I posed this question regarding IO combinations in the last post, leading up to AACR:
“Why the perception of angst then? The sentiment has been summed up as “everything will work a little, so what do we research/fund/advance? How do we choose? How will we differentiate”?
I was mulling over these questions as I prepared remarks for Jefferies Immuno-oncology conference – the slides below are taken from the deck I presented.
Even the comment “everything will work a little” now seems to be an overreach. We could instead say: “most combinations won’t work at all”, meaning they won’t work better than anti-PD-1/PD-L1 monotherapy or anti-CTLA4 monotherapy, or, that they won’t work better than those therapies used in combination with standard of care.
Remember two years ago? We were going to take an anti-PD-1 to “release the brake” and add anti-4-1BB or anti-OX40 to “step on the gas”. While it is still early, this seems to be an empty paradigm. Why? Certainly the 4-1BB and OX40 pathways are intensely potent when used to drive T cells directly (e.g. anti-CD3 + anti-4-1BB in vitro or as used in a CAR-T cell). Is it too early to tell? Have the wrong patients been enrolled in trials? Are the antibodies no good? Is it the Fc? IS THE TUMOR COLD?
So here we go, onto the next paradigm, summed up in the phrase “make cold tumors hot”. What happened to stepping on the gas?
At AACR, Dan Chen (from Genentech, a Roche company) laid out the case for using not 1, not 2, not 3, not 4, not 5 … but up to 11 different therapeutics to successfully treat a given tumor – he exaggerated to make the point that none of the current immune checkpoint inhibitors (ICIs) should be expected to work in synergy with anti-PD-1 therapy, a priori. Why not? Because the ICIs are the really big levers, and the rest are smaller levers, where smaller simply means a pathway or biology that is less fundamental to immune anti-tumor responses than the ICIs. In order to see robust activity with these smaller levers, you need to apply them to carefully selected patients. An example was given by Jennifer Michaelson (from Jounce, and before that, Biogen) who stressed the need for biomarkers to guide the clinical application of an agonist anti-ICOS antibody (another gas pedal). The “cold tumor hot” gang that includes oncolytic virus approaches, onco-vaccine approaches, TLRs, STING and so on have not yet really articulated a strategy to identify patients likely to respond except in those tumor types associated with viral infection.
All of these accessory immuno-modulatory therapies, including the agonist antibodies (anti-4-1BB, anti-ICOS), the myeloid cell modulators (anti-CSF1R), the soluble mediator inhibitors (A2AR, IDO), the innate triggers (STING) we can lump as immune-oncology (IO) drugs, to distinguish these from ICIs.
The apparent strength of some ICI-standard of care combinations, and the apparent weakness of the early ICI-IO combinations has some startling implications. Let’s look at the current landscape:
and here are the approved ICIs:
Note the concentration of indications – melanoma, NSCLC, H&N, bladder, Hodgkin lymphoma, with single approvals in Merkel cell and RCC. Certainly the list will expand but if we concentrate on melanoma and NSCLC for a moment, we can outline the key challenges:
1) get the response rates up, and 2) prevent relapses. What do we mean by this? In advanced and/or metastatic melanoma the best overall response rate (ORR) using ICI monotherapy is about 30% in previously treated patients and up to 40% in patients naive to therapy (not previously treated with anything). Within the responders there are two subsets of interest – durable responders (those that will survive for 3 years or more: about 20% of the responders) and relapses (those who initially responded, but then relapsed on ICI therapy: about 30% of the responders). So if we just call out the durable responders we have between 6% and 8% of the original patient population in the trial receiving durable benefit. The idea of course is to get this number up.
Before turning to relapses, lets look at NSCLC.
Again the lessons here are pretty clear – get the ORR up, improve durability of response, move ICI to early line therapy. The median overall survival data (OS) for advanced NSCLC patients treated with ICI looks very modest (12 months v 8-10 months with chemo) but this obscures the fact that the OS curve is pulled to the right by a relatively small number of durable responders: again, a small percentage of patients do very well.
So what next? Pharma is taking diverse approaches to improving ICI responses across many indications, To keep it simple I pulled out just two portfolios – those of Bristol Myers Squibb and Roche/Genentech. We can note in passing that the Merck (US) portfolio is relatively similar to the BMS portfolio, and the Astra Zeneca portfolio is relatively similar to Roche, as is the portfolio from the Merck (Germany)/Pfizer collaboration.
A few comments on these portfolios from the pharma level and as relates to small company programs and those who invest in those programs/companies:
The latter point is critically important for biotech and investors to the consider and revisit often: how will my program generate compelling data? How is the indication landscape shifting as I spend 2-3 years moving a program forward? Is there a milestone of sufficient signal to rise above the noise of a thousand other ICI-ICI, ICI-IO, or ICI-SOC trials? I had the uneasy experience of walking through the poster sessions at AACR17 last week, past lovely bits of work that no one was paying any attention to. That’s a lousy feeling for the person presenting the poster and a very lousy place to be if you are a small biotech company.
A final slide:
It’s an incomplete list of course.
More on resistance and relapses next time.