Asco-GU 2019 – checkpoint blockers might not be created equal after all

Until now all PD-(L)1 blockers were assumed to have broadly similar activity, with any differences being put down to trial design; the latest renal cancer data could explode this view.

A surprisingly quick US front-line renal cancer submission could see Merck & Co outfox Pfizer yet again, but this time it is down to more than just timing. The broader question is why Keytruda looks so much better than Bavencio.

A weekend of subgroup analyses and data teasing at the Asco-GU symposium failed to shake the view that Keytruda’s Keynote-426 trial is a game-changer. Dr Brian Rini, who was involved in both this and Bavencio’s Javelin Renal 101 study, told Vantage that: “There must be something in kidney cancer that would suggest that PD-1 inhibitors are better than PD-L1.”

Such a view would explode the current hypothesis that all antibodies against PD-1 or PD-L1 are broadly equivalent. “It reminds me of 15 years ago when we assumed that all tyrosine kinase inhibitors were the same,” said Dr Rini. “I think what we’re seeing [is] that there’s a genuine difference here.”

His basis for this view is the four first-line kidney cancer phase III studies of checkpoint blockers that have now read out: Keynote-426 and Javelin Renal 101, as well as Bristol-Myers Squibb’s Checkmate-214 and Roche’s Immotion-151.

“The weakest [overall survival] results are with Bavencio and Tecentriq, which are both PD-L1 inhibitors, and the strongest are with Opdivo and Keytruda, which are PD-1 inhibitors,” said Dr Rini. “It’s a pretty strong clinical hypothesis.” Dr Rini, who is affiliated with the Cleveland Clinic, was lead author of Keynote-426, as well as being one of the investigators in Javelin Renal 101.

Comparison of recent 1st-line renal cancer studies
Drug Study ORR CR PFS HR for OS
Sutent Imm-151, JR101, KN-426 26-36% 2% 8.4-11.1mth NA
Tecentriq + Avastin Immotion-151 37% 5% 9.6mth 0.81*
Bavencio + Inlyta Javelin Renal 101 52% 3% 13.8mth 0.78*
Opdivo + Yervoy (int/poor) Checkmate-214 42% 11% 11.6mth 0.66
Keytruda + Inlyta Keynote-426 59% 6% 15.1mth 0.53
Source: Asco-GU, Dr Lori Wood. Note: *data premature.

On the basis of Checkmate-214 Opdivo in combination with Yervoy is already approved for use in intermediate/poor prognosis patients, but could now lose ground to combinations of either Bavencio or Keytruda with Inlyta, the Pfizer small molecule that seems capable of broadening checkpoint blockade’s applicability to good-prognosis patients.

“Favourable-risk patients are more angiogenesis-driven, so when you include a VEGF-targeting agent [like Inlyta] you’re probably going to include more of those in the benefit,” explained Dr Rini. He speculated that Inlyta might also be responsible for the surprisingly high efficacy of Bavencio and Keytruda in PD-L1-negative subjects, revealed at Asco-GU in subgroup analyses.

A staggering difference

That said, the more relevant battle now will feature Keytruda, which Dr Rini described as showing a staggering survival difference versus standard of care, and Bavencio, which did not – with very similar follow-up and baseline patient characteristics (Asco-GU – Bristol’s renal cancer lead looks to be short-lived, February 11, 2019).

Pfizer/Merck KGaA and Merck & Co announced near-simultaneous US filing acceptances last week, meaning that the FDA will be reviewing their respective Keynote-426 and Javelin Renal 101 datasets at the same time. The action date for Keytruda plus Inlyta is June 20, while that for Bavencio plus Inlyta is probably a few days earlier.

The Keynote-426 data are clearly superior, so Bavencio looks likely to lose any first-mover advantage it might have had – a disappointment for Pfizer/Merck KGaA, who had sat on the Javelin Renal 101 data since last September’s Esmo conference. The Bavencio trial has so far demonstrated only a progression-free survival benefit, but precedent suggests that this might be enough for approval.

If the VEGF plus PD-1 inhibition thesis really holds true then its next test will be the Checkmate-9ER study of Opdivo plus Exelixis's Cabometyx, due to read out later this year. Dr Rini’s take on the data is that “it would be a shock if they’re not positive at least for PFS and response rate”.

But he quickly cautioned: “I think it’s going to be hard for any [study] to beat Inlyta plus Keytruda.”

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