FDA Clinical Hold Hits Keytruda Multiple Myeloma Studies
Executive Summary
Development of the leading immune-oncology agent has hit the buffers for multiple myeloma but failure in this relatively small market should not materially impact the product's prospects.
The FDA has placed a clinical hold on three combination studies of Merck & Co. Inc.'s core immuno-oncology product Keytruda (pembrolizumab) in multiple myeloma, just weeks after enrolment in two of them was suspended on the back of reports of increased deaths in patients receiving the drug.
The US agency's decision, which affects the KEYNOTE-183, KEYNOTE-185 and KEYNOTE-023 studies, follows a review of data by the Data Monitoring Committee in which more deaths were observed in the Keytruda arms of KEYNOTE-183 and KEYNOTE-185 – it was this imbalance that led to the original pause in new patient enrolment in June.
Merck said the FDA had determined that the data available at the present time indicated that the risks of Keytruda plus Celgene Corp.'s immunomodulatory thalidomide analogues pomalidomide (Pomalyst) or lenalidomide (Revlimid) outweighed any potential benefit for patients with multiple myeloma.
As such, all patients enrolled in KEYNOTE-183 and KEYNOTE-185 and those in the Keytruda/lenalidomide/dexamethasone cohort in KEYNOTE-023 will discontinue investigational treatment with Keytruda (see box for further details of each of the studies). No other Keytruda studies are affected.
Modestly Negative
Analysts were largely unmoved by the development, and pointed out that multiple myeloma is by no means an important market for the leading anti-PD-1/L1 product.
"The clinical hold for Keytruda in myeloma is modestly negative, but not surprising; expectations should have been very low. Based on available data, there is nothing to indicate that there is a more serious underlying issue that could compromise Keytruda's solid tumor opportunities," said Alex Arfaei from BMO Capital Markets in a research note.
The following studies have been placed on full clinical hold:
KEYNOTE-183: A Phase III study of pomalidomide and low-dose dexamethasone with or without pembrolizumab in refractory or relapsed and refractory multiple myeloma.
KEYNOTE-185: A Phase III study of lenalidomide and low-dose dexamethasone with or without pembrolizumab in newly diagnosed and treatment-naïve multiple myeloma.
The following study has been placed on partial clinical hold:
KEYNOTE-023 Cohort 1: A Phase I multi-cohort trial of pembrolizumab in combination with backbone treatments for subjects with multiple myeloma. Cohort 1 of KEYNOTE-023 evaluated pembrolizumab in combination with lenalidomide and dexamethasone in patients who received prior anti-multiple myeloma treatment with an immunomodulatory (IMiD) treatment (lenalidomide, pomalidomide or thalidomide).
He added that more clinical trial failures should be expected in immuno-oncology as "the industry's frenzied rate of IO combo development is outpacing our understanding of the underlying mechanisms". Other companies are unlikely to be immune to this, but Merck is perhaps more exposed because of its particularly broad program with Keytruda.
A more significant threat to Keytruda's position is likely to come from competition in the commercially more critical lung cancer indication, particularly from AstraZeneca PLC's Imfinzi (durvalumab) for which the MYSTIC data are keenly awaited, and Bristol-Myers Squibb Co.'s Opdivo/Yervoy combination now being tested in CheckMate-227. Whether these products can differentiate themselves to a meaningful extent to compensate for their later arrival remains to be seen.
Analysts at Barclays agreed. "Overall, we see today’s announcement as a modest setback for Merck, but note that multiple myeloma was never a key driver of our Keytruda sales forecasts… We continue to see lung cancer as the primary driver of Keytruda sales near term."
The multiple myeloma market has become increasingly crowded of late, with more recent additions including Bristol-Myers Squibb Co.'s Empliciti (elotuzumab) and Janssen Pharmaceuticals Inc.'s Darzalex (daratumumab), making Keytruda a latecomer to the market.
The only other anti-PD1/L1 product that appears to be in industry-sponsored Phase III studies for multiple myeloma is Bristol-Myers Squibb's Opdivo (nivolumab) together with its SLAMF7 inhibitor Empliciti in combination with pomalidomide and dexamethasone in relapsed and refractory patients (CheckMate 602).