The rush of the new generation of immunological cancer agents has been remarkable, but perhaps most remarkable is how compressed clinical development has become in the class of projects that target the programmed death-1 (PD-1) pathway.
Merck & Co believes that the speed of its programme for pembrolizumab has been down to a willingness among investigators and regulators to rip up the usual blueprint of clinical trial design and instead build on a phase I study to develop supporting data. By doing so, the New Jersey group has been rewarded with an opportunity to receive the first regulatory approval of the three companies racing to put a PD-1 agent onto the market, as the FDA has set an October 28 action date in metastatic melanoma.
“It’s only been three years since we dosed the very first patients,” says David Mauro, Merck’s executive director of oncology clinical research, speaking to EP Vantage on the sidelines of Asco. “Usually when those timelines happen they’ve happened in [haematological] malignancies. You haven’t seen that typically in solid tumours.”
It was at Asco in 2012 that Merck presented the very first data on pembrolizumab (MK-3475) in just 10 patients. This trial was expanded to 135 in 2013 and 600 in 2014. Now, what is technically the very first study Merck initiated on the antibody in 2011 has enrolled more than 1,000 patients. It may very well be the largest ever phase I study, thanks to its numerous dose, disease stage and tumour cohorts.
Mr Mauro said that this was the best way to streamline development.
“We maintained the ongoing phase I study and just expanded that, rather than the traditional paradigm of finding a signal in phase I, starting a new study in phase II, and expanding it and moving it to phase III,” he says. “What we tried to do was leverage the phase I design and evaluate the dose and safety as quickly and thoroughly as possible.
Mr Mauro adds that the idea of filing on phase I data might make people might suspicious. “But if you look at the size of the trial and the trial design and how it was evaluated, we’re putting together a very robust data package that is equivalent to a phase III.”
Not just melanoma
Merck had good news to report from continued expansion of its programme with data in head and neck cancers: the phase Ib study found that pembrolizumab achieved a 20% overall response rate, with human papillovirus (HPV) status having no bearing on patient response. It was viewed as good, if not overwhelming, that it improved on Erbitux response rates.
However, the fact that there was a signal was in concert with one of the themes of the 2014 Asco, that the PD-1 pathway is active in more disease types than previously thought. Merck’s competitors Roche and Bristol-Myers Squibb released data on bladder and ovarian cancers respectively, indicating that the target may have use in tumour types that have not been identified with immunogenic response in the past.
The data on head and neck cancer, which is largely defined by squamous cell histology, will mature in the coming months and Merck hopes that the next catalyst will be signs of durable response. But Mr Mauro acknowledges that this is becoming a difficult space.
“What we’re finding, as with almost all tumour types, is that just because it’s head and neck [the patient population] doesn’t all behave the same,” he says. “The science is going to continue to differentiate these tumours into subpopulations. Trying to find those subpopulations based on histology, based on functional anatomy or based on biomarker definition [is] going to be important.”
Put it together
With the clinical profile of pembrolizumab becoming ever more clear, Mr Mauro says the company wants to try combining it with multiple agents, and is looking to form new collaborations. In this it has been in a race with Bristol-Myers Squibb, which in just the past month signed deals with Celldex to test nivolumab with that company’s CD27-targeting antibody varlilumab and with Incyte to launch trials with the IDO inhibitor INCB24360.
Merck is also working with Incyte’s project, and in addition has signed deals with GlaxoSmithKline for Votrient, Amgen for the oncolytic therapy T-Vec, and Pfizer for Inlyta.
Mr Mauro says immuno-oncology has loosened business development in pharma companies because of the number of compounds in play and the ways various mechanisms of action might work well together to extend survival or bring cancer under control.
“Strategically what we’re trying to do is find the best combinations that make the most sense regardless of who has the compound,” he says. “Collaboration strategies in years past have been difficult to pull together because of proprietary issues. [But] the collaborations we’ve announced and ones that we’re pursuing are coming together extremely easily because companies are willing to work together in ways that I haven’t seen.
“What we’re trying to do – because it’s still extremely early in the game of immunotherapy – is go after balance, going fast, and trying to pick what we think are the best combos.”