ASCO 2021: Unanswered Questions in the Management of Advanced Renal Cell Carcinoma

(UroToday.com) The American Society of Clinical Oncology (ASCO) 2021 Annual Meeting’s kidney and bladder cancer poster discussion included a discussant presentation by Dr. Anil Kapoor addressing unanswered questions in the management of advanced renal cell carcinoma. Dr. Kapoor notes that there are many unanswered questions, including the following:


  • What is the optimal sequence in metastatic kidney cancer?
  • How do we select for first-line treatment in metastatic RCC?
  • What are the treatment options for patient subgroups traditionally excluded from registration trials?
  • Which patients benefit from cytoreductive nephrectomy?
  • What are the optimal treatments for non-clear cell histologies?
  • What is the role of adjuvant treatment in high-risk resected RCC?
  • How do we utilize biomarkers?

The three abstracts Dr. Kapoor discussed are attempting to answer several of these questions. The first abstract discussed was “Outcomes of patients who progressed while receiving avelumab + axitinib and received subsequent treatment in JAVELIN Renal 101” by Dr. Laurence Albiges. Dr. Kapoor notes that based on the NCCN April 2021 guidelines for first-line and subsequent therapies for clear cell histologies, as well as the Canadian mRCC 2021 Consensus Guideline, there are many options available, making sequencing difficult. For context, the following is a summary of PFS and OS among the key practice-changing trials:

ASCO_avelumab_axitinib.png

In this subgroup analysis of the JAVELIN Renal 101 trial, Dr. Kapoor highlighted the findings in this study. At the cutoff date for the third interim analysis, 346 of 442 patients (78.3%) in the avelumab + axitinib arm discontinued treatment with avelumab, and 338 of 442 (76.5%) discontinued axitinib. At least one second-line anticancer drug therapy was received by 204/442 patients following first-line avelumab + axitinib treatment:

ASCO_JAVELIN_Renal_101.png

The summary of second-line anticancer drug therapy is as follows:

ASCO_JAVELIN_Renal.png

The most common second-line treatment was VEGF(R) received by 132 of 204 patients, and cabozantinib was the most frequently used VEGF(R) TKI treatment. Second-line PD-(L)1 treatment was given in 19 of 024 patients, with nivolumab being the most frequently used agent. The median OS in patients receiving second-line VEGF(R) or PD-(L)1 inhibitors was 29.8 months (95% CI 24.1-42.2) and not evaluable, respectively:

ASCO_VEGFR.png

There were 20 of 204 patients that received second-line combination therapy with VEGF(R) + other, with the combination of lenvatinib + everolimus being more frequently used, while 21 of 204 patients received any other combination therapy. The median OS in patients receiving second-line combination VEGF(R) + other or any other combination therapy was not reached in either arm. As follows is the summary of OS:

ASCO_lenvatinib_everolimus.png

The key take-away points from this study according to Dr. Kapoor are as follows:

  • Treatment with second-line treatment after first-line TKI/immunotherapy progression likely confers a benefit over no second-line treatment
  • The most common second-line agent in JAVELIN was a single agent TKI
  • The optimal second-line strategy is still unknown
  • Strengths: robust phase 3 randomized controlled trial (JAVELIN) sub-analysis
  • Ongoing studies: more data is needed to determine optimal second-line strategies

The second abstract discussed was “Safety and efficacy outcomes with nivolumab plus ipilimumab in patients with advanced renal cell carcinoma and brain metastases: Results from the CheckMate 920 trial” by Dr. Hamid Emamekhoo. In CheckMate 920, there were 28 treated patients with brain metastases, 85.7% were men; median (range) age was 60 (38–87) years, and 14.3% had sarcomatoid features. With 24.5 months minimum follow-up of the 28 patients enrolled, median duration of therapy (range) was 3.4 (0.0–23.3) months for nivolumab and 2.1 (0.0–3.3) months for ipilimumab. No grade 5 immune-mediated adverse events occurred. Grade 3–4 immune-mediated adverse events by category were diarrhea/colitis (7.1%), hypophysitis (3.6%), rash (3.6%), hepatitis (3.6%), and diabetes mellitus (3.6%). Of the 25 patients who were evaluable for objective response rate, the objective response rate was 32.0% (95% CI, 14.9–53.5). No patients achieved complete response, 8 achieved partial response, and 10 patients had stable disease. Median time to response (range) was 2.8 (2.4–3.0) months. Median duration (range) of response was 24.0 (3.9–NE) months, and 4 of 8 responders remain without reported progression. Of 28 patients, 7 (25%) had intracranial progression. Median PFS was 9.0 (95% CI, 2.9–12.0) months:

ASCO_Kapoor.png


and median OS was still not reached (95% CI, 14.1 months–NE):

ASCO_Emamekhoo.png

Dr. Kapoor’s takeaway points from the CheckMate 920 trial are as follows:

  • There were no new safety concerns in patients with brain metastases from metastatic RCC treated with nivolumab plus ipilimumab
  • Response rates in patients with brain metastases on nivolumab plus ipilimumab are encouraging

The final abstract discussed was “Survival benefit of nephrectomy prior to immunotherapy-based combinations in patients with metastatic renal cell carcinoma: An FDA pooled analysis” by Dr. Jaleh Fallah. Dr. Kapoor highlighted that CARMENA1 showed that sunitinib alone was not inferior to cytoreductive nephrectomy in patients with mRCC, with an HR for death of 0.89 (95% CI 0.71-1.10; non-inferior if upper boundary <= 1.20). Additionally, the median OS was longer in the sunitinib-alone arm for all patients and in intermediate-risk and poor-risk subgroups. The clinical benefit rate was significantly higher in the sunitinib-alone arm (47.9% versus 36.6% with nephrectomy à sunitinib, p = 0.02), and 22.5% of patients never recovered enough to receive sunitinib after cytoreductive nephrectomy.

The conclusion of this study was that cytoreductive nephrectomy should no longer be part of standard of care for patients with mRCC requiring medical treatment. However, there are limitations associated with this study, including (i) slow enrollment of 0.7 patients/site/year, (ii) incomplete enrollment (450/576), (iii) exclusion at the investigator’s discretion, (iv) high-proportion (43%) with poor-risk disease, and (v) in the era of TKI first-line therapy, immunotherapy is now first-line therapy.

In the study presented by Dr. Fallah, there were five trials that met inclusion criteria, all of which evaluated immunotherapy in combination with a kinase inhibitor. Data for stage at initial diagnosis was available in 1,708 patients who received immunotherapy-based combination therapies. The majority of patients were male (72%) and white (80%). Among the 849 patients (50%) with stage IV RCC at initial diagnosis, 523 patients (62%) had nephrectomy prior to immunotherapy-based combination therapies. All patients had clear cell histology and sarcomatoid differentiation was present in tumor pathology of 25% and 10% of patients with and without prior nephrectomy, respectively. The proportion of patients with favorable, intermediate, and poor-risk disease was 10%, 70%, and 20%, respectively. OS appeared better in those with stage IV disease at diagnosis who had prior nephrectomy compared to patients without nephrectomy (HR 0.53, 95% CI 0.42 to 0.68), even after adjusting for age and prognostic risk group (HR 0.59, 95% CI 0.46 to 0.75):

ASCO_nivolumab_plus_ipilimumab.png

Dr. Kapoor’s take-away points from this analysis are as follows:

  • We now have more data suggesting benefit of cytoreductive nephrectomy in the immunotherapy era
  • Strengths: a comprehensive FDA review
  • Caveats: a retrospective exploratory analysis

Dr. Kapoor concluded by highlighting that given the complex nature of advanced kidney cancer management, decisions regarding cytoreductive nephrectomy should ideally be made in a multidisciplinary setting.

Presented by: Anil Kapoor, MD, FRCSC, McMaster University, Hamilton, Ontario, Canada

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021

References:

  1. Mejean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal cell carcinoma. N Engl J Med 2018 Aug 2;379(5):417-427.