Future Studies of Neoadjuvant Treatment in Kidney Cancer Need to Focus on Improving Survival, Says Expert

Future research on the neoadjuvant management of kidney cancer must focus on approaches that improve patient survival, according to Jose Karam, MD, FACS.

Jose Karam, MD, FACS, associate professor in the Department of Urology and Department of Translational Molecular Pathology at the University of Texas MD Anderson Cancer Center

During the 2022 Society for Urologic Oncology (SUO) Annual Meeting,CancerNetwork^® spoke with Karam, an associate professor in the Department of Urology and Department of Translational Molecular Pathology at the University of Texas MD Anderson Cancer Center, about updates in the clinical management of metastatic kidney cancer.

Karam emphasized the necessity of conducting additional research to further optimize treatment for patients with kidney cancer across multiple disciplines. For example, he described the neoadjuvant space as “less mature” than the adjuvant and metastatic spaces, underscoring the importance of studying drug interactions to improve surgical procedures and patient outcomes.

“This is a point that still needs to be studied,” Karam said. “It has been studied in other spaces, but not yet specifically for neoadjuvant therapy.”

Additionally, Karam discussed his takeaways from various clinical trials read out at the meeting as well as continuing research surrounding the use of radiotherapy in patients with kidney cancer.

CancerNetwork^®: What were some important trial updates that were read out at this year’s meeting?

Karam: The phase 3 KEYNOTE-564 study [NCT03142334] was one of the clinical trials that was published within the last year was positive as far as improving disease-free survival. This was a study that [randomly assigned] patients to pembrolizumab [Keytruda] vs placebo, and that showed improvement in disease-free survival in patients with clear cell kidney cancer that were high-risk for disease recurrence.¹

However, we do have more data that has been presented recently. At the 2022 European Society for Medical Oncology (ESMO) Congress, the phase 3 PROSPER trial [NCT03055013], which involved presurgical nivolumab [Opdivo] followed by adjuvant treatment, was not positive.²

Another trial in the adjuvant space that was not positive was the phase 3 IMmotion010 trial [NCT03024996], which randomly assigned patients to atezolizumab [Tecentriq] vs placebo.³ And the third one that was not positive was the phase 3 CheckMate 914 trial [NCT03138512]. That also randomly assigned patients for nivolumab with ipilimumab (Yervoy) vs placebo for 6 months and was not positive.⁴

Most of these trials have not been fully published as manuscripts, yet, and they each employ different agents and combinations. It will be interesting to see when the trials are fully published. What happened with these trials, and what can we learn from them? When should we use adjuvant immunotherapy on our patients who have a higher risk for disease?

What are your takeaways from these trials?

The negative trials teach us that we shouldn’t be using the agents that were used in those trials, but we also learned from them on how to design future trials using different agents or different combinations of agents. Although the lead trials were labeled as negative, it does not mean we cannot learn from the trials.

In fact, we should learn from the trials to not discount them. That’s why it’s important to publish any clinical trial that is completed whether it’s negative or positive, because we will learn from any trial that has been done well and completed whether it’s positive or negative.

What is your view of the management of kidney cancer in the neoadjuvant space?

The neoadjuvant space is still less mature than the adjuvant space and the metastatic space, for sure. Neoadjuvant therapy in patients with kidney cancer is generally not standard-of-care. It’s not within the guidelines. We mostly use it in certain cases; for example, radiation on a resectable tumor to try to make it resectable with therapy for patients who have one kidney and a very large tumor while we’re trying to avoid dialysis.

We try to shrink the tumor and make partial nephrectomy possible. And the other reasons we use it are to try to better understand how these drugs interact with the tumors and with our patients.

Ultimately, we have to study these drugs not only to shrink the tumor or change the type of surgery we do, but to help improve patient survival. This is a point that still needs to be studied. It has been studied in other spaces, but not yet specifically for neoadjuvant therapy.

Have there been any other important updates in the management of kidney cancer?

One other therapy that we haven’t talked about yet is radiation therapy. There are a lot of studies that are ongoing right now and basically reinvigorating delivery of patient care with kidney cancer. Traditionally, it has been limited to treating symptomatic bone metastases or brain metastases.

Now, with the use of stereotactic ablative radiation therapy (SBRT), you can target tumors less frequently. So, we give a much higher dose less frequently, rather than a small dose over a very long period of time. So, there is some value in using stereotactic radiation therapy in a select group of patients, whether it’s locally or radically.

The field is maturing, and we will learn a lot over the next 5 years in ongoing clinical trials. Some of these studies that have been done tried to use radiation therapy as care. Some of these trials are ongoing to combine that with systemic therapy and see if they work more effectively together.

[I am] pretty sure we’re going to learn more over the next 3 to 5 years about what radiation therapy can do to help our patients with metastatic disease.

References

1. Powles T, Tomczak P, Park SH, et al. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022;23(9):P1133-1144. doi: 10.1016/S1470-2045(22)00487-9
2. Allaf ME, Kim SE, Master VA, et al. PROSPER: Phase III RandOmized Study Comparing PERioperative nivolumab versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN EA8143). J Clin Oncol. 2021;39(suppl 15). doi: 10.1200/JCO.2021.39.15
3. Pal SK, Uzzo R, Karam JA, et al. 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. Lancet Oncol. 2022;400(10358):P1103-P1116. doi: 10.1016/S0140-6736(22)01658-0
4. Motzer RJ, Russo P, Gruenwald V, et al. Adjuvant nivolumab plus ipilimumab (NIVO+IPI) vs placebo (PBO) for localized renal cell carcinoma (RCC) at high risk of relapse after nephrectomy: Results from the randomized, phase III CheckMate 914 trial. Ann Oncol. 2022;33 (suppl 7):S808-S869. doi: 10.1016/annonc/annonc1089