(UroToday.com) The 2024 GU ASCO annual meeting featured a kidney cancer session and a discussant presentation by Dr. Pedro Barata discussing strategies on how to optimize patient selection for the new standard of care in the adjuvant treatment of RCC.
This discussion is from the previously presented abstracts “Adjuvant nivolumab monotherapy vs placebo for localized renal cell carcinoma at high risk of relapse after nephrectomy: Results from Part B of the randomized, phase 3 CheckMate 914 trial” by Dr. Robert Motzer, and “Overall survival results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab versus placebo for the treatment of clear cell RCC” by Dr. Toni Choueiri. Approximately 50% of post-nephrectomy patients with high risk features will eventually recur, with factors such as disease stage, size, nuclear grade, and regional lymph node involvement associated with disease recurrence and survival:
Dr. Barata notes that adjuvant anti-angiogenic therapies across solid tumors have historically struggled, including in RCC and colorectal cancer:
In the first line metastatic setting, we know that single agent pembrolizumab and nivolumab are active with median progression free survivals of 7-8 months:
Dr. Barata emphasized that the CheckMate 914 trial is an important study, given that it tests the activity of an active regimen (nivolumab + ipilimumab), and evaluates the individual contribution of nivolumab and ipilimumab. Furthermore, it explores the shorter duration (6 months) of immunotherapy. Patients in Part B were randomized 2:1:1 to nivolumab (240 mg every 2 weeks × 12) + placebo vs nivolumab (240 mg every 2 weeks × 12) + ipilimumab (1 mg/kg every 6 weeks × 4) vs placebo, and stratified by pathological TNM stage and type of nephrectomy. Treatment was planned for 24 weeks (approximately 5.5 months) or until disease recurrence/unacceptable toxicity. With 27.0 months median study follow-up (range, 18.0–42.4), the primary efficacy endpoint of disease-free survival per BICR with nivolumab monotherapy vs placebo was not met (HR 0.87, 95% CI 0.62–1.21; p = 0.3962).
Dr. Barata provided the following thoughts regarding the CheckMate 914 trial:
- There is a clear lack of benefit with a shorter duration of nivolumab + ipilimumab
- The two year disease free survival with the control arm was ~73%, which was slightly higher than that reported in the control arm of KEYNOTE-564 (~68%)
- The nivolumab + ipilimumab combination increased grade 3/4 toxicity, high dose steroid rate, and discontinuation rates, which may have impacted the efficacy of this generally active regimen
Shifting gears to discuss the KEYNOTE-564 trial, this trial randomized high risk patients after nephrectomy 1:1 to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for ≥17 cycles (~1 year) or until disease recurrence, intolerable toxicity, or withdrawal of consent. This was the third interim analysis, noting a statistically significant improvement in overall survival observed with pembrolizumab vs placebo (medians not reached, HR 0.62, 95% CI 0.44−0.87; p = 0.0024). Additionally, there was a continued disease-free survival benefit with pembrolizumab vs placebo was consistent with prior interim analyses (HR 0.72; 95% CI 0.59−0.87):
As such, this is the first immune checkpoint inhibitor to improve disease free survival in RCC, and the first immune checkpoint inhibitor to improve survival in any GU tumor. In fact, Dr. Barata emphasized that the chance of this being a falsely positive trial is only 0.2%, which is roughly the chance of being struck by lightning in a lifetime in certain high risk regions of the world. Furthermore, pembrolizumab is the first PD-1 inhibitor to show a disease free survival AND overall survival benefit in the pure adjuvant setting, across solid tumors (n = 12 phase 3 trials):
With regards to how we manage disease progression, Dr. Barata notes that there were no major differences in the next treatments between the cohorts, however, there were several important findings:
- In the placebo arm, many patients eventually received immune checkpoint inhibitor therapy, including 69.7% receiving an anti-PD-(L)1 therapy
- Over ~5 years, 1/4 of patients received local therapy during the study period
- We need to know more about the biology of tumors that recur after adjuvant immune checkpoint inhibitor therapy. We do know that salvage PD-L1 inhibitor + TKI is not superior to TKI alone if there is progressive disease in < 6 months based on the CONTACT-03 trial1
From perhaps a somewhat speculative approach, Dr. Barata highlighted that ~50% of patients are cured from surgery, ~8% of patients have a long remission and are perhaps cured from immune checkpoint blockade, but ~40% of patients progress despite immune checkpoint inhibitors:
The following summarizes the phase 3 adjuvant RCC immune checkpoint inhibitor trials:
Additionally, the following is Dr. Barata’s in depth approach for assessing and treating patients with RCC after nephrectomy:
Given that we have now seen several iterations of the KEYNOTE-564 trial results (with this being the third interim analysis), it is curious to see that over time, the community has remained consistent in primarily offering adjuvant therapy to patients with high-risk/M1-NED only:
From a patient experience standpoint, most patients only experienced mild toxicity (similar to M1 treatment), with no significant differences in health related quality of life. However, some patients will experience severe adverse events, require high dose steroids, and discontinue immune checkpoint inhibitor therapy early:
Survey data from KCCure among 639 RCC patients (113 offered adjuvant treatment, 67% received adjuvant therapy) notes that the number one factor impacting the decision to receive adjuvant therapy is risk of dying from cancer (76% of respondents), followed by the severity of the side effects (43% of respondents). Thus, efficacy and living longer matter to these patients above and beyond even side effects of adjuvant treatment.
So, now that we have overall survival data from KEYNOTE-564, Dr. Barata notes that the scales are tipping further for benefit of adjuvant pembrolizumab in our high risk patients after nephrectomy:
Before concluding Dr. Barata highlighted several upcoming trials in the adjuvant RCC disease space, including RAMPART, LITESPARK-022, and NCT06146777:
Dr. Barata concluded his discussant presentation with the following take-home points:
- This is the first time we have seen a survival advantage with a PD-1 inhibitor in the pure adjuvant setting in RCC, which is a huge breakthrough for our patients
- The fact that only pembrolizumab to date has worked is likely multifactorial and based on histology, PD-1 vs PD-L1, duration of treatment, and patient characteristics: higher risk, sarcomatoid, PD-L1+/M1 NED, safety, discontinuation rates, etc
- Approximately 50% of post-nephrectomy patients with high risk features do not require any adjuvant treatment, thus we will probably continue to select the patients who will receive pembrolizumab and the post-PD-L population will grow
- Further questions remain:
- How do we better select patients for pembrolizumab?
- What do we do after progression on pembrolizumab? (Timing/number and site)
- Is there any activity beyond clear cell histology?
Presented by: Pedro C. Barata, MD, MSc, University Hospitals Seidman Cancer Center, Cleveland, OH
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Jan 25 – Sat, Jan 27, 2024.
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