ASTRO 2023: Multidisciplinary Management from Medical Oncology

(UroToday.com)The 2023 American Society for Radiation Oncology (ASTRO) 65^th Annual Meeting held in San Diego, CA between October 1^st and 4^th, 2023 was host to a session on stereotactic radiotherapy for renal cell cancer. Dr. Rana McKay discussed the multidisciplinary management of renal cell carcinoma (RCC) from the medical oncology perspective.

SABR has a potential role for the treatment of RCC across the various disease stages:

• Localized disease (renal primary)
• Oligometastatic disease
• Oligoprogressive disease
• Metastatic disease (palliation)

In the localized setting, SABR offers the potential advantages of being a minimally invasive treatment option for patients with contra-indications to surgery (bilateral tumors, solitary kidney, comorbidities), while offering excellent local control with a minimal decline in eGFR. However, SABR does not offer the pathologic staging upside seen with surgical approaches, can be challenging to assess response post-treatment, and there is currently sparse data for the treatment of higher stage tumors (e.g., Stage 3).

Dr. McKay noted that we have witnessed an ‘explosion’ of treatment options for patients in the advanced/metastatic RCC disease space, summarized in the figure below:

Briefly discussing the current 1^st line combination therapies for the treatment of advanced/metastatic RCC, Dr. McKay noted that there are pros and cons to each treatment approach (I0-IO regimens versus IO-VEGF). Long-term, landmark analysis of the CheckMate-214 trial (nivolumab + ipilimumab) has demonstrated long-term progression-free survival rates of 30% at 5 years. Similar long-term follow-up data from the IO-VEGF trials is still lacking. However, 18% of patients treated with nivolumab and ipilimumab have evidence of progressive disease, which is much higher than the proportion seen in those treated with an IO-VEGF regimen (5- 12%).

What about the role of cytoreductive nephrectomy in the advanced disease setting? During the cytokine era, results from the SWOG-8949¹ and EORTC trials² demonstrated overall survival improvements with cytoreductive nephrectomy in the metastatic disease setting. This carried over to the targeted therapy era, whereby data from the International Metastatic RCC Database Consortium (IMDC) continued to support the role of cytoreductive nephrectomy in patients with favorable/intermediate risk disease and Karnofsky Performance Status >80%.

In 2018, the results of the CARMENA non-inferiority trial were published and demonstrated that sunitinib alone was non-inferior to nephrectomy followed by sunitinib for the primary outcome of overall survival.³ While this trial has several important limitations including over-enrichment with poor risk patients (43% of overall cohort), imbalances between the treatment groups (higher percentage of T3-T4 tumors in the treatment arm: 70% versus 51%), and significant protocol deviations, this trial did cause a shift in the treatment paradigm of such patients with decreased utilization of cytoreductive nephrectomy, which has allowed for the evaluation of alternate treatment modalities for local disease control, such as SABR. 
The phase II SAMURAI trial is evaluating the role of SABR in patients with metastatic RCC. This trial will randomize patients with metastatic RCC, 1+ IMDC risk factors, and primary lesions 8 cm in size or less amenable to SBRT to either:

• Standard immunotherapy-based regimen
• Standard immunotherapy-based regimen + SABR to the primary lesion (42 Gy in 3 fractions)

The primary endpoint is progression-free survival, and this trial is currently enrolling patients.
The phase II CYTOSHRINK trial will similarly evaluate the role of addition of SABR (30 – 40 Gy in 5 fractions) to systemic ipilimumab + nivolumab for patients with IMDC intermediate/poor-risk disease, with a primary endpoint of progression-free survival.
What about the oligometastatic/progressive disease setting? Current single arm phase II trials in this setting have demonstrated that the local control rate following SABR to these lesions is 92 – 100%. Additionally, the time to change in systemic therapy appears to be just over a year.
The RAPPORT trial was a prospective, open label, single arm, phase II trial that evaluated single fraction SABR (20 Gy) plus pembrolizumab 200 mg every 3 weeks x 8 doses in patients with oligometastatic (1 – 5 lesions) clear cell RCC (n=30). In this trial, the objective response rate was 63%, with a disease control rate of 83%. The 1- and 2-year overall survival rates were 90% and 74%, respectively.

The SOAR trial is currently ongoing and is randomizing patients with oligometastatic RCC (2 – 5 lesions) to sequential SABR to all metastases followed by systemic therapy at progression on SABR versus systemic therapy alone.
Dr. McKay noted that PSMA-PET is emerging as a staging tool for patients with metastatic RCC. A retrospective review by Siva et al. of 61 patients with RCC undergoing a PSMA PET demonstrated that 84% of patients had PSMA positive disease, with 49% of patients having a change in management secondary to the PSMA PET results.
Another emerging tool in the RCC, namely clear cell, space is ⁸⁹Zr-DFO-Girentuximab which has demonstrated accuracy of approximately 90% for the detection of clear cell RCC in the localized disease setting. Dr. McKay noted that work is ongoing to evaluate the performance of this imaging modality in the advanced clear cell RCC setting, particularly the post-nephrectomy setting.

Ongoing trials are investigating the combination of single or dual agent immunotherapy along SABR in the oligometastatic disease setting.

Dr. McKay concluded her presentation with the following take home messages:

• RCC is not a radioresistant disease
• SABR can be a treatment option for patients with a primary renal tumor who are not operable candidates
• SABR can be utilized for oligometastatic and oligoprogressive disease
• SABR is associated with good oncologic outcomes and a favorable toxicity profile
• Novel imaging modalities are being explored to better detect disease and assess response to SABR
• Novel combination strategies with IO are being explored to optimize efficacy

Presented by: Rana McKay, MD, Associate Professor, Department of Medicine, University of California, San Diego, CA

Written By: Rashid K. Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 American Society for Therapeutic Radiation Oncology (ASTRO) 65th Annual Meeting held in San Diego, CA between October 1st and 4th, 2023

1. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy Followed by Interferon Alfa-2b Compared with Interferon Alfa-2b Alone for Metastatic Renal-Cell Cancer. N Engl J Med. 2001;345:1655-9.
2. Mickisch GH, Garin A, van Poppel H, et al. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001;358(9286):966-70.
3. Mejean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal cell carcinoma. N Engl J Med. 2018;379(5):417-27.
4. Siva S, Bressel M, Wood ST, et al. Stereotactic Radiotherapy and Short-course Pembrolizumab for Oligometastatic Renal Cell Carcinoma-The RAPPORT Trial. Eur Urol. 2022;81(4):364-72.