A Wave of Optimism for New Kidney Cancer Drugs

Twenty-five years ago, the FDA approved the first systemic therapy for renal cell carcinoma (RCC), interleukin-2. But it would be another 13 years before a powerful surge in treatment developments arose.

The initial breakthrough occurred when the agency approved Nexavar (sorafenib), the first targeted therapy for RCC. Since then, there's been a steady hum of FDA approvals — more than 20 new treatments for the disease, including additional targeted drugs and immunotherapy agents that prolong overall survival (OS) and even offer the potential for a cure in a subset of patients.

The newer drugs are generally for stage 4 disease, because earlier-phase kidney cancer tends to be treated primarily with surgery and radiation. Chemotherapy drugs aren’t typically used, because they do not have activity against kidney cancers. Luckily, targeted drugs do, and while they have different mechanisms, the basic goal of treatment remains the same: Find a way to cure the patient’s cancer while preserving quality of life. The downside of this progress is that the rapid pace of drug approvals for RCC has left oncologists with many unanswered questions about the optimal way to use the new agents, including the order in which to administer them, says Robert A. Figlin, M.D.

Figlin, the Steven Spielberg Family Chair in Hematology-Oncology at Cedars-Sinai, in Los Angeles, hashed out those issues recently as moderator of a panel of experts in genitourinary malignancies at a Peer Exchange hosted by OncLive®, a sister publication of CURE®. The panelists reviewed data from clinical trials that can help guide treatment decisions in the firstline setting and beyond.

“New data continue to emerge to help us navigate a pathway for each individual patient, often through multiple lines of therapy,” Figlin said.

FIRSTLINE THERAPY

After kidney removal (nephrectomy) and before medication is started, medicine may not even be needed. It’s reasonable to consider active surveillance of disease spread in some — particularly those with slow-growing cancer, a small number of lesions and metastasis that is focused in the lungs, especially if the patients are otherwise healthy and active, the panelists agreed.

When the time does come to choose a first therapy for metastatic RCC, Toni K. Choueiri, M.D., director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, in Boston, starts with the kinase inhibitor Torisel (temsirolimus), administered by intravenous infusion, if the patient is hospitalized. For outpatients, he starts with a VEGF-targeted agent that the patients can take at home, as a pill. When the extent of metastatic disease is greater than the volume of disease in the kidney, Choueiri, who is also director of Dana-Farber’s Kidney Cancer Center, considers systemic therapy with a targeted drug to shrink the cancer before surgery.

But what side effects do the drugs bring? Panelist Eric Jonasch, M.D., of the Department of Genitourinary Medical Oncology at the University of Texas MD Anderson Cancer Center, in Houston, said the TKIs Sutent (sunitinib) and Votrient (pazopanib) are equally viable options for firstline systemic therapy, with the greatest differences being in tolerability. Jonasch said that head-to-head trials of the two drugs associated Sutent with higher rates of fatigue, taste changes and hand-foot syndrome, whereas Votrient was associated with a higher risk of hair loss, elevated transaminase levels (which can indicate liver problems) and nausea.

Jonasch also noted that clinicians are increasingly deviating from the standard four-weeks-on/two-weeks-off schedule for Sutent to minimize side effects. A recent study showed that extending the number of weeks off the drug for patients with at least a 10 percent reduction in tumor burden was feasible and did not compromise treatment efficacy. He said the strategies are allowing patients to take Sutent longer, which is translating into improved survival outcomes.

Cabometyx (cabozantinib), another VEGF-targeting agent, may soon also be available as a first-line treatment for patients with metastatic, poor-risk kidney cancer. In a recent study, it improved progression-free survival and overall response in these patients when compared with Sutent.

AVOIDING RASH DECISIONS

Although the choice of firstline therapy may be clear, knowing when to switch to another therapy is not, Figlin suggested. “We see many patients who may have had their therapies prematurely stopped and went on to a second-line treatment when they may have still been able to benefit, with some modulation, from the firstline therapy,” he said. Michael R. Harrison, M.D., assistant professor of medicine at Duke Cancer Institute, in Durham, North Carolina, agreed, saying that when he reviews the files of patients referred to him, it is not always clear whether they discontinued a VEGF TKI because of disease progression or side effects that were not optimally managed. In those cases, he said he sometimes puts patients back on a VEGF TKI and finds it effective. One issue that can lead to unnecessary abandonment of a targeted drug is that scans may be misleading, said David I. Quinn, M.B.B.S, Ph.D., director of the University of Southern California Norris Cancer Hospital, in Los Angeles.

“We need to be aware that there’s an oscillation in the disease that should not be confused with progression,” he advised. Jonasch agreed that there is a need for better ways to identify progression, whether via imaging or analyzing specifics in the circulating tumor microenvironment, such as cytokines and angiogenesis factors.

PROGRESSION AFTER FIRSTLINE THERAPY

Although many drugs have been approved for second-line therapy, Figlin said, data to guide clinicians in choosing among them are scarce because these agents have never been compared in studies in the second-line setting. Harrison said his choice for patients with progression after a VEGF TKI is generally between Cabometyx and the immunotherapy Opdivo (nivolumab). He said his choice is guided by the patient’s symptoms and quality-of-life concerns, time taking a VEGF TKI, side effects and the potential need for a break from that agent.

“If a patient is symptomatic, especially those patients who have sites of disease in the bone or the liver, I’m thinking a little bit more about (Cabometyx). If (it is) a patient who has clear progression but maybe just in the lung or other sites like lymph nodes, then I’m probably thinking more about (Opdivo),” Harrison explained. Quinn said that, although Cabometyx is “a great drug,” he typically uses Opdivo in the second line because “it’s well tolerated, and I think (patients) want a break from VEGF inhibitor toxicities.” He said he reserves Cabometyx for patients who have contraindications to immunotherapy, such as an organ transplant or an autoimmune disease.

Choueiri added that he uses Cabometyx for patients who are experiencing faster disease progression, especially if they have gut metastases. He said studies have shown a low rate of progressive disease and significant tumor shrinkage with Cabometyx.

“I do not want to lose the battle — I want something to hold the patient quickly and effectively,” he said. Choueiri concurred with the other panelists that Opdivo is a good option for patients who have struggled with the side effects of a VEGF TKI, for whom there is no immediate urgency to treat, and who are willing to go to the clinic for treatment.

CONSIDERING AFINITOR

Although the targeted drug Afinitor (everolimus) is a standard treatment for patients whose cancer has progressed on other kinase inhibitors, clinical trials have found that it doesn’t match the effectiveness of Opdivo or Cabometyx in that setting. That doesn’t mean Afinitor will disappear from use, but, perhaps, that it will be used even later in the course of treatment.

Using Afinitor upon disease progression becomes more feasible when it is given with Lenvima. That drug was approved last year in combination with Afinitor as a secondline option for patients with advanced RCC. Approval was based on results from a randomized phase 2 study, which showed that adding Lenvima to Afinitor significantly prolonged median overall survival compared with Afinitor alone (25.5 months vs 15.4 months, respectively).

Choueiri said that Opdivo, Cabometyx and Lenvima have never been studied head-to-head, and probably won’t be.

FUTURE DIRECTIONS

Although Opdivo, Cabometyx and Lenvima are not approved for firstline treatment, the panelists discussed the possibility that they eventually could be. “Firstline immunotherapy may be worth pursuing,” said Quinn, who noted that trials of that strategy are expected to report data soon; changes in practice will occur if they show an overall survival benefit. Other firstline options that may emerge are immuno-oncology agents or vaccines combined with VEGF TKIs, he said.

Jonasch said that studies are also combining new and older agents, such as the PD-L1 inhibitor Tecentriq (atezolizumab) and the targeted drug Avastin (bevacizumab). Several studies are looking at post-surgical therapy with Sutent, Votrient or other agents in populations with a high risk of recurrence. Limited data show promise, but Jonasch said the trials need to show a survival benefit and that confirmatory studies are needed.

SEEKING BIOMARKERS

Harrison expressed his hope for discoveries of biomarkers — genetic clues about what drives each case of kidney cancer. “Basically, (we need to be) moving toward precision medicine to develop biomarkers to find the right drug for the right patient at the right time,” he said. Some information in this regard has already been established. So far, there are 16 known genes that cause kidney cancer and at least 13 types of inherited kidney cancer, W. Marston Linehan, M.D., recently told CURE®. That’s why it’s important for patients and their doctors to understand that kidney cancer is not one disease, and that its treatment should be based on the genetic mutations and pathways that drive it in each individual case, said Linehan, chief of the Urologic Oncology Branch of the National Cancer Institute.

Despite that line of study, Figlin said that doctors do not have all the answers they desire. He encouraged patients and physicians never to hesitate “to get another opinion from someone who spends their life — like my colleagues — thinking about kidney cancer and how to address, answer and ask the right questions for the individual patient.”