Bristol-Myers Squibb’s Opdivo might have overshadowed Exelixis’s Cometriq at the recent European Cancer Conference, but both agents have clearly earned a place in the treatment of renal cell carcinoma and will jostle for position as the post-Sutent agent of choice.
The phase III studies for Opdivo and Cometriq in second-line RCC both used as control Novartis’s Afinitor – the standard of care in the setting. While it is probably still too early to call the outcome of this particular two-horse race, the invitation to do side-by-side, across-trial comparisons is irresistible.
Bristol-Myers’ trump card is Opdivo’s 5.4-month median overall survival (OS) advantage over Afinitor in the Checkmate-025 trial, something against which Exelixis, with its data still immature, cannot yet make a claim.
But the hazard ratio for survival in the Meteor study suggests that Cometriq confers a greater risk reduction relative to Afinitor than does Opdivo, something that could translate into an OS win. More mature survival data on Cometriq, which will become available next year, will likely provide the definitive answer.
For now, Exelixis has a clear advantage in terms of progression-free survival (ECC – Cometriq plays wallflower as Opdivo’s dance card fills, September 25, 2015).
|Second-line RCC data comparison|
|ORR||21% vs 5%||25% vs 5%, p<0.001|
|mPFS||7.4 vs 3.8 months (HR=0.58, p<0.0001).||4.6 vs 4.4 months (HR=0.88, p=0.11)|
|mOS||Not reached (HR=0.67, p=0.005)||25.0 vs 19.6 months (HR=0.73, p=0.002)|
A post-hoc analysis by Exelixis suggests that Cometriq might offer a more substantial improvement in PFS in the subset of patients who received Pfizer’s Sutent first line than the study’s intent-to-treat population, where some patients had received another therapy such as Nexavar.
This “Sutent-first” subset showed a 5.4-month PFS increase over Afinitor, with a hazard ratio of 0.41. Moreover, cross-trial comparisons suggest that this is much greater than for any other agent, the next best being Pfizer’s Inlyta, which offers a one-month increase over Afinitor.
|“Sutent-first” subgroup data|
|Product||Study||Number of pts||ORR||PFS (months)|
|Cometriq||Meteor||153 (40% of pITT)||22%||9.1|
|Afinitor||Meteor||77 (41% of pITT)||1-3%||3.7|
|Afinitor||Record-1||124 (5% of ITT)||1-3%||3.9|
|Inlyta||Axis||194 (54% of ITT)||11%||4.8|
|Nexavar||Axis||195 (54% of ITT)||8%||3.4|
Cowen analysts view Cometriq’s profile as highly competitive, given that it will likely obtain an eventual OS claim. They model Cometriq capturing a 23% share in second-line RCC, and a US price of $13,000 a month with an average seven months’ duration of therapy, backing a $450m 2020 US sales forecast. Cometriq costs just under $10,000 per month in its approved indication of differentiated thyroid cancer.
With Opdivo and Cometriq both on track for use in RCC, interest is turning to a combination. The NCI has already started a phase I trial of this combo, with or without Yervoy, in patients with genitourinary cancers including RCC.
This study also hints at the ace up Bristol-Myers’ sleeve, as the Opdivo/Yervoy combination is already in a phase III study in the first-line setting against Sutent. A result is expected in 2018, and if positive the combo could displace Sutent. Cometriq is also being tested in the first-line setting, albeit in a phase II study one run by an academic consortium, with data due next year.
The Opdivo/Yervoy combo is one of only three pivotal studies under way in RCC, all of which are in the first-line setting.
|Ongoing Phase III programmes in renal cell carcinoma|
|Drug(s)||Company||Study||No of pts||Design|
|Opdivo + Yervoy||Bristol-Myers Squibb||Checkmate-214||1,070||Vs Sutent|
|Rocapuldencel-T||Argos Therapeutics||Adapt||450||Sutent +/- rocapuldencel-T|
|Atezolizumab + Avastin||Roche||IMmotion151||550||Vs Sutent|
Argos Therapeutics’ dendritic cell therapy AGS-003, or rocapuldencel-T, is due a phase III read-out next May. Meanwhile, Roche’s PD-L1 inhibitor atezolizumab is being given in combination with Avastin, which is approved for first-line use in RCC in combination with Interferon-alpha, but is rarely used.
Eisai is known to be planning a phase III study of Lenvima in second-line RCC, although it is far from clear what agent it will use as control. Earlier this year the Japanese firm reported positive results from a phase II study of the drug when given in combination with Afinitor, showing improvements in ORR, PFS and OS (25.5 vs 15.4 months; HR=0.51).
Meanwhile, many agents are in phase II, though only four appear to be in company-sponsored studies directed towards gaining approval in the indication. The start by Pfizer and Merck KGaA of a phase II first-line study of avelumab in combination with Inlyta will be keenly awaited.
|Phase II studies for renal cell carcinoma*|
|Project||Company||No of pts||Design||Setting|
|Dalantercept||Acceleron Pharma||130||Inlyta +/- dalantercept||Second line|
|TRC105||Tracon Pharma||168||Inlyta +/- TRC105||Second line|
|CRLX101||Cerulean||110||CRLX101 + Avastin vs SoC||Third/fourth line|
|Vargatef||Boehringer Ingelheim||99||Vs Sutent||First line|
|*Industry sponsored, controlled studies with >c100 patients.|