The loss of $4.3bn in market value yesterday shows how Asco went for Bristol-Myers Squibb this year – in the minds of investors at least. Despite laying out plans for its next wave of immuno-oncology assets at an event over the weekend, the company failed to quash concerns that it is falling even further behind Merck & Co.
Underwhelming two-year survival data from Opdivo plus Yervoy in a phase I lung cancer study probably did most damage; the stakes are incredibly high here ahead of a crucial pivotal read out early next year. Even Bristol’s announcement that it would be fast-tracking its in-house IDO inhibitor into pivotal studies could not lift spirits.
Given that IDO is emerging as the next I-O mechanism to watch, this is perhaps surprising. Data released on the Incyte-partnered asset epacadostat showed intriguing response rates across a range of tumours, presenting ways forward for both Merck and Bristol-Myers here (Asco – Solid progress for IDO inhibitors, June 6, 2017).
The strong response rates seen in non-small cell lung cancer patients in the Keytruda-epacadostat study Echo-202 were likely interpreted as a further threat to Bristol-Myers’ Opdivo-Yervoy combo strategy in this tumour type. The data are far too early to make an informed call on this; however, Bristol’s announcement on BMS-986205 is telling of the potential seen in the IDO mechanism.
This in-house IDO inhibitor will be quickly pushed into several registrational studies, including in NSCLC, the company revealed in Chicago, while the collaboration with Incyte will also continue. Having already learnt a painful lesson in lung cancer, with the IDO combination Bristol is clearly making sure every base is covered.
Place at the front
While confirmation of the potential of any PD-1 + IDO combination in lung cancer is still a couple of years away, Bristol’s bet on PD-1 + CTLA4 will read out sooner. The confirmatory Checkmate-227 study is due to yield data in the first half of next year – interim read outs could emerge sooner.
This trial will determine whether Opdivo plus Yervoy has a place in the first-line setting, a space where Merck won early approval for Keytruda in combination with chemotherapy last month (Merck cements its lung cancer lead, May 11, 2017).
Checkmate-012 is a phase I test of Bristol’s combination strategy, although as a very small study (n=77) with no randomised control arm it has clear limitations.
Updated two-year survival data unveiled at Asco appear to show little incremental benefit to adding Yervoy to Opdivo in all comers at two years. When stratified for PD-L1 expression, those in the ≥1% do appear to show a benefit, however notably in the ≥50% group, at two years the Opdivo monotherapy group had a better rate of survival.
|Searching for a signal in Checkmate-012|
|All patients||≥1% PD-L1 expression||≥50% PD-L1 expression|
|(n=77 for combo/52 for mono)||(n=47 for combo/32 for mono)||(n=13 for combo/12 for mono)|
|1-year PFS rates (%)|
|Opdivo + Yervoy||43%||53%||64%|
|2-year PFS rates (%)|
|Opdivo + Yervoy||29%||38%||54%|
|1-year OS rates (%)|
|Opdivo + Yervoy||76%||87%||100%|
|2-year OS rates (%)|
|Opdivo + Yervoy||49%||58%||62%|
In Keynote-021G, the data on which Keytruda won its early approval, only a progression free survival benefit was seen – overall survival data were confounded by patient crossover. And on PFS, the Opdivo plus Yervoy combination in Checkmate-012 also showed consistently better results than monotherapy.
For what the cross trial comparison is worth, the two strategies appear to show similar survival benefits at one year.
|Keytruda vs Opdivo|
|Keytruda + chemo||chemo||Opdivo + Yervoy||Opdivo|
The signals from Checkmate-012 are mixed, but with so much a stake it is not surprising that investors are reading into the negatives. And while Checkmate-227 is a very different trial – patients are stratified into PD-L1 expressors (≥1%) and non-expressors (<1%) and it includes a chemotherapy doublet as well as the combination and Opdivo monotherapy arms – the additional toxicity of an anti-CTLA4 agent will be a relevant consideration.
Concerns that Bristol-Myers has conceded much ground in first-line lung are well founded, but there are wider issues here. At Asco, Merck left the impression it had more to say about near-market combinations, which will not satisfy Bristol-Myers investors looking for a quick return to form.