brain MRI is also indicative if there are symptoms, and that’s in most guidelines. Personally, if I have somebody with poor- risk bulky disease who is very symptomatic, before I start treatment, I do a brain MRI as long as the insurance doesn’t push back. I find you can handle many lower-volume asymptomatic brain masses with stereotactic brain radiotherapy, such as gamma knife, easily enough.
ORNSTEIN: I do the same. In general, I’ll for sure get brain imaging, and I get bone imaging if it’s clinically indicated.
What are your thoughts on the treatment options given in this poll?
MORTAZAVI: So if you look at the NCCN [National Comprehensive Cancer Network] guidelines for poor to intermediate, all 3 choices are acceptable options.1 Ipilimumab [Yervoy]/nivolumab [Opdivo] and axitinib [Inlyta]/pembrolizumab [Keytruda] have category 1 [recommendations] based on the data, and cabozantinib [Cabometyx] is an option, especially in a patient for whom you would consent to using immunotherapy.
ORNSTEIN: I’m always interested to hear how people make these decisions because, personally, I struggle with them. Part of the reason is 10 to 15 years ago, the median survival for patients with kidney cancer, metastatic RCC specifically, was probably less than 2 years. You look at the numerous options or numerous positive trials that we’ve had recently, including pembrolizumab and axitinib, avelumab [Bavencio] and axitinib, ipilimumab and nivolumab, cabozantinib, and a couple new trials that have not yet led to approvals but for which we are starting to have some data, and what’s interesting in all these trials [is the] OS [overall survival]. Pembrolizumab and axitinib demonstrated a hazard ratio for death of 0.53, and that was a statistically significant value [P < .0001]. Axitinib and avelumab were not statistically significant in terms of survival [HR, 0.78; P =.14], but ipilimumab and nivolumab were [HR, 0.68; P < .001].2 Cabozantinib versus sunitinib [Sutent] is not yet reported in terms of the P value, but the HR was 0.8, and the confidence interval crossed 1.3
The nivolumab/cabozantinib is not [yet] approved. But all these other agents are approved in the frontline setting. And I think part of the discussion should revolve around this: When these agents are approved, how do we decide between giving somebody an immuno-oncology [IO]/tyrosine kinase inhibitor [TKI]–based regimen versus an IO-IO regimen versus monotherapy with a TKI?
The objective response rates [ORRs] seem to be the highest at 59% for pembrolizumab and axitinib and definitely higher in the immunotherapy-based regimens as opposed to with the single-agent TKIs. You’ll see different ranges of median follow-ups when the data were first reported. But there are a variety of options— the 2 most common ones being axitinib and pembrolizumab, and nivolumab and ipilimumab.
I normally give axitinib and pembrolizumab. Although for patients with sarcomatoid features, I have a little bit more of a debate.
What trial led to the approval of pembrolizumab/ axitinib as one of these recommended frontline treatment options?
ORNSTEIN: The KEYNOTE-426 trial [NCT02853331] was a phase 3 randomized trial that included patients of all IMDC risk groups. They were treatment naïve and were randomized to the combination of axitinib and pembrolizumab versus sunitinib, which at the time was really the standard of care in the frontline setting.4 Importantly, the dual primary end points were OS and progression-free survival [PFS] in the intent-to-treat [ITT] population. In some of the other trials, it was in the PD-L1–positive population or just in intermediate and poor risk. But KEYNOTE-426 was unique in the ITT populations across the board, all risk groups, and looked at OS and PFS, not based on PD-L1 staining, just all-comers, so fairly representative of what we see in the clinic.
The baseline characteristics [are] again representative of what we see in clinic, maybe a slightly higher percentage of favorable- risk patients. In clinic, we probably see 15% to 20% favorable-risk patients. And in this trial, in both arms, it was approximately 31%. The rest were intermediate and poor risk. The breakdown of PD-L1 based on the combined positive score [was about 60% with PD-L1 positivity]. And most of the patients in both arms have prior nephrectomies. We’ll highlight the sarcomatoid features in 17% or 18% of the patients essentially in both arms, and that’ll play a role as we look at some of the data.
Updated data at about 23-month minimum follow-up [show] the OS in the ITT population [median not reached with pembrolizumab/axitinib vs 35.7 months with sunitinib]—this was the primary end point—[had] an HR of 0.68 and a P value of less than .001. I think what’s important to take a look at, and this is one way I describe treatment decisions to patients, is looking at landmark OS. In other words, being able to tell patients, “Yes, with this combination in the trial and the attempt to treat all-comers, 90% of patients were alive at 12 months; 74% of patients were alive at 24 months.” It also helps me as I decide between treatment options, given we have so many these days. I’m getting a sense of those landmark analyses and seeing which regimens are potentially superior based on that.
The axitinib and pembrolizumab curves separated fairly early and seemed to be leveling off at the 33- to 36-month mark, demonstrating the promise of immunotherapy in the setting of having sustained responses over the course of time.
The other coprimary end point was the PFS in the ITT population [15.4 months with pembrolizumab/axitinib vs 11.1 months with sunitinib]—and again, significant values with an HR of 0.71 favoring axitinib and pembrolizumab. It’s a 24-month mark—in other words, at 2 years on therapy, 38% of patients had not yet had progression.
We don’t like comparing across trials, but we have to do that if we’re going to get any sense of how we decide on one regimen versus another. So if you look at the ORR for the patients on pembrolizumab/axitinib versus those patients on sunitinib, you see 60.2% for pembrolizumab/axitinib and 39.9% for sunitinib. I want to highlight the complete response [CR] rate [of 8.8% vs 3.0%, respectively]. The medium duration of response with this follow-up was 23.5 months [vs 15.9 months].
One concern you have when you see a patient with newly diagnosed [disease] is you want to get benefit ideally added to that initial regimen. So you have your 2 features favoring pembrolizumab/axitinib, and one of them is the response rate where 60% of patients responded in the trial. The other thing I want to draw your attention to is the best response of disease progression in only 11.3% of the patients. In terms of saying with confidence that you’re going to give patients a regimen and [that] 90% or so, at the very least, won’t have tumor progression at the time of their first scans, that’s an important thing to be able to tell patients.
We discussed a lot about the IMDC risk groups. So taking a deeper [look], because the patient in this case has intermediate/poor-risk metastatic RCC, at the OS Kaplan-Meier curve [by intermediate/poor risk]—that landmark OS at 24 months of 69% still being alive in the pembrolizumab/axitinib arm. If you also look at the separation between the curves and what at least appears to be a leveling off or the tail of the curve, which if it is at that mark around 33 to 36 months, that would be impressive. There was a separation in the intermediate- and poor-risk group for PFS, as well.
Would this treatment choice be a good option for this patient and why?
So the reason the sarcomatoid feature was thrown into the question stem was just to reinforce the idea that although sarcomatoid features in metastatic RCC are historically extremely difficult to treat and carry with them a very poor prognosis, it seems that with all regimens that are IO based in the treatment of sarcomatoid RCC, the responses have been incredibly impressive. Looking at the responses for patients on pembrolizumab/ axitinib if they had sarcomatoid features, the response rate was 59%, which was close to double the sunitinib arm.5 I’m telling you that although, historically, perhaps these patients would have done worse compared to the patients who did not have sarcomatoid features, using axitinib and pembrolizumab is certainly reasonable in patients with sarcomatoid features. In the waterfall plot [for patients with sarcomatoid features], looking at the overwhelming majority of patients, almost all of them had at least some tumor burden shrinkage.
The IO-based regimens for sarcomatoid features work, and you can see that in looking at the PFS for patients with sarcomatoid features treated with axitinib and pembrolizumab [not reached vs 8.4 months with sunitinib; HR, 0.54].
Which factors help you choose one regimen over the other?
ORNSTEIN: For me, when I see a patient who has a heavy disease burden—maybe has some symptoms, has some fevers, chills, is just systemically sick from the disease—the question I might ask is not necessarily how the patient is going to do in the long run but maybe more about which one of these combinations is most likely to give me a response right now. I think, for that patient, I would at least consider an IO-based regimen but with a TKI because the response rates are higher in those patients. The CR, maybe for a patient who needs a response right now, might be a bit less important. You might counter that the sarcomatoid features lead you to give full IO.
MORTAZAVI: It’s going to come down to each individual. So we’re not even going to talk about other comorbidities, how concerned you are about the immunotherapy part of adverse effects [AEs], or TKI AEs, and if somebody has some underlying autoimmune [disease], do you want to go with the pembrolizumab/axitinib? All [of these things] play a factor. What matters to the patient at the time of treatment is to get a response because the patient is very symptomatic; the tumors are getting to wider organs or going to drop the lung by blocking airway or encasing great vessels. All those play a factor like, “Do I need a response right now, or am I thinking more down the road?” I do the exact same approach. For that reason, I favor IO-based therapy. For the sarcomatoid features, we can talk within nivolumab/ipilimumab versus pembrolizumab/ axitinib. Just for that I think they both have a close response rate and also CRs, maybe nivolumab/ipilimumab a little more CR again, not to really do a cross comparison. That’s my approach to the treatment of frontline metastatic RCC.
What is the toxicity profile like for the pembrolizumab/ axitinib regimen compared with that of sunitinib?
MORTAZAVI: This is [similar to] what we already know about the TKIs. On the sunitinib side, you can see the diarrhea, hypertension, a lot of the on-target [effects of] VEGF and hypothyroidism, the hand-foot syndrome, and fatigue. [With] axitinib, we see some dysphonia, which is known to be more with axitinib, a little more hypertension, some higher-grade hypertension, but all along not hugely different. Typical incidences that we were expecting.4
When it comes to more of the AEs of interest, autoimmune is going to obviously be more on the pembrolizumab/axitinib side. Under sunitinib, we still have hypothyroidism and hyperthyroidism to some degree. The incidence of immune-mediated AEs was higher with pembrolizumab/axitinib but not drastically [different from] what we know about the single-agent immune checkpoint inhibitors.
How would a dual IO regimen compare?
MORTAZAVI: The CheckMate 214 study [NCT02231749] was in a similar setting as the other study—that first-line patient with treatment-naïve metastatic clear cell RCC, stratification by IMDC and the region of enrollment. The patients were randomized 1:1 to nivolumab and ipilimumab versus sunitinib. They received standard-dose sunitinib, and they also had the dual primary end point of OS and PFS. Treatment went until disease progression or toxicity.6
For the intermediate/poor-risk patient population at a 42-month follow-up, [there was a] 52% OS rate for the nivolumab/ipilimumab [arm] compared with 39% for sunitinib. And similar to the other studies, you get early separation of the curves, and it’s sustained with the tail in favor of nivolumab/ipilimumab. At 42 months, it has a ratio of 0.66 with a very strong P value.
As for PFS, at 42 months we have a 35% [PFS rate for nivolumab/ipilimumab] versus 19% [for sunitinib]; again, a strong P value [and HR] of 0.76, both primary end points favoring nivolumab/ipilimumab.
For the ORR, we see 42% versus 26%, so nivolumab/ipilimumab again superior, and we have a 10% [CR rate]. We’re not cross comparing, but higher than other studies for the CRs; the overall ORR altogether was lower than pembrolizumab/axitinib, but it’s still significantly higher than sunitinib.
As for the treatment-related AEs, [they were] very similar. [With] sunitinib, you see the TKI-AEs of hand-foot [syndrome] and gastrointestinal—diarrhea, nausea, vomiting—hypertension, and then cytopenia is more common. [With] nivolumab/ipilimumab, you have diarrhea and fatigue and skin toxicity with a different mechanism, itching, and then less of the electrolyte and cytopenias.
How did patients with sarcomatoid features fare in the CheckMate 214 trial?
ORNSTEIN: The nivolumab/ipilimumab trial had 139 patients who had sarcomatoid [features], and the axitinib/pembrolizumab trial had less. They had 51. Another trial that was reported had close to 70. So certainly the bulk was seen in the nivolumab/ ipilimumab trial. The response rates were slightly higher, and the CR rates were slightly higher as well, for patients with sarcomatoid [features] in the nivolumab/ipilimumab trial. In terms of the degree of tumor burden reduction, that was higher with axitinib and pembrolizumab, and maybe [that’s] not surprising because there’s a TKI in there.
I think that’s why most people who are polled would probably say that you can pick either one. You want to factor in how acutely a patient’s going to need a response up front. And you might want to have a TKI on board for that. But I think they’re fairly interchangeable. The HRs for PFS are nearly identical, but the HR for survival in sarcomatoid patients treated with nivolumab/ipilimumab was lower than it was for patients with axitinib and pembrolizumab.
How do you manage and mitigate AEs in patients receiving an IO-TKI combination?
ORNSTEIN: [Compared with] a lot of oncologists, I don’t treat a lot of malignancies. But for oncologists that give combination immunotherapy or a lot of immunotherapy for other malignancies, they might say that they’re extremely comfortable managing any -itis that shows up because you throw steroids at it, you taper the steroids, you figure out if you’re going to resume, but once a TKI is added to that, it can be a bit more complicated.
One of the reasons that I like this combination of axitinib and pembrolizumab is that the half-life for axitinib is extremely short; it’s about 4.5 hours. We know that there are overlapping toxicities; for instance, diarrhea. But if a patient is having a toxicity and you’re not sure if it’s coming from the checkpoint inhibitor or from the axitinib because the half-life is so short, if a patient stops axitinib for a couple of days and the AE goes away, then it’s probably from the axitinib. If the AE is still there, then you have to start considering that it might be coming from the immunotherapy.
As axitinib/pembrolizumab is approved, as cabozantinib/ nivolumab might be potentially coming down the pipeline, [as well as] lapatinib [Tykerb] and pembrolizumab—as these combined IO-TKI regimens are making their way into clinic, [it’s important to have] a practical approach to tell you if there’s a toxicity. You just stop the axitinib, and within 2 maybe 3 days, the AEs should be totally gone or mostly gone because of that extremely short half-life. That’ll tell you if this is a TKI-based toxicity or an IO-induced toxicity.
What are some of the management strategies for common AEs from the pembrolizumab/axitinib?
ORNSTEIN: For grade 1 diarrhea, you can just observe the patient, manage them symptomatically. Once it hits a grade 2, holding the axitinib for a couple of days, even just 24 to 48 hours should be sufficient. If they improve, then we can continue giving this patient axitinib. We might have to lower the dose [and/or] we might have to give them a couple of days of a break every few weeks because we know these to be on-target toxicities from axitinib. But if after a couple of days, there’s no improvement, well, then the culprit is most likely the immunotherapy, and then we would go down that pathway of treating patients with corticosteroids and deciding on other immunosuppressants, depending on response.7
The same algorithm is going to show up essentially for all toxicities or for many of the toxicities, at least with the combination of something like axitinib and pembrolizumab.
What are your thoughts on the patient case at this point? How would you manage the patient now?
ORNSTEIN: The key is that the patient wasn’t having abdominal pain, cramping, or fevers, or things that usually come with colitis. And the assumption here was that it’s likely related to the axitinib.
What are your thoughts on this approach?
ORNSTEIN: The management for this patient up front was basically to continue therapy and see if they could get control over the diarrhea. And once that didn’t happen, holding therapy for 3 days did resolve the diarrhea. Again, with the emphasis here being that we have to figure out, especially up front—this is 12 days into treatment, and you don’t want to give up on a regimen that has an OS benefit—how we’re going to manage this patient with what will, hopefully, be a chronic condition.
MORTAZAVI: For those who would hold and start antidiarrheals, I’m not saying that’s wrong, but that would not be what I would do. The reason is, when I hold, I want to see how the patient recovers. This was not a high-grade diarrhea that you have to slow down the output of the patient in just a grade 2 diarrhea. I prefer to hold and observe without any other intervention because that will help me understand better how quickly the patient recovers from this and clear the drug.
ORNSTEIN: I agree. I think you want to get as much information as possible. And again, for a [twice a day] drug, if you hold for 2, 3 days over the course of a month, they’re still getting the overwhelming majority.
I think holding the medication for a few days will give you more information. Then if you were to restart, you could consider restarting at the same dose with antidiarrheal. Or you could consider lowering the dose and seeing how the patient does.
I think it’s a matter of trying to tease out what you and your team are comfortable with. These patients are likely to be on therapy for a long time. You might have to do this a couple of times.
MORTAZAVI: The other thing I want to add is that you can just also pay attention to what else is happening to the patient. In my opinion, there’s a difference between the diarrhea from axitinib versus having a whole series of other issues—palmoplantar, and leukocytes, cytopenia, or other organ dysfunction. When I see all that, that’s usually when I know that I need dose reduction versus, in this case, when I would be quite comfortable with resuming the same dose.
What would your next step be in this patient, considering their case so far?
MORTAZAVI: Assuming the patient only had diarrhea, I would comfortably restart axitinib, but I wouldn’t start at the same dose. Some of these patients behave differently. You may see a rechallenging cause the same thing with the same pattern early on. Sometimes it happens later. I think there are other factors playing [a part here]. When I ask my patient what else they eat, you find a pattern—like when the patient is on these TKIs and they eat such and such, that triggers the diarrhea. So you can sometimes find those patterns and [then have] the patient just avoid [those foods]. So I would be comfortable to do the same dose for this patient.
The instruction this time is going to be “Just call us immediately,” especially if the patient says, “Yes, I waited 2 to 3 days.” And that’s a common pattern. So now they’re more educated on this issue and want to get us involved right away.
How would you handle this patient now?
MORTAZAVI: So now the patient has a lot more symptoms. The diarrhea is worse, and you’re worried about more toxicity.
You want to do more work-up on a patient who’s quite symptomatic. So you’re going to hold a drug again and then schedule [the patient] to come for an office visit with blood work. You check the complete blood count, liver enzymes, chemistry, and you look for hepatitis and you look for nephritis. Then, for diarrhea, this time because it’s more severe; you want to rule out other causes and check parasites, especially [Clostridioides difficile] if they’ve been on antibiotics; they basically are going to need IV [intravenous] hydration. Because the patient was hypertensive, they hold the blood pressure medication.
Then the patient got supportive care, went home, and then called the next day and reported no diarrhea, feeling better, appetite is good, blood pressure is normal now, and all these stool tests are negative.
Do you agree with the approach for this patient up to this point?
MORTAZAVI: That’s a good thing because my approach is I stay full force until I get into the first set of scans. I’ll obviously do it safely, when I see the symptoms. I think we’re going to get into more of an overlapping toxicity: Now the patient has had a nice response to therapy but has elevated creatinine, whereas the creatinine may have been normal previously.
ORNSTEIN: I do the same. Again, I tried to be aggressive with symptomatic management, at least initially. If a patient is going to get to grade 2, grade 3, and we have to reduce, then that’s OK. The message I try to give to patients and other clinicians is just not to give up on the medication before we can see if it’s working. We can always lower the dose; we can always add some more antidiarrheals, assuming the patient is not dehydrated, to try to optimize management of the symptoms.
How do you confirm nephritis?
MORTAZAVI: I think the poor man’s test for nephritis is just to give steroids. If you give steroids and it gets better, well, you probably have your answer there. Sometimes I know the nephrologists get upset because they like to have a biopsy if possible; we get worried because the patient’s already down to 1 kidney, so we like to start steroids sooner. But I think the key is to hold both.
Again, if you have an improvement within a couple of days, it’s the [axitinib], and it’s fine. If you don’t, you probably want to start steroids sooner rather than later, unless you have a sameday nephrology appointment.
What would you do as the next steps for thispatient’s care?
MORTAZAVI: You have to figure out whether you’re going to restart the axitinib. So, now you have a scenario where the renal function is improving [and] you have a presumed nephritis.
I would have no issues restarting the axitinib because we have our answer as to what caused this AKI [acute kidney injury]. And then again, I’d be holding pembrolizumab until there’s complete renal function recovery. It’s important.
In summary, I think the key is that with axitinib, you have the benefit of having multiple doses. You have the benefit of a very short half-life. You have the benefit of being able to stop therapy, wait a couple of days, and see if there’s improvement to help you decide whether this is an IO-induced toxicity or a TKI-induced toxicity. So certainly leveraging that while managing patients can optimize their care.