Syndax Pharmaceuticals Inc (SNDX) 2017 Q4 法說會逐字稿

Good day, ladies and gentlemen, and welcome to the Syndax Pharmaceuticals Fourth Quarter 2017 Results Conference Call. (Operator Instructions) And as a reminder, this conference may be recorded.

I would now like to turn the conference over to Ms. Melissa Forst of Argot Partners. Ma'am, you may begin.

Thank you, operator. Welcome and thank you to those of you joining us on the line and the webcast this afternoon for a review of Syndax's fourth quarter financial and operating results. I'm Melissa Forst with Argot Partners, and with me this afternoon to discuss the results and provide an update on the company's progress are Dr. Briggs Morrison, Chief Executive Officer; and Rick Shea, Chief Financial Officer. Also joining us on the call today for the question-and-answer session is Michael Metzger, President and Chief Operating Officer of Syndax.

The call is being accompanied by a slide deck that has been posted on the company's website, so I'd ask that you please turn to our forward-looking statements on Slide 2. Before we begin, I would like to remind you that any statement made during this call that is not historical is considered to be a forward-looking statement within the meaning of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these statements as a result of various important factors, including those discussed in the Risk Factors section in the company's most recent quarterly report, Form 10-Q as well as reports filed with the SEC. Any forward-looking statement represents our views as of today, March 5, 2018, only. A replay of this call will be available on the company's website at Syndax.com.

And now please turn to Slide 3, and I'm pleased to turn the call over to Dr. Briggs Morrison.

Thank you very much, Melissa, and thank you to everyone joining us on today's call and on the webcast. This afternoon, I'll share the progress we've made during the fourth quarter as we continued to execute on our corporate strategy in support of our primary mission, which is to realize a future in which people with cancer live longer and better than ever before.

Slide 3 briefly summarizes our corporate strategy, which includes developing 3 potential best-in-class molecules: entinostat, SNDX-6352 and our Menin-MLL-r portfolio, which are being tested in 5 ongoing clinical trials across 6 different indications.

An important component of our corporate strategy is the opportunistic in-licensing or acquisition of products that have both a compelling strategic fit and a potential return on our investment, something I will say more about at the end of my prepared remarks.

Slide 4 provides a summary of the investment highlights for Syndax. During this call, I will primarily focus on the progress we are making with our lead program, entinostat. I will discuss both our Phase III trial for breast cancer, for which we received a breakthrough therapy designation from the FDA as well as our exciting ENCORE clinical trial program, which combines entinostat with PD-1 antagonists.

Slide 5 provides a summary of the milestones that we communicated on our last call back in November 2017. We've now completed our regulatory consultations concerning a development strategy for entinostat in melanoma, and I will update you on the remainder of these milestones throughout the call.

Let me now turn to Slide 6 and give you an update on our Phase III trial of entinostat in hormone receptor positive breast cancer. Slide 6 summarizes the trial design and the endpoints of the trial. We've also summarized a key upcoming milestone. As we communicated previously, in the fourth quarter of last year, the ECOG Data Safety Monitoring Committee completed the final PFS analysis and the first interim OS analysis of this trial. And these analyses are held confidentially by the ECOG-ACRIN study statistician and the Data Safety Monitoring Committee. No communication regarding this analysis will be released until the completion of enrollment. The trial is 89% enrolled as of the end of February. Our colleagues at ECOG-ACRIN maintain a goal of completing enrollment by the end of June, and we continue to work with ECOG to bring this important trial to completion.

Nonetheless, if we were to conservatively project the timing of completion of enrollment based upon an average of the enrollment rate over the last 12 months, we would anticipate enrollment completing sometime in the third quarter of this year. We will continue to update you about the precise timing of the completion of the enrollment of the trial as the final enrollment progresses. Once final enrollment is achieved, we will learn of the results of the final PFS analysis, and if positive, we are poised to file an NDA by the end of this year.

I would also like to remind you that the Data Safety Monitoring Committee will examine updated overall survival every 6 months. Should any of those interim analyses of overall survival show a statistically significant benefit, the trial will end, and all data will be released to ECOG and Syndax. We remain confident in the potential outcome of 2112 given that it's based upon a strong Phase II data, which, of course, led to the FDA breakthrough therapy designation.

Slide 7 emphasizes potential for the entinostat-exemestane regimen that we're studying in E2112 to be the preferred agent after a CDK4/6 therapy for HER2 -- for HR+, HER2- breast cancer. We know that CDK4 therapies, most notably, Ibrance, are being used increasingly as first-line agents, but there's a clear need for an effective treatment after patients progress. Our current estimate is that between 30% and 50% of patients in E2112 will have received a CDK4/6 inhibitor prior to entering the trial, and thus, we will have a highly relevant data set in this population.

Importantly, as shown on Slide 7, we have tested entinostat in 3 distinct preclinical models of palbociclib resistance and have found no cross resistance with entinostat. That is the median effective dose of entinostat in these model systems is the same whether or not the cell line is resistant to palbociclib. This preclinical data suggests that the fact that patients have received a CDK4/6 inhibitor prior to entering E2112 should not affect the ability of entinostat to provide a clinical benefit. Together, we believe these data uniquely position entinostat to be the preferred agent after CDK4/6 first-line therapy.

Slide 8 makes the same point and notes that this population of patients is relatively large, with an estimated 34,000 patients who go on to receive hormone therapy after failing first-line therapy and could, therefore, potentially be eligible to receive entinostat.

Let me now turn to Slide 9, which summarizes our exciting ENCORE clinical trial program, in which we are testing entinostat in combination with PD-1 pathway antagonists, either PD-1 antibodies or PD-L1 antibodies. We are now exploring entinostat in combination with a PD-1 antagonist in 6 different tumor types. We have previously talked extensively about our studies in melanoma, non-small cell lung cancer, microsatellite stable colorectal cancer, triple negative breast cancer and ovarian cancer. In January, we announced that in addition to studying triple negative breast cancer, Genentech extended its collaboration with us to also study hormone receptor positive breast cancer with the combination of atezolizumab and entinostat.

It's important to note that we've already presented the clinical data establishing that entinostat can reverse resistance to PD-1 antagonist, both in melanoma and in non-small cell lung cancer. Our trial in colorectal cancer is open label. We've already seen promising data in that population as well.

This broad clinical trial program is supported by an extensive correlative science program that is designed to identify biomarkers that can predict which patients will respond to our combination therapy, an effort that is starting to yield exciting preliminary results. We're extremely encouraged by the results we are seeing across this clinical trial program. And as we complete our initial clinical trial in each tumor type, we will prioritize which indications to advance to registration trials based upon unmet medical need, the competitive landscape and our ability to generate a return on our investment.

Slide 10 is a summary of where we are with our program in melanoma. We presented the initial cohort of 13 patients at ASCO in 2017, where we saw a 31% response rate. Based upon continued discussions with melanoma physicians, it's clear that a response rate of about 20% or greater would be highly clinically relevant, especially in patients whose disease has progressed after having received both a PD-1 antagonist and a CTLA-4 antagonist. Given the tremendous enthusiasm for this combination from our investigators, we've allowed continued enrollment in this cohort of patients and now are enrolling up to a total of 52 patients. We anticipate presenting a full update of this cohort at ASCO. Given that we have now concluded our regulatory consultations as well as a number advisory boards with physicians who are expert in the treatment of melanoma, we will also be providing details on our registration program sometime in the first half of this year.

Slide 11 is data that we presented at SITC in 2017 that shows the impressive durability of the treatment effect of entinostat in combination with pembrolizumab. Indeed, at this point, we now have 3 of the first 13 patients who have been on therapy for over a year.

Slide 12 is a summary of where we are with our program in non-small cell lung cancer. We presented the initial cohort of 31 patients whose disease had progressed on a PD-1 antagonist at SITC in November of 2017. Response rate in that cohort was 10%. While that response rate was on the lower end of our aspirations, we've continued to receive strong feedback from physicians participating in the trial. And as I noted earlier, we are making exciting progress with our extensive correlative science program designed to identify biomarkers that could enable us enrich the responding patients in future clinical trials. We've allowed continued enrollment in this cohort to aid in our biomarker discovery effort. We are now enrolling up to a total of 70 patients, and then anticipate presenting updated data at ASCO this upcoming June.

Slide 13 highlights that biomarkers are routinely used today to select the most appropriate therapy for patients with non-small cell lung cancer. Outside of immuno-oncology, tests for EGFR mutations and ALK rearrangements are now routine, and there are a number of commercially successful therapies that are specifically used for patients with those genetic lesions.

KEYTRUDA, of course, is indicated as monotherapy for newly diagnosed lung cancer patients with high PD-L1 expression. And BMS recently communicated that tumor mutational burden may be a marker to select newly diagnosed patients who benefit from the combination of OPDIVO and YERVOY. Based upon this established approach to treating non-small cell lung cancer, we are focusing our efforts on developing a patient selection strategy that may enable us to enrich for a specific population of patients as we progress our development of entinostat in non-small cell lung cancer.

Slide 14 is a summary of where we are with our program in colorectal cancer. We completed enrollment of the first cohort of patients at the end of the third quarter of last year and are continuing to monitoring these patients. We anticipate presenting data on this cohort at ASCO and hope to decide whether to expand this cohort by midyear.

Based upon continued discussions with physicians who are expert in the treatment of colorectal cancer, it's clear to us that a response rate of even 15% would be highly clinically relevant in this population of patients who have failed all standard therapies. Indeed, there are no responses reported in this population of patients treated with a PD-1 antagonist as monotherapy, and the Stivarga label reports a response rate of just 1%.

Slide 15 summarizes some of the recent industry data presented in this regard and emphasizes that the threshold for approved efficacy is modest in microsatellite stable colorectal cancer. On the left is the recently published data from KEYNOTE-028, where the median PFS with KEYTRUDA monotherapy was 1.8 months and no responses reported in the PD-L1 positive microsatellite stable patient.

On the right is data recently presented at ASCO G.I. of a combination of TECENTRIQ and Cotellic, where response rate of 8% and a median PFS of 1.9 months was reported. The combination of TECENTRIQ and Cotellic compared to Stivarga is being studied in a Phase III trial. Again, the main point, in our view, is that the threshold for approved efficacy is modest in microsatellite stable colorectal cancer.

Slide 16 makes the point that microsatellite stable colorectal cancer represents a significant market opportunity for entinostat if we can demonstrate efficacy in the third-line setting.

And finally, on Slide 17, we summarize ENCORE 602 and 603, our Phase II trials in triple negative breast cancer and ovarian cancer. Both of these trails are currently enrolling and anticipate data from ENCORE 602 at the end of this year and from 603 in the first half of next year. Again, we're very pleased with the breadth of our ENCORE clinical program and the excitement we are sensing from physicians who are conducting this important clinical trial.

Let me now turn to Slide 18 and SNDX-6352, our potential best-in-class monoclonal antibody therapy targeting the CSF-1 receptor. We presented the Phase I healthy volunteer data at SITC in November of 2017, and the multiple ascending dose study in cancer patients is ongoing. In January of this year, we were very pleased to announce our collaboration with AstraZeneca to study the combination of 6352 with IMFINZI. A Phase Ib combination study is anticipated to start the next quarter. We've now designed a focused clinical development program for this molecule, and we'll say more about that clinical development program later this year.

Slide 19 summarizes our Menin-MLLr program, which I covered extensively on our last call, and which spans a broad range of leukemias and potentially other indications, as shown on the slide. We remain on track to file an IND in the first half of 2019, and there will be an oral presentation at AACR this coming April discussing the exciting preclinical data that has been generated with our molecule.

And finally, on Slide 20, summarizes how the transactions that we have completed to acquire both 6352 and the Menin-MLLr programs prove that we have an ability to strategically expand our pipeline. Our management team and board have established relationships that allow us to identify quality assets, and the extensive clinical development experience of our team gives us a competitive advantage in closing agreements. We continue to spend significant effort in this area, and we consider this capability to be a core strength of our company.

And with that, I'll turn it over to Rick for the financial update.

Thank you, Briggs. Turning to Slide 21. For the 3 months ended December 31, 2017, Syndax reported a net loss of $19.1 million or $0.80 per share compared to $10.8 million or $0.59 per share for the comparable prior year period.

Fourth quarter 2017 research and development expenses increased to $16.6 million from $8.5 million for Q4 2016. R&D expenses for the year ended December 31, 2017 increased to $48.2 million compared to $31.7 million for the prior year. The increases were primarily due to increased trial activities related to our clinical pharmacology studies; increased enrollment in ENCORE 601, 602 and 603; costs related to the 6352 trials; as well as CMC activities, increased headcount, legal and consulting expenses, facility costs and travel costs. Included in R&D expenses in Q4 2017, we expensed a nonrefundable upfront payment of $5 million to Allergan for the Menin assets. And in 2016, we expensed the nonrefundable upfront payment of $5 million related to the UCB license agreement for 6352.

General and administrative expenses totaled $4.1 million during the fourth quarter of 2017 and $15.9 million for the year compared to $3 million and $13.3 million for the respective prior year periods. The increase in G&A expenses was primarily due to increases in headcount, pre-commercialization work, professional fees and costs related to being a public company. And these increases were partly offset by decreases in legal expenses.

As of December 31, 2017, there were 24.4 million common shares outstanding. On a fully diluted basis, using the treasury stock method, we had 26.9 million shares outstanding. Additional financial details will be available in our annual report on Form 10-K, which we intend to file this week. Syndax ended the fourth quarter of 2017 with a cash balance of $133.2 million, which we believe is sufficient to fund development into 2019, enabling us to reach key development milestones. Looking ahead, our 2018 revenue, which consists of the amortization of payments from KHK, will be $0.4 million per quarter. We expect R&D expenses to be $18 million to $22 million for the first quarter and $67 million to $76 million for the full year 2018. And total operating expenses are expected to be $22 million to $26 million for Q1 and $86 million to $96 million for 2018.

Now I'd like to turn the call back over to Briggs.

Thanks very much, Rick. Looking ahead, we anticipate several key upcoming milestones, which are summarized on Slide 22. We'll be communicating our registration strategy for entinostat in melanoma in the next quarter, along with data presentation from the melanoma, non-small cell lung cancer and colorectal cancer populations of ENCORE 601. We anticipate to be able to make a decision regarding the expansion of the colorectal cohort by midyear.

As I indicated earlier, the timing of the completion of enrollment of our Phase III trial of entinostat in hormone receptor positive breast cancer has some uncertainty, which we have illustrated as sometime between the second and third quarter of this year. Top line results from ENCORE 602 remain on track for the end of this year. And with regards to SNDX-6352, we look forward to sharing both the data from our multiple ascending dose trial and our focused clinical development strategy. It will certainly be a busy year for us here at Syndax.

As always, I would like to thank the team here at Syndax, our collaborators and most importantly, the patients, trial sites and investigators involved in our clinical programs. With that, I'd like to open the call for questions.

(Operator Instructions) And the first question will come from the line of Chris Shibutani with Cowen.

And just making sure that we fully understood the factors that contributed to the shift in time line for the breast cancer study with entinostat moving into Q2, Q3, so is it fair to say that this is primarily related to the ECOG group and the pace of their enrollment? Are there any other factors that have shifted this time line at all?

Yes -- no, it's really just -- we're getting to the end of the enrollment. And there's some month-to-month variation in that. And we just wanted to clarify for people that, again, as I said, if you draw a straight line around the average enrollment, it comes out a little bit later than the end of June. ECOG, of course, is still trying to do everything they can to finish the enrollment by the end of June.

Great. If I could shift quickly over to the CSF-1R opportunity. I noticed you used the phrase potential best-in-class, and obviously, there are several ongoing. Can you talk about how you're thinking about potentially positioning this given that there are sort of several simultaneous trials going on with different indications? Can you talk about where you think, perhaps, the best opportunity is? Obviously, we've all seen some competitor data in pancreatic, et cetera. If you can help us how to think about that, that would be great.

Sure. So as I said in my prepared comments, Chris, I think what we'd like to do is, through maybe the middle of the year, give you a full update on the clinical development strategy. As you've correctly noted, there is a fair amount of competition here, and so we want to be a little careful about what we talk about until we're sort of well underway. So we have a lot of efforts ongoing to set up some trials in areas where we think we can differentiate from what some of the others are doing, and we look forward to sharing that plan with you probably in the middle of the year.

Great. And then lastly, I think you used the word encouraging when you characterized some of the early signs and data that you're seeing in the CRC opportunity. Any chance I could bully you into, perhaps, elaborating on that?

Well, so what I would say is, as you well know, the ASCO abstract deadline has passed. So we have submitted abstracts for CRC, for non-small cell lung cancer and for melanoma. And those abstracts I don't think come out until middle of May or so, I think just before the meeting. But when those abstracts come out, I just wanted to highlight that you'll see some data in the colorectal cohort that we find promising.

And the next question will come from the line of Christopher Marai with Nomura.

First, I wanted to touch upon the last question, just on the CSF-1R data and maybe the focus that you may have of bringing that forward in the clinic. Recent data, I'm not sure preclinical data, suggests that this drug may be helpful beyond the I/O space. How should we think about your positioning? Would you look at this development pathways more of an I/O-specific focus or potentially outside that, for instance, combinations with chemo, et cetera? And maybe could you frame that in light of your recent collaboration with AZ?

Sure. So I think, Chris, yes, you're absolutely right. If you review the literature for this target, you'll find evidence for using it in combination with PD-1s, in combination with chemotherapy, in combination with radiation therapy, in combination with cell therapy, in combination with hormonal therapy. So there's lots of opportunities, we believe. That's why I think the opportunity set is a little broader, perhaps, than people have talked about, and that's what we'd like to talk more about at the -- in the middle of the year. Clearly, the combination with a PD-1 or PD-L1 is on our list because we have an agreement with AZ to do combination work with durvalumab. So that is one of the things that we're interested in. But I think your question -- sort of backs up our view -- of we should take a broader view of the potential of this molecule than just the combinations with PD-1.

Great. And then just a follow-up. With respect to the correlative biomarker studies that you have been doing for, really, the I/O combos, I was wondering if you could further elaborate on some of the biomarkers that you are looking at and some that may appear most promising in your view.

Sure. So you saw on the slide, we're looking at things that probably wouldn't surprise anybody. PD-L1 expression, tumor mutational burden, various immune cell subsets, both in the tumor and the peripheral blood as well as NanoString assays of the tumor specimen. So I think we're really quite fortunate that our Chief Scientific Officer, Peter Ordentlich, has set up a really comprehensive approach. And as I said in my comments, I think as we look at that, it's still early days, but as we look at some of that biomarker data coming in and look at it relative to the clinical activity, we're seeing -- there are some encouraging data there that, I think, makes us feel optimistic that we'll be able to find a way to segment patients, which is why I spent a little bit of time talking about segmentation in lung cancer. It's obviously what we do today, and we think if we can similarly find a segmented population, it could give us an efficient path forward in that disease.

And the next question will come from the line of Bert Hazlett with BTIG.

I realize you're going to be discussing some of the melanoma registration strategy a little later in the year, Briggs. But could you just give us a little bit of an understanding of what the pushes and pulls with regard to that strategy may be?

Sure. So I think, Bert, Michael Meyers and his team have done a wonderful job speaking to regulators, not just to the U.S. but in Europe as well. So I think we have a very good view of what regulators around the world would expect from either an accelerated approval or full approval strategy. His team has also done a terrific job talking to melanoma physicians, again, from around the world, not just in the United States, so we have a pretty good sense of what melanoma physicians are looking for. I think the -- what's evolved in the melanoma space, I think, perhaps, compared to when we set up the trial and sort of what's evolved over time is really the issue of the combination of PD-1-CTLA-4. So there are patients today who get treated with PD-1 monotherapy. There are patients who get treated with PD-1-CTLA-4 combination therapy, either in combination from day 1 or in sequence. And those 2 populations are probably distinct from both the clinical and regulatory point of view. So the patients who have failed both the PD-1 and CTLA-4 probably represents a patient population of the highest unmet medical need, patients who have failed a PD-1 monotherapy and have not yet received the CTLA-4 or still have an option of receiving the CTLA-4. So we're sort of looking at those different, if you will, patient journeys and understanding the regulatory view of those patient journeys and how this -- how therapy is evolving. So that sort of factors into the way that we think about our final registration program.

Okay. Just kind of a blocking and tackling question. Is the ECOG-ACRIN group going to announce it themselves in terms of the results? Or is this yours to announce in terms of the PFS 1 -- the PFS data?

Yes. It will come from us. The Data Safety Monitoring Board will communicate to ECOG and to us. And again, our clinical team will sort of review what they communicate to us, but the communication on whether PFS -- whether the PFS data was statistically significant positive or whether we just continue the trial, that will come from us.

Okay. And then just one last one. You look to have a number of abstracts, including the oral presentation at AACR. You highlighted the Menin program previously. Is there any other abstract or are there other abstracts of particular importance at AACR that we should be focused on?

Yes. I'll leave that -- maybe Peter Ordentlich can take that question. Peter?

Yes, sure. I think there are some interesting abstracts. As you know, our focus in the past has been on the myeloid compartment and effects of entinostat. We'll have data at AACR on effect of entinostat on the T cell compartment. That's the collaboration with a [similar co-disease], so that will be interesting to see. And then you -- I have noted the collaboration with Nectar and the combination of entinostat with NKTR 214. And this was a follow-up to the original data that was shown with high-dose IL-2. And so those are just studies done in a couple different tumor models, looking at effects on various immune endpoints and tumor efficacy.

And the next question will come from the line of Tony Butler with Guggenheim Securities.

Briggs, 3 questions, if I may. It's all around 2112. And apologies if I had missed this previously. Was there a futility analysis when the last interim was done? Point one. I'll just go ahead and announce all 3 of these, if I may. The second is let's assume for the moment that the trial is positive. Do you -- or have you thought of other plans with entinostat monotherapy in breast cancer or other tumors where -- maybe it's RCC, for example, where you think there may be some utility again, monotherapy? And then the third question relates to the notion of -- you showed some -- or there were some interesting data on the CDK4/6 inhibitor and not showing interference. So the question is, are the 30% to 50% of patients who've been on palbo, for example, are those patients still on palbo when they get entinostat? Are they also allowed to switch, perhaps, to another CDK4/6 inhibitor? Regardless of that, if they're on palbo and during the drug holiday, I assume they're going to still take the entinostat. Is that the case?

Thanks very much for all your questions. So first, let me just take them in order. The question on the futility analysis, there is a -- the protocol calls for a futility analysis in overall survival only if the PFS analysis is negative. So we don't know whether a futility analysis was done on overall survival or not because we don't know the result of the PFS analysis. But the protocol does allow for a futility analysis. And in all subsequent OS analyses, there is also a -- the protocol allows for futility analysis as well. Your second question about what if 2112 is positive, what will we do next in terms of monotherapy, it's a good question. In the case of 2112, of course, the rationale for the combination is that essentially, what entinostat is, in simple terms, the way I think about it, is essentially restoring estrogen sensitivity. And so therefore, you want the anti-estrogen in the form of an aromatase inhibitor, that's how you get activity. There was some monotherapy work done with entinostat early in its development, more in hematologic malignancies. We haven't given that much thought to doing monotherapy trials either in breast cancer or other tumors at this point. But that, of course, is part of the life cycle management. And then the last question about the CDK4/6 is the way -- if a patient came into 2112, they would not remain on their CDK4/6 inhibitor. They will be patients who had received CDK4/6 probably with an aromatase inhibitor, progressed, and then they commenced the trial and get randomized to either exemestane monotherapy or exemestane plus entinostat. Now that's not to say that -- again, to your question about life cycle management, somewhere down the road, would we do a trial where we combine entinostat with a CDK4/6 inhibitor? That's certainly something that would be of interest. But the way 2112 is designed, they do not take a -- they did not stay on the CDK4/6 inhibitor.

The next question will come from the line of Joel Beatty with Citi.

The first question is on the Phase III 2112 trial and the dynamics between the PFS and the OS endpoints. Could you share how the powering is split between those 2 analyses? And then also, I know we're still waiting for the trial to finish enrollment to find out about the PFS results. But I believe there's also been an OS analysis. And if that was positive, would the trial have been stopped early? Or conversely, if the futility analysis was met on OS, would the trial have stopped early? Or can't we read into how OS is performing either?

Thanks, Joel, for your question. So first, on the separation of PFS and OS. As you may know, the trial has essentially 2 independent endpoints. And so the alpha spend is split between the 2. So for PFS, 0.002 of the alpha is assigned to PFS and 0.048 of the alpha is assigned to OS. And your question about the OS analysis, so at the time that the protocol calls for -- at the time that the final PFS analysis is done, the first interim analysis of OS would also be done. And there's a very, very small amount of [alpha] spend to do that interim analysis. If that trial -- if the trial had been positive on OS at that point, that would have been communicated to us. So if at any of the interim OS analyses, the trial is positive, the trial ends, and that's communicated. So what we can say is based upon that interim OS analysis, the trial was not positive on OS at that first interim. To be honest, that's not all that surprising because the level of significance and treatment effects you would have needed to see, we estimate probably no more than 10% of the OS events have occurred. So you would have had to have seen a fairly large OS benefit for it to be declared positive on that first interim. So we don't read very much into that. But again, as I pointed out in my prepared remarks, there are additional OS analyses every 6 months, so they're roughly May and November of each year. So by the end of this year, we will have 2 additional interim analyses of overall survival.

And then one other question on the melanoma-I/O combo studies. I know we're waiting to hear about the trial design. But now that you've finished the communications with FDA, on that, are you doing anything to help prepare the start of Phase III trial before this final melanoma data reads out?

Yes. Thanks for the question, Joel. Yes, indeed, we are. Our Chief Medical Officer and the clinical operations group is actually working quite diligently to get the program up and running. We haven't yet sort of communicated to you what exactly that program is, but that's not deterring them from taking a lot of work on the clinical operations piece.

The next question will come from the line of David Lebowitz with Morgan Stanley.

With the expansion of the melanoma and refractory non-small cell lung cancer cohorts, how did you decide on the new population sizes?

Yes. David, thanks very much for the questions. So the -- as I indicated in my comments, the investigators in both trials are quite excited about what they're seeing clinically. And so our team adjusted essentially the power calculations to give us more precision around the point estimates, and that's what led to the specific numbers. But to be honest, it was really, in large part, driven by the investigators just wanted to be able to enroll more patients.

And the next question will come from the line of Madhu Kumar with B. Riley FBR.

My first question relates to the cyclicality of patient recruitment in the 2112 trial. Is there any reason to think that the fourth quarter recruitment rates tend to be slower than other quarters? Or as you mentioned, is the straight line of recruitment kind of the best way to think about the pace of recruitment in the breast cancer trial?

Yes. I'll let Michael Meyers, our Chief Medical Officer, answer that question. He's probably closest to the data.

Yes. So I don't think there's any evidence that recruitment is that cyclical, certainly not quarter by quarter. What is obvious is that on a month-to-month basis, there are variations which do not appear to play out from a year-to-year and have been rather unpredictable.

Okay, great. And now thinking about the melanoma trial, looking at the Phase II, you have enough patients to be able to distinguish the effects of entinostat with pembro in combination -- in patients who are post PD-1 alone versus post PD-1 and CTLA-4.

Yes. I don't -- I think -- Madhu, thanks very much for the question. I don't think any -- certainly, we did not power the trial to be able to make that distinction. So we can certainly look at those from sort of a point estimate point of view, but I wouldn't say we have a large enough sample of patients to make that distinction. Obviously, since we've increased the sample size, again, mostly driven by investigator interest, we'll have some information on that. But I wouldn't say that it would be -- we haven't powered for that question.

And from a kind of operation expenses perspective, when you gave the ranges for 2018 OpEx, what kind of trials does that encompass? I mean, you've had 2112, you've got the Phase II in melanoma, the Phase II in non-small cell, the Phase II in microsatellite stable colon. Is that kind of the base case of trials you'll have running through 2018? Or does it assume, for example, a registrational study in melanoma?

Yes. Rick, you want to take that one?

Yes, I will. Yes, it -- right now, it does not include the full impact of a registration study in melanoma. So at that time we announce that study, we'll be updating that guidance on operating expenses. Now since that trial would be starting in the second half of the year, the impact would be more felt in 2019, less so in 2018.

The next question comes from the line of Hartaj Singh with Oppenheimer.

This is Emma on for Hartaj. So you said that the Menin-MLL-r program is on track for an IND filing in the first half of 2019. Could you just expand a bit on where you are now in the preclinical work and what exactly we can expect to see at AACR and then just what the remaining gating factors are for getting that IND submitted and entering the clinic?

Right. So AACR, it will be a presentation on, of course, the rationale for the development of the molecules and preclinical efficacy models, some of the standard models that people use as well as PDX models. In terms of where we are with the work, it's sort of standard preclinical work up at this time of scaling up the molecules, getting through -- getting the GLP tox studies done and putting the IND together.

And I'm showing no further questions at this time. I would now like to turn the conference back over to Dr. Briggs Morrison, CEO, for closing remarks.

Thank you very much, everybody, for joining us on the call. We look forward to updating you on our exciting program as the year progresses. Have a good evening.

Ladies and gentlemen, thank you for participating in today's conference. This does conclude your program. You may all disconnect. Everyone, have a great day.