Finance News

Vantage View – Latest checkpoint failure gives regulators a fresh headache

Vantage View – Latest checkpoint failure gives regulators a fresh headache


EP Vantage


Merck & CoRegeneron PharmaceuticalsBristol-Myers SquibbMerck KGaARocheSanofiPfizerISA Pharmaceuticals 


Trial Results, Free Content, Comment, Revised Labelling, Immunology, Monoclonal Antibody, Oncology, Clinical Setback


December 18, 2017

As of last week critics of the US FDA’s generous approach to approving cancer drugs have another reason to wonder what it will take for the agency to revoke a conditional approval: the failure of Keytruda ’s gastric cancer trial Keynote-061.

This result, in a second-line setting, comes hot on the heels of Bavencio ’s flop in the third-line Javelin Gastric 300 trial, providing strong evidence that checkpoint blockade alone simply does not work in this cancer type. And yet Keytruda , having secured a flimsy accelerated third-line US approval less than two months ago, looks safe in its market niche.

Part of the issue lies in patient demand, of course. With doctors increasingly speaking of patients clamouring for anti-PD-(L)1 therapy, for approved as well as unapproved cancer types, it would harm regulators’ image to start restricting access to these drugs, which in some settings have clearly proved revolutionary.

But there has to come a point where science must back up the hype, and if it does not then everyone risks looking foolish. This had already been seen in head and neck cancer, where failure of the potentially confirmatory trial Keynote-040 did absolutely nothing to the approved status of Merck & Co ’s Keytruda .

And in bladder cancer the FDA went out of its way to grant accelerated approvals, based solely on remission rates, to Roche ’s Tecentriq , Bristol-Myers Squibb’s OpdivoAstrazeneca ’s Imfinzi  and  Merck KGaA /Pfizer ’s Bavencio  – just before the  Roche  drug flunked its confirmatory Imvigor-211 trial. All remain on the market.


Keynote-061 adds gastric cancer to the list of questionable accelerated approvals – in Keytruda ’s case this had been backed by the uncontrolled Keynote-059 trial, whose third-line PD-L1 -positive cohort showed an 11.2% overall remission rate in data reported at Asco.

Merck & Co  said on Thursday that in the second-line Keynote-061 trial  Keytruda had failed to extend overall and progression-free survival versus  paclitaxel  chemo – despite the company upping the chances of success by  enrolling  only patients expressing  PD-L1 .

The group somewhat optimistically pointed to the ongoing Keynote-062 trial, in first-line gastric cancer, where Keytruda  is being given either as monotherapy or combined with chemo. If PD-(L)1 blockade simply does not work in this cancer then this study too should be written off by investors.

One problem is having to beat chemo, which appears to be moderately effective even in third-line gastric cancer. And there are reasons  why  Opdivo ’s Attraction-2 trial – in an exclusively Asian population and versus placebo – yielded a survival advantage (Bavencio’s gastric failure calls into question rival approvals, November 29, 2017).

Studies of Keytruda  in gastric cancer



Trial ID



Uncontrolled, several cohorts, including 3rd-line monotherapy 


ORR 11.2%, basis for accelerated US approval 


Vs chemo, 2nd-line, PD-L1 +ve 


Failed to extend OS or PFS 


Monotherapy or on top of chemo, vs chemo, 1st-line, PD-L1 +ve 




On top of chemo, vs chemo, neoadjuvant or adjuvant 



If accelerated approvals now guarantee checkpoint inhibitors a permanent green light then investors tracking other approvals on this basis can rest easy. These include Opdivo ’s thumbs up in liver cancer on the basis of Checkmate-040, Keytruda ’s go-ahead in mismatch repair-deficient tumours, and of course Bavencio ’s registration in its first indication, Merkel cell carcinoma.

As a strategy, therefore, it still makes sense for checkpoint inhibitor  latecomers to secure an accelerated approval in a rare cancer just to get a drug into the market. This seems to be the plan for  Sanofi  and  Regeneron , which last week initiated a rolling US BLA for cemiplimab  – in advanced cutaneous squamous cell carcinoma.

If it is approved cemiplimab  stands to become the sixth anti-PD-(L)1 agent to hit the market.  Regeneron  seems undeterred by  such  a disadvantage,  today striking a deal with the private group  ISA Pharmaceuticals  to combine  cemiplimab  with  ISA101 , a vaccine targeting HPV16-induced cancers.

With the FDA apparently willing to let approvals granted on flimsy grounds stand there is still a market worth playing for. That is, of course, until the ultimate arbiters – the payers – have their say.