KEYNOTE 564 Design, Criteria, and Endpoints

KEYNOTE 564 Design, Criteria, and Endpoints

Dr Nizar Tannir: Here is the layout of KEYNOTE-564. Key eligibility criteria included confirmed clear cell RCC [renal cell carcinoma]nephrectomy within 12 weeks prior to randomization, that’s important, good performance status and stratification factor M0 vs M1 NED [no evidence of disease]. This trial recruited patients who had metastatic disease, oligometastases that were resected without evidence of disease status. That’s the M1 NED. That is a layer. The other within the M0 group was further stratified by ECOG 0 vs. ECOG 1 and US vs. non-US sites. The experimental arm in KEYNOTE-564 was pembrolizumab 200 mg IV [intravenously] every 3 weeks for 1 year vs. placebo for 1 year. The primary endpoint was disease-free survival. [DFS] per researcher. The key secondary endpoint was OS [overall survival]. The other secondary endpoint was safety. In the next slides, we will see the efficacy results of KEYNOTE-564.

Here are the patients who were eligible. There were 3 cohorts of patients. The vast majority of those patients were in the upper-intermediate level. [risk cohort], and fewer patients (5% to 8%) had M1 HEN and high risk defined by pT4, or any tumor, any pT, any grade, but node positive. Those plus the M1 NED made up approximately 13% of recruitment, and the vast majority of patients were upper-intermediate. [risk]pT2, grade 4, or sarcomatoid, N0, M0, then any grade except pT3, N0, M0.

At the bottom are the disease-free survival data at 5 years by UISS [UCLA Integrated Staging System] and for M1 NED, the ECOG 2810 study. The probability of relapse is higher for M1 NED, followed by node-positive patients. Then there are patients who have T4 disease, and then pT3 disease, which this patient had. That patient will have a relapse rate of 20% to 45%. The pT3 [category] It comes in different flavors: pT3a, pT3b or pT3c. The higher the degree, the greater the probability of relapse. That speaks to why I’m not sending those patients to Scott. [Tykodi] or Moses [Ornstein] in their institutions. Those patients have only a 20% chance of relapse at 5 years if they have pT2, grade 4 disease.

The list of criteria is on the slide. As I mentioned, 86% or 87% of those patients had M0, intermediate-high risk. Those were T2 disease, grade 4 or sarcomatoid, and T3. Eighty-five percent of high-risk M0 [patients] they were M1 NEDs.

[Let’s look at] the pair of markers for the primary endpoint, disease-free survival. This is intention to treat per investigator assessment. The green curve represents the patients treated with pembrolizumab and the red [curve] are patients treated with placebo. At the 2-year mark, there is a delta of about 11% for the probability of disease-free survival between the 2 arms. That had a hazard ratio of 0.68 at the time of the initial analysis at ASCO [American Society of Clinical Oncology Annual Meeting] 2021. That was a statistically significant difference for DFS between the 2 arms. At subsequent follow-up with a minimum follow-up of 2.5 years, that difference of 11% is maintained, with a slightly lower hazard ratio of 0.63. [This is] a significant difference for the delta for the probability of disease-free survival at 2 years.

Looking by risk category (intermediate-high risk, high risk, and M1 NED) for the 3 cohorts, there is a separation of the curves for disease-free survival between the treatment arm, pembrolizumab versus placebo, with hazard ratios of 0.68 , 0.60, and 0.28. But a note of caution here: For high risk and HEN M1, because the number of patients is small, I would interpret this with caution. If you look at the confidence interval for high risk, the upper bound is 1.10. Cross the 1. The hazard ratio is 0.6. The difference is numerically larger, but it is a small number of patients, so care must be taken in interpreting this.

When you’re on adjuvant therapy and you haven’t shown significant improvement in OS because the OS data is still immature, safety becomes important. One will look in the subgroups for trends or suggestions. You can look at the forest plot and discuss whether forest plots are useful. When you look at the phase 3 randomized trials, you can see pembrolizumab-treated patients in all of those subgroup categories, including age, gender, ECOG [performance status], region and tumor grade. PD-L1 status favored pembrolizumab over placebo, although care should be taken not to place too much emphasis on forest plot subgroup analysis of these trials.

This is the interim operating system in the intention-to-treat population. The primary analysis had a median follow-up of 24.1 months on the left, and [the updated analysis] had a median follow-up of 30.1 months. The upper curve, the green curve, represents patients treated with pembrolizumab; the red curve represents patients treated with placebo. The hazard ratio is 0.54, but only one third of deaths have been observed. This is still immature data for the operating system. We need a longer follow up to say if this will cross the pre-specified statistical significance. However, it is important to know that there have been more deaths in the placebo group. You can see patients with events at last follow-up: 43 versus 23. There is a difference there, but the median has not been reached for either arm.

[Looking at] adverse events [AEs]if we focus on [updated analysis]there are higher [rates of] All-cause AEs in the pembrolizumab arm versus the placebo arm, especially when you look at adverse events of grade 3 and above, which were nearly twice as high with pembrolizumab than with placebo. That’s no surprise. But there were only 2 deaths in the pembrolizumab arm and 1 death in the placebo arm. Those 2 deaths are not necessarily from the study. They were not necessarily related to treatment. Serious adverse events were nearly twice as high with pembrolizumab versus placebo, and serious adverse events leading to treatment discontinuation were 10% versus 1%, which was not surprising. Even in the fit and healthy population, such as post-nephrectomy patients, there are patients who develop anti-PD-1 toxicity, leading to discontinuation. Grade 3 and 4 treatment-related adverse events were 18.6% vs. 1.2%. Immune-related adverse events were lower: about 9% vs. 0.6%. About 8% of patients required high-dose corticosteroids to manage immune-related adverse events.

[This slide] talks a little more about adverse events. We are all familiar with the adverse events of pembrolizumab monotherapy. Side by side in that tornado diagram are the pembrolizumab-treated patients and the placebo-treated patients. From top to bottom are the adverse events we expect from an anti-PD-1: fatigue, rash, pruritus, thyroid disorder, diarrhea, arthralgia, nausea, myalgia, and asthenia. The median time to first occurrence of these adverse events in the pembrolizumab arm is approximately 6 months.

Transcript edited for clarity.

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