RCC Advances Shake Up Drug Choices

Eric Jonasch, MD

Axitinib (Inlyta) never reached the frontline potential in metastatic renal cell carcinoma (RCC) once envisioned. Nevertheless, the tyrosine kinase inhibitor (TKI) established a lucrative niche as a preferred second-line treatment for RCC, and it held that niche until newer medications displaced it.

It is not unusual for newer medications to displace older ones, of course, but the story of axitinib is worthy of note because it is not an old medication by any traditional definition of the word “old.” Axitinib was first approved in 2012.

The rapidity with which axitinib sales reached a peak and began to decline may well be a harbinger of things to come. If so, it is both a vivid illustration of how quickly options are improving for patients with many tumor types and how hard oncologists must work to keep abreast of rapidly changing treatment protocols. Looking forward, the story of axitinib may end up illustrating yet another important point: that an apparent weakness in a medication can, in some cases, turn out to be a strength.

“The treatment of advanced metastatic RCC was largely stagnant for decades on end, but when the first VEGF inhibitor was approved for RCC in 2005, it began a series of upheavals that continues to this day,” said Eric Jonasch, MD, a professor of genitourinary medical oncology at The University of Texas MD Anderson Cancer Center and vice chair of the Kidney Cancer Guidelines Committee for the National Comprehensive Cancer Network (NCCN).

“The approval of nivolumab as second-line therapy suggests that several other immunotherapies may join the VEGF TKIs and the mTOR inhibitors, and there are trials of both immune oncology combinations and immune oncology-targeted therapy combinations underway that have the potential to change the standard of care,” he said.

Just 15 years ago, the only consistently effective treatment for RCC was the surgical removal of localized disease. Trials of systemic treatments, including numerous chemotherapies, immuno- therapies and combinations thereof, typically demonstrated no significant benefit for the vast majority of patients. A small number of patients exhibited complete or partial responses to interferon and/or interleukin-2,¹ which is still a first-line therapy option for patients with excellent performance status and normal organ function.

That changed with the approval of VEGF inhibitors. The first VEGF inhibitor to be approved for the treatment of RCC was sorafenib (Nexavar), which earned the indication in 2005 on the strength of a phase III trial in 769 previously treated patients with advanced RCC. Median progression-free survival (PFS) was 167 days in the sorafenib group and 84 days in the placebo-controlled group.² It was, by the standards of the day, a triumph.

By the start of 2012, all 4 of the then-approved VEGF inhibitors—sorafenib, sunitinib (Sutent), pazopanib (Votrient), and bevacizumab (Avastin)— had indications for the treatment of advanced metastatic RCC, as did the 2 mTOR inhibitors that had been approved by that date, temsirolimus (Torisel) and everolimus (Afinitor).³

RCC ranks among the most responsive of all tumor types to VEGF inhibition, in part because of a highly angiogenic mutation of the von Hippel-Lindau (VHL) gene that is common in such tumors, a mutation that greatly increases the number of VEGF proteins.³

This tumor biology, along with the history of success that VEGF inhibitors already had in RCC trials, led to high expectations for axitinib, a second-generation VEGF inhibitor that offered increase potency against VEGF receptor-1 (VEGFR-1), VEGFR-2, and VEGFR-3 along with activity against 2 other tyrosine kinases, PDGFR and c-KIT, but fewer off-target effects than first-generation VEGF inhibitors.⁴

The FDA approved axitinib as a second-line treatment for RCC on January 27, 2012, after reviewing the results of a phase III trial that randomized 361 previously treated patients to axitinib and 362 previously treated patients to sorafenib. Median PFS was 6.7 months for patients who received axitinib and 4.7 months for those who took sorafenib.⁵

This success in a head-to-head trial against sorafenib in previously treated patients led many to expect that axitinib would also prove more effective than sorafenib in treatment-naïve patients and thus become a preferred first-line therapy for metastatic RCC. However, a trial in such patients found no significant difference in PFS.⁶ Treatment guidelines from oncology societies therefore listed axitinib as 1 option for first-line treatment rather than a preferred option like sunitinib or pazopanib.⁷

Axitinib’s failure to demonstrate superiority in the first-line setting ended any hopes by Pfizer that the drug would become the clear market leader in RCC, but the medication occupied a significant niche as a nonpreferred first-line option and 1 of 2 preferred second-line options. Total worldwide sales climbed to $430 million by 2015.⁸

A Stream of New Agents

Then, during what was just the fifth year since axitinib’s initial approval, sales began to fall. The global decline for all of 2016 was a relatively modest 7%, but the decline in the American market, where competing products had first become available, was a more dramatic 22%. What’s more, the move to substitute newer alternatives for axitinib appeared to gain considerable momentum as the year progressed. Fourth-quarter sales declined 19% globally and 38% in the United States.⁸The decline in axitinib’s fortunes stems mostly from the subsequent approval of 3 medications that appear to be significantly superior in the second-line treatment setting: cabozantinib (Cabometyx), lenvatinib (Lenvima), and nivolumab (Opdivo).

Lenvatinib was approved as a treatment for patients with RCC in combination with everolimus in 2016, after a trial that randomized 153 previously treated patients with metastatic disease evenly among lenvatinib monotherapy, everolimus monotherapy, or combination therapy arms. Median PFS was 14.6 months in the combination arm versus 5.5 months for patients in the everolimus arm.⁹

Cabozantinib’s 2016 approval hinged on a trial that randomized 330 previously treated patients to the new medication and 328 previously treated patients to everolimus, which had been 1 of 2 preferred second-line treatments for RCC (along with axitinib). Median PFS was 7.4 months among patients who received cabozantinib and 3.8 months among patients who took everolimus. Median overall survival (OS) in the intent-to-treat population was 21.4 months in the trial arm and 16.5 months in the control arm.¹⁰

The apparent survival benefits of cabozantinib were enough to overcome concerns about its significantly greater toxicity. Treatment guidelines soon listed the newer drug as the preferred second-line treatment for RCC over everolimus and axitinib, which had never been tested head-to-head with everolimus but was thought to be about equally effective in the second-line setting.⁷

Cabozantinib is not the only preferred second-line therapy for RCC, however. Current guidelines give equal preference to nivolumab, which was approved as an RCC treatment in late 2015. That drug’s approval rests on an open-label, randomized study of 821 patients whose disease worsened during or after treatment with an antiangiogenic agent. The median OS for patients treated with nivolumab was 25 months versus 19.6 months for participants who received everolimus (HR, 0.73; 95% CI, 0.60-0.89).¹¹ In RCC, nivolumab produces responses regardless of PD-L1 expression, with the confirmed objective response rate of 21.5%.

“As nivolumab and cabozantinib have individually been the first therapies to demonstrate an improvement in overall survival compared with everolimus in patients previously treated with an antiangiogenic agent, the historical approach to second- and third-line treatment has been significantly altered,” said Vivek Narayan, MD, MS, an assistant professor of medicine at the University of Pennsylvania in Philadelphia.

“In terms of selection between nivolumab and cabozantinib as the preferred second-line therapy, we don’t currently have prospective evidence to guide us, and either choice is reasonable,” Narayan said. “Both agents demonstrated efficacy across clinical subgroups, and tumor cell PD-L1 expression does not appear to inform a clinical strategy. The decision, therefore, largely rests on the expected toxicity profile, availability, and patient or provider preference.

“Notably, nivolumab generally exhibits a favorable toxicity profile relative to cabozantinib, which often requires dose-reduction for toxicity mitigation,” Narayan continued. “In addition, retrospective data indicate that VEGFR-targeted therapies appear to retain efficacy after PD-1 directed therapy, suggesting that cabozantinib can be effectively used as a third-line systemic agent and potentially provide patients with a much-needed break from TKI toxicities.

“However, while nivolumab may provide durable treatment response, this is enjoyed by only a minority of treated patients,” said Narayan. “Future efforts will strive to improve appropriate patient selection for such therapies, and also turn to synergistic combination strategies to improve response rates and other clinical outcomes.”

Perhaps surprisingly, none of the medications approved since the arrival of first VEGF inhibitors has won a spot as the preferred first-line treatment for metastatic RCC. Sunitinib remains the preferred first-line treatment, along with pazopanib.^12,13 That may change soon, however.

Cabozantinib has already demonstrated the ability to increase PFS among untreated patients with poor and intermediate prognoses in a head- to-head phase II trial against sunitinib.¹⁴ Similar results in a phase III study would likely make cabozantinib the preferred first-line treatment for many patients with advanced RCC.

An Era of Discovery in RCC: Drugs and FDA-Approved Indications (CLICK TO ENLARGE)

mTOR indicates mammalian target of rapamycin; OS, overall survival; PD-1, programmed cell death protein 1; PFS, progression-free survival; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.

It is impossible to say how much currently approved medications have increased the expected lifespans of patients newly diagnosed with advanced and unresectable RCC because at least 4 of them are too new to factor into the most recent 5-year survival rates. The expected survival period for newly diagnosed patients before the first VEGF inhibitor arrived was about 1 year;¹⁵ the expected PFS is about 10.5 months for patients who use sunitinib as first-line therapy¹⁶ and the median OS is 21.4 months in patients who use cabozantinib as second-line therapy.¹⁷

In order for patients to reap the full benefits of these new medications, however, oncologists must stay current. This obviously requires them to keep up with rapidly changing treatment guidelines which, Jonasch noted, have undergone significant changes each year for more than a decade. It also requires that clinicians digest dozens of studies each year so that they have the relevant data they need to make good choices. And, there still is plenty of discretion to be exercised, even as doctors face increasing pressure to follow guidelines.

“Current guidelines certainly call for first-line sunitinib or pazopanib for most patients, followed by cabozantinib or nivolumab as second-line treatment, but the key word in that sentence is ‘most.’ The proper treatment of metastatic RCC currently can involve any of the approved medications because various factors can make the preferred medications inappropriate for a significant number of patients,” said Naomi Haas, MD, director of the Prostate and Kidney Cancer Program at Penn Medicine in Philadelphia.

“For example, most people don’t respond to nivolumab and a significant number of them cannot tolerate cabozantinib. Axitinib, on the other hand, works in a large percentage of patients and it’s very well tolerated at its standard dose. Also, you can adjust the dose, so even those patients who cannot tolerate it at full strength can derive some benefit...

Combinations May Spur Change

“Oncologists certainly shouldn’t be using axitinib as much as they once did, but there are certainly times when its unique properties make it valuable,” Haas said.The rapid decline in axitinib sales, particularly here in the United States, might lead some to conclude that the drug is doomed to occupy a very small niche. Indeed, analysts have long predicted that competitive pressures would limit axitinib sales,¹⁸ although consensus projections did not see US sales plummeting last year. However, the untold portion of axitinib’s story may provide yet another warning against giving up on a medication too soon.

Aside from the combination of lenvatinib and everolimus mentioned earlier, all of the other approved treatments for metastatic RCC are monotherapies. The move toward combination therapy that has improved results in other tumor types has thus far not changed practice in RCC.

Toxicity limits the use of the FDA-approved lenvatinib-everolimus combination despite its impressive trial results. Some 71% of the patients in the pivotal trial’s lenvatinib-everolimus needed to cut back on lenvatinib because of toxicity.¹⁹ Other combinations have proved even more toxic, particularly those that paired sunitinib with an mTOR inhibitor.^20,21

Such toxicity problems have led researchers who hope to use the power of combination therapy against RCC to take another look at axitinib’s relatively mild adverse event pro le. The very thing that makes it less seemingly less effective than the competition as monotherapy—the fact that it hits fewer targets than a drug like cabozantinib— may allow patients to tolerate it in combination with other treatments. Axitinib is currently being evaluated in phase III trials as first-line RCC therapy in combination with pembrolizumab (Keytruda)²² and with avelumab (Bavencio)²³.

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