Immunotherapy’s Survival Benefit Opens New Doors in the Adjuvant RCC Setting

Preventing recurrence of renal cell carcinoma (RCC) after nephrectomy is a high priority in RCC research, in light of the 40% of patients with localized disease whose disease recurs.¹ Micrometastatic disease present at the time of resection puts even patients with early-stage disease at risk of distant recurrence.

Treatment in the metastatic setting has revolved around VEGF tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitor therapies, and these have also been the focus of trials for adjuvant therapy to prevent recurrence. Despite a wide variety of trials, most have been unsuccessful in showing benefit for adjuvant therapy over surveillance.

Now, pembrolizumab (Keytruda) is the first agent showing overall survival (OS) benefit as adjuvant therapy, leading oncologists to adopt adjuvant therapy for many of their patients.² However, the history of trials and their patient selection by stage and risk factors leaves uncertainty about which patients should receive adjuvant therapy. Additionally, there are questions as to how this will change the treatment paradigm going forward.

“There’s an important philosophical element to adjuvant therapy when we think about this and how we explain it to our patients,” Claud M. Grigg, MD, said in a Case-Based Roundtable discussion he moderated for physicians in Virginia and Pennsylvania. “How to frame it really matters, because our patients are [ultimately] deciding whether they want to do this or not, and we have a lot of power to frame this idea for them to help them make this decision, for better or for worse.”

In a pair of recent Case-Based Roundtable discussions, Grigg, a genitourinary medical oncologist at Atrium Health Levine Cancer Institute in Charlotte, North Carolina, and Scott S. Tykodi, MD, PhD, an associate professor at the University of Washington and oncologist at Fred Hutchinson Cancer Center in Seattle, discussed how they approach adjuvant therapy and how the treatment paradigm for recurrent disease will change for patients who received prior systemic therapy.

Failure of Adjuvant Targeted Therapy

Targeted therapies, including TKIs, resulted in a surprising series of negative adjuvant trials despite changing practice in the metastatic setting. Sunitinib (Sutent) and sorafenib (Nexavar) failed to show improvement in disease-free survival (DFS) in the ASSURE trial (NCT00326898), as did axitinib (Inlyta) in the ATLAS trial (NCT01599754) and pazopanib (Votrient) in the PROTECT trial (NCT01235962).^3-5 Additionally, everolimus (Afinitor) failed to show superior recurrence-free survival in the EVEREST trial (NCT01120249).⁶

One notable study in this setting was the S-TRAC trial (NCT00375674) of sunitinib, in which 1 year of treatment was superior to placebo in DFS, with an HR of 0.76 (95% CI, 0.59-0.98).⁷ However, this trial lacked an OS benefit and brought considerable toxicity. At 5.5 years, the OS showed no difference (HR, 0.92; 95% CI, 0.66-1.28; P = .6).⁸

Although sunitinib did not show benefit in the ASSURE trial, this trial included patients with non–clear cell histology whereas S-TRAC did not. The National Comprehensive Cancer Network gave a category 3 recommendation for adjuvant sunitinib for patients with stage III disease, clear cell histology, and high risk for relapse.⁹ A subgroup analysis showed a DFS benefit for the prespecified subgroup of patients with higher-risk disease (HR, 0.74; 95% CI, 0.55-0.99; P = .04).⁸

Despite being the first agent to show promise in the adjuvant setting, sunitinib has not been widely accepted. Tykodi said it was difficult to know how the difference in the trial designs could have led to sunitinib’s success and which patients in particular benefited.

Positive Outcomes With Immunotherapy

As with targeted therapy, adjuvant immunotherapy (IO) failed to show benefit in multiple studies; however, in this case, the first trial to release data had strongly positive results. In the KEYNOTE-564 study (NCT03142334), pembrolizumab achieved a DFS benefit, with a favorable HR of 0.63 (95% CI, 0.50-0.80; P < .0001] at 30 months’ follow-up.¹⁰ In contrast, results from trials of atezolizumab (Tecentriq), nivolumab (Opdivo) plus ipilimumab (Yervoy), and nivolumab alone were negative.^11-13

In data first presented in 2023 and recently published in The New England Journal of Medicine, OS benefit with pembrolizumab was reported at 57.2 months’ median follow-up (HR for death, 0.62; 95% CI, 0.44-0.87; P = .005), and the DFS benefit was also maintained with an HR of 0.72 (95% CI, 0.59-0.87).² The OS rate at 4 years was 91.2% with pembrolizumab vs 86.0% with placebo, for a 5.2% absolute benefit.

In terms of safety, the rate of serious adverse events (AEs) was 20.7% with pembrolizumab vs 11.5% with placebo, and the rate of grade 3 or 4 AEs related to pembrolizumab was 18.6% vs 1.2% with placebo. Treatment-related AEs led to discontinuation in 18.2%, and 21.1% discontinued treatment due to AEs of any cause. “That’s higher than [what] we see in the metastatic setting,” Grigg observed. “A patient with stage IV disease [is] going to tolerate a little bit more toxicity than someone who is in the adjuvant setting.”

Interpreting the Results

When surveyed, nearly all participants in the events said they would use adjuvant pembrolizumab following nephrectomy, and many have already treated patients with it. Still, a key question the participants discussed in response to the KEYNOTE-564 results was whether the negative results of the other IO trials could be seen as a failure to replicate its benefit, considering the similarity of the agents and their trial designs.

Shiven B. Patel, MD, MBA, an associate professor at the University of Utah School of Medicine in Salt Lake City, commented in Tykodi’s group that it didn’t seem fair to judge pembrolizumab negatively based on its competitors, and he didn’t see this as a reason to deprive patients of an efficacious therapy. He added that pembrolizumab is easy to tolerate compared with adjuvant therapies given in other disease types, such as chemotherapy in breast cancer.

Raj Manchandani, MD, of LMG Cancer & Infusion Center in Lansdowne, Virginia, said he was expecting a greater absolute difference in OS than approximately 5%. Grigg said he felt similarly at first but found that when compared with other diseases where adjuvant therapy is used, such as bladder and lung cancer, the number of patients needed to treat to see DFS and OS improvement was comparable and sometimes even smaller with pembrolizumab in RCC.

Grigg suggested that KEYNOTE-564 enrolled a higher-risk population, including grade 4 tumors and sarcomatoid features, explaining the greater difference between the pembrolizumab and placebo arms. This trial also included patients who had M1 status and no evidence of disease, meaning they had resectable metastases at the time of nephrectomy. He also noted that atezolizumab’s performance in the metastatic setting was relatively poor, suggesting that PD-L1 antibodies are not equivalent to PD-1 antibodies in RCC. When discussing the subgroup analysis of OS, Grigg said he did not observe any subgroup that clearly benefited more than others with pembrolizumab that would limit the interpretation of KEYNOTE-564.

George J. Kannarkat, MD, PhD, of Riverside Health in Virginia, said the negative trials did concern him, but given the benefit of IO in metastatic RCC and other diseases, oncologists were anticipating a positive result. “It’s almost like we were waiting for 1 trial to let us do it,” he said. In his personal experience, 1 patient remained recurrence free, whereas the other experienced disease progression during the year of treatment. “In the high-risk patients, I’m still favoring doing something rather than nothing,” Kannarkat said. Grigg acknowledged that, unlike in the metastatic setting, the physician can’t tell whether the adjuvant therapy is working or not.

Counseling Patients

Grigg asked participants whether counseling patients on adjuvant therapy should include the negative results or focus on KEYNOTE-564 alone. Asit Paul, MD, PhD, of VCU Health in Richmond, Virginia, said he participated in several of the trials. Considering the varied eligibility criteria and outcomes, he said it would be complicated for patients to understand how the positive trial stood out, so he focuses on the recurrence rate data from KEYNOTE-564.

Michael Rachshtut, MD, an associate professor at Cooper Medical School of Rowan University in Camden, New Jersey, agreed, citing the lack of available options for patients in this setting. “Our patients are looking for something else, especially with high risk, to try and give them some hope for a longer time of remission [before] relapse. I don’t try to explain because I don’t think they’ll understand the nuances of why [a trial] was negative.”

In Tykodi’s event, Xiantuo Wu, MD, of Intermountain Health in Las Vegas, Nevada, said he talks to patients about the other negative trials when offering pembrolizumab, as well as the cost and 1-year treatment time. Although he recalled an eligible patient refusing pembrolizumab, it was because of the barriers of cost and time commitment, not because of the mixed trial data.

Use of Pembrolizumab

Patel and Tykodi each said that they typically do not receive referrals from surgeons and urologists for patients who have T2 disease with grade 4 tumors/sarcomatoid features who are at less risk, though they did show benefit in the trial.

“I’ve heard very prominent colleagues say they don’t offer pembrolizumab to patients at the lower-risk range [who] would have qualified for [KEYNOTE-564], which I find interesting because, within the [KEYNOTE-564 data, you cannot find] a subset that did not benefit from pembrolizumab,” Tykodi said. “It’s not coming from the trial; it’s your own calculus about what makes the most sense in terms of balancing benefit vs risk.”

Spencer Shao, MD, of Compass Oncology in Portland, Oregon, agreed, saying that the trial’s findings must be taken at face value even though other immune checkpoint inhibitors were not as effective. Wu added that he has used it in patients with pT3 and pT4 disease.

Recurrence After Adjuvant Therapy

Should RCC recur in the adjuvant setting, oncologists have no consensus on which treatment should come next. For oligometastatic progression, Patel suggested that ablation or stereotactic body radiation therapy could be employed to avoid moving to systemic therapy for metastatic disease.

He added that giving dual IO as frontline metastatic therapy following pembrolizumab would be questionable, but it might be possible to add on lenvatinib to the existing pembrolizumab because it is an approved frontline combination.⁹ However, simply moving onto a single-agent TKI could also be considered. The approach could vary depending on whether progression occurred during or shortly after pembrolizumab treatment was used, or whether patients had been off treatment for a significant period, in which case they might respond better to a second IO.

Recent data from a poster presented at the 2024 American Society of Clinical Oncology Annual Meeting addressed the question of subsequent therapy. Retrospective findings were reported on patients at 29 international centers who were treated with adjuvant IO, 76 of whom received systemic therapy for metastatic disease (37 with pembrolizumab).¹⁴

Of these, 37 (40%) received VEGF-TKI at recurrence, 26 (28%) received TKI/IO, 12 (13%) received dual IO, and 1 (1.1%) received TKI plus mTOR inhibitor. The study demonstrated that patients could derive benefit from subsequent systemic therapies, including both TKI and IO, and most patients did not require dose reduction or treatment discontinuation due to treatment-related AEs.

In those who received adjuvant pembrolizumab, response rates appeared higher in those whose disease recurred after completing 1 year of pembrolizumab vs those whose disease recurred during adjuvant therapy, though the numbers were small. Two patients who had discontinued their adjuvant IO because of toxicity were rechallenged with IO. Both had a best response of stable disease, although 1 developed an immune-related AE.

In addition to its success in boosting the curative approach in localized disease, the increased use of adjuvant pembrolizumab will have a ripple effect on the approach to therapy for metastatic disease. As more patients are treated, more research will be needed to identify which candidates are the best for adjuvant therapy, as well as the ideal regimen for those whose disease progresses after IO.

“It’s a brave new world with patients getting exposed to [immune checkpoint inhibitors] in the adjuvant setting, and then as time wears on, we’re going to have a larger and larger fraction of patients [whose disease progresses] and have to decide what to do without a lot of data,” said Tykodi.

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