Immunotherapy Could Still Play a Role After Progression in Patients With RCC

Supplements And Featured Publications, 2022 Genitourinary Cancers Symposium, Volume 01, Issue 01

In Partnership With:

Partner | Cancer Centers | <b>Cleveland Clinic</b>

Moshe Ornstein, MD, MA, discusses trials exploring second-line immunotherapy in patients who have progressed on immunotherapy, plus key clinical trial data on kidney cancer and other pressing areas of need for research in renal cell carcinoma.

Treatment with a tyrosine kinase inhibitor (TKI) remains the standard of care for patients with metastatic renal cell carcinoma (RCC) who progress following immunotherapy in the frontline setting. However, ongoing clinical trials are investigating whether immunotherapy agents could still play a role after progression, according to Moshe Ornstein, MD, MA.

For example, the phase 3 CONTACT-03 trial (NCT04338269) is exploring the combination of cabozantinib (Cabometyx) plus atezolizumab (Tecentriq) vs cabozantinib monotherapy, and the phase 3 TiNivo-2 trial (NCT04987203) is investigating tivozanib (Fotivda) plus nivolumab (Opdivo) vs tivozanib monotherapy. Ornstein noted pending data from both studies could help answer a pivotal question in the treatment space for RCC.

“We have seen tremendous progress in the treatment of patients with metastatic clear cell RCC who receive immunotherapy-based combinations up front,” Ornstein said. “We have ipilimumab [Yervoy] and nivolumab, axitinib [Inlyta] and pembrolizumab [Keytruda], cabozantinib and nivolumab, lenvatinib [Lenvima] and pembrolizumab, etc. [We have] all these immunotherapy-based combinations, but a real question that remains unanswered in the field is what the role of immunotherapy [is] in patients whose cancer has progressed having already received immunotherapy.”

In an interview with OncLive® during the 2022 Genitourinary Cancers Symposium, Ornstein, a genitourinary medical oncologist at the Taussig Cancer Institute at Cleveland Clinic, discussed the trials exploring second-line immunotherapy in patients who have progressed on immunotherapy, plus key clinical trial data on kidney cancer presented at the conference and other pressing areas of need for research in RCC.

OncLive®: Could you provide an overview of the phase 2 NeoAvAx trial (NCT03341845) which investigated neoadjuvant avelumab (Bavencio) and axitinib in patients with localized RCC who were at high risk for relapse following nephrectomy?1

Ornstein: There is a lot of talk about adjuvant therapy for patients who are at high risk of recurrence after their kidney cancer is removed, but there is a lot of rationale to give therapy before surgery, as well. [One] of the reasons to give therapy before surgery is to downsize a tumor to make the surgery either easier or to allow for additional nephron sparing. [Surgeons] are not going to have to remove as much of the kidney as one might otherwise have to remove.

Another reason to give therapy before surgery, especially when it comes to giving immunotherapy before surgery, is that, theoretically, giving immunotherapy when the primary tumor is in place produces better results. There are some data from other tumor types that [show that] giving immunotherapy before surgery can improve disease-free survival [DFS], compared [with] when you give it after surgery, and that is what this phase 2 trial did with axitinib and avelumab. Axitinib is a VEGFR TKI, and avelumab is a PD-L1 inhibitor. Combinations of these treatment classes are approved for patients with metastatic kidney cancer.

We know axitinib and avelumab, when combined, are active for patients with metastatic kidney cancer. The question was: If we select patients in the neoadjuvant setting, will there be a response in those patients, as well? [This study included] patients who were at high risk of relapse, patients who had clinically node-positive disease, a high T stage, a high Fuhrman grade, and treated them with 6 doses of avelumab. [Avelumab] was given every other week for 6 cycles, so basically 12 weeks of treatment before surgery. Axitinib, which is a pill, was given at the standard dosing with dose-escalation parameters built into the trial.

What this study was looking at was a primary end point of objective response rate [ORR]. If patients get this combination before surgery and then get a scan at the time of surgery: What is the rate of patients who have a 30% tumor burden decrease? Secondary end points [included] DFS, overall survival [OS], safety, and tolerability.

What were some of the key efficacy findings that read out from this trial?

A total of 40 patients were enrolled in the trial. The median age of these patients, [like] what we generally see in our kidney cancer clinics, was 63 years. [It was] predominantly a male population [as] 70% of the patients in the trial were males. The population did span the range of high-risk categories: 43% of the patients had node-positive disease, 20% were T4 [positive], and 28% had Fuhrman grade 3 or 4 disease.

The high-level results are as follows: 12 of the 40 patients [30%] had what is considered a partial response. The ORR was 30%. Interestingly, 10 of those patients, so 83% of the patients who had a response, remained disease free at the time of study follow-up. The median DFS and the median OS were not reached. However, at a median follow-up of close to 2 years, recurrence occurred only in approximately one-third of patients. In other words, two-thirds of patients remained disease free at that time of follow-up.

What was the biggest takeaway from the data found in this trial with this combination?

Any time we talk about a neoadjuvant or an adjuvant trial in patients who have localized kidney cancer, we must take the efficacy in the context of the toxicity. For patients who have metastatic kidney cancer, most of those patients are not going to be cured. We will accept the higher rate of toxicity. But when we talk about a patient who has localized kidney cancer, even though many of those patients will have disease recurrence, many of them are going to be cured without treatment. We must set the bar for toxicity a little lower for what we are willing to accept.

What is important in this trial is that this combination before surgery was well tolerated. There were not any unexpected toxicities; all serious adverse [effects] were resolved. Also important in the neoadjuvant setting is the toxicity at the time of surgery, and there did not appear to be any notable surgical complications.

There is activity for this combination prior to surgery, and it does not come with worrisome toxicity. Although it is not a standard of care to give this combination prior to surgery for patients with localized kidney cancer, it does establish a standard where this can be done safely if it is needed in the right patient. There are some data now to support its use, but it is not a standard of care.

Regarding the 30-month follow-up of the phase 3 KEYNOTE-564 trial (NCT03142334) presented at the symposium, could you highlight some notable takeaways from the data read out of that study?2

KEYNOTE-564 was a randomized trial in which patients who had some degree of high-risk kidney cancer, either intermediate-high risk, high risk, or metastatic disease that was resected after surgery. Such patients who had surgery were then randomized to receive either pembrolizumab or placebo for 1 year. The initial results had previously been reported, and the initial results have already demonstrated a DFS [improvement] in this population. [Initial results] led to the FDA approval of pembrolizumab for patients with high-risk kidney cancer after nephrectomy. [Pembrolizumab] has become a standard in many clinics for patients who have high-risk kidney cancer. After their surgery, they are receiving pembrolizumab for 1 year.

The primary analysis was done with 24 months of follow-up, and the updated analysis was done with 30 months of follow-up. What is important to note with the follow-up is that DFS was still strong, with a hazard ratio of 0.63. The 24-month DFS rate was 78.3% in patients receiving pembrolizumab and 67.3% in patients who were on the placebo arm, showing a nice risk reduction for patients receiving pembrolizumab after surgery.

One of the interesting things reported was [data on] some of the subgroups. For patients with intermediate-high risk, the benefit was about 9% in terms of the difference in recurrence between patients receiving pembrolizumab vs placebo. The risk difference between the patients receiving pembrolizumab and placebo was even greater in patients with higher risk and in patients with M1 no evidence of disease. In other words, patients who had some metastatic disease that was resected after surgery.

This highlights that patient selection here is critical. This is probably not going to be the right treatment for all patients, but as patients move into higher-risk groups, the DFS benefit becomes more significant. Importantly, we always talk about sarcomatoid features, and patients who did have sarcomatoid features had a significant difference in the DFS benefit between receiving pembrolizumab and placebo.

[Regarding] OS, it is still early. Fortunately, not enough events have occurred, although the curves have started separating and remain separated at the 2-year and 3-year marks. These data further solidified pembrolizumab for 1 year after surgery in patients with high-risk kidney cancer, but an individual discussion on a case-by-case basis is important to have with patients to balance that benefit of DFS with the still unknown OS benefit.

Could you provide an overview of the objectives for the CONTACT-03 and TiNivo-2 trials?

There are 2 trials that are investigating [immunotherapy following progression on immunotherapy] in a randomized fashion, and the data from those trials will go a long way to drive clinical decision making in the clinic. One of those trials is the CONTACT-03 trial, and that trial is randomizing patients who have already received an immunotherapy-based treatment for metastatic kidney cancer to receive either cabozantinib, which is a standard-of-care monotherapy, or cabozantinib with atezolizumab, a PD-L1 inhibitor.

Another trial investigating this question is the TiNivo-2 trial, which is investigating tivozanib as a monotherapy, [which is] a highly selective VEGFR TKI, vs the combination of tivozanib with nivolumab. [This trial is] once again looking to answer that critical question of [whether there is] a role for immunotherapy-based treatment in patients whose kidney cancer has already progressed on immunotherapy. The standard of care right now is essentially just to give a TKI, and this will help drive whether we give immunotherapies in combination with TKIs, or [whether there is] any role for immunotherapy in what is technically immunotherapy-resistant kidney cancer.

What areas still need to be addressed in future research in RCC?

A lot of progress has been made over the past 5 to 10 years in the treatment of patients with metastatic kidney cancer, but there are still a lot of questions that the field has, and we look forward to seeing the research and the clinical trials that yield these results to benefit our patients. Much of the progress has been in treatment-naïve metastatic RCC. Patients receiving their first line of therapy are now getting immune-based combinations, but what to do and how to manage those patients after their cancer progresses on frontline therapy remains a challenge.

Most of the agents that are available for refractory RCC have response rates of maybe 20% to 30% and a short progression-free survival, and at that point, patients tend to cycle from 1 therapy to the next. Is there some form of novel therapy? Is there some therapy that can produce a durable benefit in patients with refractory RCC? Those studies are ongoing.

These trials that have led to the remarkable results we see these days are predominantly in clear cell kidney cancer. Although clear cell RCC makes up 75% to 80% of all patients with RCC, that still leaves a lot of patients who do not have clear cell kidney cancer and need treatment options. We look forward to seeing additional research to help benefit those patients with non–clear cell kidney cancer.

Another area of research is the duration of therapy. In many of these treatment options, patients are treated until they have toxicity that they cannot handle any more or until their cancer gets worse, and they do not have a chance to get off therapy. [It is important to keep] thinking about trial designs that take advantage of treatment-free intervals [and] thinking about the duration of therapy patients need to have that durable response.

Lastly, we still [think of] kidney cancer in a one-size-fits-all approach. At the Genitourinary Cancers Symposium 2022, a lot of data was presented on prognostic and predictive biomarkers, genomics, etc., but we do not have a personalized approach to know which treatment option is likely to benefit which patients. I am excited about trials that are emerging that are going to be genomically driven, that are going to harness the biology of an individual patient’s tumor to help guide what treatment that patient needs. Ultimately by doing that, we can improve response rates, we can improve cure rates, we can improve deep, durable responses, and that is ultimately the goal: to provide long-term benefits for our patients.


  1. Bex A, Abu-Ghanem Y, Van Thienen JV, et al. Efficacy, safety, and biomarker analysis of neoadjuvant avelumab/axitinib in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy (NeoAvAx). J Clin Oncol. 2022;40(suppl 6):289. doi:10.1200/JCO.2022.40.6_suppl.289
  2. Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab as post nephrectomy adjuvant therapy for patients with renal cell carcinoma: results from 30-month follow-up of KEYNOTE-564. J Clin Oncol. 2022;40(suppl 6):290. doi:10.1200/JCO.2022.40.6_suppl.290