Clovis Oncology, Inc.
Q1 2015 Earnings Call Transcript

Published: 7 May 2015

[Operator:]

Welcome to the Clovis Oncology Q1 2015 Earnings Conference Call. [Operator Instructions]. I would now like to introduce your host for today's conference, Breanna Burkart of Investor Relations. Ma'am, please begin.

[Breanna Burkart:]

Good afternoon and welcome to the Clovis Oncology first quarter 2015 conference call. You should have received the news release announcing our first quarter financial results. If not, it is available on our website at www.clovisoncology.com. Remarks may be accessed live on our website during the call and will be available on our archives for the next several weeks. The agenda for today's call is as follows; Patrick Mahaffy, Clovis' President and CEO will discuss the highlights of the first quarter and provide an update on our clinical development program. Then Erle Mast, Clovis' Chief Financial Officer, will cover the financial results for the quarter in more detail. Patrick will make a few closing remarks and then we will open the call for Q&A for which Dr. Andrew Allen, our CMO, will also be available. Before we begin, please note that during today's conference call we may make forward-looking statements within the meaning of the Federal Securities Laws, including statements concerning our financial outlook and expected business plans. All of these statements are subject to risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. Please refer to our recent filings with the SEC for a full review of the risks and uncertainties associated with our business. Forward-looking statements speak only as of the day on which they are made and Clovis undertakes no obligation to update or revise any forward-looking statements. Now I'd like to turn the call over to Patrick Mahaffy.

[Patrick Mahaffy:]

Thanks, Breanna. Welcome everybody. Thanks for joining us this afternoon. Certainly an exciting time for the company. We're preparing for regulatory submissions for rociletinib beginning next month and for the commercial launch of rociletinib before year-end. We received breakthrough therapy designation for rucaparib for advanced ovarian cancer earlier this quarter, based on very encouraging data in mutant BRCA patients. With breakthrough therapy designation in place for two of the three products in our pipeline and two NDA submissions planned in the next 12 to 15 months or so, we're clearly accelerating our development of the company. Let me start with rociletinib. We were very pleased the data from the TIGER-X study were highlighted in the April 30 edition of the New England Journal of Medicine. These data published last week were sourced from a data cut that followed our ASCO 2014 update and preceded our data update at ENA in November of 2014. Rather than recap these data, I'll point out that all of our presentations have demonstrated compelling and consist activity and safety in patients with EGFR mutant non-small cell lung cancer. Let me review some of the differentiating factors in our data set. First, our data are derived primarily, almost solely, from western patients who are heavily pretreated and have very advanced disease. As you are well aware, it is widely believed that western patients do not fare as well as Asian patients do with EGFR TKIs. And as a result, we believe our data demonstrate the safety and activity of rociletinib in a uniquely relevant patient population from a U.S. market point of view. Second, a significant percentage, about 80%, of our patient population in the TIGER-X study were treated with rociletinib immediately following progression on an approved EGFR TKI therapy, such as erlotinib, gefitinib or vetinib. This treatment pattern precludes the possibility of a retreatment effect artificially increasing the objective response rate. Third, as reported in the New England Journal of Medicine article, patients enrolled in our study had received a median of four prior therapies. 72% in that data cut had progressed on an immediate prior TKI and nearly 50% had a history of brain metastasis. These patients, we believe, are representative of the heavily pretreated Phase I patient typically treated at U.S. academic cancer centers and given their advanced disease, underscore the compelling efficacy that has been reported with rociletinib. Four and as we discussed previously and also mentioned in the you New England Journal of Medicine article, we've shown encouraging response rates from progression free survival in the centrally confirmed T790M-negative patient population. This activity could be due to [indiscernible] of course, but may also be related to anti-IGF-1R activity from the human metabolite, rociletinib. Our data also do not demonstrate the containeous toxicities which are the hallmark of wild-type EGFR inhibition, such as acneiform, stomatitis and paronychia. All of these can significantly impact patients' quality of life, result in treatment discontinuation and cause patient distress which may especially be an issue for patients transitioning to a subsequent treatment following erlotinib or afatinib therapy where these side effects occur frequently as well. Overall, rociletinib is well tolerated with treatment related adverse events generally infrequent and mild, with the only grade 3 adverse event of note, hypoglycemia which when observed in requiring treatment is typically managed with a commonly prescribed oral agent. Moving to our regulatory plans for rociletinib, in the United States we're going to tighten up the mid-year guidance we have provided. We're planning to commence the rolling NDA in June with completion of the submission targeted for July or early August. As a reminder, data from the TIGER-X and TIGER-2 studies forms the basis of this submission. Our MAA timeline is similar to that of the NDA. As you know, rociletinib was granted breakthrough therapy designation in May 2014. We continue to prepare for a potential U.S. launch by year-end. Our marketing, market access and sales leadership is in place and our MSL team was fielded last quarter. We continue to invest in disease education in the United States and in Europe with the focus on educating physicians about the role of T790M and acquired resistance to currently available EGFR inhibitors. Our educational efforts also focus on the impact that wild-type EGFR related toxicity, specifically the constellation of cutaneous toxicity, have on patient compliance and quality of life. Recruiting the leadership of our field sales organization has begun and we've been extremely pleased with both the quality and quantity of candidates who are interested in joining us to build a world class oncology commercial organization here at Clovis. Let me review our ongoing development strategy for the drug. In addition to TIGER-X, there are three global registration studies enrolling in the TIGER program in EGFR mutant non-small cell lung cancer patients. This program spans four continents now with over 150 sites. TIGER-1, a randomized Phase 2/3 global registration study versus erlotinib in newly diagnosed patients. TIGER-2, a single-arm study in second line patients directly after progression on their first and only TKI therapy. Importantly, TIGER-2 includes both T790M-positive and T790M-negative patients and includes sites in the U.S., Europe and importantly, Asia. TIGER-3, a randomized comparative study versus chemotherapy in both T790M-positive and T790M-negative patients with acquired TKI resistance. Phase I study of rociletinib in Japan has completed enrollment and a Phase II study in Japanese patients, agreed upon with the Japanese regulatory authorities, is expected to initiate in the second half of 2015. Furthermore, beginning later this year, Japanese patients will be enrolling in TIGER studies 1 and 3. To update on our plans for combination trials, given that rociletinib has been demonstrated to be highly active and well-tolerated as monotherapy, we intend to initiate combination studies with several targeted therapies and checkpoint inhibitors. We expect that three of these combinations, with inhibitors of PD-L1, PD-1 and MEK will initiate in the second half of 2015. Lastly, but very importantly, we expect the next updated clinical data to be at ASCO 2015, where rociletinib has been granted an oral presentation. Spoiler alert. Please do not expect the data in the abstract when it publishes May 13 to provide a preview of this update because it does not. The clinical data update will, however, be incorporated into the oral presentation titled efficacy of rociletinib and plasma genotype T790M-positive non-small cell lung cancer patients on Sunday, May 31. We were very pleased to get our second consecutive oral presentation of rociletinib at ASCO this year. Turning now to our PARP inhibitor, rucaparib, it's been a really exciting time for rucaparib. We've shown very consistent and very compelling activity in a substantial number of ovarian cancer patients, including both germline and somatic mutant BRCA patients as well as patients whose tumors have other DNA repair deficiencies that cause them to respond similarly as to those with BRCA mutations. I'll refer to these patients as BRCA-like or those with a BRCA-like signature. We announced last quarter, that these recent data were so encouraging that we've been able to accelerate the development of rucaparib and that we now intend to file an NDA with the FDA for the treatment of advanced ovarian cancer in 2016. These data were encouraging not only to us. We're very pleased that in April we received breakthrough therapy designation from the FDA for rucaparib as monotherapy treatment of advanced ovarian cancer in patients with BRCA mutated tumors, inclusive of both germline and somatic BRCA mutations. Rucaparib is the only PARP inhibitor on the market or in development to have received breakthrough therapy designation. In fact, it is the only drug under development for ovarian cancer that has received breakthrough therapy designation. To remind you of the data from SGO presented in late March, we showed updated data for 61 ovarian cancer patients from the ARIEL2 study. From the 23 patients with germline or somatic BRCA mutations, an overall response rate of 70% was observed. This is highly consistent with the 25 germline BRCA patients from the Phase 1-2 study which showed an overall response rate of 76%. Combined, these 48 patients from ARIEL2 and the Phase 1-2 study, show a 73% overall response rate. Moving back to the SGO presentation and the 25 patients with the BRCA-like signature, an overall response rate of 48% was observed. And as expected, in the 13 patients who are biomarker negative, an overall response rate of 8% was observed. All response rates include both RECIST and CA-125 responses. These are clearly the highest response rates seen in a meaningfully sized mutant BRCA ovarian cancer patient population and the only evidence of activity in a prospectively defined BRCA-like population for any PARP inhibitor. Frankly, with these response rates, rucaparib stands apart from all other PARP inhibitors for the potential treatment of advanced ovarian cancer. We're very encouraged by these results which demonstrate the identification of a tumor BRCA-like signature, may identify a broader but still selective population of ovarian cancer patients likely to benefit from the drug. No targeted therapies exist today for these patients with a BRCA-like signature. We're enthusiastic about rucaparib's observed activity in the selected patient population. One last comment on the data. They also demonstrate that rucaparib is well tolerated. Mostly grade one and two treatment related adverse events. The only grade three/four toxicity of note was anemia. Let me walk through, again, the rucaparib development strategy. As we announced last quarter we expanded ARIEL2 into what is now a registration study for the treatment of ovarian cancer patients who have failed at least three prior therapies. We have added approximately 300 patients into the ARIEL2 extension and data from this study are expected to serve as the basis of an NDA submission in 2016. Since ARIEL2 is an extension of the ongoing ARIEL2 study, enrollment is going very well. As an important reminder, the ARIEL2 study prospectively assesses and correlates rucaparib efficacy with the molecular characteristics of each patient's tumor resulting in three prespecified subgroups of ovarian cancer patients. First, those with tumors with germline or somatic BRCA mutations. Second, those with the BRCA-like signature, sometimes referred by others as BRCAness and third, biomarker negative patients. The ARIEL3 study continues to move forward as well and we expect to complete enrollment in ARIEL3 in the first quarter of 2016. As a reminder, the ARIEL3 Study is a Phase III registration study comparing the effects of rucaparib to placebo. The study will evaluate whether maintenance rucaparib in platinum-sensitive high-grade ovarian cancer patients can extend the period of time for which a response to a prior chemotherapy is maintained. Efficacy in this trial will be assessed in a prespecified step-down manner. First, in tissue mutant BRCA patients. Second, in the larger group of patients with the BRCA-like signature, as defined and validated in our ARIEL2 study, with or without BRCA mutations and finally, in all randomized, of course, platinum-sensitive patients. I want to remind you again of the steps we have followed in the development of a BRCA-like signature in ovarian cancer, since these will be highlighted again at ASCO in an oral presentation. We designed an algorithm using public data sets from ovarian cancer patients and prespecified it for the ARIEL2 clinical trial. We enrolled over 200 women with recurrent ovarian cancer in the ARIEL2 single-arm study of rucaparib. Tumor specimens were collected from all women for genetic analysis. We prospectively studied response rate to our drug in the three prespecified genetic subgroups. Tumor BRCA mutant, again, germline and somatic. The BRCA-like population. And biomarker negative. As described earlier, we presented interim data from this analysis in Chicago in March and demonstrated a response rate to 70% inpatient's with BRCA mutations, 48% in the BRCA-like population and only 8% in the biomarker negative patients. We further improved our algorithm using the ARIEL2 data and will apply this optimized algorithm prospectively in the 300 women with current ovarian cancer in the treatment ARIEL2 extension study. We will also apply the optimized algorithm prospectively in over 500 women in the maintenance ARIEL3 study. [Indiscernible] this is the only company with the successful definition of BRCA-like that has been prospectively tested, confirmed and validated in human patients. As a result, we believe that both rucaparib data to date and our development program itself, differentiate rucaparib in ovarian cancer from our PARP inhibitors approved or in development today. Lastly, we have elected not to pursue, for now, the development of rucaparib in mutant BRCA pancreatic cancer. Although we have seen clear evidence of activity, it does not appear to be sufficient to pursue as a single arm study for an accelerated approval. Our investigators remain enthusiastic about the potential role of rucaparib in mutant BRCA pancreatic cancer and we will continue to discuss with them alternative means of developing rucaparib for this very difficult to treat patient population. In addition, the strategic decision earlier this year to accelerate the ARIEL2 program provides us with an alternative and clearly defined accelerated development path for advanced ovarian cancer. With the receipt of breakthrough therapy designation for rucaparib last month, this path is now even more clearly defined. We're continuing to work with investigators and cooperative groups to explore rucaparib in other solid tumors where mutant BRCA and a BRCA-like signature, may play a role and we can utilize our uniquely validated BRCA-like assay, including ongoing exploratory work in breast and in gastro esophageal cancers. Turning now to lucitanib, this is our oral potent inhibitor of the tyrosine kinase activity of FGF, VEGF and PDGF receptors. Lucitanib is unique among tyrosine kinase inhibitors, being developed for cancer therapy and effectively targeting these receptors with minimal off target activity. This cell activity profile allows lucitanib to provide a potential benefit to cancer patients by targeting multiple pathways of tumor development. Lucitanib has previously demonstrated impressive response rates with manageable side effects in heavily pretreated patients with solid tumors. During 2014, we initiated two Clovis sponsored Phase II trials, including a U.S. Phase II study in treatment refractory FGF aberrant patients with advanced breast cancer and a global Phase II study in advanced lung cancer patients with FGF receptor aberrations. We continue to enroll patients in these studies and expect that the next update for lucitanib will be data from the breast cancer study at the end of 2015. Now let me turn the call over to Erle to discuss first quarter financial results.

[Erle Mast:]

Thanks, Pat. Hi, everyone. Our first quarter 2015 financial results are included in this afternoon's press release, so I'll review the highlights of the results and I'll provide some additional commentary. We reported a net loss of $63.1 million or $1.86 per share for the first quarter of 2015 and that compared of to a loss of $30.7 million or $0.91 per share for the first quarter of 2014. The increase in our net loss was primarily due to increased investment in research and development activities in 2015, as well as the lack of milestone revenue in 2015 as compared to 2014. Research and development expenses totaled $56.8 million for the first quarter of 2015 and that compared to $24.2 million for the first quarter of 2014. This increase is due to expanded enrollment in the TIGER-X and TIGER-2 studies for rociletinib, as well as the ARIEL2 and ARIEL3 studies for rucaparib, the initiation of the TIGER-1 and TIGER-3 studies and higher personnel cost to support each of these activities. Research and development expenses also include disease education and other launch preparation activities for rociletinib. An expansion of these activities in the first quarter of 2015 contributed to the higher cost that we experienced. General and administrative expenses totaled $6.8 million for the first quarter of 2015 and that compared to $5.3 million for the first quarter of 2014. The year-over-year increase is primarily due to higher share-based compensation expense, as well as increased facility costs. Operating expenses for the first quarter of 2015 include $8.7 million in share-based compensation expense and that's up from $4.9 million for the first quarter of 2014. We ended the first quarter with $433 million in cash. Our net cash burn for the first quarter of 2015 was $49.3 million and as expected, this increased significantly from our Q4 2014 cash burn of just over $34 million. On our fourth quarter earnings call, we noted that our cash burn had not yet caught up to our operating expense growth and this occurred in the first quarter of 2015. We expect that the increase in the quarterly cash burn will continue throughout 2015 as enrollment in our clinical studies continue to grow and our launch preparation activities for rociletinib expand. With that I'll turn the call back over to Pat for some closing remarks and then we'll open it up for Q&A.

[Patrick Mahaffy:]

Thanks, Erle. Let me review our at anticipated near term key activities before opening up the call. For rociletinib, we look forward to presenting updated clinical results and an oral presentation at ASCO. We intend to complete enrollment of TIGER-X and continued enrollment in TIGER-1, 2 and 3 and we'll commence the Phase II study in Japan as well as the combination studies discussed. Most importantly, we're actively preparing our first NDA and MAA for submission mid-year and continue to buildout our commercial and medical affairs teams to prepare for potential U.S. product launch at the end of 2015. For rucaparib, we're pleased to provide the next update of ARIEL2 in an oral presentation at ASCO. We will continue to enroll ARIEL2 and ARIEL3. While not a milestone for 2015, but very important, we continue to plan for 2016 NDA submission to the FDA for rucaparib treatment in ovarian cancer patients who have failed three prior therapies. And for lucitanib, we'll continue enrollment in our Phase II studies underway and anticipate the first update from the breast cancer study to be presented in late 2015. With that, thanks again for joining us today. We look forward to seeing many of you at ASCO and hope you'll be able to join us for an investor event and webcast on Sunday, May 31. Let's open up the call for Q&A.

[Operator:]

[Operator Instructions]. Our first question comes from the line of Peter Lawson with Mizuho Securities. Your line is now open.

[Peter Lawson:]

I just wonder if you could talk through the rociletinib combination trials with checkpoint inhibitors in MEK? Are they from existing approved molecules or are they from several partners? Any color you can provide around that would be appreciated.

[Andrew Allen:]

Yes. So we publicly disclosed that the MEK inhibitor we'll be using is trametinib which is the only approved MEK inhibitor that as you know recently reverted to or converted to being under the control of Novartis from GSK. That study will begin, as Pat said, first patient in expected third quarter. We've not disclosed the nature of the checkpoint inhibitors that we're working with, but it is a plural.

[Peter Lawson:]

And then, wonder if you could give us an update on the EU submission for rociletinib, please?

[Andrew Allen:]

Yes. The EU submission timeline is consistent with the timeline we have for the U.S. NDA.

[Peter Lawson:]

And then the next update for the T790M-negative patients, is that an ASCO within the TIGER-2 data?

[Patrick Mahaffy:]

Yes, there will be an update at ASCO.

[Operator:]

Our next question comes from the line of Corey Kasimov with JPMorgan. Your line is now open.

[Corey Kasimov:]

First of all, following up on the T790M-negative patients we'll see at ASCO, can you tell us roughly how many patients worth of data we should expect to see and is this going to be both PFS in addition to response rate?

[Patrick Mahaffy:]

We're still preparing the presentation. It's oral, so we don't have to print a poster. But one of the things we've said to everybody is we will provide an update, but the [indiscernible] of patients isn't going to be hugely larger than the other patients you've seen. As you're aware, the patients we presented have come primary from the Phase II TIGER-X study. We're just now expanding the TIGER-2 to include a new group of T790M-negative patients. That group is, or will shortly begin enrolling, but won't be presented at ASCO. So it will be modestly larger, Corey, but not hugely larger. Andrew, anything to add to that?

[Andrew Allen:]

That's right. Data will be coming from the TIGER-X study. The TIGER-2 trial we'll be holding until the fall when we'll be able to give a more complete presentation of mature data. At the moment, the TIGER-2 trial doesn't have negative patients in it, but as I think you know, that amendment is going through right now to include negative patients in TIGER-2. So we may have some of those in the fall, but for ASCO we'll be on the TIGER-X study.

[Corey Kasimov:]

Okay. And then relative to the data that you have presented to date, can you remind us whether you've been presenting investigator assessed data or centrally reviewed data and what kind of difference you've maybe even seen between the two on response rate in PFS?

[Andrew Allen:]

We've been presenting investigator assessed because obviously in a typical Phase I study that's what one uses. We obviously are doing central assessments and they're tracking closely and we'll show a little bit of those data at ASCO.

[Patrick Mahaffy:]

One quick thing, Corey, from a regulatory and hygiene standpoint, we've seen a great amount of consistency between the investigator assessment and from the independent assessment and the local assessment which is a really positive thing.

[Corey Kasimov:]

Okay. Yes, agree. And then one question on rucaparib, the breakthrough designation you have is in BRCA positive or BRCA mutant patients. Did you also ask for it in BRCAness patients?

[Patrick Mahaffy:]

We never disclose what we've done. Okay, I'll disclose. We did not. We only requested breakthrough for the mutant BRCA population. We did not, in our view, have sufficient patient numbers yet to consider breakthrough for the BRCA-like. We certainly have had a dialogue with FDA about them and in the event we have the opportunity to over the course of the next 12 months or so, we will go back to them for that population as well.

[Operator:]

Our next question comes from the line of Charles Duncan with Piper Jaffray. Your line is now open.

[Unidentified Analyst:]

It's Will in for Charles. Thanks for taking the question. Can you guys tell us the cut date of the data at ASCO will be?

[Andrew Allen:]

Yes. We'll include patients up to the end of 2014 mostly and I'm hedging a little because the ASCO presentation actually has a lot of data on plasma positive patients as well. And so the cutoffs for inclusion vary a little to try to make sure we present as much data as we coherently can. The efficacy cutoff obviously will be at least two cycles beyond that because obviously we'll be presenting data on patients who are at least evaluable for efficacy.

[Unidentified Analyst:]

Okay, two cycles beyond the end of 2014.

[Andrew Allen:]

Correct.

[Unidentified Analyst:]

And then sorry for the long winded question, but given that your patients are heavily pretreated, do you think a relevant comparison is the maintenance setting for erlotinib and gefitinib? And given the impact of those agents on the wild-type receptor and the not so impressive efficacy results, why not file for a broad EGFR mutant population using the T790M-negative data that you have? Thanks. I'll jump back.

[Patrick Mahaffy:]

First, as to the T790M-negative, we've been really consistent about this. We have a clarity between FDA and us on the N of patients who are refused to have a 90M-positive and the maturity within that patient population that are going to be required at the time we submit. As we've said several times, the N of patients we have in the T790M-negative population is quite a bit lower than the N of patients we have in the T790M-positive. And we do not feel that at this time it would be appropriate to go to them and include it in this NDA. Our goal is to get a submission into FDA and ideally an approval before the end of the year so we can begin providing this drug on a commercial basis to the T790M-positive population. We're running TIGER-2. If those data were really encouraging even before we had data from TIGER-3, we obviously would consider going to FDA and other regulators with the T790M data as a supplemental and of course couldn't occur until next year sometime and we're very enthusiastically enrolling TIGER-3 because that's the comparative study that, to remind you, includes both T790M-positive and negative patients.

[Unidentified Analyst:]

Right, the agency is going to want to see the negative data in the NDA filing, no?

[Patrick Mahaffy:]

I think we will likely provide data, but I guess I want to really publicly state what we absolutely believe; we're not going to get the T790M-negative population in our initial label. We have no dialogue with FDA about it, no belief it will occur and no expectation that it will occur. We do believe we have a great data set in the T790M-positive population and we're pursuing that first and we're encouraged by what we've seen in this initial smaller patient population who are T790M-negative and we will, over time, pursue that as well, either through TIGER-2 or of course in the comparative TIGER-3 study.

[Operator:]

Our next question comes from the line of Yaron Werber with Citi. Your line is now open.

[Unidentified Analyst:]

This is [indiscernible]. For rociletinib, could you elaborate on the potential mechanism behind why we're seeing activity in T790M-negative patients?

[Patrick Mahaffy:]

Andrew, I'll kick it to you. I think we probably had this dialogue every call we've had, but we can go through it again. Go ahead Andrew.

[Andrew Allen:]

Sure. So the first potential explanation is heterogeneity. Bear in mind that T790M is not what's termed now a truncal mutation, meaning that it is not expected to be present in every tumor cell in the entire tumor population, the tumor mass that a patient has. That's different from the activating mutation which is a truncal mutation, meaning that it is not expected to be present in every tumor cell in the entire tumor population that you've amassed that a patient has. That's different from the active [indiscernible] mutation which is a truncal mutation which is found in every tumor cell in every patient. T790M is not truncal and, therefore, we do expect that as quiet resistance develops in a patient, this will not be found uniformly in every cell in that patient's resistant tumor mass. And there is abundant evidence to show that this is true and it's probably particularly true in the later line patient. Because when a patient's had two, three, four lines of prior therapy stretching over several years, there's obviously a lot of opportunity for cloneal evolution to happen and for different regions of different tumor masses within the same patient to evolve somewhat differently under the various and changing selection pressures of multiple lines of therapy. So heterogeneity is clearly a real phenomenon in this disease for T790M. And you can see that just by the fact that we have patients who are tissue T790M-negative and plasma T790M-positive. So clearly in that patient the needle biopsy would miss the positive pieces of the tumor and yet they exist because we're picking it up in the plasma. So heterogeneity is the first explanation. But it probably isn't sufficient to fully explain the activity we've observed. And I say that because another third generation T790M inhibitor in patients who are essentially confirmed T790M-negative has a response rate of around 10% and we reproducibly have been tracking at least three-fold higher than that. And so we'd like to think that there is probably something else explaining the activity we've observed. The hypothesis, the leading hypothesis that adds into the heterogeneity issue is inhibition of the insulin like growth factor 1 receptor, i.e. 1-R and perhaps the insulin receptor. And as we've discussed previously in public, we know that a metabolite of rociletinib is a potent inhibitor of IGF1R and insulin receptor. And there is now accruing evidence that in patients with acquired resistance to first generation TKI, the IGF1R pathway may be playing an active role in the development of progression of those resistant clones. And therefore, suppression of that pathway through this metabolized rociletinib may plausibly be explaining some of the activity we observed and essentially confirmed T790M-negative patients. There are a couple of other possible explanations which I don't think are relevant here, so I'm not going to labor them, but TKI retreatment effect is a possible explanation for why you might see activity in negatives. And this means that a patient who's got mutant EGFR lung cancer, if they receive first generation drugs such as erlotinib, they've progressed, they're put on chemotherapy. When they progress on chemotherapy, if you put them just back on erlotinib again, you will see some responses. They're not terribly durable, but they do exist. Now that's not relevant to our population because around 90% of our patients these days are coming straight off of the TKI. Obviously that obviates the possibility of that as an explanation. And finally, assay insensitivity I don't think is also relevant here. We've extensively tested many samples with the QIAGEN assay that we use and also with the Roche COBAS assay and they perform identically. And so the assays are -- these are FDA approved assays. In fact, the QIAGEN assay that we use is the only assay that is FDA approved for the detection of T790M in formerly fixed path and embedded tissue sections. That's the assay we use. The FDA's approved it for that use. It is a good assay. It is a sensitive assay. So that's not a relevant explanation either. So that hopefully answers the question adequately.

[Unidentified Analyst:]

And then one other question. For ARIEL2, what patient population characteristics are you seeing? Is it any different from the original study?

[Andrew Allen:]

For the ARIEL2 extension, it is a little different from the original ARIEL2 study because per the FDA's request we're studying patients who have received at least three prior lines of sized toxic chemotherapy and that is -- that was not a requirement for the first couple of hundred patients in the ARIEL study. So that's the one meaningful difference.

[Operator:]

Our next question comes from the line of Terence Flynn with Goldman Sachs. Your line is now open.

[Terence Flynn:]

Can you just [indiscernible] August? Any more clarity there would be useful. And then the recent New England Journal of Medicine Publication--

[Patrick Mahaffy:]

I'm really sorry, you broke up so much that I couldn't hear those questions.

[Terence Flynn:]

Okay. Apologies.

[Breanna Burkart:]

Do you mind calling back in, Terence and seeing if we can get a better connection.

[Terence Flynn:]

Okay. No problem. Is this any better?

[Patrick Mahaffy:]

Well, it could be better but it's in and out.

[Operator:]

Our next question comes from the line of [indiscernible]. Your line is now open.

[Unidentified Analyst:]

Hope you don't mind me asking question about T790M-negative patients. My question is about the [indiscernible]. Which one is earlier is the one for data presented at JPMorgan or the New England Journal of Medicine publication?

[Patrick Mahaffy:]

The New England Journal publication had a cutoff date of mid or late June of 2014. The JPMorgan presentation was actually a modest update from the ENA presentation that was made in November of 2014. So the most recent data for T790M-negative patients was at JPMorgan.

[Operator:]

Our next question comes from the line of Howard Liang with Leerink Capital. Your line is now open.

[Howard Liang:]

For ARIEL2 I think you said it will be Alcom's [ph] data presented. Can you elaborate on what Alcom data from ARIEL2 at ASCO?

[Andrew Allen:]

Yes, we'll show the primary efficacy analysis for ARIEL2 is PFS, progression free survival which we've not shown previously because the data have not been sufficiently mature. So those will be presented at ASCO, together with an update on the response rate data and of course safety and tolerability.

[Howard Liang:]

Okay. Regarding the submission, can you talk about -- for rociletinib, can you talk about what will go in in June and what will be submitted later in July and August?

[Patrick Mahaffy:]

No, no, I don't think so. The ruling submissions you can submit different modules of which there are several. The first of those modules will go in at the end of June, the last will go in at the end of July or early August.

[Howard Liang:]

Sorry, I was asking can you tell us what will go in first, what will go in later?

[Patrick Mahaffy:]

No, I'm sorry, Howard. I heard your question.

[Howard Liang:]

Okay. That's fine. Lastly, on TIGER-1, should we still expect -- can we expect Phase II -- data from the Phase II portion this year?

[Patrick Mahaffy:]

It won't be complete data by any means. We'll look to provide an update at one of the later fall meetings, so it can be as useful as possible. What cannot be in that yet, just given the time to achieve this maturity is really anything beyond response rate. I don't think you should expect any PFS data because it just won't be anywhere near enough to interpret. So that would be kind of an update on tolerability and maybe response rate, but I think that's going to be -- that's almost certainly going to be about it.

[Operator:]

Our next question comes from the line of Brian Klein with Stifel. Your line is now open.

[Brian Klein:]

Just a couple of quick questions. First, do you anticipate the need for an advisory panel following the NDA submission for rociletinib. Secondly, have you guys conducted any preclinical work on the combo with the PD-1, PD-L1 and the MEK inhibitors that would suggest one type of immune targeted agent would work better with rociletinib? And then maybe a third question for Andrew. Can you just give us a sense of what's good enough in terms of a T790M-negative response rate and PFS that you think the FDA would be comfortable with? Thanks.

[Patrick Mahaffy:]

Andrew, I'll jump on the advisory panel one and then if you want to address the preclinical with oncology and a guesstimate of what we think FDA would desire in T790M-negative for both PFS and response. As to the advisory panel, we've all learned that it's really unwise to predict what FDA will do. However, this is an accelerated approval on a single-arm study for a drug that has breakthrough status and it certainly would be unusual to expect a panel. I don't believe it has occurred for any kind of analogous drug. I will say very clearly, I clearly do not anticipate that 9291 would have an advisory panel either just to be fully balanced. Our best guess is that it's unlikely, but one should never predict FDA. Andrew?

[Andrew Allen:]

In terms of preclinical modeling, it's difficult to do useful preclinical modeling with checkpoint inhibitors because of course you need an intact immune system. So you can't use the traditional xenografts. You're more limited to things like genetically engineered mouse models. So we've not done extensive work. Frankly, I think the human is the relevant species there and we'll begin doing those studies imminently. In terms of MEK inhibitor which I think was also part of your question, we can do those studies preclinically. The in vitro data are fairly straightforward and obviously strongly supportive of combining the two agents. It can be a little harder to find a cell line which has acquired resistance mediated through MEK directly. So that xenograft model that adequately recapitulates is harder, but we do have sufficient preclinical evidence now to begin the clinical study that we've talked about. Your other part of the questions was around the bar for approval in single-arm studies. So again, single-arm studies, PFS is not part of the efficacy assessment that a regulatory agency will typically perform, because they will assert that it is uninterpretable in the absence of a control-arm. And therefore, one typically is reliant upon response rate for single-arm studies and the bar obviously varies, indication to indication. The more advanced the patient population, the generally lower that bar will be. I think it's hard to know exactly in advanced mutant EGFR lung cancer in a patient who's exhausted all previous therapies exactly where that bar sits, but I think a rule of thumb would be somewhere in the 20% to 25% range is about as low as you would want to go. Of course, we have the TIGER-2 study which is including negative patients and that has a control arm and for that study PFS will be the relevant efficacy metric judged using the control arm as the comparator. That's the way we've been approaching the T790M-negative population.

[Patrick Mahaffy:]

One last thing on that, in studies for afatinib, they did a comparative study, in a similar population, of very advanced EGFR mutant lung cancer. The control arm which was chemo which is what we're using, showed a 2.8 months PFS and a response rate in the 10% to 15% zone. So obviously we have to do better than that. But unfortunately, the standard of care that's available right now represents a pretty low bar.

[Operator:]

Our next question comes from the line of Terence Flynn with Goldman Sachs. Your line is now you open.

[Terence Flynn:]

I was just wondering if you can tell us what's gating of your completing the NDA filing in July or August?

[Patrick Mahaffy:]

Hopefully a fairly thoughtful effort by a company to give itself a little wiggle room. I don't know of an event or a data set that are gating. It's just we're putting together and preparing the NDA that we hope to and plan to submit on the timeline described in both this script and in the press release.

[Operator:]

I'm showing no further questions from the phone lines at this time. I'd like to turn the call back to Breanna Burkart for closing remarks.

[Breanna Burkart:]

Thank you everyone for your interest in Clovis Oncology today. If you have any follow-up questions please call me at 303-625-5023 or Anna at 303-625-5022. You can access the call via replay on our webcast at www.clovisoncology.com. Again, we appreciate your interest and time. Thank you and have a good evening.

[Patrick Mahaffy:]

Thank you.

[Operator:]

Ladies and gentlemen, thank you for your participation in today's conference. This concludes the program and you may now disconnect. Everyone have a great evening.