Mitch Higashi: Thank you very much. It is a great honor to be here, thanks so much. Last month, October 2018, the Nobel Prize in Medicine was awarded to two cancer researchers, right? Dr. Allison at MD Anderson here in the U.S. and Dr. Honjo in Japan for their breakthrough work in immunotherapy. Understanding how the immune system is activated and works against cancer cells. The Nobel Committee called this quote, “an entirely new principle in how we treat cancer”. Why am I saying this? We are all now connected to this new principle in how we treat cancer, okay? Real-world evidence will feature prominently and critically in how we all go forward. All of us from different disciplines, all of us as different stakeholders, working together in real-world data to make advances in cancer.
So our story began with YERVOY in 2011, our first approval in immunotherapy for advanced melanoma. And so YERVOY, a CTLA-4 inhibitor, and our story continued in 2014 with the approval of NIVO or OPDIVO, also in advanced melanoma. And so, the idea here is that cancer, one of the ways that cancer allows itself to grow is by inhibiting the braking system, right, so if you think about a T-cell? What cancer wants to do is activate that braking system, okay, so CTLA-4 wants to activate the braking system and prevent the proliferation of the T-cells. It wants to activate the braking system of PD-1, prevent the immune system from recognizing the tumor cells and attacking them, okay? So, after 2014 we had a pretty simple working theory, which was combine both drugs. Combine both drugs, in our first and deepest area of expertise, which was advanced melanoma. And the idea was, shut down the tumors ability to deactivate these braking systems and basically make it harder and harder for the tumor to evade. Make it harder and harder for the tumor to activate it's cloaking device.
Now, in our opening remarks from Zach, he talked about out exponential growth in understanding in this field. Basically, we are doubling our knowledge, doubling our understanding every year now. What that also means, is that last year, we knew about half as much as we know this year. So, heading into ESMO 2017, our story begins with an interim result. So this is the presentation of at least three years follow up. What this means is that every patient in this trial has at least two years of follow up for overall survival. And so, you can see here on the left hand side of the slide, promising, right? Promising. You see a numerical trend. You see a signal that the IO combination appears or suggests that it is of more durable response than either NIVO, that's OPDIVO monotherapy, or IPI, which is the YERVOY monotherapy. We don't have statistical significance but it is suggestive.
However, on the right hand side of the slide, you now see a new question. And this was a big question for us. What you see is that in the U.S. population versus the European trial results, you have a statistically significant overall survival. And we are immediately faced with a question. Okay, what is going on? Can we validate this in real-world data? We have to try to validate it because we need to develop new working theories. Right, so why is it that the U.S. population could respond better in a randomized trial versus the European population? So we immediately turn to Flatiron. I won't go into great detail on this slide, Amy did a wonderful job taking you through the methods, but the reason why we were confident in partnering with Flatiron, both for overall survival in a real-world mortality endpoint, and also progression free survival.
The way I would summarize this in one word is, transparency. Transparency, very honest, open, and transparent with us about, look, here's where we are with version 2.0, work in progress but this is what we've got so far, we're using the SSDI, we're augmenting it with obituaries, we're using algorithms to link it to the EMR, and we're trying to validate this with the National Death Index. And similarly, with progression free survival, Amy alluded briefly to the Health Affairs Paper. So both Sean and Amy are co-authors on this paper that talk very openly about their methods for inter-rater reliability and intra-rater reliability. So, inter-rater reliability, two different abstracters can look at the same chart and come to the same conclusion. Intra-rater, meaning that one abstracter can look at that same chart at different points in time, and come to the same conclusion.
So, heading in ESMO 2018, this is what we are able to present from the Flatiron study. The first thing that you see here is that we have raised the bar, because with Flatiron we are now able to track and evolve our understanding about standard of care. So we actually wanted to benchmark against OPDIVO monotherapy, right, because that was becoming the new, if you will, predominant standard of care. What you see here is that the IO, IO combination is more durable and is the most durable of the response curves. Similarly, what you see here with overall survival, overall survival for the IO, IO combination appears more durable than the NIVO monotherapy.
Now, perhaps most importantly, I'll say two things. What we have seen most recently this year at ESMO from our report out of the randomized trial, so this is the extension of that three year followup, into four year followup, we see essentially the same thing, that the IO, IO combination produces the most durable OS response. And that appears to be supported here in the Flatiron study. Perhaps, more important for us, as outcomes researchers, as explorers of real-world evidence, what we were able to see was that in the European trial population, they had more advanced or a higher burden of disease so they had a higher proportion of distant metastasis. That higher proportion of distant metastasis was different, was higher than the U.S. trial population and the U.S. Flatiron population. So, we now have a new understanding, a new approach, a new way to think about burden of disease, and how patients are going to progress. So with that, I believe that is my last slide. So we have some time to call up the panel. Just like to acknowledge all of our collaborators, both at Flatiron and our co-authors for this important work, thank you.