Immunotherapy Makes Comeback in RCC, But Challenges Remain

Robert G. Uzzo, MD

Immunotherapy is making a big comeback in the landscape of renal cell carcinoma (RCC), says Robert G. Uzzo, MD.

“For a long period of time, everyone recognized that kidney cancer was an immune-responsive tumor and there was a lot of excitement about various types of first-generation immunotherapies including interleukin-2 (IL-2), interferon, and vaccines,” said Uzzo, chair, Surgical Oncology, senior vice-president, Physician Services President, professor of Surgery, Temple University Health System. “They all showed some signal, but then it all sort of went away for a while because the tyrosine kinase inhibitors were big and they were effective. Now it’s coming back, and it’s coming back with renewed enthusiasm and with far more efficacy. That is really an exciting thing.”

The FDA approved the PD-1 inhibitor nivolumab (Opdivo) as a treatment for patients with metastatic RCC following prior antiangiogenic therapy in November 2015, based on an improvement in overall survival (OS) in the CheckMate-025 trial.

In the pivotal phase III study, nivolumab reduced the risk of death by 27% versus everolimus (Afinitor), representing a 5.4-month improvement in median OS.

OncLive: How has immunotherapy evolved in kidney cancer?

Immunotherapies are currently being investigated in multiple settings and in combinations in RCC. In an interview with OncLive, Uzzo discussed the promise of immunotherapies as well as the challenges with using them across different indications. He also provided insight on the challenges facing the field of RCC overall.Uzzo: The concept of immunotherapy—for the most part, 10 years ago—had almost died. People thought that we had tried that for a long period of time, and we really hadn’t hit a home run. There was a low-level signal and we didn’t know how to use it.

Several trials are investigating the use of immunotherapy in the neoadjuvant setting in kidney cancer. Do you see potential for this?

However, now it’s back, and it is back big time. It really resonates with physicians and the patients. The concept of a therapy that harnesses your immune system to fight the tumor is really one that patients feel a great deal of kinship to, as opposed to a cytotoxic. The excitement is there. We haven’t hit the home run yet but we are getting very close.There are some challenges to accruing patients on trials using immunotherapies in the neoadjuvant space. Currently, there is not a lot of neoadjuvant therapy being given in the kidney cancer space for lots of reasons.

Most people with localized renal cancer have a visceral response and they want it surgically excised. With a clinical trial, putting a neoadjuvant arm in front of that excision delays surgery.

It is probably a couple of weeks to enroll and check eligibility, a couple of weeks until randomization, and then a month’s worth of the novel agent used. This is similar to the case of 1 trial, the PD-1 inhibitor nivolumab (Opdivo), followed by 2 or 3 weeks after that before surgery. That really delays, what is considered by many to be the primary therapy, by about 8 to 12 weeks. That is 1 hindrance to using immunotherapy in the neoadjuvant setting.

There is a good experience with giving PD-1 inhibitors for a short period of time, and they are generally well tolerated. However, somewhere upward of 30% to 40% of patients can have adverse side effects after 2 doses. Those side effects can sometimes lead to autoimmune dysfunction, change the hemoglobin levels, and increase white counts.

If adverse events do occur, they are often treated with steroids. Putting a patient on steroids in the preoperative setting would certainty change things. Additionally, some patients may take weeks or months before they recover from certain toxicities. Granted they are not very common, but they can be pretty significant and severe when they do occur—whether it’s pneumonitis, thyroiditis, autoimmune colitis, hepatitis, or even significant rashes. These toxicities may impair the patient’s readiness to undergo surgery. That is another potential barrier.

Ultimately, the patient also has to be willing to be randomized to receive the drug before and after, and also to undergo biopsies before the operation.

What are the biggest challenges in kidney cancer right now?

Practically speaking, many patients have a visceral desire to have surgery as quickly as possible and, in many cases, surgery may be curative. It may be simpler and easier for urologists to absorb adjuvant immunotherapy into their clinical practices as opposed to neoadjuvant followed by adjuvant immunotherapy.The field of adjuvant therapy for kidney cancer is rapidly evolving. There were 2 decades’ worth of adjuvant trials in kidney cancer, none of which have come up and changed clinical practice.

Currently, for patients with high-risk, fully resected disease, there is no way to decrease their risk of recurrence. That risk may be from 15% to 50% for high-grade locally advanced kidney cancer.

Other trials have been explored in that space, and none of them has been definitively a game changer. One recent study that many people know about is the ASSURE (E2805), which I was the urology principal investigator on. That trial was negative; it didn’t demonstrate any improvement in disease-free survival or OS. It compared sunitinib (Sutent) to sorafenib (Nexavar) to placebo in 1900 plus patients.

More recently the S-TRAC trial reported out, which included a higher-risk population of clear cell patients. In that trial, there was an improvement in disease-free survival in a reviewed group of patients, but it was not significant for OS. That was a bit of a mixed signal.

We have now moved past some of the questions as to whether clinical trials in the adjuvant space could accrue. The answer is clearly yes, as there are at least 3 or 4 others that we are waiting to read out.