A One-Two Punch in Kidney Cancer

When it comes to treating advanced kidney cancer, more may be better.

Since the April 2018 approval of two immunotherapies given together for patients with advanced disease, additional combination strategies have emerged, further transforming treatment options.

Primarily, these involve combining immunotherapies known as checkpoint inhibitors with targeted drugs — agents that affect cell functions such as growth, invasion and cell death that are relevant to their malignant behavior.

In April of this year, the Food and Drug Administration (FDA) approved the combination of the immunotherapy Keytruda (pembrolizumab) and the targeted drug Inlyta (axitinib) for initial treatment of patients with advanced kidney cancer, also known as renal cell carcinoma (RCC). Earlier, in February, the agency granted an expedited review to the experimental combination of Inlyta and a different immunotherapy, Bavencio (avelumab), in these patients.

Checkpoint inhibitors disable proteins that normally keep the immune system in check; this allows the immune system to rev up so it can better recognize and kill cancer. Targeted drugs inhibit the activity of proteins, genes or their microenvironment that help a cancer grow and survive.

With these novel regimens come unique side effects, dosage schedules and administration methods, so it’s important to carefully match treatments to the patients most likely to benefit from them, according to Dr. Bradley McGregor, clinical director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston and senior physician and instructor in medicine at Harvard Medical School.

“The field of RCC is changing at a rapid rate, and there are lots of options for our patients,” McGregor said in an interview during the 2019 OncLive ® State of the Science SummitTM on Genitourinary Cancers. (OncLive® is a sister publication of CURE ®.) “Determining which option for which patients is going to involve a balanced discussion with the patient about side effects, convenience, (oral) versus intravenous (administration) and how they want to manage their care going forward.”

GAME-CHANGING TREATMENTS

The spate of regimens approved in the past couple of years amounts to no less than “a revolution in the first-line (initial treatment) setting,” McGregor said.

The evolution started when the combination of the immu- notherapies Opdivo (nivolumab) and Yervoy (ipilimumab) generated an improvement in overall survival in patients with advanced-, poor- and intermediate-risk kidney cancer that had not been treated before. Rates of complete response — all the cancer disappeared — reached 10%, a previously unheard-of level in this population, and the responses were relatively long-lasting. McGregor cautioned that the regimen does not work for everyone; the overall response rate, which includes all complete and partial responses, is 40%.

Then came the pairing of targeted drugs such as tyrosine kinase inhibitors with immunotherapies. Using Keytruda plus Inlyta as initial treatment for advanced kidney cancer generated an overall response rate of close to 60% and more of a survival benefit than with Sutent (sunitinib), a targeted drug that is a standard treat- ment for these patients. Those results led to the FDA’s recent approval of the combination.

Another advantage of Keytruda/ Inlyta: Patients can benefit regard- less of the risk classification of their disease. That makes the combination a better standard of care than Sutent for patients with good-risk disease, McGregor said.

Meanwhile, a similar combination of Bavencio plus Inlyta looks promising in clinical trials. “What stands out is the tolerability,” McGregor said. “Only 11% of patients required

high-dose steroids (to ease side effects caused by the immune system attacking healthy organs). It seems to be a well-tolerated regimen, and so it certainly offers another potential option for our patients; it’s exciting to see the data mature.”

Doctors are still sorting out which patients should get which regimen, but McGregor follows some guidelines in his own practice.

If a patient experiences a crisis such as symptomatic liver or lung metastases and needs immediate help from an anticancer medication, McGregor favors tyrosine kinase inhibitor/immunotherapy combinations because of their 50% to 60% response rate.

On the other hand: “I might have a younger patient who has minimal, small-burden disease, but I want to do whatever has the best chance to get (them) off therapy in the future,” he said. “Based on what we know right now ... some of these patients (are) able to stop therapy with Opdivo/Yervoy and maintain their complete response."

WHAT LIES AHEAD

With numerous regimens being investigated, there is no sign that the breakthroughs will slow down anytime soon.

An immunotherapy/targeted drug duo that generated promising results in clinical trials combines the checkpoint inhibitor Tecentriq (atezolizumab) with Avastin (bevacizumab), which kills the blood vessels that tumors rely on to survive.

“We have seen (Tecentriq/Avastin) data in the IMmotion150 and IMmotion151 studies compared with (Sutent),” McGregor said. “Again, responses were similar to what we see with (Opdivo/Yervoy) — right around 40%.

“The combination is certainly a well-tolerated regimen, and from my experience in non-clear cell RCC (a minority of kidney cancers that respond less to treatment), there seems to be activity. However, we are waiting for more data to see where the role is going to apply in kidney cancer going forward. It is being studied in combination with (the targeted drug) Cabometyx (cabozan- tinib) right now in the front-line setting, both in non-clear cell and clear cell RCC, so it continues to evolve.”

Cabometyx, which simultaneously disables several cancer-driving proteins, is a standard RCC treatment for advanced renal cell carcinoma. It may soon also be used as an initial treatment for that condition, McGregor said.

The drug is being investigated as a first treatment for patients who are ineligible for immunotherapy or have autoimmune disease. In these patients with intermediate- or poor-risk disease, data shows that Cabometyx delayed disease progression compared with Sutent, he said.

In addition, Cabometyx is being studied in combina- tion with novel drugs to treat kidney cancer. One trial pairs it with CB-839, a glutaminase inhibitor. “It is impressive that there is no increase in toxicities (when CB-839 is added), but there is a great disease control rate,” McGregor said. He added that a HIF-2 inhibitor has also been paired with Cabometyx in trials.

“What we really need are novel approaches,” he said. “Unfortunately, even with the great responses of these combi- nations in the front-line setting, there are still patients who don’t respond. We need novel agents and rational combinations. Looking for new targets to help those patients who don’t respond to what we have is going to be critical.”