CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: April 18, 2022
Expiration: April 17, 2023
Toni K. Choueiri, MD:
At ASCO GU 2022, I presented on behalf of my colleagues an updated analysis of the randomized double-blind phase III KEYNOTE‑564 trial.21,22 This was the first adjuvant study showing immunotherapy benefits patients with renal cell carcinoma (RCC) who are at risk of recurrence. A total of 994 patients with clear-cell RCC with intermediate‑high risk, high risk, or M1 NED after surgery were randomized to receive pembrolizumab or placebo. Patients could not have received prior systemic treatment, and available tissue samples were required for PD-L1 evaluation. Stratification was by metastatic status (M0 vs M1 NED). Patients received pembrolizumab or placebo once every 3 weeks for up to 17 cycles (~1 year of therapy).
The primary endpoint of KEYNOTE-564 is investigator-assessed DFS, and secondary endpoints are OS and safety. At the interim analysis, which had a median follow-up of 24.1 months, the primary endpoint was met with an HR: 0.68. The current analysis is an update with a median of 30.1 months follow-up and a data cutoff of June 14, 2021.
Toni K. Choueiri, MD:
Baseline characteristics were well balanced between arms.21 The most common disease risk category was M0 intermediate-high in 86% of patients in each arm. Tumor stage and grade were well matched between the arms.
Toni K. Choueiri, MD:
In this updated analysis, the HR for DFS stayed stable at 0.63 (95% CI: 0.50-0.80); in the earlier analysis, the HR was 0.68.21 Recall that the data cutoff was more than 1 year after pembrolizumab therapy was stopped, so the DFS benefit persisted even without pembrolizumab. The 24‑month DFS rate was 78.3% with pembrolizumab and 67.3% with placebo.
I also presented new subgroup analyses by recurrence risk and sarcomatoid status.21 In patients with intermediate-high risk at baseline, the HR for DFS was 0.68 (95% CI: 0.52-0.89), indicating that pembrolizumab remains clinically relevant in this subgroup. The DFS benefit was similar in the high-risk subgroup, with an HR: 0.60 (95% CI: 0.33-1.10), but the greatest benefit was observed in patients with M1 NED (HR: 0.28; 95% CI: 0.12-0.66). Patients with and without sarcomatoid features also had a DFS benefit from pembrolizumab, with HR: 0.63 and HR: 0.54, respectively.
Toni K. Choueiri, MD:
The OS data remain immature, with only 66 events at the time of this updated analysis.21 The final analysis is planned after approximately 200 events. Nevertheless, comparing the primary and updated analyses, which includes an additional 6 months of data, the HR for OS remains solid at 0.54 but did not meet the prespecified threshold for significance.
Toni K. Choueiri, MD:
Toxicity data in the updated analysis were similar to those reported in the primary analysis.21 The rate of all-cause grade 3-5 AEs was higher with pembrolizumab vs placebo (32.2% vs 17.7%), as was the rate of serious all‑cause AEs (20.7% vs 11.5%). There was also a higher rate of grade 3/4 TRAEs with pembrolizumab (18.6% vs 1.2% with placebo). The rate of high‑dose systemic corticosteroid use to treat immune-mediated AEs was also higher with pembrolizumab (7.6% vs 0.6%).
Toni K. Choueiri, MD:
I also presented our updated analysis on the median time to first onset of AEs, which was less than 6 months across the TRAEs shown here.21
Toni K. Choueiri, MD:
In this updated analysis of KEYNOTE-564 that included an additional 6 months of follow-up, adjuvant pembrolizumab maintained a statistically significant DFS improvement vs placebo in patients with RCC post nephrectomy (HR: 0.63; 95% CI: 0.50-0.80) 21 The DFS benefit was consistent across patient subgroups. The OS data remain immature, but additional follow-up is planned. With longer follow-up, adjuvant pembrolizumab was not associated with increased rates of TRAEs or high-dose corticosteroid use for immune-related AEs, and few TRAEs had late onset.
The updated analysis supports the use of adjuvant pembrolizumab as the standard of care for patients with RCC at risk for recurrence. Indeed, based on data from this trial, the FDA approved pembrolizumab in November 2021 for adjuvant treatment of patients with RCC at intermediate-high risk or high risk of recurrence following nephrectomy alone or nephrectomy and resection of metastases.23
Dr. Petrylak, what is your take on this updated analysis?
Daniel P. Petrylak, MD:
I want to see the final OS data, but the DFS data are pretty impressive with an HR: 0.63. I agree that pembrolizumab is the standard of care at this point.
Toni K. Choueiri, MD:
The next trial is relevant for patients with adrenocortical carcinoma, a very rare malignancy.24 Adjuvant mitotane is the current standard of care for patients at high risk of relapse after resection, but this is based on retrospective data rather than a prospective, head‑to‑head comparison.25,26 ADIUVO is the first randomized phase III study comparing mitotane vs observation, and results from the trial were presented by Berruti and colleagues27 at ASCO GU 2022.
ADIUVO enrolled 91 patients with stage I-III adrenocortical carcinoma at low or intermediate risk of relapse and an ECOG performance status of 0-2. The study had initially planned to enroll 200 patients, but accrual was stopped due to slow enrollment from March 2008 - December 2018. Patients were stratified by stage (I/II vs III) before randomization to adjuvant mitotane or observation. The mitotane dose was adjusted to target a plasma concentration of 14-20 mg/L. The primary endpoint was relapse-free survival (RFS), and secondary endpoints were OS and safety.
We should also note that in addition to the randomized patients, a nonrandomized ADIUVO Observational study was initiated for 95 patients who met the same eligibility criteria as for the randomized ADIUVO trial. Treatment was selected by the physician in collaboration with the patient; ultimately, 53 patients opted for observation and 42 opted for adjuvant mitotane.
Toni K. Choueiri, MD:
The treatment arms were well balanced.27 Most patients had stage II or III disease, and one half had secreting tumors. Mitotane was not started in 5 of the patients randomized to the mitotane arm.
Toni K. Choueiri, MD:
Unfortunately, this was a negative trial despite the promising retrospective data on adjuvant mitotane. There was no difference in RFS in the ITT population (HR: 0.74; 95% CI: 0.30-1.85).27 The 5-year RFS rate was rather high in both arms, at 79% with mitotane vs 75% with observation.
Toni K. Choueiri, MD:
There was no significant difference in OS observed between the arms (HR: 0.46; 95% CI: 0.08-1.92).27 The 5‑year OS rate was very high in both arms, at 95% with mitotane and 86% with observation, which is better than our clinical experience over the last several decades.
Toni K. Choueiri, MD:
The safety profile was consistent with that established for mitotane.27 Grade 3 AEs affected the liver in 3 patients, GI system in 2 patients, neurologic system in 2 patients, and hematologic system in 1 patient. Mitotane was discontinued before 2 years in 8 patients.
Regarding pharmacokinetics, 62.5% of patients achieved the target plasma mitotane concentrations ≥14 mg/L.
Toni K. Choueiri, MD:
The ADIUVO trial was designed to assess the safety and efficacy of adjuvant mitotane in patients with stage I-III adrenocortical carcinoma with R0 and Ki-67 <10%.27 Trial enrollment was stopped early due to slow accrual, limiting statistical power to detect benefit. Good prognosis was observed in both arms, particularly in the observation group where the 5-year risk of relapse was 25% and the 5-year mortality risk was 14%. The investigators concluded that adjuvant mitotane may improve outcomes in this setting, but this could not be conclusively demonstrated due to the low number of events.
I do not know if I am going to change my standard of care here. I do give adjuvant mitotane to high-risk patients. In my clinic I do not see such a high rate of 5‑year survival.
Dr. Petrylak, what is your take here?
Daniel P. Petrylak, MD:
It is disappointing that mitotane did not show a benefit. I thought this was a unique phase III trial design with the dosing based on serum drug levels. Ultimately, this was a negative trial.
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