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Intrinsic Value is all-important and is the only logical way to evaluate the relative attractiveness of investments and businesses.
Intrinsic Value is all-important and is the only logical way to evaluate the relative attractiveness of investments and businesses.
Good day and welcome to the Bristol-Myers Squibb 2017 Fourth Quarter Results Conference Call. Today's conference is being recorded.
At this time, I would like to turn the conference over to Mr. John Elicker, Senior Vice President, Corporate Affairs and Investor Relations. Please go ahead, sir.
Thank you, and good morning, everybody. Thanks for joining really on a Monday morning. We have a lot of information to discuss today, both from our Q4 earnings, our 2018 outlook, as well as results from 227. We are going to read the slide deck today, which we normally don’t do. So, if you on our distribution list, we have added about 15 minutes ago, the slides are also available on our website.
With me this morning, are Giovanni Caforio, our CEO; Tom Lynch, our Chief Scientific Officer; Charlie Bancroft, our Chief Financial Officer, and Murdo Gordon, our Chief Commercial Officer. Giovanni, Tom and Charlie will have prepared remarks. And then, as will be available for Q&A.
On slide two, is our Safe Harbor language, I’ll review it quickly. The presentation contains about company's future plans and prospects that constitute forward-looking statements and purposes of the Safe Harbor Provisions, under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these results of various important factors, including those discussed in the company's most recent annual report on Form 10-K and reports on 10-Q and Form 8-K, the documents are available on the SEC, our website or the Investor Relations Group.
Any forward-looking estimates represent our estimates on as of the day and should not be relied upon as representing our estimates as of any subsequent date. While we never like to update forward-looking statements at some point in the future. We specifically disclaim any obligation to do so, even if our estimates change. The presentation also contains certain non-GAAP financial measures, which are adjusted to include certain costs, expenses, gains or losses and other specified items. Reconciliations of these non-GAAP financial measures to the most comparable GAAP measures are available on our website.
Giovanni?
Thank you, John, good morning, everyone. We have a lot to discuss today, so let me share an overview of the call. As you have seen, we have made an exciting announcement this morning, on our Lung Cancer Program. We consider today’s results as a break-through in cancer research, and we are excited for what this means for patients and for the treatment of lung cancer. These results is a through example of the innovation that its core to our strategy. Based on our understanding of this disease, we made bold and innovative changes to our program as the science of all. Today’s results validate our approach. I am really proud, of what our R&D organization has accomplished, to advance the understanding of biomarkers, in the treatment of lung cancer. And Tom will walk you through the details in a few minutes.
We also announced, a very good quarter there and strong performance overall in 2017, which Charlie will share in more detail.
From my perspective, we are starting 2018 with good momentum in our business and we see number opportunities in oncology and outside of oncology that we will be focusing on this year. And as I started to discuss in San Francisco last month, looking beyond 2018, there are multiple growth drivers, that position us well for the longer term. I’ll talk more about this, a little later in the call. And with that I’ll handed it over to Tom, to discuss today’s announcement. Tom?
Thank you, Giovanni. If I could ask everyone to turn to slide six. Today we are excited, to announce the Study 227, met the co-primary endpoint, of improved progression free survival for the Opdivo Yervoy combination versus chemotherapy, for patients with high tumor mutational burden, or TMB, regardless of PD-L1 expression. And remember, that we're looking at both pathologies in CheckMate-227. And as we also announced, the DMC has recommended that the trial continue to completion for overall survival in a PD-L1 selected population in Part 1A. While we planned to present the results in upcoming medical meeting, what I can tell you now is that this PFS data is highly statistically significant and clinically meaningful. I strong believe that this will make a difference for patients with advanced lung cancer.
Let's just put this into context. When I first began seeing one cancer patient 30 years ago, the only options were chemotherapy and radiation, both marginally effective and significantly toxic. Since then, lung cancer has become a group of related diseases defined by distinct biomarkers that brought biology and treatment. EFGR, ALK, ROS1, RET and PD-L1 just to name a few. Today we add TMB to this list to define a subtype of patients who clearly drive benefit from combination immunotherapy treatment regardless of their PD-L1 status. As I've consistently said, Bristol-Myers Squibb is a science driven company. These results demonstrate the strength and importance of our translational capabilities and validate the innovative changes we made to the trial design in light of how quickly the science was evolving.
Perhaps most importantly, the results today further validate the role of the CTLA-4 mechanism. Lung cancer is now the third tumor where we've showed benefit with the Opdivo-Yervoy combination in a randomized trial. And we look forward to the overall survival analysis from 227 as the data matures in the TMB population.
Now if I could ask you to turn to slide 7. What I'd like to do is tell you or answer the question, why do we choose to include TMB in our analysis plan. First from a machinist perspective, TMB measures the number of somatic mutations that are present in the DNA of a tumor compared to the DNA of normal tissue. We believe some of these mutations can drive expressions of neoantigens. And then these new neoantigens could be more visible to immune system and thereby driven an immune response.
Second as you know for Bristol-Myers others have generated data showing improved outcomes for patients with high TMB. We've shown this across multiple endpoints, and those includes response rate PFS and overall survival across multiple tumor types including non-small cell lung cancer, bladder cancer and small cell. And we've shown this for both Opdivo monotherapy and the combination of Opdivo and Yervoy. This support our hypothesis around TMB being an important potential biomarker.
Now if I could ask you to turn to slide 8. Now let me take a step back and explain how we adapted 227? On this slide, you see the overall study design. As you know 227 was originally designed as two companion studies. Part 1A looking at PD-L1 expressers, and part 1B looking at PD-L1 non-expressers.
As more data emerge we made three important changes to 227 to reflect the evolving science all of these were key. First, we increased the size of Part 1A, this gave us more statistical optionality and lowered the potential for imbalances in the PDL-1 positive patients. Second, we added the second part, part 2 to 227. This is a study of about 750 patients who are enrolled regardless of histology and across the PDL-1 spectrum comparing Opdivo plus chemotherapy versus chemotherapy alone. And the third change we made was to our analysis planned for part-1 which allowed us to include TMB. I will disclose in details of that today.
Now if could ask you turn to slide 9. As I mentioned, part-1A and part-1B are technically two companion trials running at the same time. However, in discussions with the FDA we executed and integrated analysis planned but brought together the Opdivo, Yervoy arms and the chemo arms across all of part 1 in a predefined population of TMB patients.
Turn to slide 10 please. Within that integrated analysis planned, we defined two co-primary endpoints across part-1 and that is what we’re reporting today. The first is comparing the combination of Opdivo Yervoy versus chemotherapy for PFS in a PMB selected population. And the second is comparing the combination versus chemotherapy for overall survival is a PDL-1 selective population.
If I could as you know to turn to slide 11. Through the PFS endpoint, we were able to access the TMB status of the majority of patients across Part-1 which I’ll remind you is more than 1,200 patients, actually its more than 1,700 patients. And here you can see that of all those assessed roughly 45% or above a cut-off upgraded in 10 mutations per mega base which is what we defined as high TMB. In our study, TMB was evaluated using foundation medicine analytically validated assays foundation one. Now I ask if you could turn to slide 12.
We’re very encouraged by today’s results which establish TMB as an important new independent biomarker for selecting patients that respond to immunotherapy. Clearly, we’ll be sharing these data with health authorities and we look forward to presenting the complete results at the future Congress.
We believe TMB could be important more broadly. We started to incorporate it across our IO trials not just for Opdivo and Yervoy but also far for our next generation oncology assets. In fact, we’re studying TMB in over 100 studies in multiple tumor types and programs. If we could now turn to slide 13.
As a reminder, what we’re reporting today is just the first of many significant data opportunities from our broad long program. For CM-227, the analysis for patients from Part-1 B is now finally complete. Part-1A continues for overall survival, in PDL-1 patients remember that the overall survival is event driven. In know that the interim occurred later than we expected and we anticipate that the final results will be later this year or early next year. And part-2 of the trial is ongoing which we don’t expect in 2019.
I also remind you that the 9LA trial, looking at Opdivo plus Yervoy concurrent with two cycles of chemotherapy is also ongoing, with results expected in the second half, of 2019. And of course, we have the initiation of our IDO, Opdivo combination trials, with both insights IDO and our own compound which we are eagerly are waiting to see.
I could now ask you to turn to slide 14. Beyond lung cancer, we have significant data milestones, with Opdivo in the combination over the next 24 months, with trials reading out in hepatoma, gastric cancer, small-cell lung cancer, and head and neck cancer.
As I had said, we are a science driven biopharma company. I am particularly excited about our opportunities across the areas of neuro science, fibrosis and cardiovascular disease, and we continue to accelerate the development of our most promising assets in those areas, as well as immuno-oncology.
With that, I’ll turn it back to Giovanni.
Thank you, Tom. I want to reiterate that I am really proud, of what our organization has accomplished. This is an important result for lung cancer patients and we are very excited by the opportunity ahead of us.
Turning to slide 16 please. 2017 was a very strong year, thanks to strong superior commercial execution and good progress in our clinical programs. We are now entering 2018, with good trends and momentum in our business.
Moving to slide 17. We are starting the year, in a very strong position, with good top and bottom line growth, in our business. There are a number of pillars in our business, that can grow in 2018 and beyond and I am really excited about the prospects. First, Eliquis is a very important and growing franchise for us. As we exit 2017, Eliquis is the leading NOAC and its approved indications, and has tremendous opportunity to continue to grow.
With Opdivo, the existing business going into 2018 has a strong momentum. We see continued strength across the current indications for Opdivo and beyond our excitement about the First-Line Lung, results announced today. We have a number of opportunities this year, that we are focused on, including adjuvant melanoma and the upcoming PDUFA for First-Line renal, with study 214.
With today’s results, I even more confident, that we will play a meaningful role in first-line lung cancer, and I am looking forward to continue data readouts later this year and into next year, that will build on today’s announcements. And thinking beyond the 2018, we see a sustained - of growth, driven by important opportunities for Eliquis and Opdivo. So, let me remind you, of what those are.
I previously mentioned Reno, as part of our growth in 2018, and it also plays a role beyond this year, in what we see as a significant opportunity for Opdivo. It's an area where we started to make a difference in second-line and see significant growth potential in first-line now, based on study 214. With the first-line indication, Opdivo will have a presence across the continuum of care in renal cancer.
Two other areas, with a billion dollar plus potential, where we are focused, our gastric cancer and HCC. Diseases with high unmet need and poor outcomes. Based on what we have seen from Phase 1 and 2 data on opdivo on these tumors, and anticipating data readouts from our Phase 3 program this year and next year, we believe these are important areas driving growth in the near and in the medium term. In addition to this, we have important opportunities in small-cell lung cancer later this year and head and neck in 2019.
Finally, our emerging pipeline across all therapeutic areas is one of the most promising in our history with several opportunities contributing to sustained growth. We are excited with several programs moving forward, such as IDO and LAG-3 in oncology and from our non-oncology pipeline, where we'll see FGF21 and TYK-2 moving to the next stage of development this year. All of what I just described gives me confidence in our future, and in our ability to continue to deliver on our strategy. The significant opportunities are ahead of us requires to ensure the right level of investment behind R&D and certain commercial capabilities, and we are doing just that.
And turning to slide 18 please. A year ago, I spoke about the work we were doing to evolve our operating model. And today, I'm pleased to say we are delivering across the company, with a disciplined approach to resource allocation. We are creating a better company, which moves fast and is more competitive. We are strengthening our capabilities, particularly in translational medicine, and we are investing in our pipeline and commercial capabilities to support future growth. These will continue to be a critical focus going forward.
With that, I'll hand it over to Charlie Bancroft, who will discuss some specifics on the quarter and how we are thinking about our financials.
Thank you, Giovanni and Tom, for your very exciting comments, all tapped off from my Philadelphia Eagles winning the Superball.
Let me start by saying, we delivered a very good 2017 with robust revenue and earnings growth, driven by strong execution across the company.
Moving to slide 20. While total revenues grew 7% for the year, and our prioritized brands were up 27% as Giovanni just highlighted. The exceptional product performance on key brands drove the EPS growth.
With that, I'll provide some color on the strong trends we are seeing Opdivo. It was another solid quarter for our Opdivo franchise. We delivered $1.4 billion of worldwide revenue and almost $5 billion in sales on a full year basis. Similar to previous quarters, we were successful in maintaining our leading share in second line lung and saw strong performance in other tumors such as renal cell. While the trends are early, Opdivo has rapidly penetrated the second line HCC market and we are seeing good uptake of Opdivo in the adjuvant melanoma setting.
Outside the U.S., Opdivo continues to lead in key markets such as Germany, France and Japan. Excluding the sales deferral impacting Q4 of 2016 international sales of Opdivo were up over 64% in the quarter. With these strong Opdivo trends in today's announcement, we see meaningful opportunities for growth in both the near and medium term.
Turning to Yervoy. We are seeing pressure on U.S. sales due to the adoption of Opdivo in the adjuvant melanoma setting. Going forward, we expect these trends to stabilize and our outlook remains positive with the potential launches in the first line renal cell and first line lung. From the franchise perspective, we expect the growth of Opdivo in adjuvant melanoma were more than offset the erosion of Yervoy. Our strong commercial execution across the portfolio also resulted in substantial growth for -- in the quarter. In the U.S., Eliquis extended its leadership position with almost 50% TRx share of the NOAC market. Internationally, we are seeing similar trends and strong brand momentum in leading new-to-brand share in top European markets. With this performance in mind, we believe Eliquis is well positioned for period of sustained growth going forward.
Now turning to slide 21 and our non-GAAP P&L. I’ll start with our gross margin which continues to be strongly influenced by product mix. The strong growth of Eliquis and declining of virology franchise erode most of pressure on our margin in the quarter.
Moving to OpEx and building on Giovanni’s comments about resource allocation, the increased investment in R&D during 2017 while prioritizing spend in MS&A. This was enabled by our ongoing operating model evolution that we will continue to execute going forward.
With respect to our tax rate, the favorability in the quarter was primarily driven by earnings mix. And thinking longer term and taking into account tax reform we expect our tax rate to be in high teens within the coming years. With tax reform in mind, turning to slide 22 we see no change to our balanced approach to capital allocation.
Business development remains a top priority for us and 2017 was a very active in which we executed over 50 transactions. We expanded our translational capabilities, we licensed new assets and technologies and we entered several late stage clinical collaborations. The ISM acquisition are partnership with Foundation Medicine and our new relationship with Halazyme were few important examples of transactions we executed last year.
We also remain committed to our dividend, 2018 marks a ninth consecutive annual increase. With respect to repurchase, we bought back 250 million in the quarter and nearly 2.5 billion for the year. Taking together we returned over 5 billion to shareholders in 2017.
Turning to slide 23 for additional color around 2018 guidance. Our full year and non-GAAP EPS guidance represent strong growth over 2017 in spite of the roughly $200 million impact from the change in accounting rules effecting how certain royalties are recorded. On gross margin, we expect additional pressure to be driven by the continued growth of Eliquis and erosion of virology to be somewhat offset by the growth of Opdivo.
Our approach on OpEx reflects the continued prioritization in R&D while we drive efficiencies in MS&A. In conjunction with today’s announcement, our guidance includes investments supporting the educational efforts to commercialize TMB.
A quick note on OI&E. We have restructured a portion of our future AV royalty rights and therefore will receive higher royalties in 2018 and 2019. Our tax rate of 20 to 21% takes into account tax reform and as I mentioned the potential for further favorability over the next few years.
In conclusion, we have a very solid 2017 with strong execution across the board. We are well positioned to grow in 2018 and today’s announcement increases our conviction in the growth outlook for the company. I’ll now turn it back to John for Q&A.
Thanks Charles and I think we’re ready to go to the Q&A session. So as a reminder we have Giovanni as well as Murdo here for any of your questions. Go ahead please.
[Operator Instructions]. And we will take our first question from the queue, Seamus Fernandez from Leerink Partners. Please go ahead, your line is now open.
Seamus, we can’t hear you.
Sorry, Alex Arfaei from Bank of Montreal Capital Markets. Please go ahead, your line is now open.
Good morning, thank you very much for taking the questions and congratulations on the results. I am just curious, why is overall survival is not being evaluated, based on TMB as well. And we know from CheckMate-26 that Opdivo monotherapy showed very encouraging results in this setting. How come opdivo monotherapy is also not being included in the TMB analysis? Thank you very much.
Alex, thank you. I’ll take both of these questions, and I think let me just take the second one, I can do the second one probably quicker, than we will talk a little bit about the end points in the first one. So, just to remind everybody, what we were reporting today are the two co-primary endpoints, so we are reporting the PFS in the combination a therapy, which is a co-primary endpoint in TMB high group and there we’re reporting the fact that the second co-primary endpoint which is the test for overall survival in the PL-1 group is continuing for maturity.
We have not seen any overall survival data, I think that’s very important to mention. So, we have not seen any overall survival data. The second thing to say, is we are not going to be reporting any secondary endpoints on the call. The data is very fresh to us, we look forward to reporting those in important medical meeting and we also look forward to publishing that as soon as we possibly can.
Let me just say a few things about endpoints and trials. So, a couple of things. I think as a physician we think that, that I think that PFS and overall survival are both important endpoint, doctors use both endpoints, PFS and OS, be able to make decisions. I’ll also say, when you have PFS particularly in a very large well powered trial, you are able to, to get a very good sense of potential benefit and that does predict for good benefits with patients, whom are very encouraged by the PFS spend its today, that we see in the TMB population.
I really want to stress something else about this result. This is highly statically significant and its clinically significant as well. I think that’s an important point to drive home with the PFS, we look forward to seeing the OS data, when it matures, in the TMB group, just like I am sure you are excited about seeing it and we think that that’ll be something that will also be important for doctors in terms of making decisions.
I also want to stress one another point Alex, is this was across all PD-L1 expressing groups, and I think, one of the other things, we think is important, is that you know right now, PD-L1 is important decision-making factor for doctors, when deciding, how to treat people with lung cancer, and there are some people who are not getting, immunotherapy because their PD-L1 negative.
I think what TMB gives us, is the opportunity to identify patients, who clearly benefit from low dose - added to opdivo in that setting, we could not be more excited to tell you about that today.
Thank you, and now we take our next question from Seamus Fernandez from Leerink. Please go ahead, your line is now open.
Okay great. Some problem with my phone system here. Well, first of on the eco the sentiment on the eagles from so what of you said, in Boston, it was a unique event. So, thanks for that comment there, Charlie.
Second, in terms of the difference in the study design. Congratulations on the creative change to incorporate TMB. Just hoping that you could just give us a little bit of color on whether or not do you guys have a relatively complete understanding of the benefits of the combination over Opdivo monotherapy? I know that you did comment a little bit on that on the margin, but the clinical significance, is the clinical significance applied more to TMB and the analysis therein or the combination of Opdivo plus Yervoy?
And then secondarily, as we think about the longer-term opportunities Giovanni. Just hopping that you guys could give us a little bit color on how you're feeling about the Opdivo plus Yervoy combination as a continuous treatment given some of the safety concerns or at least the safety information that we're seeing out there? Again, the significance I think is clear, but we're just trying to get a better sense of directionally how confidence you are that the Opdivo plus Yervoy regimen particularly as a continuous combination therapy after 6-week treatment dynamic is something that you think is going to really work its way into the lung cancer regimen overtime? Thanks.
I've got to say as a Patriots fan, die hard Patriots in the sea of Eagles fans here, it's been a rough morning. If we didn't have 227 reports, I don't think I get through it. So, let me just address a couple of your points here that I think are well crafted and are important. The first thing I'll say is that I feel very confident that this is both a TMB story and an Opdivo-Yervoy story. And I think both are important. Because first, understanding the biology, selecting the patients are going to benefit most. TMB looks like a very powerful biomarker. And as I mentioned, we're looking at across our spectrum of IL agents including our next-gen agents.
The second point comes down to the contribution of components and how important Yervoy is? And for me, I have felt for some time that Yervoy is performing extremely well in a number of different settings. Remember, benefit in melanoma, benefit in renal cell cancer and now benefit in this case, in non-small cell lung cancer it can be high. And what I can tell you is that our analysis of the data thus far makes us very confident that Yervoy is a big part of what we're seeing today. And it's not just Opdivo, but the Yervoy is part of this as well. And I want to mention as you said, its low dose Yervoy that's given every 6 weeks and has that advantage in terms of being well tolerated by patients as we move forward. So, I think that it's not just TMB or the combo it really is a story about both and I'll turn it over to Giovanni for his thoughts.
So, I just had a couple of comments. So first of all, I want to strength again, reinforce what Tom was saying about the importance of the combination about Opdivo and Yervoy. This is the third tumor type, in which we have seen data that makes us really excited about the potential of this combination, melanoma, renal now, non-small cell lung cancer.
The second thing that I want to say is that I'm quite proud actually of the work that we've done in optimizing the regimen and I think that's really important, the dose and schedule of the Yervoy as part of the combination are really important. Based on the totality of the data that we have seen so far you know our confidence and our broadline cancer program has only increased. And I think that’s important because in parallel it also strengthens overall the growth outlook for the company. So obviously it starts with patients but I think this is a really important time for the company overall as well.
Thank you. And now we’ll take our next question Jami Rubin from Goldman Sachs. Please go ahead, your line is now open.
Thank you. Just a couple of questions, maybe please first if you can address the commercial implications of TMB, just curious what payers KOL doctors are saying about TMB. I know this is new and exciting but how typical is this in their practice. And if you could talk about the size of frontline loan market effected by patients with high TMB, your press release said that 45% of patients expect high TMB but is that 45% of the total market, or is that 45% of a share of the market and I ask because we go back and look at CheckMate-26, I think you evaluated 60 of the population. So, if you could put that into perspective.
And then just lastly, maybe for you Tom, how confident are you now in hitting overall survival and for part 1A of the study and did I hear you right? I think earlier you did say that in the earlier question that you would also look at OS and TMB although I wasn’t clear and then just lastly is this highly registrational trial? Thanks very much and congratulations.
Thanks Jennie. First of all, I’m also excited that we were able to announce what we’ve been able to do today, clearly following the science and looking at tumor mutational burden as a biomarker has been the right scientific approach in first line lung cancer and congratulations to Tom and his team for being to deliver on that.
We are also commercially and medically are very excited about TMB. It appears to be a highly predictive biomarker, as you know it's the foundation 1 test recently was recently FDA approved. And in parallel to that FDA approval, they are pursuing a national coverage determination for CMS Medicare coverage and reimbursement of that test upon indication as companion diagnostics.
So, we’re very, very excited about that and in terms of size of the front-line lung cancer population, clearly you know the design of 227, we designed this trial to exclude ALK- and EGFR positive patients. So, the 45% number applies to the TMB patients that were tested in the trial.
And I think you alluded to the ascertainment rate while it was 60% in the trial, we have a lot of confidence that that will rise with improvements to methodologies, pathology techniques as well as surgical techniques. So, we’re hopeful that, that will improve overtime and I would say that we’re very ready for this, the team at Bristol-Myers Squibb has been focused on the translational side but also on helping educate physicians. I would say in the academic centers, there is a high degree of awareness of TMB and there is already quite substantial testing today. I would say it gets much lower than that when you go out into community oncology and that’s where we’re focusing a lot of our educational and continuing research efforts. We have an ongoing safety clinical trial in first line lung cancer looking at patients with Opdivo and low dose Yervoy being treated after having their TMB accessed. And that’s being conducted through our I-O icon network, we have a great partnership with a large network in community oncology, so it will help to be able to generate data and describe the safety profile of the drug, on a must larger community base population. And then of course as we pursue regulatory approval, the commercial organization will be ready to focus on a number of different important audiences inclusive of the ones you mentioned.
Lastly, I would say from a payer perspective, this is very positive event. I think both clinicians and payers have been looking for a better way, to segment the first-line lung cancer market and I think with the advent and exciting information that we have, that we hope will be presented as Tom said, at an upcoming Scientific Congress and publish thereafter. We hope that we will be able to go to payers in the U.S and around the world and say, this is a patient population that discretely benefits from Yervoy, low dose Yervoy plus Opdivo. So, we are very excited about that in commercial ramp. Thanks
So, - I mean just eco something which Giovanni said, I think when you have a data set like this, which is highly statically significant and most importantly, probably more importantly, clinically meaningful, I think that does increase our confidence in a number of different elements of our entire lung cancer program, not just study 227, remember f we have got study 9LA, which is coming after this via part 2, which will only chemo combo and then we have our IDO studies. So, I think that’s an important finding today.
I think the second thing you asked is about whether we were looking at OS and TMB and as I mentioned earlier, we will be looking at overall survival and TMB as you know, that’s event driven and, when the data matures, we look forward to sharing them broadly at that point.
I think the second question you asked is about our confidence in hitting overall survival in part 1, as you know, we have not seen any overall survival data. The hurdle for stopping the study early is usually extremely high and again its event driven and we look forward to seeing that data when the required number events occur at that point.
And your final question came down of a - do we look at this data as registrational. I think as we said earlier, we are eager to share this information with regulators in the United States and in the EU, because I think Murdo put it very nicely. We think this is going to make a big difference for doctors and for patients, and as someone who's treated lung cancer for 30 years, to me this kind of data is the kind of data the doctors are asking for, they want to be able to know which patients are going to benefit and I think it's going to have the opportunity to really change the way we think about non-small cell lung cancer.
Thank you. Our next question comes from Andrew Baum, from Citi, please go ahead, your line is now open.
Thank you and congratulations. Three questions please. Obviously, we are operating in the dark so, we haven’t seen the 189 or 227 or the mono data from GT-7 but with that in mind, three questions.
Number one, is it going to be the enemy of the great care? And what I mean by that is the low friction associated with Keytruda chemo problematic in persuading clinicians to adopt the more expensive and arguably more toxic therapy which requires educational support.
And then along the same lines of that, in terms of friction, you mentioned the need for continued education but also there is a 12-day turnaround for TMB, to what extent can that be addressed and how quickly can we migrate to quickly can we migrate to the liquid TMB assets here.
And then the last question is in terms of cut off, which picked up on one of Tom's points about the relevance of TMB to identify patient populations and other indications. Do you have a firm sense that this cutoff is transferred across indications exactly which is much apparent decision and as anything driven by science in terms of identifiable number? There is that consistency here or is it going to be around the indication-by-indication basis. Many thanks and congratulations again.
Why don't you start with commercial and Tom can go?
Yeah, thanks Andrew. I think the way I would approach my view of the first line lung cancer market is, we've known for a while that PD-L1 expression has been a perfect biomarker in being able to stratify and select patients. Now with this very large dataset, we've been able to establish the value of a high predictive biomarker in TMB. And we have a compelling profile of Opdivo plus low dose Yervoy as a result. And I think that that really is an opportunity for us to redefine the way in which clinicians, payers and patients think about first line lung cancer. So, we're excited about that.
I think there will still be a role for PD-L1 expression to play to understand where other options and other treatment modalities should be used. But I think the compelling nature of these data and the predictive nature of TMB will allow us to establish a very good presence in the market. I would also say that the partnership with Foundation Medicine has been a good one for us. We're working very closely with them to understand the logistics of how TMB testing and patterns of testing are currently occurring. I would say that academic centers are doing very well in turnaround time and tissue ascertainment.
And I think that that will propagate into the community. It will take some time and obviously when physicians see a very compelling clinical profile, I think that that is likely to lead to an acceleration and testing and an improvement in turnaround times. Although, our hope is that we would establish testing for TMB as a panel type of test as a test that occurs early in the diagnosis of a patient so that it is available to the primary treating physician early in that treatment decision making process. And that's our goal really going forward. So, the turnaround time today will hopefully not be an impediment as we go forward. For the liquid biopsy question, I'll turn it back to Tom.
I think one of the things that I would start off by saying is that, I'm incredibly proud of our translational capability as Giovanni mentioned in his remarks and how we approach this. Let me give you a little sense of how we got to a cutoff of 10 for TMB. What we gave as we looked at number of studies that we have done in lung cancer. We look to study 12, study 568, we look to study 26. And then we've looked at different cut points of the tumor mutational burden that were able to best segregate outcomes and best to get for who is what have better response and better benefit than others. And we are why at a cutpoint of 10. Now I have to say, let's stress something else. This is very early in the understanding of this biomarker, this is the first important report of it applied to a randomized trial. As I remember, this is a prospective analysis that we did using our archival tissue, but it was the analysis itself was a perspective and I think that's important to keep in mind.
I think you have to think about other biomarkers. Look at how we understand how to use receptant in patients with breast cancer. You know is it two plus or was it three plus and it became understanding that amplification was the key issue and so it really is early in the process and while I think data, I’ve seen that 10 is going to be the number, I hope 10 is going to be the number forever, can I promise you that someday we’re not going to file up the numbers really 8 or 12 and as other companies and other investigators look at this in their data sets might we learn more, absolutely and I remain open to collaborating across investigators in that respect.
I think the second thing about the test that’s important, is this is the highly validated test while the number might be something with time that might get adjusted for indication by indication. The test itself is highly validated and on November 30 at 2017 it was actually approved by the FDA.
So, while we need to work with foundation on the companion diagnostic indications, we’ll obviously work with them in the FDA at that point. The test itself is solid and we feel very good about that. And that brings us to the last question we ask which is when do we think blood-based assays will come in and I think there was great promise for blood base assays and I think that will make this process much easier for patients. On the other hand, we don’t quite haven’t yet, we’re closed. And again, we look forward to working with the number of diagnostic companies that have insight into how we can create better ways of looking at TMB.
What I can tell you today is I think that our findings in study 227 may increase the imperative and the urgency of coming up with better ways and assessing TMB and I think blood base biomarkers will be one of them.
Our next question comes from Chris Schott from JPMorgan. Please go ahead, your line is now open.
Great, thanks very much for the questions and congrats on the data. Just the question on this TMB data set and the competitive landscape in front line. When you consider the other data sets from these all all-comer chemo combos data sets out there, what sort of hurdle that you consider as you think about the commercial kind of opportunity here. Basically, do we need to see improved hazard ratios in this TMB population relative to some of those overall competitor data sets for chemo combo data sets that you talked about here to see physicians adopt or do you think it's really a debate here of some physicians preferring, kind of IO-IO versus IO-chemo. So just trying to get a little bit of sense, how you’re thinking about that. My second quarter we’re just clarifying earlier comments on filing. I guess do you think there is a potential pathway to file this data earlier than lead 2018 2019 read-out from the OS arm of the 18 study. I’m sure you understand a little bit on the filing dynamics there. Thanks so much.
Let me start and then I’ll ask Murdo and Tom to jump in. So first of all, the progression free survival was the core primary end point of this study and so given the strength of the data as Tom mentioned we will discuss that with regulatory authorities but that was the core primary endpoint of the trial and in the TMB part of the study is the data is, that data is mature and ready.
With respect to your question about competitiveness, I think what’s important here obviously Tom has said many times and we believe that lung cancer is a very heterogeneous disease, is a very broad set of disease. In fact, you know 30% of it is treated by physicians in the academic and hospital setting, up to 70% is there in the community.
So, it's obvious that depending on competitive data set and our data that we’ll always be physician preferences in patient profiles that are more indicate different treatment options. But I think what’s important here, is the ability to identify a patient population that is, that has potential to respond to treatment strategy with the regiment of Opdivo plus Yervoy, what’s also important here, is the ability to identify patients that are not likely respond and both are really critical, so I think the biomarker here is very important, it identifies the population of patients that should be treated in our mind, based on the data, with Opdivo plus Yervoy, and it also helps to define which patient actually made that, which patients may benefit from a different treatment their strategy. Because it is clear that for patients with low TMB going for a combination of immuno-oncology agents may not be the right strategy. So, I think there is clearly room in this market for most evolve treatment strategies, but the data is very compelling.
Yeah, thanks Giovanni, I would also eco the way the market is right now. There is lot a lot of questions on the mind of treating physicians on what to do in lower PD-L1 expressing patients, in terms of treatment options available. We know what the - 21 G-set dataset, we haven’t as you mentioned seen the 189 datasets, but there is still a lot of patients in the market who have low PD-L1 expressions, who are not receiving an immunotherapy options. With the TMB in biomarker, we are able to look across all PD1 expression and in rich for a population with TMB and we have been able to in this clinical trial demonstrate a benefit in PFS with Opdivo plus low-dose Yervoy and I think that’s a very compelling treatment option for clinicians going forward.
The combination of PD-L1 and TMB makers to also be as Giovanni said, a very useful way to select patients out of immune checkpoint inhibition, but given the very broad program that we have with 227 and other clinical trials that Thomas described, we will be able to answer many more of those questions going forward and I am excited about that, I think that over the next year and a half, two years, we will be able to help physicians out there understand exactly when and where to use, what treatment option and I am also pleased that we are developing all of those treatments options within our own portfolio.
Now I just think I eco those two, one of those two comments and again I think that I look at this as being data that we eagerly look forward to sharing with the regulatory agencies, and I think that’s answers your question, about how we are going to proceed.
Thank you, the next question comes from Tim Anderson, from Bernstein. Please go ahead, your line is now open.
Thank you. I just want to stay on those, is your filability of this data. So, you know Bristol, sort of commonly said that PFS is an imperfect predictor of OS. And I think we have seen that in certain datasets overtime by different companies, including Bristol.
And if I think about TMB in O26 at least, what was published as a later analysis on OS, there wasn’t -- there is a big PFS benefit looking at TMB fabrication but there wasn’t much of an OS benefit. And if I -- Tom, you kind of said, we’re early in our understanding of TMB as a biomarker. So, without having OS data, I am still struggling to see how this is data that FDA were accept for approval essentially.
And if you could maybe just clarify your comments earlier on the biomarker saying, we're very early in our understanding, but at the same time you're saying it's very validated. So maybe that's just the technical point about validation. And the last question is have you seen in the Opdivo monotherapy data out of 227 such that you can put Opdivo plus Yervoy in the context?
So, Tim, thank you. Let me just I can answer the second question really quickly. And that, as I mentioned today, we're commenting on the two coprimary endpoints. And there are number of secondary endpoints in the study and we look forward to sharing those at in upcoming medical meeting and publishing those and going over those in detail.
So, to your first question which again, thank you for the chance to clarify my answer to Andrew's question earlier. What I'm saying we're early in the understanding of TMB. I'm not saying that we're early in understanding how to measure it in the validity of measuring it. So, the foundation one test has been highly validated and it's been FDA approved as a test, meaning, when you test somebody's tumor for TMB, that answer you're going to get is reproducible and is meaningful in terms of being a validated test. This is not a test that's does not have their vigor of other areas. When I was responding to Andrew's question on the question of the cutoff. Could the cutoff be different in a different cancer type of different tumor type sure could. We don't have another data yet, as I mentioned you were looking at TMB in more than 100 different studies that we're doing. And is it possible that we'll possible the TMB for colorectal cancer might be different of pancreas cancer might be different or gastric cancer might be different, it might be. And that's what it ends up by saying we're early into the, not that we're early in this scenario of 227. So, I think that's important.
The second question comes down to PFS versus OS. Now as you know, many many drugs have been approved based on PFS, in fact our own 067 experience. And Melanoma was approved first based on PFS before we have the OS data. And as you also know Tim, frequently almost always, PFS data comes before OS data comes, not always but often it comes before that in the setting.
And we look forward to seeing the OS data on this trial, we have not as I mentioned to you, we have not seen any overall survival data from 227 yet. And we have as much curiosity as you about this. What I will say is that one of the things doctors do as when I look at a study with the size and robustness of this trial, this was a total number of patients on study 227 is nearly 2400-2500 patients.
And so, it's a large trial with the result which is highly statistically significant and clinically meaningful. And in that setting, I believe particularly what's meeting an unmet medical need. When there are patients out there who are not getting IL therapy that we have excellent data for now that shows can benefit from IL therapy I think that's a very compelling case for why this matters.
Next question comes from Jeffrey Holford from Jefferies. Please go ahead. Your line is now open.
Hi, thanks for taking the questions. So just three quick here. I don't know if you going to be observe anything now about PD-L1 spaces. I assume that's going to be subgroup analysis to this, within this I remember that when we look to CheckMate-2060 high TMB PD-L1 greater than 50%. It was a stunning result there and maybe perhaps what we’re going to be looking at here is something like breast cancer where I think physicians are more than 2 points on a matrix like node status and hormone receptor status. Perhaps it could be tumor patient burden and PD-L1 status that really drives these as a combo. So maybe some comments on that.
Second do you think the rationale for tumor mutation burden also works in chemo combo and triple combo with Opdivo- Yervoy chemo, there is no reason why that rationale shouldn’t work just as well.
And then last, few questions about the file-ability of this data here. Do you not think that the Keynote-21 G approval acts as a strong president for file-ability here? Thank you.
So, let’s take this a little bit by in order. So first I think Jeff your comment about PL-1 status in TMB the interactions between the two I think is a very interesting one, we just got this data, so we look forward to looking at that and looking at many of the other potential understanding and relationships we can have once we have some time with the data to take a look at that but I do think there is a possibility that, that might help to find a population that might benefit.
I think one thing Murdo said earlier and Giovanni echoed as well what I think is really important which is you could imagine a scenario where a combination of biomarkers be the PDL-1 and TMB, good to find patients who do not benefit from IO agents at all. And might say these are patients we should treat with another type of experimental therapy or chemotherapy in that setting. So, I share your enthusiasm for looking at that interaction between the two biomarkers as well will look at the interaction among all the biomarkers that we look at in lung cancer.
Second point you rate Jeff is a question of rationalizing -- whether TMB will hold with chemo. Again, as I mentioned we’re looking at this in more than 100 different scenarios and again we just haven’t seen data yet in that setting and we look forward to seeing that because I think that will add more color to the patients and how the patients benefit in that setting.
And then the final question of file-ability, as you know we don’t comment on our relationships or actual discussions with the FDA and we certainly don’t comment on the strategy the other companies might have used in getting their trials approved.
What I will say is that we do look forward to sitting down with the FDA and the EMA and sharing with them this data set because we think it is the potential to be a highly significant for patients.
Thank you. Next question is coming Umer Raffat from Evercore ISI. Please go ahead your line is now open.
Hi, thanks so much for taking my questions. John, I figured everyone else is asking multiple, so I’ll ask multiple today as well. First, I guess the first and the main question I have is I just wanted to understand how you guys went about changing the stat plan, like what informed that decision and specifically what informed these specific sets of changes that lets pool the part-1A, part-1B let’s put only PFS but not OS and TMB positives. Just curious about that, one.
Secondly, I know the slides say the CTLA force rolled is 'validated', I was just curious if you could explain how and presumably you’ve seen the PFS curves on combo versus mono and TMB high as well.
And then finally I noticed foundation medicine defines high TMB as 20 mutations per megabit. I mean granted all that is still in flux, and I know you guys are using 10 mutations per megabit. So, I guess my question is how does your data look for combo versus chemo in 10 to 19 mutations per megabit versus 20 plus mutations per megabit and I only ask because EMA has been doing some of this in prior regulatory reviews. For [indiscernible]. Thank you.
So Umer, thank you for your questions. So, I’ll start off with the first one, which is how did we change the stat plan, and why do we change the step plan. And so just to give you a sense, the data in lung cancer has been developing an emerging incredibly quickly. And this -- the way -- our understanding of the biology of lung cancer has improved. So, we look the study 26 and I don’t know if you guys noticed, but 26 didn’t exactly hit what we were hoping for in that setting. So, we looked at in great detail about why, didn’t it work and what were the differences and let’s do a whole excellent sequencing of our patients on study 26 to be able to look in great detail, to understand what about our patient population might have been different.
And it was -- while we were doing that, that we began to understand based on some data with Yervoy and tumor mutational burden in the past and other emerging data that was being generated by a translational medicine group that TMB might turn out to be an important marker, okay.
And that’s how we came upon TMB and then we look at it, 568, which is a practice informing study of about 300 patients of lung cancer, and that gave us more depth of data to look at TMB and lung cancer and the same thing with study 12 and so those three things said - that it is looks like this might be an important biomarker. So, we change the stat plan to enable us to give us, to give us the size, remember we nearly double the size of study of part 1A of the trial. That was really important to be able to do, which gives us the statistical optionality to be able to look at a marker like TMB, while still preserving the ability to look at that - to look at OS in a PL1 defined patient group.
So that’s really, I think the background for how we got there. I think what I can say about CTLA 4 being validated in this setting, is from our look at the data we have seen so far, we believe that Yervoy is a very important part of this story, and we think that Yervoy is clearly critical to the benefit in this TMB high patient population as well, I say at this point.
And your last question is really interesting, regarding TA foundation might say, 20 is high, what happens between 10 and 19, what happens between 6 and 10, those are all excellent questions, we just haven't yet gotten to the point, where we have been able to look at all the variation across.
What I can tell you is, when we look at the three datasets, I told you about 26, 12 and 568, we found 10, was an endpoint that the distinguished in lung cancer, using the foundation 1 assay outcome. And then when we prospectively analyze that in a patient sample, using our cart tissue, we were able to show this result. I can’t tell you the patients who have got 25 don’t do even better, they might. Where the patients who have 7 might also do well. And again, those are all things I think we are going to learn with more time.
Thank you. So, next person is Geoff Meacham, from Barclays. Please go ahead, your line is now open.
Hey guys, good morning and thanks for the question. I just had a couple. On TMB, what work have you guys done in other tumor types beyond lung, and I guess at this point, what do you think is the next step in tumor types that you already have your formal approval are you think, we are doing that, or do you think the more logical path our indications, or you haven’t seen more IL activity. And then on 227, Tom as the data for Part A and Part 1A and B mature. How important do you think overall PFS and OFR on an ITT basis not the TMB segment. Thank you.
Jeff. Just the first comment on your first question. As Tom mentioned, we are measuring TMB in over 100 trials. You will remember that one of the first trials in which we started stratifying for TMB status was [indiscernible] that's included in the study design. We're looking at TMB across multiple types of tumors lines of therapy. And obviously as our clinical development program evolves, we will learn much more about the role of TMB in selecting patient populations outside of lung cancer.
And Jeff for the question on 227. I think the couple of things I want to emphasize on what we have now that what we haven't looked at yet. So, in a group of patients with high TMB regardless of PD-L1 expression. And remember these are also across histology. So, including both squamous and non-squamous. The addition of low dose Yervoy two Opdivo improve PFS in that setting. What we haven't reported the overall survival from a PD-L1 selected group. And you'll seeing that data down the road. And there is really not much more we can say about the survival data. I'd love to have the answer now as well, and I'm sure you would as well. We just don't have that data yet. And we look forward to having that dataset. Again, I keep coming back to the fact that there is, that was still early in our understanding and there is a lot of data that's going to emerge not just from our studies in lung cancer, but from other investigators working with other agents in this disease and we're going to keep learning and we're keep following that biology as we did in this circumstance to improve outcome.
Next question comes from Vamil Divan from Credit Suisse. Please go ahead. Your line is now open.
Great. Thanks very much for taking my questions. Just two more on 227. So just following up I think on prior comments. So, one, solid very positive comments and data on TMB and PFS. I'm still wondering why you've decided to stick with PD-L1 and as the driver for the OS analysis for Part 1. When you're making the changes, why you do not change that also be TMB. I know you can't talk about that end points now but, maybe you can clarify why the decision was made the way it was.
And then the second part you mentioned Part 1B is now finished. And as I'm curious as to why is that not continuing to CT OS data, why are we stopping that one. Why are you stopping that one now, was there something that you in the interim analysis or was that always the plan as you just did your stats plan to not look for OS benefit in that population. Thanks.
So, Vamil thank you for your questions. I'd say couple of things to answer them. The first question is, Part 1B is finished because we used patients from Part 1B that were PD-L1 negative, but high TMB there in the TMB analysis. And the second thing is as we then design part 2 which is acting the Opdivo chemo question across a broad group of patients regardless of their PD-L1 status. And that's the way we design in this fiscal analysis.
I think your question on, the first part of your question on overall survival for TMB versus overall survival in the PD-L1 reflected patient population. Because this study is so large, that's one of the things again one of the thing people asked earlier and how do we change it and why do we change it? We wanted to have optionality to look at a couple of the important questions and value reported PFS on this we just haven’t seen the OS data for TMB and so it's entirely that we will see OS data from TMB and we look forward to seeing that data but we just have not seen that data at this point. We’re waiting for that data set to mature. At the same time, we have this preserved ability to look at overall survival in a PDL-1 population. So, I think that those are really important points to get across. And part 1-B was the smallest of all the three parts of study-227 and part-2 has almost 750 patients. So, if you’re wondering about the chemo question with Opdivo that will be answered in part-2 of our study.
Thank you. Next question is Marc Goodman from UBS. Please go ahead, your line is now open.
Yes, couple. So first of all, I just want to try and understand remind us about O26 and when you describe that you hit on PFS but not on OS. Why in this case you feel confident that -- what are the key differences so that we can have more confidence that you’ll hit on OS financial year.
And then second each quarter you guys are pretty good about giving us Opdivo sales and the breakdown of where it comes from. So, if you could do that for the quarter, that will be helpful.
And then third you mentioned FGF I know we’ve been waiting, did you actually talk to the FDA, have you signed off on Phase 3, when will you begin and what you should be looking for as endpoints there? Thanks.
So, Mark let me start with the FGS-21 maybe. As you know we had discussed that we were in conversation with the FDA to start to the next phase of development for FGS-21 one of the veins we discussed with the FDA was the fact that we had in our original set is we have not included a post treatment biopsy of different doses, so we’ve decided to go ahead with the study that we’ll be looking at post treatment biopsies before we move into a large phase-3 study and that study is starting right now.
So just to quickly address the question on the O26 I assume you’re talking about the O26 retrospective look that we did, that we presented at ACR last year that showed a PFS, but I think you separate amount by PFS based on TMB in that setting. There is a lot of cross over remember in O26 and it was again used to generate hypotheses generating data. It was not a predefined pre-specified prospective analysis like 227 was.
Yeah, thanks for the question Mark. For Opdivo sales by major tumor type and I’ll give you US numbers and I can give you a worldwide after that. But we currently enjoy roughly 44 to 50% of our business from lung, that’s all lungs because we continue to get a bit of off label first line lung cancer usage particularly in squamous.
In renal, about 18 to 22% head in neck around 5 to 10% melanoma, 14 to 20% and then there is a kind of all others then you should think of this as probably early update in leading indications because of the approvals now in HCC and adjuvant melanoma. We’ve got about 9 to 15% there and the reason I give ranges is its very hard obviously to get specific point estimates by tumor types.
I’ll just give you the lung number, when you go worldwide, that claims to between 50 and 60% and that’s because of the strength we have in ex-US markets in lung cancer, because of the leading physician we have been able to establish through earlier access approval, particularly strength in markets like Japan and France, so, very strong performance in lung outside the U.S.
Certainly, last question is Jason Gerberry from Bank of America, Merrill Lynch. Please go ahead, your line is now open.
So just one quick regulatory question on 227. So is the thought that, you would need in TMB high favorable OS as a secondary endpoint for to gain full approval and European approval, or that the co-primary endpoints in different sub-population would be registration enabled. I just wanted to get clarification of that, in light of Merck’s comment earlier in their 3Q about needing OS to drive approval in the target population they are going after.
And then just one other question, just can you provide the proportion of -- how prevalent TMB high is in PD-L1 negative patients? Thanks.
Jason let me just, maybe answer that question. We are not going to comment more on our regulatory interactions, but I just want to stress the TMB part of the study met its primary end point and the primary end point is progression free survival in that study and we look forward to discussing that with the regulatory authorities around the world. I think that, Thomas said earlier that we have just received the topline data, there are a significant number of secondary analysis that we will be conducting and we look forward to presenting that data together with other analysis at a future meeting, obviously as we have mentioned the study looked at TMB regardless of PD-L1 expression and so it included patients across the full spectrum of PD-L1.
So, let me just close and thank everybody for participating in the call. And in closing I like to reaffirm my enthusiasm for the results we have shared with you today and during my carrier, I have many, many years in oncology, I can’t remember a time in which cancer research was advancing at the speed, that we are experiencing today and I am very proud that we at the MSR at the forefront of incredible scientific advances. We had a great year in 2017 and I am very confident in the multiple opportunities that we are pursuing to be build a strong future for the company in 2018 and beyond. Thank you.
Thanks everybody. Appreciate your time.
Thank you. So, ladies and gentlemen that conclude today’s Bristol Myers fiscal 2017 fourth quarter results conference call. Thank you for your participation, you may now disconnect.