The increasing number of treatment options for kidney cancer – with three new drugs approved for second-line advanced disease now available – is leading clinicians to become more discriminating about choices and to seek a more systematic approach to decision-making.

Novartis AG's mTOR inhibitor Afinitor (everolimus) and Pfizer Inc.'s VEGFR tyrosine kinase inhibitor Inlyta (axitinib) have been standard therapies after first-line angiogenesis inhibitors, but neither had demonstrated an overall survival benefit in pivotal trials. But the new entrants to the market are changing expectations.

Bristol-Myers Squibb Co.'s PD-1 inhibitor Opdivo (nivolumab) was approved by FDA in November for treatment of metastatic renal cell carcinoma after anti-angiogenic therapy, after a swift review ([A#14151123005]).

Opdivo demonstrated a statistically significant improvement in overall survival (hazard ratio of 0.73) over Afinitor in the CheckMate 025 study. Bristol presented long-term pooled Phase I and II survival data on June 5 at the American Society of Clinical Oncology annual meeting in Chicago ([A#14160518004]).

Exelixis Inc.'s Cabometyx/Cometriq (cabozantinib), which hits a number of targets, including VEGFR2, MET and RET, was approved in April for a new indication in second-line kidney cancer ([A#14160426005]).

The cabozantinib kidney cancer filing was supported by the METEOR study, in which cabozantinib proved significant progression-free survival (PFS) and superior overall survival (OS) against Afinitor. [Editor's note: This article has been updated to note that FDA-approved labeling did include significant OS data; ASCO marked the first presentation of full results.]

At the ASCO meeting on June 5, investigators presented OS data from the METEOR study that boosted the drug's profile. Median OS for Cabometyx was increased by almost five months in the trial, 21.4 months versus 16.5 months for Afinitor ([A#14160607006]). The hazard ratio for this result was 0.66, or a 34% reduction in risk of death. Results were published the same day in Lancet Oncology by Toni Choueiri, director of the kidney cancer center at Dana Farber/Brigham and Women's Cancer Center, and colleagues.

Results for PFS and OS were very consistent across subgroups, including severity of disease, Choueiri said in presenting results at the ASCO meeting. Patients benefited regardless of the level of MET expression, which could reflect the broad nature of the drug's targets, the clinician said.

The drug also worked well in patients who have bone metastases, who usually have a worse prognosis, which investigators deemed worthy of additional study. In METEOR, median survival for patients with bone metastases was similar to the overall population for patients on cabozantinib, whereas there was a markedly lower survival rate for patients with bone metastases who received Afinitor.

The third new option in the kidney cancer market is Eisai Co. Ltd.'s Lenvima (lenvatinib), a multiple tyrosine kinase inhibitor that acts on a number of molecular targets including VEGFR1, 2 and 3, and FGFR1-4, which was approved by FDA in May for second-line RCC for use in combination with Afinitor after one anti-angiogenic therapy. Lenvantinib had breakthrough therapy status for this indication and was approved on the basis of a Phase II study that compared the combination against Afinitor alone ([A#28160602001]). The drug, which is partnered with Novartis, demonstrated a 10.1 month increase in median OS for the Lenvima regimen over Afinitor alone (hazard ratio, 0.67).

"A Wide Open Field"

For patients, the most important results are overall survival and quality of life, said METEOR discussant Daniel George, an oncologist at the Duke University Cancer Institute.

But the approval of three new drugs complicates decision making in renal cell carcinoma, with an ever increasing number of options.

With more and more agents approved in this crowded field, "tolerability and toxicity will become a bigger consideration," Cleveland Clinic's Rini said.

George noted that National Comprehensive Cancer Network guidelines recommend nine different drugs for use after anti-angiogenic therapy, four of which have a Category 1 (the highest) recommendation: Inlyta, Cabometyx, Opdivo and Afinitor. The Lenvima/Afinitor combination has a Category 2A recommendation.

It's a "really wide open field now that seems to be getting even broader," George said.

Commenting on METEOR and a pooled analysis of Phase I/II Opdivo results, George noted the strength of the survival data for both drugs, with survival curves separating very early. The Opdivo data suggest that in RCC, the drug may benefit the entire population irrespective of treatment response.

"Getting exposure to nivolumab whether [there is] a response or not could be a good thing and associated with a long-term prognosis," and further independent studies and follow up are needed, George said.

With so many treatments, there is a lot of fluctuation in clinical practice in terms of the treatment of choice and sequencing, and it's "critical that we start to collect real world experiences and outcomes with sequences and combinations," he said.

A number of speakers at ASCO commented on the challenge of comparing drug trial results due to differences in the baseline risk of the patient population studied, and different methods for assessing adverse events and responses, among other factors.

The kidney cancer field entered ASCO with a "new paradigm" and there is a "real need to understand better how to pick and choose agents for our patients," Thomas Hutson, director of genitourinary oncology at Baylor University, said during a June 6 session on treatment decisions and sequencing therapies.

In addition to the changes in the refractory setting, the frontline treatment paradigm is under challenge. On May 23, Exelixis announced results from the Phase II CABOSUN study, in which cabozantinib demonstrated significant improvement in PFS compared to Pfizer's standard of care therapy Sutent (sunitinib) in previously untreated patients with intermediate or poor risk levels. The company said it is discussing the results with regulators, with a filing for first-line use in mind. Clinicians are anxiously awaiting the presentation of the CABOSUN results at a future meeting, Hutson said. Furthermore, a range of adjuvant trials are ongoing.

During the same ASCO session, Brian Rini, professor of medicine at the Cleveland Clinic, noted that the promise of durable responses with Opdivo in a subset of patients provides motivation to use the drug.

Rini also noted the importance of toxicity in guiding choice. Patients are more tolerant of toxicity in the frontline setting, but less so in subsequent lines of treatment.

With more and more agents approved in this crowded field, "tolerability and toxicity will become a bigger consideration," Rini said.

Cabozantinib has clear activity – there are no questions about that – but there are issues with adverse events, he said. In the METEOR trial, 60% needed to have a dose reduction from the starting dose.

Furthermore, there was a 62% rate of Grade 1-2 diarrhea, with an increase of four to six stools per day for the Grade 2 events. The rate of Grade 1-2 fatigue was 48%, with Grade 2 cases not resolved by rest. The focus is often on Grade 3-4 effects but chronic Grade 2 effects are almost worse, especially diarrhea and fatigue, he said.

"That’s bothersome to patients," Rini said.

Investigators reported a 63% rate of Grade 3 adverse events in METEOR, and an 8% Grade 4 rate. Yet, the discontinuation rate in the trial was low at 9%, and was similar across both arms.

In the Lenvima study, the rate of Grade 3 events was 57%, with a 14% Grade 4 event rate.

The rate of Grade 3 AEs for Opdivo in CheckMate 025 was 18% and the rate of treatment-related Grade 4 events was 1% (see table below).

Bristol's Opdivo Well-Positioned

In a Lancet Oncology editorial accompanying the METEOR results, Axel Bex of the Netherlands Cancer Institute noted that nivolumab was able to improve health-related quality of life in CheckMate 025, "underscoring the good tolerability of this agent."

"These data are not reported for cabozantinib, but would be of great interest because health-related quality of life is a composite measure of efficacy and tolerability," he said. Bex argued that tolerability and health-related QoL will be important to treatment selection.

"However," he noted, "the difference in the incidence of adverse events between cabozantinib and nivolumab might be caused partly by reporting: only treatment-related events were reported in CheckMate 025 versus all-causality events in METEOR."

The objective response rate was highest for the lenvatinib/everolimus combination at 35% and median overall survival of 25.5 months was on the high end, on par with Opdivo.

Past attempts of combining VEGF inhibitors with mTOR have not succeeded in terms of tolerabiliy or efficacy. Rini noted that it's unclear what makes lenvatinib more combinable and clinically efficacious in combination.

He concluded that nivolumab is likely to become the second-line standard of care based on overall survival and tolerability. Cabozantinib and lenvatinib/everolimus will be used in the second-line setting based on robust clinical data, but more work is needed to make them more tolerable, he said.

It's unclear right now whether it is better to use one drug over another after checkpoint inhibitors; some studies are ongoing to investigate this question.

Bex noted in his Lancet Oncology editorial that given different mechanisms of action, it "might seem attractive to use cabozantinib and nivolumab sequentially upon progression with either drug."

But, he continued, "only 5% of patients randomly assigned to cabozantinib in METEOR were previously given nivolumab and none of the patients in CheckMate 025 were previously given cabozantinib; therefore, the efficacy of this is unknown. Additionally, overall survival results in both studies are confounded by subsequent treatments upon progression, including axitinib and everolimus."

The Value Question

On top of efficacy and tolerability and other clinical factors, the cost of different drugs factors into treatment decisions. The June 6 session on kidney cancer featured a segment by Cedars-Sinai's Robert Figlin on assessing value of various treatment options; ASCO has been encouraging the inclusion of value assessments throughout the meeting.

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Figlin said that he doubts anyone thinks that kidney cancer patients should be given 11 drugs in sequence during the course of their disease.

Questions remain about how to afford therapy, how to define the differences between options and when to have a conversation with patients and health systems about value, said Figlin, director of the division of hematology oncology at the Samuel Oschin Comprehensive Cancer Institute.

"How do we balance what society expects us to do and what we are expected to do for the individual patient?" Figlin queried.

He presented assessments for second-line kidney cancer treatments using ASCO's value framework. The framework takes into account a range of factors, including whether there is an overall survival benefit and toxicity. Drugs also get credit for including quality-of-life assessments in trials. A net health benefit score is calculated based on all of these factors; the maximum score for treatments for metastatic disease is 130 ([A#14150821004]).

Using ASCO's tool, Opdivo had the highest NHB score (52 out of 130 points), and Inlyta and Cabometyx had the same score (32 of 130), followed by Lenvima and Afinitor (28/130). (ASCO cautions that the scores are trial-specific and should be viewed in isolation.)

Industry doesn't optimize value until very late in the course of a drug's lifetime, Figlin said.

"I would argue that that's no longer acceptable. We should start to demand that value conversations, especially in a disease like kidney cancer, start to take place very early in the design of pivotal trials so we can evaluate the value proposition sooner rather than later," he said.

Comparison of Trial Results In Second-line Treatment Of Advanced Renal Cell Carcinoma

Axitinib

Nivolumab

Cabozantinib

Lenvatinib/everolimus

Patient population

Second line

TKI refractory, 72% one prior

TKI refractory, 71% one prior

TKI refractory, 100% one prior

MCKCC risk, good/intermediate/poor risk groups

28/37/33

35/49/16

45/42/12

24/37/39

Comparator

Sorafenib

Everolimus

Everolimus

Everolimus

ORR

19%

22%

17%

35%

PFS

6.7 months

4.6 months

7.4 months

12.8 months

OS

20.1 months

25 months

21.4 months

25.5 months

Dose reduction

30% (37% increase)

n/a

60%

71%

Discontinuation due to adverse events

7%

8%

9%

29%

Toxicity Grade 4

6%

1%

8%

14%

Toxicity Grade 3

50%

18%

63%

57%

Source: R. Figlin, ASCO 2016

Value Measures, Side Effects Help Differentiate Drugs In Crowded Kidney Cancer Market

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