A little-noticed volte face in the design of Bavencio’s Javelin Renal 101 study throws into focus a dilemma that Bristol-Myers Squibb must face as it seeks to capitalise on its controversial, but still ostensibly positive, Checkmate-214 study of Opdivo/Yervoy in first-line renal cell carcinoma.
Bristol’s problem is whether it might be better to seek a narrow approval for its combo in PD-L1-positive patients rather than a broad label that might be possible based on Checkmate-214’s primary analysis. Even if Bristol refuses to accept this reality, Pfizer and Merck KGaA already seem to have done so in refocusing Javelin Renal 101 on PD-L1-positive patients (see table below).
Normally companies would look for the broadest possible label but, if competitors’ studies of anti-PD-(L)1 agents are restructured to beat Opdivo/Yervoy, Bristol’s best plan could be a defensive move to focus on those patients in which its combo performs best.
It is interesting that the Checkmate-214 results have clearly not escaped Pfizer and Merck KGaA. The changes to Javelin Renal 101 emerged two weeks ago, boosting the study from 583 to 830 patients, and switching the primary endpoint from PFS in unselected patients to PFS and OS in PD-L1 positives.
The trial will continue to recruit patients without reference to PD-L1 status, but will examine efficacy only in the roughly 25% who are PD-L1-positive. This is not the first time that Bavencio’s developers have moved with the times; they previously amended the first-line NSCLC trial Javelin Lung 100 in response to Opdivo’s failure in this setting.
And response rates from an earlier renal cancer study suggest that Bavencio and Inlyta could beat Opdivo/Yervoy even in PD-L1-positives: Javelin Renal 100 showed an overall response rate of 65.9% in PD-L1 positives, which is above the 58% seen in the same subgroup in Checkmate-214.
If Bristol does file Opdivo/Yervoy for first-line renal cancer in PD-L1-positives – the regulators might insist on this anyway – it will make its silence over the controversy in Checkmate-214 somewhat ironic. The principal investigator’s simplification of the data led to coverage failing to mention the highly differential activity by PD-L1 status (Spotlight – Medical disclosure farrago hits Esmo 2017, September 15, 2017).
|Phase III immuno-oncology studies in first-line renal cell carcinoma|
|Sponsors||Product(s)||Study||Enrolment||Primary endpoint||Trial ID||Data|
|Pfizer||Bavencio + Inlyta||Javelin Renal 101||830||PFS/OS in PD-L1+||NCT02684006||Dec 2018|
|Merck||Keytruda + Inlyta||Keynote-426||840||PFS/OS||NCT02853331||Jan 2020|
|Roche||Tecentriq + Avastin||Immotion-151||900||PFS in PD-L1+/OS||NCT02420821||Jul 2020|
|Eisai||Lenvima + Afinitor; Lenvima + Keytruda||Clear||735||PFS||NCT02811861||Nov 2020|
|Bristol-Myers Squibb/Exelixis||Opdivo +/- Yervoy + Cabometryx||Checkmate-9ER||1,014||PFS||NCT03141177||Feb 2021|
|Incyte||Keytruda + epacadostat||Keynote-679/Echo-302||630||PFS/OS||NCT03260894||May 2023|
|All studies have Sutent as control except Keynote 679/Echo-302, in which Sutent or Votrient may be used.|
As for other Bristol competitors, Merck & Co has yet to reveal whether it will follow suit with changes to Keynote-426. However, an early study of a Keytruda/Inlyta combination did show a 71% response rate in unselected patients.
Roche already designed its Immotion-151 study of Tecentriq/Avastin to examine efficacy in PD-L1-positives first. The Roche pairing showed an ORR of 46% in PD-L1 positives in phase II (Asco-GU – Roche’s renal success spells danger for all-comer studies, February 22, 2017).
Bristol’s longer-term hope for an I-O franchise in renal cancer must now rely on Checkmate-9ER, which tests Opdivo with or without Yervoy plus Exelixis/Ipsen’s Cabometyx, although this study will probably have to be restructured as well to look at cuts of PD-L1 expression and prognosis.
It is another irony that Cabometyx, the very drug over which Checkmate-214’s principal investigator has been dismissive, might prove decisive in saving the company’s renal cancer franchise. Checkmate-9ER also risks showing that Yervoy contributes little to the efficacy of an Opdivo/Cabometyx pairing and, by implication, to Opdivo in Checkmate-214.
Meanwhile, the debate about new first-line choices is having a knock-on effect on regulatory review of Pfizer’s filing for Sutent as adjuvant therapy in renal cell carcinoma.
This application is already controversial, as there has been one positive and one negative phase III study in the indication. An FDA adcom last month was split six-six on whether to recommend approval, and several panellists expressed concern that a new adjuvant use for Sutent might preclude its use later, once the condition becomes metastatic.
This was in spite of the fact that Cabometyx and Opdivo/Yervoy would now be preferred first-line choices over Sutent, based on the Cabosun and Checkmate-214 studies. The same debate migh play out again if Inlyta is positive in the Atlas study due to read out next year.
Nevertheless, in the first-line setting combinations of either Bavencio or Keytruda with Inlyta look set to give Bristol a strong run for its money, whether or not Opdivo/Yervoy are approved for all comers or PD-L1-positives only.
Bristol must now make important decisions about how best to defend a franchise that it has yet to start building.