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A panel of kidney cancer experts discuss how therapeutic strategies in the neoadjuvant and adjuvant settings are affecting outcomes and how treatment selection in the first line has shifted approaches in the second and later lines of therapy.
Despite an abundance of novel and established treatment modalities for patients in the first-line setting, surgical approaches remain the only curative option for patients with advanced clear cell renal cell carcinoma (RCC). However, for patients with intermediate/high or high-risk of recurrence prior to surgery, the 5-year recurrence rate is approximately 60%, which represents an unmet need for this patient population.1
Investigators have explored several avenues to convert patients with unresectable disease to candidates for nephrectomy with neoadjuvant regimens and to identify adjuvant treatment strategies to maintain disease control.
“It’s worth taking a step back and acknowledging that we’ve had tremendous improvement in change in the management of advanced kidney cancer over the past 10 years,” David A. Braun, MD, PhD, said in a recent OncLive Peer Exchange®.
“We’re at the point where more patients are [experiencing] long-term durable survival.” Braun added that despite improvements in treatment-free survival there is work to be done to address the number of patients who develop refractory disease. “That’s going to require careful clinical studies but also translational studies and scientific investigation, to understand mechanisms of response and resistance and combine things in a rational way,” he said.
A panel of kidney cancer experts joined Braun to discuss how therapeutic strategies in the neoadjuvant and adjuvant settings are affecting outcomes and how treatment selection in the first line has shifted approaches in the second and later lines of therapy.
Adjuvant treatment options historically included treatment with sunitinib (Sutent) for patients without evidence of disease. However, the toxicity profile of the agent makes it an unfavorable option for patients with intermediate-risk or high-risk RCC who undergo nephrectomy without receiving prior systemic treatment.
Adjuvant immunotherapy, specifically with pembrolizumab (Keytruda), affords patients a tolerable and efficacious option according to data from the phase 3 KEYNOTE-564 trial (NCT03142334).2 The data supported the approval of pembrolizumab for the treatment of patients with intermediate/high risk or high risk of disease recurrence after nephrectomy, or following nephrectomy and resection of metastatic lesions.3
In 30-month follow-up data presented at the 2022 Genitourinary Cancers Symposium, the disease-free survival (DFS) benefit of pembrolizumab was sustained vs placebo in this patient population. The intention-to-treat population included 496 patients in the pembrolizumab arm and 498 patients in the placebo arm. At baseline approximately 86% of patients in both arms had had intermediate/high-risk disease and approximately 11% of patients had sarcomatoid features. Further, most tumors were stage T3.2
The median DFS was not reached in either arm (HR, 0.63; 95% CI, 0.50-0.80; nominal P < .0001). At 2 years, 78.3% of patients in the pembrolizumab arm were progression free compared with 67.3% in the placebo arm. The benefit was observed across key subgroups, including those with PD-L1 combined positive score (CPS) of less than 1 (HR, 0.68; 95% CI, 0.37-1.24), CPS of at least 1 (HR, 0.63; 95% CI, 0.49-0.82), and tumor grade 4 (HR, 0.55; 95% CI, 0.37-0.83).
“There was an interesting benefit that we saw for the higher-risk populations,” moderator Tian Zhang, MD, MHS, said. “[Including] pathologic, T4 disease, or any T stage with node-positive disease, we saw this high-risk population with benefit of the 2-year disease-free survival rates.”
The high-risk group comprised 40 patients on the pembrolizumab arm and 36 on the placebo arm. The median DFS was 22.4 months with pembrolizumab with immunotherapy is more effective in the long term,” Zhang said. At the 30-month follow-up the 2-year OS rates were 96.1% with pembrolizumab vs 93.8% with placebo (HR, 0.52; 95% CI, 0.31-0.86; P = .0048), which did not cross the boundary for statistical significance.2 Progression beyond adjuvant therapy Tian Zhang, MD, MHS vs 11.4 months with placebo (HR, 0.60; 95% CI, 0.33-1.10). The 2-year DFS rates were 48.7% vs 35.4%, respectively.2
“The highest DFS benefit I saw was for [patients with] M1 [no evidence of disease]. In this population, there might be micrometastatic disease or disease we don’t see. In that population, the 2-year DFS rate was 38% for patients treated with placebo and 78% for patients treated with pembrolizumab for 1 year. That hazard ratio was quite different. It was 0.28 favoring pembrolizumab,” Zhang said. In this population, which included 29 patients on both arms, the median DFS was not reached with pembrolizumab vs 11.6 months with placebo (HR, 0.28; 95% CI, 0.12-0.66).2
The median DFS was not reached for either those with intermediate/high-risk disease who received pembrolizumab (n = 422) or those who received placebo (n = 433; HR, 0.68; 95% CI, 0.52-0.89). The 2-year DFS rates were 81.1% vs 72.0%, respectively.
Individuals with sarcomatoid features had a marked improvement in sustained DFS with pembrolizumab (n = 52) vs placebo (n = 59). The 2-year DFS rates were 71.8% vs 52.0%, respectively, with the median DFS not reached with pembrolizumab vs 40.5 months with placebo (HR, 0.54; 95% CI, 0.29-1.00).
Although DFS served as the primary end point of the study, Zhang noted that the long-term efficacy of adjuvant pembrolizumab requires longer follow-up. “We didn’t see enough overall survival [OS] as there weren’t enough deaths on the study to warrant further [investigation into] differences between the 2 populations. More follow-up will be necessary to decide whether we’ll see an OS benefit and whether truly this early treatment with immunotherapy is more effective in the long term,” Zhang said.
At the 30-month follow-up the 2-year OS rates were 96.1% with pembrolizumab vs 93.8% with placebo (HR, 0.52; 95% CI, 0.31-0.86; P = .0048), which did not cross the boundary for statistical significance.2
Progression Beyond Adjuvant Therapy
Principles are in place for addressing disease progression following adjuvant therapy. However, Braun noted that after pembrolizumab there are no clear directions for subsequent therapy. “For an individual who’s progressed on adjuvant pembrolizumab, we don’t have the data to know the next best thing to do,” he said. “I’ve talked to a lot of colleagues, and some are invoking the platinum paradigm—platinum sensitivity, platinum resistance, or platinum refractory—depending on when the progression occurs. I’m not sure biologically it has the same linkage between immunotherapy and cytotoxic chemotherapy, but in the absence of a better paradigm that’s a very reasonable approach.”
Braun said to guide post–pembrolizumab treatment decisions he would consider several factors including timing of progression (during or after conclusion of treatment), type of progression (radiographic vs symptomatic), and whether the progression is rapid. “It’s a very different story for a patient who got adjuvant pembrolizumab and then has progression 5 years later [vs on treatment]. I would factor differently in my mind of how I think of them as sensitive or resistant to anti–PD-1 based therapy,” Braun said.
If the progression is symptomatic, Braun noted that initiating therapy that would maximize response to an impending visceral crisis may guide clinicians toward combination therapies over single-agent therapies. Additionally, patient-specific factors may play a role. “How did the patient tolerate immunotherapy? How did the patient tolerate pembrolizumab? Was it a relatively easy course of treatment? Are there a lot of immune-related adverse events [AEs]? Some of the [AEs] are substantial. That might help us think about how much we push more immunotherapy and in what setting,” Braun said.
He suggested treatment modalities for patients who progressed during the 1-year treatment period vs those who may experience disease progression after completion of adjuvant therapy. “If a patient had progression on pembrolizumab— it was in that 1-year period of treatment—I would be more inclined to switch to TKI [tyrosine kinase inhibitor]-based therapy,” Braun said. “For patients who are the opposite—they’ve had treatment with pembrolizumab and years later they’ve experienced disease recurrence—I’m more inclined to treat them similar to how I would treat a [treatment-]naïve patient. I’d be more inclined to use an up-front immunotherapy- based combination.”
As for the patients who fall somewhere in between, Braun said that is where patient-specific factors—the timing of progression, the rapidity of progression, and the tolerance of prior therapy— will have the largest role.
Ongoing Clinical Trials
Several investigations in the adjuvant setting are exploring combination and single-agent regimens for patients with RCC, including IMmotion010 (NCT03024996), CheckMate 914 (NCT03138512), and RAMPART (NCT03288532). These studies are exploring the use of atezolizumab (Tecentriq), nivolumab (Opdivo) with or without ipilimumab (Yervoy), and durvalumab (Imfinzi) plus tremelimumab, respectively (TABLE4-6).
“Most of us want to see the data and want to look at the efficacy, not only progression-free survival but also OS, because at the end of the day, I think this is very important for this patient population,” Mehmet A. Bilen, MD, said of the ongoing trials. “We really want to cure patients in addition to delaying disease recurrence.”
He noted that toxicity will be another important factor to consider as data are reported in the adjuvant setting. “Toxicity is even more important for the adjuvant space because they are not having any AEs or symptoms from the disease itself, and whatever AE patients are going to experience is from the drug. We want to make sure that we don’t see any excessive toxicity that’s going to affect our patient. But overall, if you want to cure someone, I think this is the opportunity. I think for patients with very high risk [of recurrence] we may want to choose a doublet rather than a single agent.”
Aimed at tumor shrinkage and/or preemptively addressing residual tumor cells following nephrectomy, clinical trials assessing the role of neoadjuvant treatment strategies are ongoing.
For example, data from the phase 2 NeoAvAx trial (NCT03341845) presented at the 2022 Genitourinary Cancers Symposium showed that neoadjuvant treatment with axitinib (Inlyta) plus avelumab (Bavencio) elicited a partial response in the primary tumors of 30% of patients with advanced high-risk RCC (n = 40).7
“What is interesting about this study, is that it is one of the first to [report] data with a combination regimen in this setting after a disappointment in general efficacy in the TKI monotherapy setting. It was very interesting to see what these data looked like,” Pedro C. Barata, MD, MSc, said.
Investigators evaluated participants taking 12 weeks of neoadjuvant axitinib at 5 to 10 mg once daily and avelumab at 10 mg/kg intravenously once every 2 weeks. Surgery was conducted at least 36 hours following the last dose of axitinib. A majority of patients had T3a tumors (60%). At baseline the mean tumor diameter was 10.3 cm (range, 5.6-18.8).
The median tumor downsizing was 20% (range +3.8% to –43.5%). Of the 12 patients who achieved a partial response, 10 were disease free at the time of data cutoff. Secondary end points of DFS and OS were not reached at a median follow-up of 23.5 months. Recurrence was reported in 13 patients, and 3 died of disease.
Investigators noted that surgical AEs aligned with previously reported findings and no new safety signals were reported with the neoadjuvant immune checkpoint/VEGFR-TKI combination.
Investigators also are evaluating the use of nivolumab in the neoadjuvant and adjuvant setting vs surgery alone in the phase 3 PROSPER trial (NCT03055013). Patients enrolled in the experimental arm prior to a protocol amendment received nivolumab administered intravenously (IV) over 30 minutes on day 1 of a 14-day cycle for 2 cycles followed by partial or radical nephrectomy 7 to 28 days after treatment. After surgery patients will receive nivolumab on day 1 of a 14-day cycle for 6 cycles followed by nivolumab on day 1 of a 28-day cycle for 6 cycles in the absence of disease progression or unacceptable toxicity.8
The amendment regimen is nivolumab IV over 30 minutes on day 1 followed by followed by partial or radical nephrectomy 7 to 28 days after treatment. Nivolumab is then administered nivolumab IV over 30 minutes on day 1 of a 4-week cycle for up to 9 cycles in the absence of disease progression or unacceptable toxicity.8
“Initially it was planned for a longer time of neoadjuvant nivolumab, but the study had to be amended to be more feasible,” Barata said. “The end point here is event-free survival. This study completed accrual, and now we are waiting for events so that we can see what happens. But I think these studies will add significant information to what we saw with adjuvant pembrolizumab, in my opinion, and what we’re going to see with other checkpoint inhibitors in this setting. I think it’s a very important study to keep an eye on.”
Despite only one of the treatment approaches discussed in this segment of the Peer Exchange being FDA-approved, the investigational studies offer promise of a new treatment landscape for patients with RCC.
“Most of the investigations in the neoadjuvant setting are still just that— they’re investigational. A lot of us in our clinics have been using [these approaches] for years,” said Moshe C. Ornstein, MD, MA. “We’re hoping to spare some nephrons and avoid having that patient be dialysis dependent after a nephrectomy.”
Ornstein added that the data are helpful in terms of providing safety and tolerability data as well as efficacy data. “These data tell us that this approach is at least safe and that the patients are getting to surgery and getting through surgery OK. I wouldn’t say necessarily that this is a practice-changing trial. It must be a case-by-case decision. But it comforts those of us who do this in practice in an effort to spare some nephrons at the time of nephrectomy in the right patient in close collaboration with the urologist. There’s also some efficacy in terms of tumor burden shrinkage.”
Ornstein noted that sequencing upon disease progression will also depend on patient-specific factors. “The overwhelming majority of patients don’t have disease progression within 3 months of surgery. That’s a real minority. What’s going to happen—this gets back to what Dr Braun highlighted, in terms of taking a play out of the cisplatin-refractory lung cancer/bladder cancer space—is that most of these patients will have the therapy washed out of their system by the time the cancer progresses.” Finally, he noted that adjuvant pembrolizumab will likely have a prominent role as a frontline therapy in the metastatic setting, but that neoadjuvant therapy is less likely to have a similar affect.