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FAQ: Adjuvant Tx for RCC
Experts Answer HCP Questions on Adjuvant Therapy for Renal Cell Carcinoma

Released: April 13, 2022

Expiration: April 12, 2023

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In this commentary adapted from a live webinar, experts Brian A. Costello, MD, MS; Eric Jonasch, MD; and Elizabeth R. Plimack, MD, MS, answer questions from healthcare professionals on the latest developments in management of nonmetastatic renal cell carcinoma (RCC).

Apart from the PROSPER RCC trial, where renal biopsy is needed, what are the indications to pursue renal biopsy for patients with RCC?

Brian A. Costello, MD, MS:
For many patients with a localized kidney tumor, imaging characteristics will guide the urologist in deciding the next steps for management. For some patients, biopsy of the renal mass may not be needed if the imaging characteristics are consistent with a particular diagnosis. However, if there is suspicion for nonrenal cortical pathology (eg, lymphoma or upper tract urothelial cancer), then a renal biopsy can be considered. Renal biopsy for histologic confirmation may be necessary for enrollment on clinical trials, such as the phase III PROSPER RCC trial (NCT03055013), which compared perioperative nivolumab vs observation in patients with localized RCC.

When imaging suggests the presence of metastatic RCC, biopsy of the metastatic site is recommended for both staging and diagnostic purposes. When it is difficult to obtain tissue from a metastatic site and the imaging characteristics are suggestive of metastatic RCC, then we would consider a biopsy of the primary tumor instead.

What would be the ideal treatment for a patient progressing post adjuvant pembrolizumab? How would this treatment approach change if the patient experienced progressive disease while receiving adjuvant therapy vs 2 years after the end of adjuvant therapy?

Brian A. Costello, MD, MS:
Recall that, based on data from the phase III KEYNOTE 564 trial, pembrolizumab was approved by the FDA in 2021 as adjuvant therapy for patients with RCC at intermediate/high- or high-risk of recurrence following nephrectomy or nephrectomy and complete resection of metastatic lesions. An open question when using pembrolizumab as adjuvant therapy in RCC is how to sequence subsequent therapies if the patient develops metastatic disease during or soon after adjuvant pembrolizumab. Currently, we do not have data to guide us on this sequencing issue.

In my clinical practice, I would consider several options depending on the patient’s disease course. For a patient who received adjuvant pembrolizumab and had a disease-free interval of ≥1 year before developing metastatic disease, it would be reasonable to consider an immunotherapy-based treatment in the first-line setting. However, the window for immunotherapy is unclear and relegated to clinical judgment; a healthcare professional may even consider using immunotherapy in the metastatic setting after a disease-free interval of only 6 months. For a patient who develops metastatic disease while receiving adjuvant pembrolizumab, I would recommend cabozantinib rather than an immunotherapy combination.

What are the types and rates of adverse events (AEs) with adjuvant pembrolizumab in RCC?

Brian A. Costello, MD, MS:
In the phase III KEYNOTE-564 trial comparing adjuvant pembrolizumab vs placebo for clear-cell RCC, treatment-related AEs lead to discontinuation in 18.2% of patients on the pembrolizumab arm in the most recent analysis presented at the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium. Immune-mediated AEs occurred in 34.8% of patients on the pembrolizumab arm, with grade 3/4 immune-mediated AEs occurring in 8.8%. The median time to first onset of treatment-related AEs ranged from 3.1 weeks for hyperthyroidism to approximately 6-10 weeks for fatigue, pruritis, diarrhea, rash, and nausea. The median time to first onset was longer—approximately 12-15 weeks—for hypothyroidism, arthralgias, myalgias, and asthenia.

There is a need to weigh risk vs benefit when considering adjuvant therapy with pembrolizumab. Waiting until advanced disease develops as opposed to exposing patients to the risk of immune-related AEs in the adjuvant setting can be a trade-off. This is a matter of clinical judgment, but it is important to know the data from the KEYNOTE-564 trial.

Are there any biomarkers that might predict response to immune checkpoint inhibitors with oligometastatic disease?

Brian A. Costello, MD, MS:
At this point, no biomarkers are used in routine clinical practice to predict response to immunotherapy in the setting of oligometastatic or metastatic disease. This is an area of active investigation.

How do rhabdoid features affect treatment selection for localized RCC?

Brian A. Costello, MD, MS:
Typically, we use the same approach for treating disease with rhabdoid or sarcomatoid features. The KEYNOTE-564 trial of adjuvant pembrolizumab did not analyze patients by the presence or absence of rhabdoid features. In 2015, my colleagues at the Mayo Clinic and I evaluated the association between rhabdoid features and prognosis in more than 400 patients. It appeared that rhabdoid features, although always in conjunction with grade 4 RCC, did not confer more aggressive disease than baseline grade 4 disease itself. By contrast, sarcomatoid features did seem to increase the aggressiveness of grade 4 disease.

Elizabeth R. Plimack, MD, MS:
I agree. How I treat patients with rhabdoid features is similar to how I approach management of patients with sarcomatoid features. RCC with rhabdoid or sarcomatoid histology has been shown to be more responsive immunotherapy, and I have achieved the best results with immunotherapy plus TKI combinations in these situations. Supportive data for those with sarcomatoid features have been reported for the phase III trials of ipilimumab plus nivolumab and axitinib plus pembrolizumab.

Eric Jonasch, MD:
I agree with both of you. RCC with rhabdoid features is a subset of grade 4 disease and inherently more aggressive. Regardless of whether rhabdoid features are associated with a better prognosis than sarcomatoid features, this is still a high‑grade tumor, and we should treat these in a very similar manner.

Check the program page soon for a second commentary from our experts on the management of RCC in the first-line setting and beyond!

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