Call Start: 8:00
Call End: 9:14
Bristol-Myers Squibb Company (NYSE:BMY)
Bristol-Myers Squibb Investor Event: ASCO 2014
June 2, 2014 8:00 AM ET
John Elicker - SVP, Public Affairs and IR
Francis Cuss - EVP and Chief Scientific Officer
Michael Grobstein - Director
Fouad Namouni - VP, Development Lead PD1 and Necitumumab
Giovanni Caforio - EVP and Chief Commercial Officer
Vamil Divan - Credit Suisse
Seamus Fernandez - Leerink Swann
Mark Schoenebaum - ISI Group
Jami Rubin - Goldman Sachs
Chris Schott - JPMorgan
Dave Risinger - Morgan Stanley
[Calls Starts Abruptly] yes I was just talking to a couple of people outside and this is but, I assume last night, this is the fifth year in a row that we’ve been at ASCO talking about the field of immune-oncology. And the first year that we were here, I think about 20 people showed up at a dinner, and half of them were very skeptical about what is this going to do and it doesn’t make sense, and it is too toxic. And here we are five years later, maybe one of the most exciting things in any of our career so it’s really incredible.
So, we’ve got about -- we’re going to have some prepared remarks and hopefully have plenty of time for Q&A, the sessions start over at the Conference Center, right at 8 O’clock and a lot of our team has to be either at sessions or at different opinionated meeting, so we are going to be pretty diligent about time. Afterwards, we’ll try to hang around for five or 10 minutes. But we are really not going to have a lot of time after this session.
So here on Slide 2, for those of you who are on the phone, is our forward-looking statement. And then what we are going to do today, Francis Cuss, who is our Chief Scientific Offer he is going to make a few brief comments strategically about how we are thinking about the immune-oncology franchise. And then Michael Giordano, who is to my left, many of you know who leads oncology developments will talk about at a high level our development portfolio, our approach and hopefully give you a sense of the breadth and depth of what we are working on. And then Fouad Mooney to Michael’s left who leads the Nivolumab development team is going to go through the data that’s been presented at ASCO and then we will take your questions.
Before I get started I want to introduce a couple other people in the room. From the R&D side, Carl Decicco is here. Carl heads Discovery for the company and reporting to Carl is our facility in Redwood City that’s led by Nils Lonberg and Alan Korman who many of you know. So Carl is here. Steve Averbuch is here, who is the Head of our Pharmacodiagnostics Group. I know there has been a lot of discussion about biomarkers and Steve is our guy in that field and then Jean Viallet is also here. Jean runs our Global Clinical Research for Oncology. And then on the commercial side Adam Lenkowsky is here. Adam is basically our lead marketing guy for the immune-oncology franchise on a global basis and most recently had experienced running the Yervoy business in the United States. And then Giovanni Caforio is here, as many of you know is our Chief Commercial Officer.
So with that I am going to turn it over to Francis.
Good morning everyone and welcome. It’s a real pleasure to be here today. This is a really exciting time I think, in my career in the industry, and I think that’s nearly 30 years now. I believe we’ve never had a better opportunity to transform cancer treatment. With the potential for long-term survival and even to get closer, I think, to finding cures for patients. Now my optimism is based on BMS’ pioneering assets and our deep experience in the immunotherapy which is being garnered over the last decade or so. I am convinced that we are best-positioned in the industry. We have the breadth, the depth and the experience to bring transformational medicines to patients living with cancer. And you know that’s really good news for patients.
Now, we’re not just going after refractory patients, in areas, of unmet need in cancer, we’re looking to improve on the standard of care both in terms of durable responses and tolerability. With studying the broadest possible population of cancer patients, with that a monotherapy, biomarker directed monotherapy, or combinations. So let me take a moment to discuss combinations, because I believe they are very important. The more data we see on I-O combination, the more we are convinced that I-O combinations are the future and indeed have the potential to show the best responses. And it is not just about Yervoy and Nivo, as important as they are turning out to be in fact, but also about the number of other assets in our portfolio as you can see here.
We have a broad and a deep portfolio, in fact we are close to double the size of our development program since we met here together just one year ago. And further it is important to note that we have multiple approaches significance into Yervoy and Nivolumab, we are more than just a two-asset company. In fact what you see here is the number of assets in our portfolio. And it represents both monotherapy and combinations, both late and early in the pipeline across myriads of tumor-types. And I want to say we are far from done. We have Nils Lonberg and Alan Korman, pioneers in the I-O field, working on a host of other pre-clinical assets. Nils and Alan are committed to dramatically accelerating these pre-clinical assets into the clinic over the next few years.
And you know it’s not just about internal assets. We’re extending our leadership position through external partnerships. We have clinical collaborations, pre-clinical partnerships, and we’re working with academia to look at all the options. So after 10 years of pioneering innovation, we continue to push the boundaries in cancer immunotherapy. And as you would expect of us we will do more. So that’s why I am so excited of the potential of immune-oncology to transform the treatment of cancer.
At Bristol-Myers Squibb we talk to patients and their families all the time. The difference we are making in people’s lives is very tangible to all of us. The company is deeply invested in this field and we are committed to maintaining our leadership position and as Head of R&D I am totally committed and I have a team that is absolutely dedicated to our visions. And you know why because we realized this will truly make a difference to cancer patients. Michael?
Francis, I am going to build upon Francis’s comments and then of course turn it over to Fouad who will give you the important data that I think you will find supports the strategic view that I’ll try and give you with regard to our development approach. So, as you know our mission with regard to I-O is to bring the potential for a long-term survival to the broadest possible range of patients across multiple tumor types. I will review for you our development approach in lung renal melanoma across multiple lines of therapy. I’ll also touch upon how we are accelerating the next wave of tumor types and throughout the theme of my presentation I think you will see over and over our differential choice to invest in I-O combinations in the science driven way, and how we’re going to use the combination approach to also accelerate the next wave of our assets that are currently in Phase I.
We’ve said from the beginning of our journey that we will use a science-driven approach to biomarkers and I continue to state that that is in fact the appropriate way to use biomarkers and we’ll touch upon that. This is a great deal of work to be done and I am delighted by the last slide Francis showed in which we are having an extension of our ability to work through external collaborations and clinical research with others.
So let me begin with renal cell cancer. We have shown very exciting data on renal cell cancer and that will be continued at today’s presentation and Fouad will cover some of the details. But renal cell cancer represents a significant opportunity for Bristol-Myers Squibb and we are clearly leading the development of PD-1s in this field. The strategy for renal cell cancer clearly rests on the ability to improve overall survival and we have a very robust program that I’ll take you through and I am very pleased with the pace at which this program is progressing. So let’s dig in just a little bit.
Based upon the very promising data from our 003 study in which through our renal cohorts we accelerated the start of our Phase III program study 025 which is now completely enrolled in which Nivolumab is being compared to Everolimus. The durability of the responses and the PFS that we’ve seen in 010 as being reported at this conference really confirms the choice of that we made in the second line setting and gives me a great sense of confidence that we will be able to demonstrate a survival advantage in that head-to-head comparison. Of course until the study is over I don’t know the results if I review the study but I have great confidence based upon what we’re seeing at this conference that the study is well designed and has a great likelihood of a successful outcome.
In the first line setting the combination data that Fouad will review from study 016 shows potential for a meaningfully better efficacy more than a doubling of response rates and good tolerability compared with either TKIs in a non-direct comparison or compared to the combination of TKIs and Nivolumab, so based upon the data on efficacy and safety we plan to move forward in a phase with a Phase III study of the combination of Nivolumab and Yervoy in the first line setting with the objective of improving overall survival for renal cell cancers.
As you’ll see to both monotherapy and combination therapy Nivolumab when Nivolumab and Yervoy are very well tolerated and that makes this very well suited for an approach in the adjuvant setting and we are announcing today plans to begin an adjuvant renal cell carcinoma study with Nivolumab and/or combinations. We’ve not previously disclosed that so that’s a piece of new news for everyone.
Let me move on to lung cancer. The development program as we’ve said before for lung cancer is broad across the multiple populations across histologies across lines of therapy with regard to PDL-1 positive or PD-1 negative expressers and there are more than 10 ongoing completed or ongoing studies of significant size and an 11 study to be done shortly. The goal in our lung cancer program is to displace the current standards of care. So a very-very lofty but we believe achievable goal. There are ongoing programs in Yervoy both monotherapy Nivolumab monotherapy and combination. And so including again both mono and combination but I’m going to focus only on a few of the more important or salient points from this large program.
Let’s start with the Phase III program. As many of you know last month we announced the beginning of a rolling submission for the third line lung cancer setting, squamous sub-type using study 063 and we expect to complete that submission by the end of this year. At this Congress we will present updated data from 003 again highlighting the durability of response and the potential for survival. On the 003 study we report three year survival update on the dose being used in -- sorry two year update on the dose being used in our registrational program which demonstrates that 45% of patients are alive at the end of two years.
In the second line setting as many of you are aware, we have two ongoing Phase III studies study 017 and study 057, these studies again are designed to demonstrate overall survival endpoints and we anticipate to have data on at least 017 later this year. Embedded in the Phase III programs 017, 057 in fact all of our development programs is a robust biomarker program. The Phase III lung cancer programs allow us to assess both the PD-L1 positive and the PD-1 negative populations. This is critical because including both positives and negatives allows one to clinically validate the usefulness of a biomarker with regard to enriching the results that you’re seeing.
At this point I do want to make a few comments about our confidence in Dako, in our biomarker which we’re developing in partnership with Dako. And stop on a few points, first we’ve tested more than 2,600 tumor samples and based upon this assessment of tumor samples at various cut offs have a great deal of confidence in the reproducibility and the validity of the assay, in fact the FDA has agreed that the Dako assay is appropriate for use in beginning our Phase III study in first line lung cancer for PD-1 positive patients.
In the test we have sampled, we noticed that at the 1% and the 5% expression rates we have a very good understanding and confirmed sensitivity and specificity of the performance of the assay. And as you know the strategy that we have articulated with regard to biomarkers as to embed these into all of our clinical programs. We have Steve Averbuch here later who can provide some more details on our program.
Let me move now briefly to the first line lung cancer program. In the first line non-small cell lung cancer very little progress has been made compared to the Platinum doublet that has been used over almost 10.5 years. Our strategy is to replace them. For Nivolumab in the first line setting, we’re enrolling a pre-selected population of PD-L1 positive patients. As this is the best opportunity to demonstrate a superior outcome compared to the Platinum doublet and that is study 026. I am very impressed with the progress that is being made on the enrolment of this study and we’re rapidly making progress towards this first line indication. The data from 012 presented at this conference for monotherapy in first line setting show response rates of 50% in the PD-L1 positive population and no responders in the PD-L1 negative population. With the caveat that that’s relatively -- that's a relatively small sample size. Those results validate our confidence in the approach we’re taking in the first line lung setting and validate our confidence in the performance of the assay.
Let me address for a bit the approach that we’re taking for the combination of Nivolumab and Yervoy in non-small cell lung cancer. We’ve stated before and I will state again today that we’re confident in our ability to begin a Phase III study of the combination of PD-L1 Nivolumab and Yervoy in the first line setting for lung cancer using the combination approach. And this will include PD-L1 negative patients.
Let me expand a little bit about this. As you’ll see later from the results of study 012 the Phase I dose ranging study that explores multiple dosing regimens. The data at this conference from Yervoy plus Nivolumab combination arms are presented and provides several important insights. First it demonstrates activity in both the PD-L1 negative and the PD-L1 positive populations.
Although the response rates might not be as high as we might expect or desire, Fouad will provide some important insights on how those response rates are influenced by tolerability in premature discontinuation and our approach to manage that, as well as providing important insights on the durability and the quality of those responses that gives us a sense of confidence on how to design the Phase III program and move forward in the combination of Nivo plus, Yervoy in lung cancer. Again I am confident in our ability to apply drug development principles in regard to dosing regimens be able to begin that study.
Let me touch upon melanoma. BMS has been pioneers in achievement of melanoma and have made dramatic differences with the approval of Yervoy in the treatment of advanced melanoma, and it’s now one in four, to one in five of patients, may be able to achieve long-term survival. Yervoy is just the beginning, and now Yervoy and Nivolumab form the foundation of a very broad program, and quite frankly I feel very confident we will provide transformative therapies for patients with melanoma.
Earlier today in a press release, we announced a one and two year survival rates from an important study of the combination of Yervoy and Nivolumab in advanced melanoma. That study revealed 94% survival rate at one year and an 88% survival rate at two years at the 3 milligram dose. I sometimes step back and think about 100 patients that may be visiting a clinic or 100 of us who may be in this room, and think about the numbers 94% alive at one year and 88% alive at two years and contextualize that by the results that were available several years ago before Yervoy in which if we were lucky one in 10 will be alive at the end of one or two years. So BMS has driven a dramatic improvement and really transforms the treatment of melanoma, and I’m very confident in the combination approach. Of course, these are Phase 1b data and there are two ongoing studies Phase II and Phase III which will confirm the observation of the Phase I data and I am confident that eventually the combination of Yervoy plus Nivolumab may provide an option for patients to be treated transformatively without the need for a biomarker.
Let me just reiterate our choice and our confidence in the long-term survival. Data from 003, a longest-running cohort of any PD-1 in the treatment of melanoma, both has presented maturing data at this conference, and identified again a flattening of the curve in which 41% of the patients are alive at 3 years.
Let’s return briefly to Yervoy, which again complements our broad commitment to providing treatment options for patients with melanoma across the spectrum. We also announced this morning results from a Phase III study of Yervoy in the adjuvant setting, which identified as significant reduction in relapse rates or as we called relapsed free survival. These findings are very important and demonstrate for the first time that Yervoy has the potential of reducing the risk of cancer recurrence and support our belief as Francis outlined that immune-oncology has the potential for providing benefit across the spectrum of disease state for cancer and across a wide range of tumor types.
This has allowed us to increase and enhance our investment in a very broad program for Nivolumab. This is a busy slide and which should identifies for Nivolumab alone, 17 tumor types, more than 35 studies, many of which are in combination across a wide spectrum of diseases for which there are great unmet medical need. Earlier this month we also announced breakthrough designation for Hodgkin disease, again validating the approach of Nivolumab in immune-oncology to hematologic malignancies.
The pipeline is broad beyond Nivolumab and Yervoy. And our approach in our Phase I asset is to be able to accelerate their development through combination approaches with either Nivolumab or Yervoy, so we can identify areas of unmet medical need and bring those Phase I assets more quickly into Phase III and into patients. These studies are ongoing, various combinations of Nivolumab Anti-LAG3 or Urelumab in combination with both Nivolumab or Yervoy in a wide range of tumors and will allow us to bring patient’s solutions of various combinations across the continuum of their disease. We hope and expect to be able to present data from these combinations as early as next year.
I’ll like to turn the podium now over to Fouad Namouni who will tell us the data that supports the strategy that I’ve outlined for you.
Thank you, Michael, and everyone. I’m really pleased to share with you a piece of important data that we are excited about, as we continue to provide more and more information in terms of our research and clinical development for the whole immune-oncotherapy for physicians and patients over this ASCO 2014, I will focus on renal cell carcinoma, two studies; lung cancer two studies; and also update melanoma, two studies for Nivolumab; and the adjuvant study for ipilimumab.
Let me start with renal cell carcinoma where we reported this year, what I believe an impressive data of Nivolumab monotherapy in metastatic renal cell carcinoma. This is the first time we see a Phase II data reported in the whole PD-1, PDL-1 class. This is the Phase II that from the mild metastatic renal cell carcinoma patient 3 doses of Nivolumab 0.3 milligram, 2 milligrams and 10 milligrams every three weeks and looking at the primary endpoint the PF -- difference of PFS between those but more importantly also as responses and overall survival for the first time in this 160 patients Phase II study. These patients were heavily perceived with TKIs, two-thirds receiving more than two lines and one-fourth receiving more than three lines of TKI this is a heavily protracted population of patients.
This is the survival data for the overall survival from this large Phase II study and as I said it’s renal cell carcinoma before I go into the survival data a remarkable as you will see let me just describe the response rate. The response rate was about 20% to 22% depending on the dose cohorts consistent with our observations from previous study CheckMate 003. The PFS was around four months the medium PFS was around four months in the two high dose cohorts but more importantly for this I-O therapy class of agent is the long-term effect. Here we have Nivolumab monotherapy in heavily prepared operation of patients with TKIs and you can see in the two high dose cohorts there is 2 mg and 10 mg a 71% overall survival rate of one year, more than 50% at two years which makes the median for this two cohorts ranging around 24 to 25 months.
For those who attended the presentation given by Michael you’ve clearly have seen that when he put this into context today and toward the of recycling TKIs survival has never demonstrated in single Phase III in this major Phase III TKIs but overall TKI’s report 11 to 16 months of median overall survival. Here we are talking about 24 to 25 months of median overall survival. This is remarkable and really makes me confident in our CheckMate 025 Phase III lives on to my expectations Nivolumab versus Everolimus and so inhibitor in similar population of patients. If this Phase III turns well to confirm this data then this would be probably a major paradigm shift in the management of patients without TKIs in the metastatic setting of renal cell carcinoma.
Safety was acceptable in fact for monotherapy Nivolumab as you can see there was no grade 3-4 reported at this doses. More importantly when you think of patients receiving TKIs and the TKI study the race of this continuation of therapy is around 20% here we are only seeing 6% of patients and this continuing therapy gives us more confidence in our Phase III development program. We talked with you guys last year when we have reported the data from ipilimumab combination with Nivolumab in melanoma we said we’re going to look at renal cell carcinoma we’re going to look at in lung cancer. So this is CheckMate 016 that started back in 2012 looking at Sunitinib and Pazopanib combinations. Later on last year we added ipilimumab and Nivolumab combination cohorts and we are reporting the data this year not only for the TKI combination but also for the ipilimumab and Nivolumab combinations.
The addition of Nivolumab to ipilimumab or to ipilimumab to Nivolumab in metastatic renal cell carcinoma in patients who most of them receive at least one line of therapy of 81% or 80% overall of patients had prior treatment double the survival -- I am double the response rate of Nivolumab monotherapy from 20%-22% to 43% and 48% this data would be reported this morning at this Congress by Dr. Hans Hammers. The median duration of response has not been reached in one of the cohort and this reflects the durability of response to this class. We are not at median PFS yet given the follow-up but as you can see the 24 week PFS is 66% in non-cohort and 64% in the our cohort.
Let’s step a little bit here on the spider grams to see one more time the role of the immune systems within the tumor. Memory is very important when we are treating tumors with the immune system or enabling the immune system to do the job. And you can see not only the depth but also the durability of responses overtime.
We look at the safety of the combination of ipilimumab and Nivolumab in metastatic renal cell carcinoma and we can say that it is manageable and the tolerability was acceptable. It is worth noting that in the cohort of Nivolumab 3 and ipilimumab 1 there was almost very rare grade three and four events where the rate of discontinuation in a combination of immunotherapy was only 9.5% in this cohort. This gives us confidence and benefited profile in the Phase 1b of Nivolumab plus ipilimumab to move forward very rapidly to develop a TKI free regiment in the earlier setting of metastatic renal cell carcinoma.
We look at the combination of pazopanib and sunitinib in patients with metastatic renal cell carcinoma was reported Dr. Amin two days ago as most of you have seen when added Nivolumab to sunitinib the response rate was 52% and it was 45% when we added it to pazopanib, the median duration of response was 37 weeks and 30 weeks for pazopanib. The median PFS was 48 weeks for sunitinib and Nivolumab and 31 weeks for pazopanib and Nivolumab.
In the significant arm more than half patients were treatment naive were first line patients, which was not the case for the pazopanib arm. We can see a slight increase of the activity on what the TKIs do in this operation of patients by adding Nivolumab. But when you look at the safety profile of the combination of TKI, we clearly report an increase in grade 3 and 4 toxicities more than what they typically see with the TKI in this population of patients particularly it adds toxicity and also renal toxicity as described in this presentation by Dr. Amin.
The rate of this continuation in this cohort was 36% for the sunitinib cohort and 25% for the pazopanib cohort. When we look at the totality of the data of the TKI origin and the context of what I just described with the TKI 3 regimens Ipilimumab plus Nivolumab in similar population of patient although it was more of second line patients. We do have confidence that given the benefit profile of this combination today we’re confident of moving the combination of Ipilimumab plus Nivolumab to Phase III studies.
Overall in renal cell carcinoma remarkable data, survival data for the monotherapy more than what we typically see with TKI has given us important confidence on the potential of our Checkmate-25 Phase III to improve survival and then change the paradigm of treatments of metastatic renal cell carcinoma. The combination with Yervoy and Nivolumab is ready now to move to Phase III, we have very good understanding of this combination metastatic renal cell carcinoma and the overall benefit risk really makes us more confident about combining the TKI at this point. Study will start later this year in Phase III.
Let me move now to lung cancer. Last year at the World Lung Cancer meeting in Sydney we reported two years data from CheckMate-003. We have been able to report a 24% rate of survival at two years, these are third-fourth line lung cancer patients and reporting this type of survival in our belief is remarkable. And to you it gives indication about the potential of our last Phase III program in lung cancer.
Now as we took 3 milligram every other week to development in lung cancer, the teams wanted to go back and look by those of therapy what was the survival and here we report this year Julie Bremer reports this year a one year survival of 56% and a two year survival of 45%, this will give us again more confidence on the selection of the dose and on the potential outcome of our Phase III studies.
And then we have said last year with you here, we’re going to explore the combination, a multiple combinations in the first line setting of lung cancer. This is CheckMate-012 that explores Nivolumab monotherapy in first line lung cancer but also combination with chemotherapy, with bevacizumab with [indiscernible] and then we added in 2013 a combination with Ipilimumab, two cohorts of Ipilimumab 3, Nivo 1, Nivo 3 and ipi 1 that we just also expanded to other those cohorts.
I will start by describing the data that we generated with monotherapy looking at the biomarker status and the potential of PD-L1 expression in the tumor to predict the activity of Nivolumab in first line lung cancer and is the basis for CheckMate-26 which is our Phase III versus chemotherapy Platinum doublet is actually is up and running recruiting patients now in this country and elsewhere.
We have been working now for more than two years partnering with Dako an expert in ISG and existing development to develop a robust test to detect PD-L1 in different tumor types and we studied this very carefully we looked at the tumor cells the immune cells, we continue to look both of them but our experience with our partner Dako shows that all of this levels we look at shows that we have a very sensitive test, in fact we’re being able to detect the expression on tumor cells of PD-L1 in 76% of patients with any positive or 1% if you will and 59% of frequency in the 5% cut off.
Using this test, we have been able to report the following data. When Nivolumab is given a monotherapy in first line non-small cell lung cancer, regardless of histology, the response rate in this cohort of patient was about 30%. The breakdown by PD-L1 status was 50% responsive in the positives, there is no responder in the negative so far. The responses were not only durable it is interesting to see that we report amongst the responder here three complete responders and we’re talking about lung cancer.
The cutoff that was used to do this analysis is 5%. Again, using the immune system to find the tumor relies a lot on a powerful engine that we have in our body that has more importantly memory, when tumors are shrunk by Nivolumab as you can see on this on Slide 36, the response is not on the important it’s durable. Patient with PD-L1 negative status did not have the type of response for monotherapy. We combined Ipilimumab and Nivolumab in first line lung cancer, data would be reported this Tuesday and we studied 2 cohorts, 1 Nivo, 3 Ipilimumab, 3 Nivo 1 Ipi. And we look there is an also PD-L1 status. The response rate was 13% in the Nivo 1 Ipi 3, and 20% in the Nivo 3 Ipi 1. This response rate has probably been affected by a high rate of discontinuation.
20% to 30% of patients in this cohort could not because of this safety profile of the combination that the doses we studied first and that we brought from the endometrial lung cancer received more than one or two infusions of both agents. I was asked a multiple questions during this meeting about our approach on how to develop immunotherapy particularly in diseases where immunotherapy has not been developed before and I always bring it back to our experience as pioneers in the field and this brings back to the first days we developed Ipilimumab seeing the colitis. A lot of people thought Ipilimumab was going nowhere because of the toxicity. We learned how to manage the colitis. Today, Ipilimumab reports survival data in three studies, the adjuvant, the effect on through survival and the adjuvant setting is the last one at this Congress.
Nivolumab, three years ago, last year I received questions around the pneumonitis when we started pioneering the field and putting out this PD-1 for the first time in tumors. We reported some pneumonitis initially that we were not expecting to see and the team at Bristol-Meyers developed algorithm of management of safety that allowed with only Nivolumab to be developed as a PD-1 agent, but allowed the class the overall class of PD-1 PD-L1 agents to be developed. And here we’re applying this knowhow. We today know how to administer in an efficient way Nivolumab plus Ipilimumab in non-small cell lung cancer and we’re confident that the optimization of the dose and the schedule will lead not only to start in the Phase III in this disease but to improve hopefully overall survival not only for PD-L1 positive patients but for PD-L1 negative patients.
As you can see, 3 patients were responders on the negative. 3 patients were responders on the positive. We have not seen this in the monotherapy. The median duration of response again is not reached as we have seen consistency within immunotherapy has not been reached yet. So there is focus now on the patients who responded on Slide 38, the activity overtime. See all these tumors have responded to Ipilimumab plus Nivolumab. See the durability of response overtime. We do believe this durability of response overtime has the potential to make the difference in terms of overall survival in randomized Phase III.
These all tumors are controlled and continue to be controlled overtime when you think of chemotherapy that shrinks decently well the tumors, but when you stop chemotherapy we know that the tumor progresses. This is a safety profile of in study in CheckMate 12 with Nivolumab monotherapy and its combination with Ipilimumab and as expected, there is an increase in grade 3 and 4 toxicities when you add Ipilimumab to Nivolumab consistently what we have seen in melanoma and also with renal cell carcinoma. There were three grade 5 toxicities, one related to colitis, one to a TEN or toxic epidermal necrolysis, and one was a preliminary haemorrhage.
45% of survival at two years with 3 milligram clearly in Phase 1b study, a last Phase 1b study makes me confident in the way we have designed our Phase IIIs to these Taxotere in second and third line squamous and non-squamous lung cancer. The assay, the assay the docetaxel assay is very sensitive. Our strategies approaching the assays very clear in work where it’s really complex we have clear understanding of biomarker. We believe we are leading the way in terms of not only developing a diagnostic with Dako but also studying multiple approaches to Ipilimumab and defining the right set up to obtain that 50% response rate in first line and moving it very quickly as we were the first starting a Phase III trial in this space. Finally, the regimen of ipilimumab plus Nivolumab is being optimized, a study test in this and seeing whether we can improve survival of chemotherapy standard of care in all tumor patients including PDL-1 negatives will start later this year.
Let me go to melanoma. It is an important tumor for us and more importantly for patients, given the data, we are reporting at this conference and our confidence on our approach of developing immunotherapy in melanoma to make different for patients lives. This is the longest follow-up ever reported in terms of survival ever reported with a PD-1, PDL-1 agent in metastatic melanoma. Steve Averbuch will be presenting these data later today and we have the data that’s matured. Now we have three year survival rate of 41%, one year, inconsistently around 63% and we see that these patients continue to survive overtime. Let's keep in mind that where five years ago we'd be seeing the chemotherapy Kaplan-Meier here with no 3 year survival numbers on slide, and maybe one single digit number on the two-year survival. This is a remarkable advance in the research of the melanoma spaces in Nivolumab.
CheckMate 004 will be presented later today by Dr. Mario Sznol and he will report the totality of the data that we have. This is a study from why an ipilimumab with Nivolumab, and study this combination at different doses, also included most efficiently two months ago a cohort that had Nivolumab to ipilimumab with 3 milligram of Ipi, one of Nivo and continuing the therapy right up the four cycles only with Nivolumab. We are only going to report responses from this cohort agent very immature and premature data. We don’t have enough follow-up, but you will see later this afternoon that the response rate is identical to the other cohorts reported so the activity is pretty good. I’m going to focus the efficacy presentation, mainly on survival because probably this is one of the most impressive data, we are doing the research in melanoma, we see in this deadly disease.
We are reporting today at the dose we selected for development in melanoma, ipilimumab with Nivolumab 1, a 94% survival rate at one year, and an 88% survival rate at two years. These are remarkable data. Melanoma patients five years ago would have never -- and researchers by the way would have never thought that we would be able to achieve this plateau in survival in this Phase 1b study for melanoma patient. This is great news for patients, for us, it increases our confidence and our strategy as pioneers in the immunotherapy field that combined immunotherapy agents is the way to go in trying to fight this tumor.
The safety in this extended study is consistent. There is no new signal of safety that we are reporting at this meeting, completely consistent to have seen previously. We report in the new cohort one grade 5 and that is a consequence of colitis as expected in the profile only of ipilimumab but also of Nivolumab with overall the safety is manageable with corticosteroids and with the algorithms we described in earlier meetings.
The last but certainly not the least is the early phase, Phase III in melanoma. We moved years ago because our belief is in the immunotherapy, that immunotherapy with checkpoint inhibitor could make the difference for patients, with melanoma, the research on ipilimumab to the adjuvant study. And then in a large study, 951 patients -- researcher’s randomized patients to either ipilimumab or placebo as you can see as described in this study, in a one-to-one randomization. Certification in fact the robust phase, 3A, 3B, 3C; or by no positive nodes, 1 to 3 or 4 and more nodes, and this is a multinational study.
It is the first time ever we report positive recurrence free survival data in the adjuvant setting of melanoma with a checkpoint inhibitor. The medium RFS was 26.1 with ipilimumab at 17.1 in the competitor on the placebo arm. The RFS ratio was 0.75 and the P value was 0.0013. The two and three years rates of relapse of recurrence free survival were 51 and 46 for ipilimumab respectively and 43 and 34 for the placebo arm. With an ultra shift in the RFS the shape of the curve is very consistent working with immunotherapy plateauing going beyond three years.
This is also the third time ipilimumab shows improvement in survival in melanoma patients. The safety profile that we are reporting later today in this large adjuvant Phase III is consistent with ipilimumab safety profile that we know in the earlier trials and also in the practice and the use of ipilimumab in patients with melanoma. There probably is a slight increase in endocrinopathies in this study but overall consistent. We are also reporting a 1% drug related death in this study. So overall in this important tumor we are trying and continuing to make the difference for patients lives by doing -- by developing not only monotherapy but more importantly combined agents to increase the survival bar to a completely new high for these patients with a deadly disease.
The data that you will see today will not only show the maturity and the long-term follow-up with the PD-1 agents in the class and also the high level of survivals we have with combination in this Phase III. If this data that we are seeing in CheckMate 3 and CheckMate 4 is confirmed in our Phase III studies this will become a major paradigm shift in the management of patients and we are happy and proud to be the ones leading the way to break this to our patients as we are did in the way to show the importance of check point inhibitors in the adjuvant setting of the disease. Let me turn to back to you John.
Yes, thanks Fouad Michael and Francis. So we have time to take a few questions. And remember in addition to Michael and Fouad Francis and Carl, Steve, Adam, Jean and Giovanni are here as well. So can we go to your questions, please? Vamil, do we have a microphone over here please.
Vamil Divan - Credit Suisse
Yes, thanks. This is Vamil Divan, Credit Suisse. So, two questions, one on the biomarker side you guys touched on that a little bit, lot of focus in this meeting about PD-1 but also other potential biomarkers tumor and renal cells and other things look at -- maybe if you could talk about what you’re doing internally or any of your studies to look at some of those measures beyond PD-1 expression we’ve also seen some studies some data from say the 003 study in lung cancer where PD-1 expression may be it wasn’t as clear cut. So how confident are you on that measure again could be helpful? And then just one other one on the lung cancer side, you talked about wanting to replace chemotherapy with I-O and I-O combos we found that a combination there with chemo and even though pretty compelling just any thoughts about doing work there to get that initially approved is an interesting combination before or maybe the I-O combinations are better understood and able to be utilized in the clinic?
So I think I heard about three questions there, let me take this the last one. So I’ll take the last first one first Fouad will address the chemotherapy question and then I and Steve will address the biomarker question.
Thank you. Good question I think combinations chemotherapy are the most mature cohorts in that CheckMate 012 that started in 2012. And what we see today in terms of activity based on the response rate and combined with chemotherapy doesn’t seem to what it will be higher and -- within the rate, it looks that within the range of what chemotherapy the chemotherapy usually reports in Phase I/II study and flipped away in between 35 to 50%-55%. If we look at the chemotherapy spider grams in the poster you will also see that it seems that the durability in most of the cohort is not there and tumor progress variability. There are interesting data though in terms of seeing important and some impressive number of in some cohorts overall survival that you are probably alluding to. And what we are doing now is trying to better understand what were the components that led to that level of survival we are seeing in chemotherapy subsequent therapy which we’re using these patients to get our chemotherapy and you’ll have to better understand that which we are doing and then make decision on how to develop that in lung cancer.
I wanted to just add that this is not end either or the strategy to pursue combination I-O plus I-O is unwavering and supported by the data. But still we will follow this high end if some other approach appears to be compelling remembering however that the safety tolerability in historical performance of chemotherapy therapy and most TKIs is not wonderful so it’s not either or. I think the second question was about biomarkers and tumor infiltrating T-cells I think you referred to. So I’ll start with a broad answer which is that although we don’t talk about it in every presentation there is a broader range of biomarkers that are being embedded into all of our studies and a big translational effort underway with our international immune oncology network of experts in the field. So I am very confident that science is being progress in regard to exploratory biomarkers. The specific question is I think you point on which is we’re looking at tumor infiltrating lymphocytes as well as tumor, which have some very specific data on that Steve Averbuch can tell us about why we feel confident in the approach that we’re taking looking at PD-L1 expression on tumor cells, Steve do you want to address that?
Thank you Michael, good morning. Again I am Steve Averbuch head of Pharmacodiagnostics. So as Michael said we’re taking a very science driven approach across the program all 7,000 patients in the program are having tumors acquired and analyzed. We’re predominantly asking questions around tumor cell expression of PDL-1. We’re clearly looking at parameters including tumor infiltrating lymphocytes across all programs. I can say in general that with a very sensitive and specific assay that we have working with Dako that anywhere between, 85% to 90% of the samples that we’ve analyzed this far show tumor infiltrating lymphocytes that are PD-L1 positive. So we have no issues or questions about the robustness of the assay, we think it will have all of the data across the program in both PD-L1 positive and negative patients with respect to survival outcomes and we’ll be able to definitively comment on the relationship with the biomarker expression to those survival outcomes.
Thanks Steve, can we go to the next question please? Let’s go to Seamus over here. We’re going to try to be quick with our answers to get as far as questions as we can.
Seamus Fernandez - Leerink Swann
So a couple of quick questions, you put up the slide on survival specifically in lung cancer showing 45% of the 3 milligram dose. Can you tell us what the underlying PD-L1 positive status was in that patient population because it would be again something where that could skew the data? In addition when we think about the impact particularly as we look forward to the lung cancer survival data, you said you were certainly confident in the outcome of the results of the study versus squamous and squamous and non-squamous. But the studies are actually quite, appear quite small relative to some of the data that were presented at this meeting. So can you just help us understand again a 264 patient study in squamous we just saw another study presented with 1,200 patients that had a very modest benefit, we also saw another 1,200 patient study with a modest benefit. So just trying to get a sense of how the 260 patients study is designed to capture that survival difference and if we should be thinking about median overall survivor or hazard ratios as it relates to those studies? Thanks.
Thanks. So you want to talk about first and second one, or both of those.
Thanks Seamus with the question, so obviously when we seen the survival in the 3 milligram we asked ourselves about what are the [indiscernible] and is there any original to the PD-1 positive. In fact we do have PD-1 positive and PD-1 negative patients. So it just -- we’re following this number and gives us more confidence in the dose that we selected but it’s not the compression of PD-L1. The second question around the study and the ability and the power of the studies to show demonstrate survival, so to your very point last point of hazard ratios, we learn that the immunotherapy that the effective structure on the totality of the -- on the medians and it’s all about landmarks and rates and the totality of the curve. And we do believe the way our studies are designed they have power enough to detect efficacy based on our knowledge from Checkmate-3 and our knowledge of what docetaxel can do in these patients.
Can we go to Mark Schoenebaum, somebody was asking me earlier if I had a funny comment about Mark and I felt like I couldn’t top last year. So I’ll just leave it.
Mark Schoenebaum - ISI Group
John who do you actually make stand in the back here?
Mark Schoenebaum - ISI Group
I just had two really quick questions Seamus I guess sort of covered one of them, so maybe 1.5 questions. But I guess on the melanoma data it’s just so striking, first congratulations but why on earth can you not file on that data? And if I stage for melanoma patient I’d be ticked off. And why and when is the first interim on the ongoing Phase III? And maybe just a follow up on Seamus question, the answer may have been embedded in your comments earlier but now that we know or we think we know that in the negative patients PD-L1 negative patient you’re not really seeing much there, the efficacy is a pre-specified to look at that in a head to docetaxel trials. And might you have sufficient power to the effective P value and just preparation, if it doesn’t work out in unselected overall in terms of treatment? Thanks.
I’ll start with the melanoma question, the study 004 is a dose ranging Phase 1 study and the nature of the study conduct which goes exploration is not really conducive to submission to regulatory authorities. We have however 067 and 69 which have completed enrolment those are Phase II and Phase III studies and those studies are more robust potentially regulatory-type studies. We have us as you know as well so the 037 the post-Yervoy setting which is ongoing has its end point survival, it is our belief that characterizing survival is critical to describing the long-term performance of the medicine within 037, we have the ability to use shorter term end points to analyze the data and bring those data to regulatory authorities to bring Nivolumab more quickly to patients. We are not commenting on the specific timelines of that, but we’re very-very cognizant of the ability to use those shorter term endpoints and we’ll continue to assess the data set and optimize the timing of brining those forward.
And I will take the second question around the power that during the frequency of distribution of marker PD-L1 marker in lung cancer. So first of all let me step back, PD-L1 expression in the tumor is -- PD-L1 is very ubiquitous protein as a tumor you see from the T-cell you see them in microenvironment, you see them in the tumor cells. Now, if you have the sensitive highly sensitive test, you’ll be able to detect the good expression on the tumor cells. This is what we believe beyond seen high frequencies in the immune cells, we see also -- we’re able to detect it on the tumor cells. And we may bring it to numbers that makes it a potential marker. So the frequency of PD-L1 expression in lung cancer that we’re seeing is with any positivity, but before as 1% plus is above 70%. And then when we go to the cutoff of 5% we’re talking anywhere between 35% to 55% depending on the setting of the disease on the study, this distribution gives us confidence that in our Phase 3 trial we have enough patients to look at the positives versus the negatives and the really hopefully be the first one answering the valid question, is this real biomarker and is this real -- is there activity in terms of survival not responsive no survival in the negative versus the positive and I think it requires to do that.
Thanks, Mark. Jamie, can we go to Jamie, he is here.
Jami Rubin - Goldman Sachs
Thank you. Can you talk about your filing strategy for Yervoy adjuvant and how you and the FDA deal for the fact that Yervoy’s only available in 10 mgs per kg and the study was done in 10 mgs per kg, do you have to do another trial to get approval or is there a way forward with the study? And then secondly, you’ve described a couple of more adjuvant studies I think renal and lung, can you describe -- are addressing the same kind of high risk adjuvant patient population, if you can just help us to find the market opportunity for what the adjuvant setting might look like? Thanks.
Okay. I’ll start with the 029 Yervoy study in adjuvant. So we’re very pleased with the results of that study as Fouad indicated a reduction relapse free survival. We are going to discuss those results with regulatory authorities and identify the best approach after those discussions. The study has conducted at 10 milligram per milligram and I am not going to comment further on how we might navigate that. However, the study does demonstrate a positive result and to that the extent that it does demonstrate the positive result, we’ll discuss with regulatory and see with the path forward is. You’ve asked also that additional ongoing adjuvant studies. There is the ongoing ECOG study of 3 milligrams, 10 milligrams and interferon.
That study is relatively immature and it progresses just about completed enrollment will need to mature further before there is an answer. Those data will be intriguing but will not stop us from discussing the results of 029 with regulatory authorities. You’ve asked more broadly about our adjuvant approach and we talked about renal cell adjuvant and we talked about with regard to planning of study which we announced today for the first time. And we talked about an adjuvant setting in the Nivolumab. We didn’t talk about any lung at this point in time melanoma, I said melanoma, no, I mean lung and renal, yes, lung and renal. And both of those will move forward in the coming months.
So Giovanni, maybe Ryan, could we get a mic up here for Giovanni maybe just a quick comment on how you’re thinking about the opportunity in adjuvant.
Yes, so I think in melanoma specifically we’re thinking primarily about high-risk patients as the first opportunity and that would be the initial effort, if in fact the submission for the study progresses. With respect to your question on dosing obviously it’s early on in terms of our analysis, but there are a number of mechanisms that you can think of in terms of mediating the pricing differences, for examples, for three to ten and obviously we would work at those.
Thanks. And Giovanni maybe could just hand the mic to Chris here, depending on how this goes we get time for one or two more questions.
Chris Schott - JPMorgan
Great, I’ll put some quick ones here. Maybe first talk about ovarian cancer and the role of PD1, I think Ono had some data look but also that was non-Yervoy Phase 1 exploratory study, can you talk about a little bit of just next steps your interest in ovarian et cetera? And then second was on checkmate 12 kind epi-combo in lung, I guess just -- it just really is PD-L1 negative in terms of the opportunity and when we look at the tox here, I guess just we’re going to just step back, given the breadth, it is Ipi, Nivo the ideal combo in the setting of setting -- I know the first one when you move forward, but you put a lot of your assets in the pipeline, is this ultimately going to be the winner in terms of combo, I think we’re just trying to asses, it maybe first but just how excited are you what you’re seeing in this combo?
So two questions, ovarian cancer yes referring to the data that was done with are Ono. Let me broaden the discussion about ovarian, as you know there is also ongoing Phase 2 study of Yervoy ovarian cancer. We now have the preliminary exciting data from the Ono in the Nivolumab. We do include ovarian cancer in our signal detection, in our own signal detection work and we’ll include in some cooperative group studies. The data are exciting for both Yervoy and Nivolumab, and so we’re taking that discussion internally to figure out a more aggressive approach if you might say to ovarian and the ovarian cancer approach.
Chris Schott - JPMorgan
[Indiscernible] see this year your own stuff or is that…
No, those are our own study in Nivolumab is very early. And the Yervoy study is ongoing and two-thirds through recruitment. Paul, do you want to comment on the 012 lung and your level of comfort on the safety and I can then perhaps get context on the broader approach to lung cancer throughout the portfolio IO agents.
Thanks, Michael. So, we have seen very good activity and I’ll explain the durability of response and we understand now how to improve the dose and the schedule of given this IO combination to hopefully develop a chemotherapy-free regimen we have been as oncologist at Nivolumab since the beginning of the treatment of lung cancer. And we’re seeing activity in the negatives and the positives. We will include negative PD-L1, negative patients in this study. We do believe it’s an important opportunity for patients with negative PD-L1 status to really have this combination develop for them. I think the monotherapies as you can see within the class are mainly focused in the first line or sometime it’s even in second lines on positive patients that represent sometimes 25% to 35% or 50% depending on the assay that are used. Is the immunotherapy checkpoint the way to go, we do believe that our experience as pioneers in the field and now what we start understanding how we’re going to be able to give more treatment to this patient that the combination of Ipilimumab plus Nivolumab have a high potential in the treatment of lung cancers when we do stand behind.
And we’ve said many times about our broad approach to lung cancer, it’s a heterogeneous disease, it’s a very large opportunity -- there are likely need to have many different approaches to different segments and many sequential approaches. So, beyond the Yervoy, Nivo which we have confidence enough to move forward with Phase 3, lung cancer is included in our next wave of IO agents like anti-CD137 for example. We have -- since I’ve worked at this company, it articulates that we always follow the data and the science. And if there are data on an alternative combination that’s likely to do and even better approach, we’ll add it out our current approach, not substitute it.
Just maybe our last question from David, earlier.
Dave Risinger - Morgan Stanley
Thanks, John. I’m Dave Risinger from Morgan Stanley. I have seven questions but only four are convoluted. Actually just three one that should be relatively easy to answer they’re more forward looking. So first with respect Phase 3, lung cancer, trial readouts that you’re expecting later this year, can you update us on timing and what we should expect in terms of press release timing on those and they’re so material to those company? And then also just touch on the change in date on clinicaltrial.gov for each of them? The second question is with respect to Merck PD-1 trial head to head versus Yervoy, that’s going to readout soon, it seems extraordinarily likely that it will beat your Yervoy head to head, so how should investor think about that? And then third with respect to your Phase 3 head and neck, could just talk about the timeline for that? It seems like you’re ahead of Merck there, but I’m not sure.
Okay, we’ll answer them in reverse order. Paul will take the head and neck, and I’ll work on the other two.
Thanks. So, we started the head and neck Phase 3 study registrational intent. The study is including patients and we’re happy to announce that this -- we’re looking at patients who failed platinum-based combination in head and neck. And the study is where being very aggressive and quick in developing this drug in head and neck. Head and neck tumor where Bristol-Meyers have been developing drugs and have the only innovative agent today as proved in head and neck cetuximab or Erbitux. So our knowhow immunotherapy, our knowhow head and neck and the development that we did in multiple studies multiple properties overtime, I think help us moving very quickly in this tumor that is important to us.
So let me take the other two so. With regard to Merck, Yervoy head to head, I think that contextualized the number one why the data we’re seeing in combination and that we’re seeing 94% and 88% of patients of survive. Consistently no matter what PD-L1 you look at, Bristol-Meyers Squibb, other companies, you’ll see anywhere between 69% and 71% of patients alive at one year. I don’t know, if you can do the math, 96 minus 81 is something like a sufficient number of patients. So that there is a real difference there, so I believe the answer to your question about head-to-head study is for me answered by combinations.
And our combinations data when mature, the Phase II mature over the course of this year with regard to the timing of 017 and 057 the Phase 3 second line lung cancer studies, those are both event driven. We do anticipate the event rate. The events will mature such as we’ll analysis this year. I can’t predict what data because these are event driven. You’ve asked why the completion date of this event changed in ClinicalTrials.gov and that relates to the event rate. If you recall immune base therapies are associated with the potential for a tail or slowing of the event rate as the study matures. That can push the completion date of the trial how the experiences with the Yervoy in which had to wait on the daily basis for the event. And we actually had to wait to longer than we anticipate it. The result of that you know is a survival advantage. However that said about waiting for the tail, you believe we have sufficient events to do the analysis that we have indicated we will do, this year on 017 to inform the Phase III in second line squamous.
Okay thanks, Dave. And thanks everybody for the questions. We’re going to have to wrap it up now. Have a great day.
And that does conclude today’s conference. Thank you for your participation.
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