Atezolizumab as Adjuvant Therapy After Resection for Patients with Renal Cell Carcinoma with Increased Risk of Recurrence: IMmotion010 Trial, Journal Club - Zachary Klaassen

December 15, 2022

In this UroToday Journal Club, Christopher Wallis and Zachary Klaassen review the Lancet publication Adjuvant atezolizumab versus placebo for patients with renal cell carcinoma at increased risk of recurrence following resection (IMmotion010): a multicentre, randomised, double-blind, phase 3 trial.  Approximately 80% of patients, present initially with local regional disease. However, despite the initial localized diagnosis, recurrence following surgery is not uncommon for these patients and may be 10% in the first 5 years after surgery for low-risk disease, rising to nearly 70% in those who have high-risk disease at the time of surgery. The objective of the IMmotion010 study was to determine if adjuvant atezolizumab (vs placebo) delayed recurrence in patients with an increased risk of recurrence after resection.


Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center

Read the Full Video Transcript

Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club discussion. Today, we're talking about the recently published IMmotion010 trial of adjuvant atezolizumab versus placebo for patients with renal cell carcinoma at increased risk of recurrence following a resection. This is a multicenter, randomized, double-blind, phase III trial. I'm Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto. With me today is Zach Klaassen, an Assistant Professor in the Division of Urology at the Medical College of Georgia. You can see here the citation for this recent publication led by Dr. Pal and published in Lancet.

Renal cell carcinoma is the 12th most common cancer worldwide and the vast majority, approximately 80% of patients, present initially with local regional disease. However, despite the initial localized diagnosis, recurrence following surgery is not uncommon for these patients, and may be 10% in the first 5 years after surgery for low-risk disease, rising to nearly 70% in those who have high-risk disease at the time of surgery.

As you can see here, from the NCCN guidelines, following primary surgical treatment, the recommended approach for the vast majority of patients is surveillance. However, we do know, as just discussed, that relapse rates are not insignificant on this approach. Thus, we can potentially risk stratify those at higher risk of recurrence following nephrectomy, and these include disease stage, size, grade, and the involvement of local regional lymph nodes. Current guidelines, however, recommend observation or clinical trials rather than intervention for these patients. This is in part because, while VEGF-targeted therapy has shown a survival benefit of metastatic disease, prior randomized control trials of nearly all TKIs have showed no survival benefit, and only the abstract trial showed a DFS benefit.

Recently, we saw data from KEYNOTE-564, which, in a similar setting, assessed the role of adjuvant pembrolizumab for 1 year following surgery and showed improvements in DFS for patients receiving pembrolizumab. The IMmotion010 trial, therefore, sought to assess a similar question in patients receiving atezolizumab. And so we'll walk through each of the steps with this study scheme in the coming slides, but this is a good overview of the trial. first, we consider the inclusion criteria. These are adult patients with histologically confirmed local regional renal cell carcinoma who have either a clear cell component or sarcomatoid histology after you have undergone a surgery and have evidence of a high postoperative recurrence rate by one of these following criteria, T2 and high grade histology or sarcomatoid features, T3A and 3 three or 4 histology, T3b, T3c, or T4 regardless of grade, anybody with nodal involvement, and anyone with metastatic disease, which was fully resected.

As a result, you can see that patients could not have any radiographic evidence of disease at the time of study screening. Thus, this is truly adjuvant therapy. Patients were excluded if they received prior systemic therapy or had evidence of disease at the time of randomization.
Patients were randomized in a 1:1 fashion to receive adjuvant atezolizumab versus placebo, and patient randomization with stratified according to disease stage, geographic region, and PD-L1 status with this dichotomized less than 1% or 1% or greater. Atezolizumab was given every 3 weeks for up to 16 cycles or 1 year. Treatment continued to evidence of recurrence, toxicity, precluding illness, investigative decision, or patient decision.

The primary study endpoint was investigator-assessed disease-free survival. This is the time from randomization to the first documented evidence of local or distant recurrence or death. Secondary endpoints include overall survival, DFS by an independent central review, DFS in a PD-L1 positive subset, event-free survival, and disease-specific survival. Patients were assessed with CT or MRI cross-sectional imaging every 3 months for the first 3 years and every 6 months thereafter. Safety was assessed at the start of each treatment cycle every 3 weeks for atezolizumab and placebo.

In terms of statistical analysis, the authors plan to enroll 764 patients with DFS assessment planned at 334 events. This was expected to provide a 90% power to detect a hazard ratio of 0.70, or 30% decrease in the rate of DFS events. Efficacy is assessed in the intention-to-treat population and safety among all those who received a study drug. The authors planned alpha spending hierarchically to assess overall survival if DFS showed a significant benefit. They assess DFS using log-rank tests with Cox proportional-hazards models used to calculate hazard ratios and 95% confidence intervals. All secondary survival endpoints were assessed using the Kaplan-Meier method, and the authors perform pre-specified subgroup analyses according to age, race, region, sarcomatoid histology, PD-L1 expression, disease status, and UCLA ISS risk group. Now I'm going to hand it over to Zach to walk us through the results of the trial.

Zachary Klaassen: Thanks so much, Chris. This is the trial profile. As you can see, there was, ultimately, 778 patients that were randomly assigned. This included 390 to the atezolizumab group and 388 to the placebo group. Ultimately, 255 completed treatment in the atezolizumab group and 274 completed treatment in the placebo group.

This is the baseline characteristics and the intention-to-treat population. As you can see, these were well balanced for the most part. In terms of the median age, was roughly 60 years old in each group, roughly three-quarters of patients were male, just over three-quarters of patients were white, and the majority of these patients had ECOG 0, had an excellent performance status. With regards to histology, this was primarily a clear cell renal cell carcinoma population at over 90%, but you can see there was several non-clear cell histologies as well. In terms of the component of sarcomatoid, the differentiation, interestingly, we see that there was 17% in the placebo arm versus 9% in the atezolizumab arm.

With regards to pathological disease stage, roughly two-thirds of these patients were T2 or T3a, which was well balanced between the two groups, and roughly 20% were T3b or higher. In terms of N1, no evidence of disease, 14% in the atezolizumab arm and 13% in the placebo, which was well balanced. Additionally, at the bottom of the slide you can see PD-L1 immune expression was greater than or equal to 1% in just roughly 60% of the patients.

This is the primary outcome for disease-free survival assessed by the investigators in the intention-to-treat population. The atezolizumab arm is in blue, the placebo group is in red, and you can see that this is a non-significant primary outcome. The median DFS for atezolizumab was 57.2 months compared to placebo, which is 49.5, with a hazard ratio of 0.93 and 95% confidence interval of 0.75 to 1.15.

Looking at the subgroup analysis assessed also by the investigators. Generally, there was no benefit for atezolizumab amongst these subgroups. We do see, perhaps, a small signal among Asians and female patients, however, this should be interpreted with caution based on the small sample size of these subpopulations. In terms of secondary outcomes, with regards to investigator assessed disease-free survival, event-free survival, disease-specific survival, distant metastasis-free survival, as well as the analysis by PD-L1 immune staining. To summarize, essentially, these were all non-significant outcomes between atezolizumab and the placebo group. This is the Kaplan-Meier curve for overall survival. As you would expect, there was no difference between these two groups. Again, median overall survival for both was not reached, with a hazard ratio non-statistically significant, 0.97, 95% confidence interval, 0.67 to 1.42.

This is the adverse event profile looking at the difference of more than or equal to 5% between these two groups. The placebo group is on the right, the atezolizumab group is in blue on the left. We can see slightly more arthralgia in atezolizumab. Pruritus, 19% versus 13%. 14% hypothyroidism versus 3%. Again, we see slightly more rash and pyrexia in the atezolizumab group. And interestingly, which is sort of a new signal, is dry mouth, at 7% for atezolizumab versus placebo at 2%. The majority of these were lower grade adverse events, as you can see on the shading scheme at the bottom right.

In terms of safety, any adverse event between the two groups, 96% for atezolizumab, 89% for placebo. Grade 3 or 4 adverse events, 27% for atezolizumab, 21% for placebo. Death due to adverse event was low in each of these groups. Serious adverse events, slightly higher for atezolizumab at 18% versus 12% the placebo group, and you can see relatively low rates of discontinuation secondary to treatment.
Several important discussion points from this negative IMmotion010 study. As I highlighted in the results of the pre-specified primary analysis of IMmotion010, this trial did not meet its primary endpoint. Adjuvant atezolizumab did not improve DFS versus placebo for high-risk renal cell carcinoma. There's several strengths of IMmotion010. It had a large population, long median follow up of 45 months. Additionally, this was the primary analysis of the first initial PD-L1 trial and not an interim analysis, and it was enriched for patients at high-risk of recurrence. So those that may benefit from adjuvant therapy, including sarcomatoid and M1 NED. Additionally, the control group in this trial performed as expected, which suggests that the investigators did enroll the intended population for this trial.

So, the big question is, why and how does this differ from KEYNOTE-564? And this is a study that was published in New England Journal last year, but Dr. Choueiri and colleagues, where we saw DFS benefit with adjuvant pembrolizumab at 24 months, with a hazard ratio of 0.68 and a 95% confidence interval of 0.53 to 0.87. This was again confirmed at 30 months of follow up, with a ratio of 0.63.

There's several key differences that the authors of IMmotion010 point out, and whether this is the reason for the differences between the two trials is somewhat subject to interpretation. But nonetheless, they did note that patient eligibility was slightly different between these two groups. In KEYNOTE-564, 6% of patients were M1 NED, which did have a benefit with adjuvant pembrolizumab. Additionally, they had patients that were only patients with synchronous metastasis or metastasis resected within 1 year of nephrectomy that were eligible for that trial. In IMmotion010, 14% of patients were M1 NED, and these patients did not have a benefit to adjuvant atezolizumab. This trial did include synchronous and metachronous metastatic patients. In terms of grade of disease, in KEYNOTE-564, there was no grade specification for greater than or equal to pT3, and in IMmotion010, this was restricted to eligibility of T3a tumors only with a Fuhrman and grade of 3 or 4. Additionally, lymph node involvement was 6% in KEYNOTE-564 and 11% in IMmotion010.

In conclusion, atezolizumab as adjuvant therapy after resection for patients with RCC with increased risk of recurrence showed no evidence of improved clinical outcomes versus placebo. Of note, biomarker work is underway to determine whether tumor genomic characteristics or circulating biomarkers can identify patient populations who may derive a benefit from adjuvant atezolizumab. Unfortunately, these study results do not support adjuvant atezolizumab for treatment of renal cell carcinoma. Thank you very much for your attention. We hope we enjoyed this UroToday Journal Club discussion of the recently published IMmotion010 trial in Lancet.