A rise in patient deaths in the Keytruda arms of two late-stage multiple myeloma studies suggests that Merck & Co is paying the price for being first. The company has been at the forefront of the immuno-oncology push into this therapy area, and its pivotal programme is more advanced than competitors'.
A recent investigation by EP Vantage into the explosion of PD-(L)1 combination trials uncovered 18 active studies in multiple myeloma, 10 of which are being conducted by big pharma groups. Bristol-Myers Squibb and Celgene – which partnered with Astrazeneca in haematological cancers – are both recruiting patients at full throttle, and are no doubt watching closely to see how this safety signal evolves (see tables below).
All Merck has said is that recruitment into its two phase III trials, Keynote-183 and 185, has been “paused” while reports of deaths in the Keytruda arms are further explored. Merck's programme started more than 18 months ago; Bristol’s Checkmate-602 and Celgene’s FusionMM-03 only started last year, so data are likely to be less mature.
|Checkpoint inhibition in multiple myeloma – the trials to watch|
|Merck trials with Keytruda||Combo/setting*||Phase||Enrolment||Start date||Est. primary completion|
|NCT02576977 (Keynote-183)||Pomalyst; refractory||III||300||Oct 2015||Aug 2018|
|NCT02579863 (Keynote-185)||Revlimid; first line||III||640||Oct 2015||Aug 2019|
|NCT02036502 (Keynote-023)||Standard of care; refractory||I||115||Feb 2014||Aug 2018|
|Celgene/Astra trials with Imfinzi||Combo/setting*||Phase||Enrolment||Start date||Est. primary completion|
|NCT02807454 (FusionMM-003)||Darzalex or Pomalyst + Darz; refractory||II||144||Jul 2016||Sep 2018|
|NCT03000452 (FusionMM-005||Darzalex; refractory||II||120||Mar 2017||Jul 2020|
|NCT02616640 (FusionMM-001)||Pomalyst; refractory||Ib||138||Jan 2016||Oct 2017|
|NCT02685826 (FusionMM-002)||Revlimid; first line||I/II||138||Apr 2016||Apr 2022|
|Bristol-Myers trials with Opdivo||Combo/setting*||Phase||Enrolment||Start date||Est. primary completion|
|NCT02726581 (Checkmate-602)||Pomalyst or Empliciti; refractory||III||406||Apr 2016||Nov 2018|
|NCT02612779||Empliciti; refractory||II||60||Nov 2015||Oct 2019|
|Roche trials with Tecentriq||Combo/setting*||Phase||Enrolment||Start date||Est. primary completion|
|NCT02431208||Revlimid or Darzalex or Pomalyst; refractory||I||214||Jul 2015||Aug 2019|
|*Most studies also combine these agents with dexamethasone. Source: Clinicaltrials.gov, company websites.|
The EP Vantage report found that only 11% of all ongoing PD-(L)1 combination studies are being conducted in haematological cancers.
Still, there is sound rationale for testing these agents in multiple myeloma in combination with immunomodulatory drugs. PD-L1 has been found to be highly expressed on the plasma cells of multiple myeloma patients, and expression has been associated with higher cell proliferation and resistance to anti-myeloma therapy.
Merck’s large phase I, open-label study Keynote-023 confirmed this potential. It recruited heavily pretreated patients and tested Keytruda in combination with standard of care regimens; the latest cut of the data presented at Ash last December showed an overall response rate of 65% from 45 evaluable patients. This was obviously enough to prompt Merck to start its two phase III studies, one in a similarly refractory population and another in a front-line setting.
Merck is notable for pushing into this treatment-aive population so quickly – other than Keynote-185 only Celgene has started a trial in newly diagnosed patients, the phase I/II MM-002 study.
Celgene, however, is relying on a 2015 deal with Astrazeneca over Imfinzi in haematological cancers to give it a way into this space (Celgene signals bigger immuno-oncology push into blood cancers, 24 April 2015). The collaboration cost the US biotech $450m up front, and until recently it has also been paying all the development costs – Astra has been picking up 25% of the R&D bill since the beginning of 2017.
Should Imfinzi make it to market in any blood cancer Celgene will get a 70% royalty on sales. And given its hugely dominant position – largely thanks to Revlimid – Celgene’s work in this area should be followed with interest. Its Fusion programme now comprises eight clinical trials, including the four multiple myeloma studies.
Bristol also has a haematology position with Empliciti, which it launched 18 months ago, although the drug is not expected to become a huge player in this market. Given that the use of anti-PD-(L)1 agents as monotherapies has all but been ruled out in multiple myeloma, perhaps throwing Opdivo into the mix will improve its chances. Bristol's three-armed phase III study includes an exploratory arm testing Opdivo plus Empliciti plus Pomalyst and dexamethasone.
Finally, Roche has also started work here. A very broad phase I study of Tecentriq in various refractory settings and in combination with several standard-of-care therapies began in mid-2015.
Data from these studies are not likely to start emerging until the very end of next year. In the meantime, all will be hoping that the Keytruda signal is soon confirmed to be false. Umer Raffat, an analyst at Evercore ISI, commented this morning that there had been no clear hint of safety problems in previous trials.
After such a remarkable run of good news, perhaps Merck and Keytruda were due a setback.