Novel Combinations Offer New Hope in Kidney Cancer

CURE, Genitourinary Cancers Special Issue 2021,

Immunotherapy and tyrosine kinase inhibitors may potentially change the treatment paradigm for patients with renal cell carcinoma, the most common type of kidney cancer in adults.

After Jarod Roy was diagnosed with metastatic renal cell carcinoma in July 2018, he was put on a combination of two immunotherapy drugs — Opdivo (nivolumab) and Yervoy (ipilimumab) — which had recently been approved by the Food and Drug Administration (FDA) to be used together in previously untreated patients. But his tumors kept growing, so Roy decided to drive two hours from his home in Westlake, Louisiana, to The University of Texas MD Anderson Cancer Center in Houston for a second opinion.

MD Anderson enrolled Roy in a clinical trial of a different combination — the immunotherapy drug Keytruda (pembrolizumab) plus Lenvima (lenvatinib), a drug that works by inhibiting cancer-driving enzymes known as tyrosine kinases. Roy received infusions of Keytruda every three weeks and took Lenvima orally every day.

Six weeks after Roy started the regimen, imaging tests showed that the cancer had shrunk more than 20%. “Every scan I had showed a decrease, and the overall reduction of my cancer was 54%,” says Roy, 39, who completed 35 doses of Keytruda and is still taking the Lenvima as part of the trial. He continues to manage his company, which maintains exhaust systems for restaurants, and he enjoys skiing every year with his wife and two children.

“I’m a believer in this combination treatment,” Roy says. “It definitely did the job for me.”

Several combinations of immunotherapy drugs and tyrosine kinase inhibitors (TKIs) have been approved by the FDA for patients with newly diagnosed kidney cancer. In fact, four combinations were recently approved for the first-line treatment of kidney cancer: Bavencio (avelumab) plus Inlyta (axitinib), Opdivo plus Cabometyx (cabozantinib) and Keytruda plus Inlyta. In August, the FDA approved Keytruda plus Lenvima in the first-line setting.

With many more combinations in development, the outlook is bright for patients at the beginning of their treatment journey, says Dr. Amishi Y. Shah, an assistant professor of genitourinary medical oncology at MD Anderson.

“We have a very nice armamentarium of drugs to reach for, and now there are newer agents coming down the pike that are showing some promise,” Shah says.

In the trial that led to the approval of Opdivo plus Cabometyx, for example, the overall response rate for the combination was 56% versus 27% among patients taking the TKI Sutent (sunitinib) alone. And median progression-free survival (time when a patient lives with the disease without worsening) was 16.6 months among patients taking the combination, double that of the Sutent group.

Several experimental combinations look promising too, including the treatment Roy is receiving — Keytruda plus Lenvima. In May, the FDA granted priority review for the use of the combination in previously untreated patients, setting up a potential approval this fall.

The FDA sped up its review based on a clinical trial in which 71% of patients taking the combination responded to it versus 36% of patients taking Sutent. Progression-free survival was two years in patients taking Keytruda and Lenvima versus nine months with Sutent. And 16% of patients on the combination treatment had complete responses, meaning the cancer had disappeared or was not detectable radiographically or by physical examination.

“The responses were the highest and longest of any immunotherapy-plus-TKI study we have seen,” says Dr. Toni Choueiri, director of the Lank Center for Genitourinary Oncology at Dana- Farber Cancer Institute/Brigham and Women’s Hospital in Boston and a co-lead investigator for the trial of Keytruda plus Lenvima. “(Once) this gets approved, I would argue it should be used as the first-line treatment.”

WEIGHING RISKS AND BENEFITS

There are some caveats with new combination treatments for kidney cancer. Some patients experience onerous side effects, and oncology researchers have yet to determine whether the positive responses to immunotherapy-TKI combinations are long lasting enough to outweigh the potential risks.

The most common side effects are increases in blood pressure and diarrhea. Each TKI has potential side effects because of the blockade of specific kinases. Antiangiogenic drugs target pathways involved in tumor blood vessel formation, so side effects on normal vessels like constriction or impaired healing can cause hypertension, bleeding or clotting events. Immunotherapy causes inflammation in normal tissues like skin, gastrointestinal (GI) tract and endocrine glands, resulting in rash, diarrhea and hypothyroidism. In the trial that Choueiri co-led, more than 90% of the patients taking either the TKI-immunotherapy combination or Sutent alone reported side effects, but the need for investigators to drop the doses of the medicines to get those symptoms under control was greater among patients on the combination. And nearly 10% of patients taking the combination dropped out of the trial.

Meryl Uranga had some trouble controlling her blood pressure after she started taking the Keytruda-Inlyta combination in 2018 for kidney cancer. She had initially been treated with radiation and surgery to remove one kidney and part of her lung — a regimen that put her in an 18-month remission. When the cancer returned, she was put on two immunotherapy drugs but had only a partial response, and some of her tumors grew a little, so her oncologist switched her to the TKI-immunotherapy combination.

The fluctuations in blood pressure were unsettling at first, Uranga says, but her doctor adjusted the dose of a blood pressure medicine until the problem came under control. As for the cancer, “everything was shrunken down or gone,” says Uranga, 60, a retired telecommunications project manager who lives in the Atlanta area. “I take a microdose of blood pressure medication if I need to, and I have GI issues, but the impact to my quality of life is very minimal and manageable.”

Choueiri expects that ongoing clinical trials will show just how durable the positive effects of these new combinations are and that physicians will grow more and more comfortable with strategies for lessening side effects. “With the TKIs especially, there are a lot of adjustments we can make to figure out the ideal dose that the patient can tolerate while getting the benefit at the same time,” he said. While surgery is generally still the first step in patients with localized kidney cancer, that is no longer the case for many patients with metastatic disease. Before the advent of TKIs and immunotherapy, surgery was often the first line of treatment, says Shah, but now “the pendulum has swung” and drug treatments are tried first in many cases, she says.

When patients respond well to the drugs, subsequent surgery might offer a good way to eradicate the disease altogether, she adds. “One of the best conversations I have is telling a patient they had an absolutely phenomenal response to therapy and there’s no evidence of disease except for the primary renal tumor,” Shah says. “I’ve sent a number of these patients to surgery to basically render them clear of disease.”

TACKLING RENAL CANCER SUBTYPES

About 25% of patients with kidney cancer are diagnosed with non-clear cell renal carcinoma, which encompasses several subtypes of the disease, including papillary renal cell carcinoma. Traditionally these patients were treated similarly to those with clear cell carcinoma, although recently, some researchers have launched studies aimed at determining whether some combination treatments should be targeted specifically to patients with non-clear cell disease.

Bruce Shreffler enrolled in one of those trials in 2018, about five months after starting treatment for metastatic non-clear cell kidney cancer. He initially took a combination of two TKIs, Lenvima and Afinitor (everolimus), but only some of the tumors shrank and the GI upset and fatigue were difficult to manage.

So Shreffler traveled from his home in Albany, New York, to Memorial Sloan Kettering Cancer Center in New York City for a second opinion. He was admitted into a trial of Cabometyx plus Opdivo in non-clear cell kidney cancer. After six months, the cancer had shrunk and stopped spreading.

“A lot of the tumors were entirely resolved,” says Shreffler, 64, a computer contractor and avid outdoorsman whose pre-cancer adventures included climbing all 46 Adirondack High Peaks.

Shreffler’s treatment includes daily doses of Cabometyx and one infusion per month of Opdivo. His oncologists told him he will stay on the regimen as long as the cancer is stable, and he’s fine with that, especially since the side effects have been much easier to tolerate than they were for the combination of two TKIs. A high-fiber diet is enough to keep his digestion under control, and although he has a touch of fatigue, he’s able to ride his bicycle 15 miles in less than an hour, he says.

“I can’t climb the mountains that I used to, but I’m as active as I can be,” Shreffler says.

In June of this year, positive data from the trial of Cabometyx and Opdivo in non-clear cell renal carcinoma were released at the American Society of Clinical Oncology annual meeting. Among 32 patients with papillary carcinoma, the response rate was 47.5%, and some of the responses correlated with specific genetic mutations found in patients’ tumors.

In fact, there’s a major push underway in kidney cancer research to find biomarkers, including genetic mutations, that can help oncologists personalize treatments, says
Dr. Chung-Han Lee, a medical oncologist at Memorial Sloan Kettering Cancer Center. “We’re trying to understand how we can use genetic sequencing to predict patient outcomes,” Lee says. “Those kinds of predictive biomarkers will improve patients’ outcomes just by getting them on the best treatment earlier.”

Even though TKI-immunotherapy combinations are moving into the frontline treatment setting, for some people, starting on two immunotherapy drugs instead might still be a good idea, Lee says. For example, immunotherapy combinations can be beneficial for patients who have no other underlying illnesses and are not experiencing severe symptoms from the cancer. “In the majority of people who do get significant shrinkage of their disease from combination immunotherapies, the effects seem to be durable, meaning they last beyond three years,” he says.

It’s not yet clear how long positive responses to TKI- immunotherapy combinations will last — the clinical trials needed to determine that durability have not yet been completed. Still, starting with one of those combinations can be a good idea for patients who are very sick from the cancer “because we can see a very rapid response,” Lee says.

Now that two-drug combinations are well entrenched in the care of patients with kidney cancer, researchers are considering a new question: Could three drugs be even better than two? One ongoing phase 3 trial is combining the TKI Cabometyx with two immunotherapy drugs that stimulate the immune response in different ways, Yervoy and Opdivo. “With two different mechanisms of action, you’re able to kill more cancer cells because cancer can be sensitive to one pathway but not the other,” Choueiri explains. “The same may be true of three drugs.”

Several new TKIs are under development, and that could lead to new combination strategies for kidney cancer in the future. In March, the FDA approved Fotivda (tivozanib) for patients with advanced renal cell carcinoma who have relapsed after two or more prior therapies. The approval was based on a response rate of 18% versus 8% for another TKI, Nexavar (sorafenib).

Now a new clinical trial has started comparing Fotivda plus Opdivo to Fotivda alone. Lee says he’s looking forward to seeing the results of that trial, particularly because Fotivda seems to produce fewer side effects than other TKIs. “It’s very well tolerated,” he says, “and that can certainly be a benefit for our patients.”

MD Anderson’s Shah adds that even though there’s still a lot to learn about how combination therapies can best be matched to patients, the rapidly growing selection of treatments for kidney cancer is exciting.

“It has changed the outlook in the field,” she says, “and led to great improvements in survival.”

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