Practice-Changing Presentations in Renal Cell Carcinoma: Insights From ASCO® 2021

Oncologists recently gathered virtually for the 2021 American Society of Clinical Oncology® (ASCO®) Annual Meeting to discuss the latest research, insights, and innovations in cancer care. This year’s conference included a compelling program focused on genitourinary cancers, including educational sessions related to the meeting theme of “Equity: Every patient. Every day. Everywhere.”
 
Elizabeth Plimack, MD, provided her insights into, and key takeaways from, research on renal cell carcinoma (RCC) presented at the meeting. Dr Plimack is chief of the Division of Genitourinary Medical Oncology, professor in the Department of Hematology and Oncology, and director of genitourinary clinical research at the Fox Chase Cancer Center in Philadelphia, Pennsylvania.

There were a number of poster presentations and sessions on RCC at this year’s meeting. Which abstracts were the most interesting or clinically impactful?

An important one was the plenary session¹ presentation discussing the randomized, phase 3 trial of adjuvant pembrolizumab vs placebo in localized RCC with a high risk of recurrence (KEYNOTE-564; ClinicalTrials.gov Identifier: NCT03142334). That study was included in the plenary session for a reason — the data on disease-free survival are compelling. The next step will be to find biomarkers to identify who is most likely to benefit from pembrolizumab in this setting. 
 
Importantly, the overall survival results are not mature; the median follow-up is 2 years. Throughout this follow-up period, very few survival events have occurred. This is a great problem to have; it means very few patients in the placebo and treatment groups have experienced disease recurrence or died. We’ll need more time to see if adjuvant pembrolizumab is actually curing people, which is the most clinically relevant endpoint of any adjuvant trial.
 
Until we see an overall survival benefit to this approach, I will not be recommending it to patients, regardless of whether the US Food and Drug Administration (FDA) chooses to approve it based on disease-free survival. There are 2 reasons: I see no benefit to subjecting a broad group of patients to a year of therapy simply to delay a recurrence that will need to be treated later. And by definition, in the adjuvant space we’re treating all patients who are at intermediate to high risk. Many of those patients are cured already.
 
We are overtreating, in my estimation, approximately 50% of patients who would be receiving this therapy. They would need to come in for infusions, which is inconvenient, and as described in the presentation, there are side effects. Ideally, we would be able to determine who is cured and only administer adjuvant therapy to patients who are not cured. That biomarker work, I understand, is ongoing but results are not yet available.
 
Nevertheless, the data are compelling. I’m optimistic that we will be able to cure more high-risk patients after their surgery for localized disease, but we’ll have to wait and see over the next few years how the data pan out.
 
There were several other posters describing large, randomized, phase 3 trials in RCC that, taken together, make a really interesting point. These were reports on the CLEAR trial (ClinicalTrials.gov Identifier : NCT02811861),² CheckMate 9ER (ClinicalTrials.gov Identifier: NCT03141177),^3-5  KEYNOTE-426 (ClinicalTrials.gov Identifier: NCT02853331),⁶ and CheckMate 214 (ClinicalTrials.gov Identifier: NCT02231749).⁷ All 4 trials showed a greater overall survival benefit from combination therapy compared with sunitinib monotherapy. The CLEAR and CheckMate 9ER investigators presented this year’s survival data by risk group. There’s an International Metastatic RCC Database Consortium (IMDC) Risk Criteria scoring system by which we assign patients a favorable or intermediate risk. It’s interesting that, consistent across all 4 studies, we saw no benefit to combination immunotherapy with ipilimumab, axitinib, lenvatinib, or cabozantinib — those are how the different studies combined it — over sunitinib in patients at favorable risk.
 
This finding tells us — at least for as long as we have followed the patients in these studies — that patients who start with sunitinib may end up getting immunotherapy sequentially, and they probably do live just as long as patients who start with combination therapy. This could be the case because favorable-risk disease is very sensitive to inhibition of vascular endothelial growth factor (VEGF). That said, in the setting of favorable risk, certain tyrosine kinase inhibitor (TKI)-VEGF combinations confer benefits, such as tumor response and lack of primary progression, compared with sunitinib.
 
What’s interesting is that with the pure immunotherapy approach of ipilimumab plus nivolumab for this favorable-risk group, the hazard ratio for progression-free survival strongly favors sunitinib; the hazard ratio is 1.84, so the overall survival curves still do not separate. I think as much as we look at tissue-based biomarkers, in IMDC we have a clinical risk-assessment tool that separates these groups and really defines different outcomes to therapies. Perhaps in these favorable-risk groups, less can be more,  in terms of either observation or single-agent treatment with a VEGF-TKI.

Results of your team’s investigation — the phase 3 KEYNOTE-426 study⁶ — of pembrolizumab plus axitinib vs sunitinib as first-line therapy for advanced clear cell RCC showed that pembrolizumab plus axitinib demonstrated superior efficacy compared with sunitinib in terms of overall survival, progression-free survival, and objective response rate. Can you provide your perspective on these study results and research on the horizon for this treatment combination?

KEYNOTE-426 was a randomized, phase 3 study that enrolled 861 patients. Half were assigned to pembrolizumab plus axitinib, and the other half received sunitinib at standard dosing. As reported several years ago, the study met both primary endpoints of progression-free and overall survival benefit in the intent-to-treat population.
 
In this year’s update at ASCO we looked at further follow-up; we now have follow-up on almost all patients out to 36 months. Thus, we can measure landmark overall survival at 18 months, 30 months, and 36 months. At 24 months, the pembrolizumab in this trial ceased per protocol, so all patients in this arm only received up to 2 years of therapy.
 
What’s interesting about following these curves out further is that all overall survival benefit and landmarks are preserved. The curves don’t cross; there’s still a benefit to axitinib with pembrolizumab in the intent-to-treat population in this study. People talk about tails of curves; the tails of all these curves are heavily censored, meaning they’re unstable. But we’re seeing no inflection in the curve at 24 months when treatment stops. And we now have a minimum of 1 year of follow-up data from patients, all of whom have stopped therapy.
 
This is compelling — the idea that maybe we can peel back treatment in patients who have excellent responses. The big question that I think most clinicians have is, can you also stop the axitinib at 24 months? The data tell that story in aggregate but not specifically. About one-quarter of patients in the study stopped both drugs at 24 months; that was an option. Overall, as a group, they don’t seem to do any worse after that time point.
 
Things we want to watch for are more granular data on the subset of patients who stopped both axitinib and pembrolizumab vs those who continued treatment. As time goes on, more people will full-stop axitinib. If you have patients who are on this drug for 4, 5, or 6 years, they may be able to stop or at least go down to a very low, tolerable dose.
 
We talk a lot about potential cures in this metastatic setting and treatment-free survival where patients can get excellent treatment, have their cancer controlled, stop all treatment, and their disease will still remain under control. To define this, and the rates associated with these really great outcomes, we’re going to have to follow people out beyond 10 years. At the 3-year mark for KEYNOTE-426, the data continue to look good.

Patients with advanced RCC and brain metastases were described in one abstract as “a population with high unmet medical need that is often underrepresented in clinical trials.”⁸ The investigators found that combination treatment with nivolumab plus ipilimumab, evaluated in CheckMate 920 (ClinicalTrials.gov Identifier: NCT02982954), showed no new safety signals and “encouraging” antitumor activity. Will these results ultimately change the RCC treatment paradigm? What kind of additional research is necessary for this underserved population?

This is an update of data that we’ve seen at prior meetings. I’m glad this study was done because we do exclude patients with brain metastases from our large trials, and there’s a push from the FDA and others to stop doing that and really be more inclusive in terms of the patients we treat.
 
There’s no reason to expect that a patient with untreated brain metastases would have any worse or better outcomes from being treated with ipilimumab plus nivolumab. So, I think that’s what we’re seeing here. We’re seeing good overall survival and reasonable progression-free survival, which parallels what we see in the broader trials that excluded these patients.
 
In terms of progression, 25% of patients — only 7 patients, as this was a very small, 28-patient study — had progression in the brain. I don’t think based on this finding that we can surmise or conclude that ipilimumab and nivolumab treat cancer in the brain. We’ve always considered the brain as a separate compartment protected by the blood-brain barrier and requiring treatment with surgery, radiation, or both. I don’t think these data upend that treatment approach, so I would say this is what we expect. I’m glad there was no detriment to this group of patients, but it seems that they’re still going to need primary treatment to the brain in addition to this systemic therapy.

Results of the UNISoN study⁹ (ClinicalTrials.gov Identifier: NCT03177239), which looked at ipilimumab plus nivolumab in patients with a rare variant RCC refractory to nivolumab alone, found median progression-free survival was 2.6 months, and only 14% of participants were progression-free at 12 months. Additionally, 68% of participants experienced serious adverse events and 34% experienced treatment-related serious adverse events. Although this study did not meet its primary endpoints, do you believe these data can be used to guide the next generation of studies to find more effective therapies for patients with rare variant RCC? Are additional treatments for rare variant RCC in the pipeline?

This was a study of non-clear cell RCC looking at nivolumab therapy with salvage ipilimumab. A very similar trial¹⁰ was presented at ASCO this year by Michael B. Atkins, MD, deputy director of the Georgetown-Lombardi Comprehensive Cancer Center and vice chair of the department of Medical Oncology at the Georgetown University Medical Center in Washington, DC. These 2 reports really complement each other, and the investigators arrived at the same findings.
 
One is that non-clear cell RCC is a very heterogeneous group of diseases that have to be looked at together because they’re each so rare, but biologically it doesn’t make sense to study them together.
 
I think what we’re seeing is with pure immunotherapy, these non-clear cell variants just don’t respond as well as clear cell RCC. Both posters confirmed that: there was low response to single-agent therapy and we’re salvaging very few people by adding ipilimumab. I think our general approach to non-clear cell RCC — extrapolating from these posters and other data — is that these patients need treatment with a VEGF-TKI. For papillary RCC, which is the most common form of non-clear cell RCC, cabozantinib has emerged as the front-line standard based on the PAPMET trial (ClinicalTrials.gov Identifier: NCT02761057), which was presented at the ASCO Genitourinary Cancers Symposium a few months ago.¹¹
 
Since we now have data, on safety and otherwise, to support cabozantinib given with nivolumab in clear cell RCC, I think a lot of people who are going to use immunotherapy for papillary RCC are going to use that particular combination. I’ve heard people talk about starting patients on cabozantinib and adding nivolumab at progression to see if we can get some benefit there.
 
As with any rare disease, we look at the aggregate data and extrapolate. Coming back to the UNISoN study and to the other complementary poster, which was HCRN GU16-260-Cohort B, I don’t think we’re recommending nivolumab alone or nivolumab plus ipilimumab for non-clear cell RCC and certainly not as a front-line therapy.

Results of a National Cancer Database analysis¹² showed a significant relationship between receipt of palliative care and socioeconomic status among patients with metastatic RCC — in particular, black or Hispanic patients had decreased odds of receiving palliative care. As an oncologist, what steps can you and your colleagues take to ensure that these patients receive the necessary palliative care?

This is a really important poster, and it tells a familiar story: socioeconomic circumstances disproportionately affect care delivery in every way. This study focused on palliative care; I don’t think anyone is surprised that we’re seeing this, because we know that care of all kinds is disproportionately distributed by socioeconomic status.
 
It would be important to study the reasons for this. Some of the reasons are obvious: low-resource communities have less of everything — fewer grocery stores, fewer healthcare centers, less access to care, and less ability to take time off to seek care or to heal. Our country and our collective communities need to address the underlying issues here.
 
More specifically, something we can do — and our population science group at Fox Chase Cancer Center is very committed to this — is take steps to understand what disparities we might be able to have an impact on. Is there, for instance, a distrust of the healthcare system at play when a healthcare provider recommends hospice care? Do patients then feel like we’re giving up on them? Are there cultural attitudes around palliative care that affect that? Have some patients been put off by previous bad experiences with palliative care in their communities? I find patients whose family members have had good experiences with hospice and palliative care have a very different perspective on the potential for its benefits for themselves. In contrast, folks who have had terrible experiences — and there are, of course, difficult experiences with every sort of end-of-life situation — are less willing to consider palliative care.
 
I’m glad we’re presenting these abstracts and studying this critical need. We have to move beyond “We know there’s a problem” to “What small things can we do to understand the roots of the problem?” and then on to “What small or big efforts can we make to fix things?”
 
We can’t fix the systemic issues but we can try to understand them. Even in the short time we have with patients during visits we can understand what they’re most afraid of and what their highest priority is. A lot of people are more worried about their families than themselves, or their biggest issue is who is going to take care of their home or their pet. Everyone is different and what weighs on a person is not necessarily something that’s obvious or intuitive to us. Understanding that and building patients’ care plans around their values is something we can always do.
 
Sometimes it’s harder if there’s a language barrier or other communication issues, or if patients can’t make it to the clinic. Telemedicine really could help here. Addressing concerns on an individual level, and being cognizant of how we approach the visit, can help.

The COVID-19 pandemic has forced physicians to rethink most aspects of care. For patients with cancer, care changes can have a more significant impact on healthcare outcomes. One group of investigators¹³ found that remote monitoring and management of patients’ cancer and treatment-related symptoms reduced the symptom burden and improved quality of life during the first 2 months of monitoring. In another study¹⁴ — this one examining oncologists’ experiences during the pandemic — researchers reported that oncologists struggled with ethical dilemmas, including those brought on by the use of technology. In your practice treating patients with RCC, what challenges did you face? What adjustments have you made during the pandemic, and how have these affected patient outcomes?

That’s a great question, and I think a lot will be written about the impact of COVID-19 on health care going forward; this is just the beginning since we’re still in the midst of the pandemic.
 
We switched over to telemedicine immediately, right when COVID hit the United States in early March 2020. We called our patients, told them not to come in, and started patching together ways to communicate with them remotely, assist them, and make decisions about treatment.
 
I’m proud to say we didn’t alter our treatment recommendations for most patients. If it was appropriate to consider a treatment break, we agreed that the pandemic made it a good time to go on a break. A lot of patients were afraid to come in; we honored that, while making specific changes and improving conditions at our center so they could feel safe.
 
I think the hardest part — and part of the reason I gravitated quickly to telemedicine — is that we couldn’t have visitors in the cancer center. It’s so hard to go through surgery and chemotherapy alone, or to attend visits where a lot of dense and emotionally heavy information is being conveyed. I found that a good telemedicine visit — with a good phone/internet connection and the patient sitting comfortably at home with a loved one, family member, or spouse — provided an environment where we could connect on a different level. We were still talking about test results, outcomes, plans, and side effects, but it provided a really nice connection where we weren’t wearing masks and could take time to communicate with each other.
 
I can tell you a couple of stories about complex health conditions necessitating end-of-life and goals-of-care discussions. In one case, we were able to patch in family members from 5 states to hear, together, what I was saying and what the patient was saying. I think being able to include the extended family led to good patient care decisions.
 
The flip side was when the phone/internet connection was bad or when I’d inadvertently call the patient at the grocery store and they’d say, “No, I’m fine, let’s do the visit.” That was difficult. One of the aspects of a clinic visit that I didn’t appreciate before COVID was that encapsulated time to focus and communicate.
 
Then, of course, there’s the issue of helping patients with cancer who contracted COVID. I have a list of all my patients who got COVID; there were about 30, and a few died. Trying to get vaccines to patients receptive to being vaccinated against COVID-19 was a challenge. Now, trying to get vaccines to people who are fearful of them is the next challenge.
 
I think what you’re hearing from me and the RCC community more broadly is the same perspective as everyone in health care delivery.

That does seem  to be the consensus, in conversations with physicians across the board. Many are positive about telemedicine, and people are very open to it. It’s nice to hear about positive experiences and being able to include patients’ families. It’s like finding a silver lining during this difficult time.

Exactly, and there were some silver linings. My father was ill with cancer and passed away during the pandemic, but I was able to be with him because I could work remotely and still care for my own patients virtually. In some ways, for those in the caregiver role for patients with cancer, some of the flexibility that arose around the pandemic allowed us to be present in new ways.

Are there any final thoughts you’d like to add about the 2021 ASCO meeting?

I’m a member of the ASCO Board of Directors and I’m very proud of Lori Pierce’s platform on equity. [Lori Pierce, MD, is President of ASCO, a radiation oncologist at the University of Michigan, and director of the Michigan Radiation Oncology Quality Consortium.] I think it hit at exactly the right time, when we’re seeing in sharp relief the damage done by inequities in our society. On an ASCO-specific level, really bringing those to the forefront and focusing on them is going to be critical for the work we do in the years ahead. This was one of the most impactful themes of an ASCO Annual Meeting I’ve attended to date.
 
I do think that the virtual structure of ASCO this year made it a bit harder to generate enthusiasm and share ideas around the presentations. However, we got around this in creative ways. A group of us in genitourinary had Zoom ASCO meeting watch parties, for example. And I talked with a friend who gathered all of her breast cancer colleagues and they went away for the weekend and streamed ASCO together. Finding these innovative ways to still make the ASCO meeting a time of connection, and creating that enthusiasm and energy around the meeting, was so helpful. The hybrid format is here to stay, but I do think that with increased uptake of the SARS-CoV-2 vaccines, we will be able to be together in person in Chicago next year. I look forward to that.