Welcome to your weekly digest of approaching regulatory and clinical readouts. When Merck & Co unveils full data from its first-line renal cancer study Keynote-426 at next week’s Asco-GU conference it will be hoping to spoil three parties – those involving two established players, Exelixis and Bristol-Myers Squibb, as well as one featuring the challengers Pfizer and Merck KGaA.
Merck & Co has already revealed that in Keynote-426 Keytruda plus Inlyta had beaten Sutent on both its overall and progression-free survival co-primary endpoints – irrespective of subjects’ PD-L1 status. This took some shine off Pfizer/Merck KGaA’s Javelin Renal 101 data, featuring Bavencio plus Inlyta .
A major focus of the full Keynote-426 results will be the extent of the OS benefit seen with Keytruda plus Inlyta. This is because Bavencio plus Inlyta has so far demonstrated a positive effect only on PFS; the Pfizer combo has apparently not yet been filed for approval in first-line renal cancer.
If there is a pecking order forming, it holds that if Keytruda is a threat to Bavencio then the latter already stands as a major threat to Opdivo. The risk to Bristol is especially acute, as renal cancer is Opdivo’s main source of growth.
The Bristol drug is approved in combination with Yervoy on the basis of the Checkmate-214 trial, but only in intermediate/poor prognosis patients; and, though the combo is approved irrespective of PD-L1 status, Checkmate-214’s reported positive OS benefit was strongly driven by PD-L1-positive subjects.
As for Exelixis, this company’s Cabometyx franchise has already been hit by the Bristol approval. Cabometyx and Opdivo/Yervoy alike are approved only in intermediate/poor prognosis patients, so the data in all-comers in Keynote-426 will be key to determining the extent of Merck & Co’s overall competitive threat.
Still, as Inlyta is a Pfizer drug this could hand the Bavencio combo a commercial advantage even if it does not show greater efficacy versus Keytruda, as Pfizer could bundle Bavencio and Inlyta together. And Bristol and Exelixis still hold a joker in renal cancer: the first-line Checkmate-9ER study of Opdivo plus Cabometyx reads out this year.
|Selected first-line renal cell carcinoma trials|
|Study||Design vs Sutent||mOS||mPFS||Patient prognosis||PD-L1 status|
|Cabosun||Cabometyx||Not stat sig*||8.6mth vs 5.3mth||Intermediate/poor||Irrelevant|
|Checkmate-214||Opdivo + Yervoy||NR vs 25.9mth||Not stat sig**||Intermediate/poor||Result driven by PD-L1 +ves|
|Javelin Renal 101||Bavencio + Inlyta||Immature||13.8mth vs 8.4mth||Said to be irrelevant||Said to be irrelevant***|
|Keynote-426||Keytruda + Inlyta||Said to be stat sig||Said to be stat sig||Said to be irrelevant||Said to be irrelevant|
|Note: *26.6mth vs 21.2mth; **11.6mth vs 8.4mth; ***primary analysis was in PD-L1 +ves. NR=not reached. Source: US labels & trial reports.|
Seattle seeks its enfortumab fortune
Seattle Genetics has been working hard to reduce its reliance on the Hodgkin’s lymphoma drug Adcetris. Its most advanced asset beyond Adcetris is an anti-nectin-4 antibody-drug conjugate, enfortumab vedotin, and this faces a potentially pivotal study readout before the end of the current quarter.
The trial in question is EV-201, a phase II test in 200 progressed urothelial bladder cancer subjects. Last July enrolment was completed into the first cohort, patients who have failed platinum chemo and a checkpoint blocker; a separate cohort recruits chemo-ineligible subjects who have progressed on Keytruda or Tecentriq in these drugs’ first-line indication.
EV-201 is important because a positive hit on its primary endpoint, overall remission, could be used for an accelerated approval filing, with the phase III EV-301 study’s overall survival endpoint providing confirmatory evidence later. Seattle has not yet decided how to tackle the first-line setting with enfortumab.
EvaluatePharma sellside consensus is for the drug to generate 2024 revenue of $473m; the asset is partnered with Astellas under a 50/50 profit share.
At last year’s Asco meeting a phase I enfortumab trial generated an impressive 41% remission rate in relapsed bladder cancer – but a caveat is that this recruited nectin-4-expressing patients, who would be expected to do well given the project’s mechanism. Bicycle Therapeutics seems to be the only other company with an anti-nectin-4 conjugate in its pipeline.
As a comparator, in post-platinum patients Roche’s Imvigor-210 trial gave a 15% ORR for Tecentriq, while Merck’s Keynote-045 yielded 21% for Keytruda; the latter also showed overall survival of 10.3 months, versus 7.4 for chemo. On this basis a 20% response rate looks like the bare minimum that enfortumab must hit in EV-201.
|Selected enfortumab vedotin trials in urothelial bladder cancer|
|Study||Setting||Primary endpoint||Data due||Trial ID|
|EV-101||Various nectin-4-positive tumours; 41% ORR in bladder cancer cohort||NCT02091999|
|EV-201||3rd-line (post Pt & PD-(L)1)||ORR||Q1 2019||NCT03219333|
|2nd-line (chemo-ineligible, post-PD-(L)1)||ORR||2020|
|EV-301||3rd-line (post Pt & PD-(L)1)||mOS||2021||NCT03474107|
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