Clovis Oncology Inc (CLVS) 2014 Q4 法說會逐字稿

Good day ladies and gentlemen and welcome to the Q4 year-end 2014 Clovis Oncology Inc. earnings conference call. My name is Steve and I'll be your operator for today.

(Operator Instructions)

Now I would like to turn the call over to Breanna Burkart, Senior Director of Investor Relations. Please proceed.

Good afternoon and welcome to the Clovis Oncology fourth-quarter and year-end 2014 conference call. You should have received the news release announcing our fourth-quarter and year-end financial results. If not, it is available on our website at www.clovisoncology. com. As a reminder this conference call is being recorded and webcast.

Remarks may be accessed live on our website during the call and will be available in our archive 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 2014 and provide an update on our clinical development programs. Then Erle Mast, Clovis' Chief Financial Officer will cover the financial results for the quarter and year in more detail. Patrick will then 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 our 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.

All right. Thanks Breanna. Welcome everybody. Thanks for joining us this afternoon.

I hope and expect that 2015 will be a transformative year for us where we advance and expand our clinical development programs and, importantly, lay the foundation for the potential launch of our first commercial product. I'll begin with rociletinib, starting with a recap of the data we presented in late 2014, then we'll turn to our plans for 2015. Most importantly, are planned NDA and MAA submissions to take place midyear.

In November 2014 at the ENA meeting in Barcelona, data from our TIGER-X and TIGER-2 studies demonstrated an objective response rate of 67% in 27 evaluable T790M-positive patients, receiving either 625 mg or 500 mg BID, and what we refer to as the clinical dose group. The disease control rate for this group was 89%, the immature medium PFS was 10.4 months, with follow-up for some patients exceeding one year. These data derived from western patients who were typically heavily pretreated and typically progress from an immediate prior EGFR TKI.

As a result, we believe these data demonstrate the safety and effectiveness of rociletinib in a real-world patient population, seen from the US market point of view. Data presented to date demonstrates that rociletinib is well tolerated, with no evidence of systemic wild-type EGFR inhibition. The only common grade 3/4 toxicity recorded was hypoglycemia, which occurred at 14% of patients and was readily managed with an oral hypoglycemic agent. (sic - see press release "14%" )

We believe that rociletinib has a unique profile compared with other EGFR inhibitors on the market or in clinical development and that we do not see the cutaneous toxicities which are the hallmark of wild-type EGFR inhibition, such as acne formed rash, stomatitis and paronychia. All of these can significantly impact patients' quality of life, result in treatment discontinuation and cause patient stress, and we just don't see it. Furthermore, having treated over 400 patients we can see that IOD is rare and even when it does occur it does not always necessitate rociletinib discontinuation.

In January we also provided an update on activity in T790M-negative patients. Interestingly, we continue to see activity in this patient population as well. In 19 patients in the T790M-negative clinical dose group we reported a 42% overall response rate. 16 of the 19 patients were treated with rociletinib immediately following TKI therapy, eliminating a TKI retreatment effect as an explanation for this activity. The median PFS for the T790M-negative population was 7.9 months.

In contrast, when these advanced patients were treated with chemotherapy, the response rate shown had been around 10% to 15%, with a PFS of under three months. Clearly there is a need for new therapies for this patient population. Based on the activity we have seen, we are now actively exploring rociletinib as a treatment for T790M-negative patients. In particular we have amended the TIGER-2 and the TIGER-3 studies to include the T709M-negative cohorts to further investigate this activity. TIGER-3 of course is a comparative registration study.

Let's move now to our ongoing development strategy for rociletinib. We continue to enroll patients in the two Phase 2 expansion cohorts of TIGER-X, the original Phase 1/2 study. In addition to TIGER-X there are three additional global studies in the TIGER program in EGFR-mutant non-small cell lung cancer patients. A program spanning four continents now with over150 sites.

TIGER-1, for randomized Phase 2, 3 global registration study versus rociletinib in newly diagnosed patients, which is actively enrolling. TIGER-2, a single-arm study in second line patients, directly after progression on their first and only KI therapy. Importantly as I noted, TIGER-2 includes both T790M-positive and T790M-negative patient cohorts, and includes sites in the US, Europe and importantly, Asia. As a reminder data from the TIGER-2 study T790M positive cohort, combined with data from the TIGER-X study, are expected to serve as the basis for the first regulatory submissions for rociletinib.

After the TIGER program we also TIGER-3, a randomized comparative study versus chemotherapy, in both T790M-positive and T790M-negative patients with acquired TKI resistance. We are running as well a Phase 1 study of rociletinib in Japan which will soon transition into Phase 2, and furthermore later this year Japanese patients will be enrolled in the TIGER-1 and the TIGER-3 studies.

Given that rociletinib has been demonstrated to be highly active and well tolerated as monotheraphy, during 2015 we tend to initiate a number of combination studies. The initial combinations include rociletinib planned or initiated with PDL1, PD1, MEK and Aurora kinase inhibitors. We also anticipate announcing additional combination studies over the course of the year.

We remain on track to submit both our NDA and MAA submissions in mid-2015, and as a reminder rociletinib was ranked at Breakthrough Therapy Designation in May of last year. We do have meetings planned with the PMDA in Japan regarding the registration path and we will be in a position to update that plan later this year.

Finally, we intend to be prepared for a potential US launch during the fourth quarter. Our marketing, market access and sales leadership is in place and the US MSL team is being fielded this quarter. One last item, we expect our next update of clinical data for rociletinib to be at ASCO 2015 at the end of May, early June.

Turning now to our PARP inhibitor, rucaparib. It's been an exciting time for rucaparib. We have shown very consistent and very compelling response rates and a substantial number of ovarian cancer patients. In fact, these recent data are so encouraging that we have been able to accelerate the development of rucaparib.

In January, we showed combined data from 54 ovarian cancer patients with germline or somatic BRCA mutations. In these patients, who had received the median of two prior chemotherapy regimens, an overall response rate of 70% and a disease control rate of 80% was observed. This is clearly the highest response rate seen in meaningfully sized ovarian cancer patient population for any PARP inhibitor.

As an important reminder, the ARIEL2 study prospectively assesses and correlates rucaparib activity with the molecular characteristics of each patient's tumor, resulting in three pre-specified subgroups of ovarian cancer patients. A, those with tumors of germline or somatic BRCA mutations; b, a broader but still selected population of ovarian cancer patients, who are not mutant BRCA, but may also benefit from rucaparib therapy, a type commonly called BRCAness or BRCA-like, sometimes also referred to as homologous recombination deficiency HRD; and c, biomarker negative patients.

Might help to take a moment to recap the steps that we have followed in the development of a BRCAness signature in ovarian cancer. First, we designed the cutoff using public data sets from ovarian cancer patients and pre-specified it for the ARIEL2 clinical study. Second, 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. Third, we prospectively studied response rates to our drug in the three pre-specified genetic subgroups: BRCA mutant BRCAness and biomarker negative.

We presented interim data from this analysis in Barcelona last November, and demonstrated response rates of 70% in patients with BRCA mutations, 40% in BRCAness patients and only 8%, which represented 1 out of 13 patients who had a response, in the biomarker negative patients. We are now planning to cut off prospectively again, in 300 women with referred ovarian cancer in the treatment ARIEL2 registration extension study. We're also applying the cut off prospectively over 500 women in the maintenance ARIEL3 study.

One last and very important comment on our data presented last year, those data demonstrate that rucaparib is well tolerated. The only common grade 3 toxicity observed is anemia, which we've seen of 14% of patients with very few discontinuations. As I mentioned, based on these very compelling data we accelerated the development of rucaparib in late 2014.

We've expanded ARIEL2 in what is now a registration study for the treatment of ovarian cancer patients who have failed three prior therapies. As just described, we're adding approximately 300 patients into the ARIEL2 extension, and data from the study are expected to serve as the basis of an NDA submission in 2016.

One great thing about this plan, is that it takes advantage of our already ongoing ARIEL2 study in about 60 open and highly motivated sites. As a result, since we are not starting from scratch, we anticipate very rapid enrollment. I should also note, that the ARIEL2 extension is using a 300 milligram strength tablet, which we have developed as a commercial formulation, so rucaparib dose is now two tablets BID.

Overall, we are very encouraged by these results, which demonstrate that identification of the tumour BRCAness signature may identify a broader, but still selected population of ovarian cancer patients, likely to benefit from rucaparib therapy. No targeted therapies exist today for these patients with BRCAness and we're enthusiastic about rucaparib's observed activity in the selected patient population. With the inclusion of BRCAness patients, our target patient population potentially include between 50% and 60% of serous ovarian cancer patients.

Moving forward, we continue to actively enroll patients in both studies in the ARIEL program. The ARIEL3 study, to remind you, is a Phase 3 registration study comparing the effects of rucaparib versus 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 will be assessed in a pre-specified step down manner. First in tissue BRCA mutant patients, which includes germline and somatic mutations of BRCA, then can a larger group of patients with a BRCAness signature, as defined and now validated by the ARIEL2 study, with or without BRCA mutations and finally and in all randomized patients. We expect to fully enrolled ARIEL3 in the next 12 months.

In addition to the ARIEL program in ovarian cancer, we're exploring rucaparib in other solid tumor types, with significant BRCA and BRCAness populations, including breast, gastroesophageal and pancreatic cancers.

Turning to lucitanib, it is our oral potent inhibitor of tyrosine kinase activity of FPDF, VEGF and PDGF receptors. The [signature] is unique among tyrosine kinase inhibitors being developed for cancer therapy and effectively targeting these receptors with minimal off target activity. This selectivity profile allows lucitanib to provide potential a 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 2 trials, including the US Phase 2 study in treatment refractory FGF aberrant patients with advanced breast cancer and a global Phase 2 study that 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 fourth-quarter and year-end 2014 financial results.

Thanks Pat, afternoon everyone. Our fourth-quarter and full 2014 financial results are included in this afternoon's press release so I'll direct comments to some financial highlights and additional commentary.

We reported a net loss of $54.9 million, or $1.62 per share for the fourth quarter of 2014 and $160 million or $4.72 per share for the full year. Our operating cash earned for the fourth quarter of 2014 was $34.2 million and it was $120 million for the full year. As expected and in line with our previous guidance, we ended 2014 with $482.7 million in cash.

Research and development expenses totaled $50.1 million for the fourth quarter and $137.7 million for the full year of 2014. And both of these amounts increased significantly over comparable amounts from 2013. And that's primarily due to the significantly expanded clinical development activities for rociletinib and for rucaparib, increased manufacturing of clinical drug supply for both of those programs, and higher personnel expenses to support the expanded development activities for the Company.

Fourth-quarter research and development expenses also increased by $15 million over the third quarter of 2014. Now this increase is primarily due to increased activities in the TIGER clinical study program, the manufacture of clinical supply for rociletinib, and increased investment in disease education and another prelaunch activities for rociletinib. As a reminder, the development expenses for lucitanib continue to be fully funded by Servier, so its addition to our development activities for 2014 did not impact our R&D expenses.

Total operating expenses were $49.8 million for the fourth quarter of the year and $146.5 million for the full 2014, after excluding non-cash charges which relate primarily to share-based compensation expense. As we look toward or into 2015, there are multiple variables that will affect our operating expenses and our cash flows for the year. Most notably the timing of the potential approval and launch of rociletinib, including a payment of regulatory milestones pursuant to our license agreement. So accordingly at this time we're not providing cash guidance for 2015.

One observation I would make as you look at our 2014 operating trends for purposes of looking into 2015 and making financial estimates. Our fourth-quarter results highlight that our cash earned for the quarter did not keep pace with our expense growth, as is often the case for clinical trial and manufacturing related expenses. And we certainly expect that gap to disappear as we move into 2015. So accordingly our operating expense total is a more accurate indicator of our current cash burn trends than actually looking at the actual cash burn for the fourth quarter. And with that I'll turn the call back to Pat for some closing remarks, and then we'll open up for Q&A.

All right, thanks Erle, let me review our anticipated near-term key activities before opening up the call for Q&A. Rociletinib, we intend to finish enrollment of TIGER-X and TIGER-2, we will also present interim clinical results at ASCO 2015. We'll initiate TIGER-3 very shortly and we will commence the phase 2 portion of our Japanese study as well, as the combination studies discussed.

Most importantly, we're actively preparing our first NDA and MAA submission for midyear and continue to build out our commercial and medical affairs teams to prepare for potential US product launch for rociletinib at the end of 2015. Rucaparib, we will continue to enroll ARIEL2 and ARIEL3, we expect that an updated clinical results from ARIEL2 will be presented at SGO in late March and at ASCO 2015. And one other milestone for 2015, but very importantly, we continue to plan for a 2016 NDA submission to the FDA for rucaparib treatment in ovarian cancer patients who have failed three prior therapies. And of course, we'll continue to enroll in the ongoing lucitanib studies.

With that, we'd like to thank you for joining us today, look forward to an exciting year and we'll now open up the call for Q&A.

(Operator Instructions) Terence Flynn, Goldman Sachs.

Hi, this is Irene in for Terence, thanks for taking a question. Should we still expect to see data in the fall from your TIGER-1 study? The head to head [travers of tarcevia]. Will there be response rate MPF data available at that time or only response rate data, thanks?

We're hoping to present data from TIGER-1 in one of the fall meetings. I think it's likely that in the event we do, it will be almost solely response rate data. It's going to be really unlikely that we would have anything meaningful to show in PFS at that time

Thank you

Charles Duncan, Piper Jaffray

Hi guys, thanks for taking the question and thanks for the thorough update. First question is with regard to the NDA, can you ballpark the number of patients that you might include in that or have data on at that time?

We've never exposed that number, it is agreed to at FDA and so I'll tell you it is a sufficient number to meet FDA requirements.

Okay that's helpful, so you have discussed that and that's the basis of your plan

It is.

And then Pat, with regard to, you mentioned a real population versus -- and maybe alluded to a clinical trial population at the beginning of your prepared remarks, I'm wondering as you think about the potential compounding variables. What is the one or two that you can point to that you feel that your trial is best emulating what the real world is, versus say a clinical trial population?

I don't want to make comparative analyses or comparative claims, I think that would be inappropriate for me to do. So let me make clear what I think is appropriate and good in our trial. The difficulty of doing a Phase 1, 2 study in academic centers in the United States is this it is the hardest test possible for a drug in a very advanced patient population. The majority of our patients have been on various therapies for several years.

The majority have had -- the median have had two prior TKIs, depending on the time we present the data they've had a median of either two or three prior therapies, and they are really advanced, often motivated patients who sought out clinical studies in academic centers. But their disease has taken its toll, the performance status unfortunately can begin to diminish over the course of the disease progression and over course of their therapies. I'll give an example.

Approximately, and again depending on the time you look at the data, in general around 50% of our patients by the time they get rociletinib, and these are the data they've been presented, already have brain mass. So all we're trying to point out is, this is a real world, real difficult, real important patient population that really needs new therapies and as we come into a commercial environment this drug has been -- really been tested in the toughest patients of all for a drug of this nature.

That's helpful, and then last question go-to-market strategy, can you ballpark the number of sales folks that you think you'll need to we effectively address the market?

We've never disclosed that, but there's a pretty modest range of sales force sizes for oncology launches, oncology promotion in the United States and we're well within that range.

Thanks for the added color

Sure, thank you

Yaron Werber, Citi

Hey guys, this is actually Kenon on for Yaron, thanks for taking our questions. Had a question about the T790M negative patients. I was wondering if you could talk a little bit about the test that you used to confirm that those patients were T790M negative, whether it's a blood or biopsy? And then just a little bit about how sure you are that these are actually T790M negative patients

This is Andrew. There are two FDA approved tests for detecting EGFR mutations in embedded lung cancer tissue. One is the Roche test and one is the Qiagen test. As you know we're working with Qiagen and the reason we chose to work with Qiagen is because their test is unique in that it is analytically validated and FDA approved for the detection of T790M in (inaudible) embedded tissues. So it is the gold standard for detection of T790M.

That's a test that we use and so when we refer to a patient as being centrally negative, what we mean is that a tissue specimen from that patient obtained at the beginning of their participation in the clinical trial, has been sent to a central laboratory, tested with the approved FDA Qiagen test and has come back with a negative result. And those patients therefore represent a homogeneous century confirmed T790M negative population using the only FDA validated test, so that's what we mean.

Terrific. And at ASCO will we see data from more than the 19 patients that I think you've presented on that were T790M negative and could you just give a little more color on potentially what we'll see at ASCO?

We submitted the abstract, you'll see an update on both the T790M positive and T790M negatives. Our priority, as you know, has been to enroll the T790M positive so that's the majority of the enrollment you'll have seen between the time of the last presentation. And at ASCO there may be some additional T790M negative patients as well. But I couldn't give you guidance as to what that number would be.

Sure. Any sense of sort of how long those T790M negative patients might've been on the drug for?

That's one of the difficulties for all of us in rapidly enrolling trials or in ongoing trials presenting interim data, is you're always piling on new patients. So I can't give you a number or a time frame.

Sure, we really appreciate the color, thanks so much.

You bet, thank you.

Cory Kasimov, JPMorgan.

Hi guys, this is Whitney on for Cory. Just wanted to see if I could dig into the sales force a little bit. I think you said you're recruiting now, preparing for a 4/2 launch, so will you be bringing sales reps on ahead of time so that you'll be ready to launch immediately post approval? Or will it be kind of making offers contingent on approval or how are you thinking about that?

Well we're not actively recruiting right now. We intend to bring them on board in a timeframe that we think will be consistent with our need to be launch ready by the end of the year, and prepared to launch at the end of the year. The goal will be to have that sales force on and trained at the time of an anticipated approval, so that we can launch immediately or as close to immediately as possible upon potential approval.

Great thanks. And I may have missed it, but will we get an update on the pancreatic trial at ASCO?

Could do.

Got it. Alright. Thanks

Howard Liang, Leerink

Great, thanks very much. I have a couple questions on the ARIEL2 study. How many patients would you go to include from the already enrolled aerial patients before the additional 200 patients? I think it looks like from the presentation that most of the earlier patients were in earlier lines of therapy and I want you to confirm that.

So the first part of ARIEL2 enrolled just over 200 patients and now we're embarking upon an additional 300 patients. And the enrollment criteria for the first part where you had to have platinum sensitive recurrent disease, with no very tight criteria on numbers of cryo therapies, and as you know based upon the FDA's guidance the next phase of ARIEL2 will be in patients who progressed upon three prior cytotoxic chemotherapies. Three or more.

We do have some of those patients in that 200 patient population, but we haven't disclosed the number.

Okay. And again on ARIEL2, what is the explanation that the proportion of germline BRCA-mutated patients, I think it was 15% in the data presented that seem to be somewhat lower than what other companies have said, which are in sort of the 35% to 40% range.

So we designed ARIEL2 to help us understand a definition of BRCAness. We didn't need a lot of patients to tell us about what a germline BRCA mutation patient looks likes and how they respond to drug. So we deliberately and actively capped the number of patients with previously known germline BRCA mutations in ARIEL2. So you should not look at ARIEL2 and the frequency or the fraction of patients with germline BRCA mutation as being reflective of the population, by design it was not. It was deliberately less.

Thanks. Lastly, can you talk about the size of the T790M negative cohorts in TIGER-2 and TIGER-3?

TIGER-2 we've opened it up to T790M negative patients, and we specify the number of patients that I think is on the order of 40 or 50 T790M negative, is what we'll look for. It's an open label single arm study. In TIGER-3, as we've highlighted, it's a 600 patient comparative study.

We suspect because we're not prejudging whether you have to be positive or negative, but the characteristics of that patient group will reflect the general characteristics of the TKI failure population. So we're guessing, predicting that it will be something like 60% T790M positive patients and 40% T790M negative patients

Yes, just to add a bit of color, these are all common trials. And so the fraction of positives versus negatives just reflects the population that comes in, and as Pat said, the current best guess is roughly a six to four ratio, positive to negative.

Thank you very much

Thank you

Peter Lawson, Mizuho Securities

Patrick, with the checkpoint inhibitor studies could you give us any further details around that? Is that one or multiple partners and when you expect those trials to start?

We'll be starting -- this is Andrew, we'll be starting the first half of this year. And we haven't given specifics yet as to who the sponsored study partner is, obviously we're contracting with another company on the PD-L1 combination. We have been public that there is an investigator-sponsored trial in line with MD Anderson, in combination with Merck's PD-1 antibody (inaudible).

Thank you and then on the launch for rociletinib, could that be year-end as well for Europe?

No. It could be year-end in the United States given regulatory time lines, but the review process as you know is longer in the EU. And so we would not anticipate a launch in the EU and it will be, sort of country by country as you also know, despite getting a central approval that would probably begin, I would guess toward the middle of next year.

Thank you. And then just finally on the inclusion of the T790M negative patients, has that delayed the enrollment or could it potentially delay data releases on that?

No. The T790M negative population that has been added to each of TIGER-2 and TIGER-3 will not impact our NDA submission time lines at all. I'm glad you asked that. We are not in this first submission including T790M negative patients. The submission is limited to the T790M positive population, our investigators to answer the other part of your question, have been really excited to enroll patients who are T790M negative, because in their minds the T790M positive population is now being reasonably well addressed through not just our, but other drugs in clinical development. The T790M negative population really have nowhere to turn. And so their enthusiasm to enroll in this trial is very, very high -- in these trials is very, very high.

Great. Just one follow-up for Erle around R&D spend, how should we think about that, does that increase from 4Q levels?

I think as you look out into 2015 -- the studies we have ongoing will continue to enroll more patients. Currently all of our prelaunch planning spending goes into that R&D line, so yes you will see that trend that will continue to go up as we get into 2015 and invest in all these activities.

Great, thanks so much.

Bob Al, Waha Capital

Thank you for taking my question. I also have a couple questions on this T790M negative patients. First, so there's seeing some high activity for patients immediate of the prior TKI, is there rational for that or just by chance?

The other question is given the amount of medical need for these patients, and you mentioned earlier the options are really terrible, I'm not sure the requirement for another application, have you thought about applying that for the T790M negative patients?

Well, if you are looking for an announcement for that today you're not going to get one. I'm just teasing. It's really intriguing data. For those of you familiar with the general sort of whispered requirements for a breakthrough designation submission, most believe you need to have something like 50 patients or more with a compelling story to tell, as you've seen we have 19 or so, there are a few more now so it hasn't been on our mind.

We also great interaction and advice from FDA and so we clearly could at the appropriate time interact with them about it, but it is not front and center for us as something we're thinking much about now. I do think that in the event our data hold, frankly even don't hold but are still really good, there's a real possibility of getting approval here. And that's why we're pursuing it, because there's a real unmet medical need and it clearly changes practice if the clinician knows that they can prescribe this drug and see activity independent of T790M status. So we're pursuing it, whether breakthrough becomes part of that pursuit it's too early to tell.

I think I can answer your second question and Andrew may add to it, it's not so much that we don't see activity in patients who are not immediately come off the TKI, it's what's surprising here and compelling here, is really good evidence that we're not seeing a retreatment effect. Because the vast majority, 16 of 19 I think of the patients in that trial, had just come off a TKI and the vast majority of the patients who had responses had also just came off TKI. It clearly is not just EGFR mutants coming back -- becoming sort of a driver mutation following around the chemotherapy.

Okay, thank you.

You bet.

Brian Klein Stifel

Hi this is Justin Collishaw in for Brian, thanks for taking my questions. I have just two. I was wondering, one was a PD-1 combination question. I believe both EGFRs and PD-1 clinical profile in regards to safety are pretty well-characterized at this point. I was wondering if you could share your thoughts about potential synergy with toxicities of combining the two agents. Where are your concerns, where there might be, and do you believe that zero compound or AstraZeneca might have a better safety profile to combine with PD-1?

And then my other question was in regards to the diagnostic, from a commercial standpoint would you ever consider giving away the diagnostic for free to minimize hurdles to your treatment? Do you think you would need to do that or do you think it's a nonissue, payers will pay for it? Thank you.

This is Andrew here I'll take the toxicity question. They're largely non-overlapping toxicities. Because obviously the mechanisms are very, very distinct between small molecule TKIs and anti-checkpoint inhibitor antibodies. So we don't anticipate or fear combinatorial tox. I think if you look at the list, maybe the one that you would just be paying a little bit more attention to would be pneumonitis, which obviously has been described with TKIs and has also been described with PD-1 antibodies.

Doesn't make you do anything differently, we always exclude patients with pre-existing from trials anyway, but you obviously just would keep a particularly vigilant eye for a new symptom, early predictor of pneumonitis, but that's about it. In terms of diagnostic --

In terms of diagnostic, we do not anticipate giving it away, in fact to the contrary. I think that payers see that relatively inexpensive diagnostic as an important gate keeper to ensure that is only T790M positive patients in the current plan. We'll gain access and be reimbursed for, in our case rociletinib. We've not heard of anybody doing this we certainly aren't planning to do it ourselves.

Thanks for taking my questions.

You bet, thank you.

Now I would like to turn the call over to Breanna Burkart for closing remarks.

Thank you 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. This call can be accessed via replay of our webcast, beginning in about one hour and will be available for 30 days. Again, we appreciate your interest and time, thank you and have a good evening.

Thank you for your participation in today's conference. This concludes the presentation. You may now disconnect. Thank you very much and have a very good day.