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Edited Transcript of EXEL earnings conference call or presentation 12-Feb-19 10:00pm GMT

Q4 2018 Exelixis Inc Earnings Call

SOUTH SAN FRANCISCO Feb 13, 2019 (Thomson StreetEvents) -- Edited Transcript of Exelixis Inc earnings conference call or presentation Tuesday, February 12, 2019 at 10:00:00pm GMT

TEXT version of Transcript

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Corporate Participants

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* Christopher J. Senner

Exelixis, Inc. - Executive VP & CFO

* Gisela M. Schwab

Exelixis, Inc. - President of Product Development & Medical Affairs and Chief Medical Officer

* Michael M. Morrissey

Exelixis, Inc. - CEO, President & Director

* Patrick J. Haley

Exelixis, Inc. - SVP of Commercial

* Peter Lamb

Exelixis, Inc. - Executive VP of Scientific Strategy & Chief Scientific Officer

* Susan Hubbard

Exelixis, Inc. - EVP of Public Affairs & IR

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Conference Call Participants

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* Andrew Ross Peters

Deutsche Bank AG, Research Division - Former Director

* Asthika Goonewardene

Bloomberg Intelligence - Senior Biotech Analyst

* Boris Peaker

Cowen and Company, LLC, Research Division - MD and Senior Research Analyst

* Edward Andrew Tenthoff

Piper Jaffray Companies, Research Division - MD & Senior Research Analyst

* Jeff Hung

Morgan Stanley, Research Division - Equity Analyst

* Justin Hayward Burns

RBC Capital Markets, LLC, Research Division - Senior Associate

* Kennen B. MacKay

RBC Capital Markets, LLC, Research Division - Co-Head of Biotechnology Research

* Kyuwon Choi

Goldman Sachs Group Inc., Research Division - Equity Analyst

* Michael Werner Schmidt

Guggenheim Securities, LLC, Research Division - Senior Analyst & Senior MD

* Peter Richard Lawson

SunTrust Robinson Humphrey, Inc., Research Division - Director

* Silvan Can Tuerkcan

Oppenheimer & Co. Inc., Research Division - Associate

* Stephen Douglas Willey

Stifel, Nicolaus & Company, Incorporated, Research Division - Director

* Timothy Colin Call

The Capital Management Corporation - President, CIO & Chairman of the Investment Policy Group

* Tsan-Yu Hsieh

William Blair & Company L.L.C., Research Division - Senior Research Analyst

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Presentation

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Operator [1]

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Good day, ladies and gentlemen, and welcome to the Exelixis' Fourth Quarter and Full Year 2018 Financial Results Conference Call. My name is Andrew, and I'll be your operator for today. As a reminder, this call is being recorded for replay purposes.

I would now like to turn the call over to your host for today, Ms. Susan Hubbard, Executive Vice President of Public Affairs and Investor Relations. Please proceed.

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Susan Hubbard, Exelixis, Inc. - EVP of Public Affairs & IR [2]

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Thank you, Andrew, and thank you all for joining us for the Exelixis' Fourth Quarter and Full Year 2018 Financial Results Conference Call.

Joining me on today's call are Mike Morrissey, our President and CEO; Chris Senner, our Chief Financial Officer; P.J. Haley, our Senior Vice President of Commercial; Peter Lamb, our Chief Scientific Officer; and Gisela Schwab, our Chief Medical Officer, who together will review our corporate, financial, commercial, research and development progress for the fourth quarter ended December 31, 2018.

During the call today, we will refer to financial measures not calculated according to generally accepted accounting principles. Please refer to today's press release, which is posted on our website for an explanation of the reasons for using such non-GAAP measures as well as tables reconciling these measures to our GAAP results.

During the course of this presentation, we will be making forward-looking statements regarding future events and the future performance of the company. This includes statements about possible developments regarding discovery, clinical, regulatory, commercial, financial and strategic matters, all of which involve certain assumptions, risks and uncertainties. Actual events and results could, of course, differ materially. We refer you to the documents we file from time to time, with the SEC, which, under the heading Risk Factors, identify important factors that could cause actual results to differ materially from those expressed by the company verbally and in writing today.

And with that, I will turn the call over to Mike.

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Michael M. Morrissey, Exelixis, Inc. - CEO, President & Director [3]

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All right. Thank you, Susan, and thanks to everyone for joining us on the call today. Exelixis had a strong fourth quarter from a clinical, commercial and financial perspective, which is a reflection of our momentum and overall success throughout the full year of 2018.

As you'll hear from the team today, revenues, earnings and cash continued to grow in Q4 as we executed on our strategy to make CABOMETYX the #1 TKI in renal cell carcinoma, or RCC. We're using the momentum from the last year to move aggressively in 2019 as we work to launch CABOMETYX in a new indication, initiate the next wave of potential label-enabling studies with cabozantinib and rebuild our pipeline.

As was the case in the third quarter, we again saw a meaningful growth for the CABOMETYX RCC business in Q4, while demand notably decreased for the other TKIs in this indication. Our cumulative data from 2018 supports the projection that cabozantinib's best-in-class TKI profile can continue to drive strong growth in the face of emerging competition from immune checkpoint inhibitor or ICI-based therapies.

The fourth quarter and full year 2018 results highlight that the foundation of our business has never been stronger and that the prospect for future growth remains high in the face of widely anticipated competition.

I'll begin today by providing a brief summary of our key Q4 milestones and then turn the call over to Chris, P.J., Peter and Gisela for details on our Q4 financials, the commercial performance for CABOMETYX and update on our emerging discovery efforts and finally, cabozantinib's development activities.

Key highlights for Q4 2018 includes first, the significant growth in revenue, earnings and cash based on the strong commercial performance for CABOMETYX in advanced RCC. Net cabozantinib franchise revenue for the quarter and full year 2018 was $176 million and $619 million, respectively.

Non-GAAP Q4 net income was $116 million with non-GAAP diluted earnings of $0.37 per share. Importantly, we ended 2018 with $852 million in cash and investments. Chris will cover the fourth quarter and full year 2018 financials shortly.

Second, the continued strong performance of the RCC business where CABOMETYX maintained its leadership position as the best-in-class TKI for advanced RCC. CABOMETYX continued to gain additional market share throughout fourth quarter, supported by its broad label for advanced RCC and the recent NCCN update as the preferred TKI for the majority of both previously untreated and refractory RCC patients. The depth and breadth of the METEOR and CABOSUN data continues to differentiate CABOMETYX from all other TKIs approved in this indication.

Third, we continue to advance our cabozantinib and regulatory -- our cabozantinib regulatory and development program with the recent approval and immediate launch of CABOMETYX in second-line HCC. We are aggressively pursuing the next wave of cabozantinib late-stage clinical trials. Three pivotal trials, including CheckMate 9ER with the CaboNivo combination in first-line RCC, COSMIC-311 with single-agent cabozantinib in second-line DTC and COSMIC-312 with the cabo atezo combination in first-line HCC, highlight recent progress in this area and set the stage for additional late-stage trials to start throughout 2019.

Fourth and finally, our reinitiated internal discovery efforts have begun to bear fruit with the advancement of XL092, a next generation VEGFR MET inhibitor to IND status. Through a combination of internal efforts and external collaborations, we seek to rebuild our portfolio of development candidates and efficiently move them into the clinical setting.

Our progress throughout the fourth quarter and full year 2018 reflects the team's outstanding performance across all components of our business. We seek to grow revenues, manage expenses carefully and reinvest free cash into our business to build long-term sustainable growth. As we enter our 25th year since Exelixis' founding, we are determined to stay focused and deliver on our goals every single day for both patients and shareholders.

So with that, I'll turn the call over to Chris, who will provide more details on our fourth quarter and full year 2018 financials.

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Christopher J. Senner, Exelixis, Inc. - Executive VP & CFO [4]

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Thanks, Mike. I'm very pleased to share with you our strong financial results for the fourth quarter and full year 2018. We're proud to say this is our eighth consecutive quarter and second consecutive year of operational profitability.

The company reported total revenues of $228.6 million in the fourth quarter of 2018 and $853.8 million for the full year of 2018. Total revenues, including cabozantinib net product revenues of $176.2 million for the fourth quarter and $619.3 million for the full year 2018.

Total revenues for the fourth quarter and full year 2018 also included the recognition of $27.9 million and $164.4 million, respectively, of milestones from the company's commercial collaboration partners, Ipsen and Takeda.

On a quarter-over-quarter sequential basis, our CABOMETYX net product revenues increased by approximately $13.4 million or 8%. This is a result of an approximate $9.9 million increase in CABOMETYX patient demands and increase in wholesaler inventory of approximately $3.3 million and approximately $3.3 million, which reflects the positive impact of the price increase we took at the end of the third quarter. Offsetting this price increase was an increase in our deductions from gross sales in the fourth quarter of 2018, which increased to 17.4%. This was a 1.5 percentage point increase when compared to the third quarter of 2018, which was 15.9%. The increase in our deductions from gross sales was primarily related to year ending wholesaler inventory that will be dispensed to Medicare patients, many of whom will be entering the donut hole in the first quarter 2019 as well as commercial patients that utilize our copay system program more frequently during the start of the calendar year.

Overall, for the year, our CABOMETYX gross-to-net came in at approximately 16.3%, which is in line with our guidance that gross-to-net for the full year would be approximately 16%.

Additionally, over the last 2 quarters, we've seen an approximate 700-unit increase in wholesaler inventory. Some of this inventory increase was to support the increased patient demand, but the majority of the increase was related to an increase in wholesaler inventory weeks on hand. As has been reported by several other biopharma companies when discussing their Q4 results, it appears that some wholesalers carried more inventory exiting 2018 than what was seen previously. As is always the case, there is the potential that wholesalers may reduce their inventory levels of CABOMETYX during the first quarter of 2019.

Total revenues also include collaboration revenues of $52.4 million for the quarter ended December 31, 2018. Collaboration revenues for the fourth quarter 2018 include the recognition of $27.9 million in milestones from our commercial collaboration partners, Ipsen and Takeda. Collaboration revenues also includes $12.3 million of royalty earned from Ipsen, $3.4 million of profit share and royalties from Genentech and $8.8 million of additional license, research and development and product supply revenues that were recognized from the company's collaboration.

Our total costs and expenses for the fourth quarter 2018 were $117 million compared to $100.2 million in the third quarter 2018. Within total cost and expenses, the largest increase was in R&D expenses and is primarily the result of increases in our clinical trial spend and, to a lesser degree, increases in personnel costs.

Selling, general and administrative costs increased by approximately $4 million. The increase in SG&A expenses was primarily related to increases in expenses for consulting and outside services, personnel and stock-based compensation. Income tax benefit for the quarter and year ended December 31, 2018 was $243.7 million and $238 million, respectively. The income tax benefit for the fourth quarter of 2018 was primarily related to the release of substantially all of the valuation allowance against the company's deferred tax assets.

The decision to release the valuation allowance was made after we determined that it was more likely than not that these deferred tax assets would be realized. Due to the release of the valuation allowance in 2018, starting in 2019, the company will record income taxes on GAAP income using an estimated effective tax rate, details of which I will provide when discussing our guidance for the year.

The company reported GAAP net income of $360.1 million or $1.15 per share on a fully diluted basis for the fourth quarter and $690.1 million or $2.21 per share on a fully diluted basis for the full year 2018. The company reported non-GAAP net income of $116 million or $0.37 per share on a fully diluted basis for the fourth quarter and $446 million or $1.43 per share on a fully diluted basis for the full year of 2018.

Non-GAAP net income includes the current period income tax provision of approximately $400,000 for the quarter -- fourth quarter 2018 and $6.1 million for the full year 2018, but excludes the $244.1 million noncash income tax benefit recorded during the fourth quarter of 2018.

Cash and cash equivalents short- and long-term investments and long-term restricted cash and investments totaled $851.6 million at December 31, 2018 compared to $457.2 million at December 31, 2017.

Now turning to our financial guidance. The company is providing the following financial guidance for 2019, which is more detailed in nature than previous years. We've opted to provide this additional color in order to provide more visibility in the drivers of our expense growth per line item, as we continue to invest in our business to drive long-term growth. Cost of goods sold is expected to be between 4% and 5% of net product revenues. Research and development expense is expected to be between $285 million and $315 million and includes noncash expenses related to stock-based compensation of approximately $20 million.

Selling, general and administrative expense is expected to be between $220 million and $240 million and includes noncash expenses related to stock-based compensation expense of approximately $35 million.

Guidance for the effective tax rate in 2019 is between 21% and 23%. And starting in the first quarter of 2019, the company plans to begin reporting non-GAAP financial measures that excludes stock-based compensation expense from the financial results.

With that, I'll turn the call over to P.J.

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Patrick J. Haley, Exelixis, Inc. - SVP of Commercial [5]

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Thank you, Chris. I'm very pleased to discuss in detail with you today the strong performance of CABOMETYX in the fourth quarter. We achieved our goal of establishing CABOMETYX as the TKI of choice in RCC as demonstrated by the strength of the Q4 business fundamentals, updated NCCN guidelines, positioning Cabo more favorably and continued gains in market share in the TKI market.

CABOMETYX demand grew at 6% in Q4 relative to Q3, an increase over the 5% demand growth rate in Q3 relative to Q2. The prescriber base of CABOMETYX continued to expand and grew by approximately 10% in the fourth quarter. Also, we saw broad utilization across academic and community settings, lines of therapy and clinical risk groups. We are pleased that CABOMETYX continued to grow in Q4 despite the increased competition. In order to get a better sense for the evolving competitive dynamics, we analyzed the IQVIA National Prescription Audit data for the RCC oral tyrosine kinase inhibitor, or TKI, market comprised of sunitinib, pazopanib, axitinib and CABOMETYX.

Based on this publicly available prescription data, CABOMETYX has continued to grow in market share, increasing to 34% in Q4. This represents significant progress and a share point increase of 2% relative to the last quarter and 11% from Q4 2017 a year ago.

In fact, these data also show that CABOMETYX became the #1 newly prescribed TKI for RCC. This trend continues, and we are using it promotionally to ensure physicians are aware of this fact, which is reinforced by the current NCCN guidelines in RCC. You may recall, in September, the NCCN published updated guidelines for kidney cancer. Cabo is now the only TKI that is a preferred regimen for poor and intermediate risk first-line patients, a population that makes up approximately 80% of the first-line market.

Importantly, cabo is also the only preferred TKI regimen for subsequent therapy, thus making cabo the primary recommendation for patients who have already received an immune checkpoint inhibitor, or ICI, combination. This strong positioning in the guidelines lends added credence to the broad label and robust totality of data from METEOR and CABOSUN, and ultimately, further strengthens the differentiation for CABOMETYX relative to other RCC TKIs.

The RCC market will continue to be driven largely by the sequencing of therapeutic options. Most patients will have the opportunity to receive either CABOMETYX followed by immune checkpoint inhibitor therapy or an ICI combination followed by cabo and sequence. The number of second-line patients who have progressed on the combination of NivoIpi increased in Q4, and we expect that trend to continue in the coming quarters.

CABOMETYX is well positioned to be the treatment of choice for these patients. Our market research indicates approximately 90% of key opinion leaders surveyed would choose CABOMETYX as their therapeutic option after a first-line ICI combination regardless of whether it is NivoIpi or PD-1 TKI. The RCC business has strong momentum heading into 2019. According to data, from IQVIA brand impact, CABOMETYX new patient market share increased in both the first line and the second line in Q4. Furthermore, since the approval of NivoIpi in April, majority of the patients who have progressed on this combination received CABOMETYX as their second-line agent. In fact, data from IQVIA brand impact suggest that CABOMETYX captured approximately 90% market share of patients in Q4 who have progressed on NivoIpi, consistent with our market research that I just mentioned above.

Given the patient flow dynamics and the strength of the CABOMETYX data, we expect RCC demand to continue to grow in 2019. In addition to the continued momentum of CABOMETYX in RCC, we are excited to also drive growth in the newly received indication in HCC, representing a third tumor type and fourth indication for the cabozantinib franchise.

Liver cancer is a significant unmet medical need accounting for over 600,000 deaths globally on an annual basis. In the U.S., over 40,000 patients are diagnosed with liver cancer and there are approximately 29,000 deaths each year. The HCC market will have the potential to grow significantly in coming years as new therapies are introduced, and Exelixis intends to play a key role in the development -- excuse me, in the advancement of therapeutic options for these patients, with potentially both single-agent cabo and cabo ICI combination approaches. HCC key opinion leaders indicate that as more systemic therapies become available, more of their patients will receive systemic therapy and increasing number of patients will receive multiple lines of treatment. The market research firm, Decision Resources Group, predicts an increase in the U.S. of first-line drug-treated patients of 37% by 2025 and the increase in second-line drug-treated patients is even greater at 69%. The difference is attributed not only to the increasing incidence of the disease, but even more so, due to the increase in drug treatment rates expected to occur as more therapeutic options become available. We are pleased with the initial strong launch execution of our team.

Upon approval on January 14, we mobilized the sales force within minutes after our press release, we quickly executed many personal and nonpersonal promotional tactics. As it is very early in the HCC launch, I will limit my comments at this time to the qualitative feedback we've received.

ASCO-GI was held in San Francisco from January 17 to 19 and provided a great opportunity to have discussions with top HCC specialists and GI oncologists immediately on the heels of approval that week. We had a large commercial and medical affairs presence at this meeting and used it as an opportunity to discuss the new label in the CELESTIAL data with the majority of the top KOLs on HCC. The early feedback from prescribers on the totality of the CELESTIAL data in the label has been positive. Importantly, the HCC approval has increased account access for our sales force and facilitated not only productive HCC discussions, but has increased the number of meaningful RCC discussions and interactions with prescribers as well.

In fact, our preapproval RCC sales footprint covered approximately 95% of the combined RCC and HCC market potential, and we began calling on the remaining HCC specific prescribers immediately following approval.

Our market research had indicated that there would be an increased interest in prescribing CABOMETYX for HCC if the physician had previous experience using cabo in RCC. This segment represents a large proportion of oncologists in the community setting, and early feedback is confirmatory of the research. We are pleased with the results of Q4, but believe that many more RCC patients and now, HCC patients, could benefit from CABOMETYX. CABOMETYX has added another trifecta of strong data in terms of improvement in OS, PFS and response rate to the label with the addition of the HCC data. This approval continues to augment the overall positive perception of the brand and gives our customers more options as they strive to help patients with difficult-to-treat cancers. CABOMETYX is now the #1 prescribed TKI in RCC, and we look forward to building on this momentum in RCC, HCC and other potential future indications as the cabozantinib development program expands. Our team is focused and motivated to compete every day to bring the benefit of CABOMETYX to every eligible patient as we continue to build the franchise.

With that, I will turn the call over to Peter.

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Peter Lamb, Exelixis, Inc. - Executive VP of Scientific Strategy & Chief Scientific Officer [6]

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Thanks, P.J. I'll provide an update on our partnered programs and also on our ongoing efforts directed toward expanding our development pipeline.

I will start with an update on our partnership with Daiichi Sankyo. We were delighted to announce in January that MINNEBRO, the commercial name for esaxerenone, received regulatory approval in Japan for the treatment of patients with hypertension. MINNEBRO is a potent and selective mineralocorticoid receptor blocker identified during the research collaboration with Daiichi Sankyo from 2006 and is the third compound emerging from our discovery efforts to receive regulatory approval.

Exelixis will receive a $20 million milestone payment from Daiichi Sankyo upon its first commercial sale of MINNEBRO, and we are eligible for additional commercial milestones and low double-digit royalties. The approval was based on positive data from a registrational Phase III trial in Japanese patients with essential hypertension. There is a significant need for effective new agents in the treatment of essential hypertension in Japan, given that there are approximately 43 million adults who have high blood pressure.

In addition, in the fourth quarter of 2017, Daiichi Sankyo initiated a second Phase III trial in Japanese patients with diabetic nephropathy, which builds off the Phase IIb trial previously conducted in this patient population.

Switching now to our collaboration with Roche/Genentech, the ongoing cobimetinib development program includes 2 Phase III clinical trials in melanoma patients. These are the IMspire150, or TRILOGY, trial combining cobimetinib with vemurafenib and atezolizumab in previously untreated BRAF mutant-positive locally advanced metastatic melanoma and IMspire170, which was initiated in the fourth quarter of 2017 in studying the combination of cobimetinib and atezolizumab in previously untreated BRAF wild-type metastatic melanoma. Both trials are now fully enrolled and Roche is guiding for potential regulatory filings later this year, if the data are supportive. Roche is also sponsoring multiple additional earlier stage cobimetinib trials, which are currently in progress and include studies in 13 different tumor types.

I'll finish with a quick update on our internal pipeline rebuilding efforts, which encompass both the reestablishment of our internal small molecule discovery capabilities and an active business development process aimed at identifying oncology assets that could feed into our development pipeline. We now have active chemistry and biology groups advancing discovery programs in our new labs in Alameda that are approaching full capacity. As announced today, I'm pleased to report that the first compound to emerge from our restarted discovery efforts, the next-generation MET VEGFR inhibitor designated XL092 is now the subject of an active IND. Gisela will provide some details regarding the initial clinical development plan for XL092 in a moment.

On the BD front, we're making good progress with our first 2 collaborations, one with StemSynergy to advance a novel class CK1-alpha activator compound that inhibit Wnt pathway signaling and the other with Invenra to advance novel bispecific antibodies.

Finally, we had a busy week at the JPMorgan conference in January, reviewing multiple opportunities and are currently in the process of further evaluating the ones that best fit our strategy going forward.

We look forward to updating you with our progress on this front as things materialize. I'll now pass the call on to Gisela.

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Gisela M. Schwab, Exelixis, Inc. - President of Product Development & Medical Affairs and Chief Medical Officer [7]

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Thank you, Peter. I'm pleased to provide an update on the progress of the cabozantinib development program in the quarter. I will start with a brief regulatory update with second-line HCC as the fourth quarter was marked by important milestones.

First, in November 2018, the European Commission approved cabozantinib as one-off therapy for the treatment of HCC in adults who have previously been treated with sorafenib, the approval formed a positive recommendation by CHMP for this indication in September 2018. And in late breaking news, FDA approved our submission for second-line HCC on the PDUFA date of January 14, 2019, in the United States. These important regulatory approvals expand the indication for CABOMETYX beyond advanced RCC into a new indication HCC, and we are very pleased with this progress that allows us to bring CABOMETYX to more cancer patients in need of new therapy.

With these important milestones achieved, we are fully focused on the broader development and life cycle management plan for cabozantinib, including single-agent evaluation and combination with immune checkpoint inhibitors through our collaborations with BMS and Genentech-Roche. As we have mentioned on prior calls, we have been planning to start multiple pivotal trials with cabozantinib in various tumor types in 2018 and in 2019 and have made progress in our work for such trials as planned. Two Phase III studies have already advanced to initiation in quarter 4 of 2018, and I'm pleased to provide a little more color on these Phase III trials today.

In October, we announced the initiation of a placebo-controlled Phase III trial of cabozantinib for the treatment of advanced radioiodine-refractory differentiated thyroid cancer patients who have received prior VEGFR-targeting therapy. In this trial, COSMIC-311 will enroll a total of 300 patients globally. And co-primary endpoints of the trial are objective response rate and progression-free survival. The objective response rate will be analyzed among the first 100 patients enrolled and with appropriate follow-up, while PFS will be an event-driven analysis among all 300 patients involved.

There is a planned interim analysis for PFS that will be conducted at the time of the objective response rate analysis. This study has been designed based on cabozantinib encouraging activity in previously treated differentiated thyroid cancer with durable response rate of 40% to 54% reported into separate Phase I and II evaluations.

Regarding combination with checkpoint inhibitors, we are very pleased with the progress of our clinical collaboration with Genentech-Roche. In December, we initiated a Phase III study combining cabozantinib with atezolizumab in the first-line treatment of HCC. This study compares the combination with a standard of care sorafenib. Co-primary endpoints for the study are PFS and overall survival. It also includes an exploratory single-agent cabozantinib arm to address the contribution of cabozantinib to activity of the combination of cabozantinib and atezolizumab.

The study will involve 640 patients and will be executed globally involving more than 200 sites. We're pleased that this study is now underway. The combination dose for cabozantinib and atezolizumab was evaluated in our ongoing Phase Ib trial, COSMIC-021. Evaluating the combination in an initial dose-ranging studies with planned cohort expansion in various different tumor settings.

We have identified an active dose of cabozantinib, the 40-milligram dose, in combination with atezolizumab with good tolerability for the combination in the dose ranging part of the trial. Initial data for this combination represented at the recent ESMO conference in Munich by Dr. Neeraj Agarwal. The combination of cabozantinib and atezolizumab was generally well tolerated with few grade III adverse events and no grade IV or V events observed. There were no dose-limiting toxicity seen, and the combination showed encouraging clinical activity with 8 of 10, or 80%, previously untreated clear cell RCC patients achieving a durable confirmed response, including 7 partial and 1 complete response.

Antitumor activity was observed regardless of PD-L1 expression. This Phase Ib trial is now actively enrolling patients into 20 different expansion cohorts, including histologies across a variety of tumor types, such as GU cancers, non-small cell lung cancer, GI malignancies and gynecologic malignancies.

Our clinical collaboration with BMS combining cabozantinib with nivolumab alone or both nivolumab and ipilimumab is also making great progress. The Phase III CheckMate 9ER study in treatment-naïve RCC patients evaluating cabozantinib in combination with nivolumab versus sunitinib is enrolling patients globally.

We are expecting results from this study in the second half of 2019 as was shared on BMS' recent quarter 4 call. This trial is co-funded by ourselves and our collaboration partners, Ipsen and Takeda, together with BMS who is conducting the study.

Additionally, the triplet combination of cabozantinib, nivolumab and ipilimumab continues to be evaluated in an ongoing Phase Ib trial in patients with advanced genitourinary malignancies that has established the preliminary safety and tolerability and recommended dose for this combination. And start-up activities for a separate Phase III trial investigating the triplet combination versus nivolumab and ipilimumab in first-line RCC are advancing as planned.

For the late-stage, the checkpoint inhibitor combination studies in indications, including bladder cancer and non-small cell lung cancer are also anticipated, and we will provide more detail as we get ready to initiate this trial. And lastly, as Peter mentioned, we are actively working on expanding our development pipeline. Late in quarter 4 of 2018, we filed a new IND for a next-generation tyrosine kinase inhibitor targeting VEGFR and MET, which emerged from our internal discovery efforts, and the IND is now active. Data dependently, we plan on advancing this compound quickly through dose finding and disease-specific single-agent cohort expansion as well as combination approaches, setting the stage for late-stage development.

So in summary, I'm very pleased with the progress made in our development program and with the important regulatory milestones reached during this quarter and look forward to updating you in the future. Also, later this week, the ASCO GU Annual Conference is taking place in San Francisco. We are looking forward to the conference where 15 cabozantinib-related abstracts will be presented and to the opportunity for us to conduct in person with key opinion leaders and partners.

And with that, I'll turn the call back to Mike.

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Michael M. Morrissey, Exelixis, Inc. - CEO, President & Director [8]

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All right. Thanks, Gisela. Exelixis had a strong fourth quarter and continues to see solid growth in all aspects of our business as we move into 2019.

Our notable regulatory commercial and financial performance in 2018 provides a strong platform for rebuilding our product portfolio with future cabozantinib label-enabling trials and adding new product opportunities through internal and external R&D efforts. I would like to emphasize 2 key issues that are important to keep in focus.

First, Exelixis will continue to build on the strength of CABOMETYX and its status as the TKI of choice for RCC. Our commercial efforts target the broad RCC opportunity, and we continue to target every eligible RCC patient every single day, so that RCC patients can potentially benefit from CABOMETYX at some point in their journey from first- to third-line therapy. We are not surprised by the success of ICI combination strategies in RCC and expect that the vast majority of these patients will need subsequent therapies as they become refractory to frontline ICI-based combinations. Based on market research, KOL feedback and most importantly, the real-world trends that we've seen recently, CABOMETYX appears to be the TKI of choice for current and future ICI refractory patients.

As we said previously, we see the eventuality of an evolving first-line RCC dynamic with multiple ICI combinations as standard of care, as an opportunity for CABOMETYX to fortify its position as the go-to standard of care for second-line ICI refractory patients, which could provide a compelling growth opportunity for years to come.

Second, we seek to expand cabozantinib's indications and advance next-generation molecules to build on the potential of this approach. Cabozantinib has demonstrated broad clinical activity in multiple tumor types as a single agent and shows encouraging activity, tolerability and safety when combined with ICIs. Our deep, fundamental knowledge of cabo's pharmacology and its impact on tumor cells, the tumor vasculature and the immune microenvironment provides us with a compelling rationale to pursue next-generation compounds, such as XL092. We plan to pursue this approach in a data-driven, iterative and highly rational manner to aggressively expand the range of potential indications and combinations. At the same time, we will use our growing cash position and financial depth to partner or acquire compelling assets that are valued appropriately.

In closing, I want to thank the entire Exelixis' team for their dedication and commitment as we work to write our next chapter of the EXEL story. As we enter our 25th year, Exelixis has never been stronger from a clinical, commercial and financial perspective. The EXEL team continues to be energized and inspired by the opportunities ahead of us, and we are committed to making every day count as we discover, develop and commercialize the next generation of our medicines for cancer patients in need of better and more effective therapies.

So with that, we look forward to updating you on our progress, and we thank you for your continued support and interest in Exelixis and we're happy to now open the call for questions.

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Questions and Answers

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Operator [1]

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(Operator Instructions) And your first question comes from the line of Andy Hsieh with William Blair.

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Tsan-Yu Hsieh, William Blair & Company L.L.C., Research Division - Senior Research Analyst [2]

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First question for P.J. In the field of HCC, as we see more options for patients, just wondering, if you have experienced an evolution in patient management dynamics recently. What I mean is, do interventional radiologists feel more comfortable sending their patients to their oncology -- oncologists or hepatologists colleagues?

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Patrick J. Haley, Exelixis, Inc. - SVP of Commercial [3]

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Andy, thanks for the question. Certainly, as I mentioned, excited to be approved in HCC. It's early days for us in the launch. And I think as we've kind of indicated previously, this is a market that will have to be built by us and by others as you kind of indicated with many recently approved therapies. What we are seeing and hearing from the KOLs is that the sort of patient flow dynamic, if you will, with regards to the interventional radiologists is sort of starting to flow more quickly into the oncology setting, which isn't really surprising given that there are many more options now sort of beyond sorafenib, which was the only option for a long time. I think the Decision Resources Group data that I referred to in our script quantifies this patient sort of dynamic over time. And in the first line, it's expected to increase by 37% drug-treated patients by 2025 and in the second line, to an even higher number, 69% increase and that's been driven by the patient flow dynamics and just the fact that the drug treatment rates are expected to rise. So very pleased with the indication and happy that it gives us the opportunity to have sort of these multi-tumor discussions with the community oncologists where we can talk about the great gain in HCC as well as RCC, which is going really well for us.

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Tsan-Yu Hsieh, William Blair & Company L.L.C., Research Division - Senior Research Analyst [4]

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Yes, that's helpful. So second question has to do in the RCC setting. So obviously, strong data from KEYNOTE-426, which, in my view, at least, reinforcing the potential for the I/O TKI combination, and one of the unique, I guess, chemical aspects of cabo is that it targets AXL, which is unique among all the approved TKIs. I'm just wondering, if, Peter, you could remind us, what are some immunological or, I guess, tumor escape mechanism implications have been published out there?

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Peter Lamb, Exelixis, Inc. - Executive VP of Scientific Strategy & Chief Scientific Officer [5]

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Yes, Andy, thanks for the question. I'd be happy to answer that one and in sense -- in a broad sense, it's kind of modern version of a kind of broader question we've been asked for a while. If we go back to the original development of cabozantinib as a single agent in renal cell carcinoma, I think people were reasonably comfortable with the idea that VEGFR innovation would result in clinical benefit. And the question always was, what the -- for the additional targets that cabozantinib inhibit, that you mentioned, AXL is one, MET obviously is another one. What are they going to add? So we would usually answer that question around the role of MET and AXL in the tumor biology of RCC, throw in the vasculature and then more recently, as I'll get to in a minute, the role of tumor immune microenvironment. I think the kind of culmination of that was really came with the CABOSUN data comparing cabozantinib head-to-head with sunitinib, which is a very good VEGFR inhibitor, but does not inhibit some of those other targets that showed cabozantinib was superior and led to our approval in frontline RCC and now it's positioned as the leading TKI in renal cell. So now, as you indicated, the question is, in the context of combination with immune checkpoint inhibitor, what might we expect beyond the VEGFR inhibition and what would be the 426 data with axitinib and pembro kind of lays a kind of baseline or benchmark, if you like. Axitinib is a very selective VEGFR inhibitor. So what might the role of MET and AXL be in this particular setting? And I think there is some pretty compelling scientific rationale and also data with cabozantinib that suggest that those targets may be impactful, so with AXL, since you mentioned it, it's known to be expressed -- given it's closely related, kind of sibling known to be expressed in tumor-associated macrophages. And their role there is really to put those macrophages in an immunosuppressive state. So by inhibiting those kinases, we might expect to flip those macrophages over into a more immune-permissive state. With respect to MET, there is also going to be a role for MET on the innate immune systems, specifically dendritic cells, which is kind of the premier human antigen-presenting cells in the microenvironment. Activation of MET is known to suppress their activity. And actually, also specifically, with respect to resistance to immune checkpoint blockade, I found a very interesting paper that was published last year, looking at escape from immune checkpoint blockade in preclinical models, you see mobilization of a suppressive subset of natural killer cells and that is completely dependent upon MET activity. So we certainly believe that adding in both MET and AXL inhibition as in the cabozantinib profile is going to be impactful. And as you look at the data that's emerged over the last couple of years with respect to cabo's impact on the human-associated immune system, we basically see kind of 3 things going on. So preclinically, we see a direct effect on tumor cells when you upregulate Class I MHC expression to make the tumor cells more visible to the immune system. Both preclinically and the clinic, we see increased numbers of activated and cytotoxic T cells, both either in the periphery and/or in the tumor itself in preclinical models. And finally, we see kind of inhibition of both the numbers and activity of immunosuppressive immune cells, such as Treg and MDSCs. So we kind of like that profile impacting both the adaptive and the innate immune system and generally, pointing towards creating a more immune-permissive environment.

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Tsan-Yu Hsieh, William Blair & Company L.L.C., Research Division - Senior Research Analyst [6]

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Wow, great. Thanks for that really detailed answer. So last one from me for Chris. I think last quarter, you talked about the inventory on hand 2.5 weeks. Is there any sort of update in terms of the quantity for this quarter?

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Christopher J. Senner, Exelixis, Inc. - Executive VP & CFO [7]

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Yes. I mean, I guess so -- I'd answer that in a couple of ways here. So I guess, the focus for us is really on the demand growth, right? We've seen, as P.J mentioned, we saw a 6% demand growth in Q4 that was preceded by a 5% demand growth in Q3. And as P.J pointed out, it's also starting -- we are starting to see patients roll off ICI and into CABOMETYX. And so we continue to think this as a demand story. Now that being said, we saw some fluctuation in the wholesale inventory levels. And so we did see weeks on hand rise from around 2.5 weeks to around 2.9 weeks. But again, we do still think this is very much a demand story and not an inventory story. You can refer to Slide 10 in the slide deck, because that lays it out for you pretty well there.

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Operator [8]

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And your next question comes from the line of Michael Schmidt with Guggenheim Securities.

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Michael Werner Schmidt, Guggenheim Securities, LLC, Research Division - Senior Analyst & Senior MD [9]

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Great to see some of the next IND being active here, XL092. Could you maybe comment a little bit more how that molecule might be similar or different compared to CABOMETYX? And how you think about potential development paths, especially if it's similar? Do you see that sort of as a life cycle management type opportunity? Or are there maybe other indications that might be interesting based on the mechanism?

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Peter Lamb, Exelixis, Inc. - Executive VP of Scientific Strategy & Chief Scientific Officer [10]

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Yes, this is Peter. I'll take that one. So obviously, over the last several years, at this point, we've developed an enormous amount of information and understanding of cabozantinib clinically, but as well as preclinically. And I think there's been advances in our understanding of the kind of relevance of the various targets of cabozantinib to the treatment of cancer, as I just outlined. So we think there is something special about the kind of MET and VEGFR combination of this kind of core of the cabozantinib profile, if you like. So XL092 retains that core with MET, VEGFR inhibitor. It's a normal TKI, has the potential for a differentiated clinical profile. The Phase I trial that Gisela described earlier is obviously aimed at getting us the data to see whether the preclinical profile that we see, and that obviously we like, as we translate into people. And based on that data, we guided about how and where to further develop the compound.

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Michael Werner Schmidt, Guggenheim Securities, LLC, Research Division - Senior Analyst & Senior MD [11]

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Okay, great. And then a question on guidance, just on your R&D guidance for 2019. Just curious if you could share what do you have included there in terms of additional potential cabo Phase III trials starts throughout the year?

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Christopher J. Senner, Exelixis, Inc. - Executive VP & CFO [12]

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Yes, Michael, it's Chris. So thanks for the question. I'd say the biggest driver of our expense increase 2019 versus 2018 is really just the ongoing enrollment in 021 and 311 and 312. And there is a very small amount related to new studies that we budgeted for, but we haven't talked about yet, but it's -- the majority is around the new -- the studies that have already started in either 2017 or 2018.

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Michael Werner Schmidt, Guggenheim Securities, LLC, Research Division - Senior Analyst & Senior MD [13]

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Okay, great. And then how should we think about additional data disclosure from COSMIC-021 in terms of some of the extension cohorts here that some of those are fully enrolled for some time now, I believe.

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Gisela M. Schwab, Exelixis, Inc. - President of Product Development & Medical Affairs and Chief Medical Officer [14]

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Yes, this is Gisela. Thank you for the question. COSMIC-021 is actively enrolling across the 20 expansion cohorts. And certainly, we are very excited about the different indications that we are generating data on. Just to say that we are not going to present or publish premature data. We are looking to accumulate sufficient data that is mature, and that will be presented at the appropriate time at conferences and publications. So we'll certainly update you on that. Just referring back to one such presentation, and that was the dose escalation experience presented at the ESMO conference. I referred to the data earlier on in the call. I'm very pleased with the tolerability profile of the combination. There were no dose-limiting toxicities, and we saw good signs of clinical activity in RCC.

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Operator [15]

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And your next question comes from the line of Kennen MacKay with RBC Capital Markets.

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Justin Hayward Burns, RBC Capital Markets, LLC, Research Division - Senior Associate [16]

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This is Justin on for Kennen. A couple of quick ones from us on the increased inventory build that you sort of saw to close out 2018 across the board. Wondering if you're getting any feedback on potentially what drove that. And then going forward into 2019, how you expect that to potentially impact growth in cabo sales moving forward?

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Christopher J. Senner, Exelixis, Inc. - Executive VP & CFO [17]

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Yes, this is Chris. So looking at it, we do think that a big portion of that is the future demand that wholesalers would see. But we also saw, generally over the biopharma industry, several companies talking about their increase in fourth quarter wholesaler inventory. Some of that could be related to the price transparency measures that have been put in place, including SB 17 in California, where you have to -- in certain circumstances, you have to report in advance your price increase to the government. So nothing specific that we can point to, but those are some of the things that we think may have driven it.

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Operator [18]

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And your next question comes from the line of Boris Peaker with Cowen.

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Boris Peaker, Cowen and Company, LLC, Research Division - MD and Senior Research Analyst [19]

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Great. I'd like to add my congratulations on the excellent quarter. And I just want to probe a little bit further on the kidney -- on the liver cancer opportunity. Can you just comment -- you mentioned there is an overall growth in HCC. What fraction of this growth is driven by TKI versus checkpoint inhibitors right now in the marketplace?

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Patrick J. Haley, Exelixis, Inc. - SVP of Commercial [20]

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Boris, this is P.J. I'll take that question. I kind of referred to it as sort of early days for us in the approval. So I wouldn't really want to speculate on certainly a dynamic market with new approvals both on the I/O front as well as TKI moving forward. What I would say is that I think we're certainly well positioned. We have a concentrated sort of customer universe in terms of the value of HCC that 95% of which we already covered with our RCC sales force, and we know that prescribers through market research and sort of early anecdotal feedback, if they've used RCC -- or excuse me, maybe used CABOMETYX in RCC, which at this point is a significant number they're more likely to use it in HCC. So I think those are all encouraging signs, but recognize that it's early in the launch and wouldn't really want to speculate beyond that.

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Boris Peaker, Cowen and Company, LLC, Research Division - MD and Senior Research Analyst [21]

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Got you. And just a follow-up question, maybe kind of similar in the RCC space. I mean, we obviously saw the KEYNOTE-426 data, which is I/O-TKI combo and we saw updated results for Opdivo plus Yervoy. How do you see that dynamic playing out for front-line setting? Do you see maybe Opdivo and Yervoy giving way to more TKI use in the front-line setting or just your general take on this data dynamic?

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Michael M. Morrissey, Exelixis, Inc. - CEO, President & Director [22]

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Boris, it's Mike. I'll be happy to provide some color there. As I mentioned a few minutes ago, I think we've always viewed the different, either I/O-I/O or I/O-TKI combinations as being potentially very enabling and successful and moving into the first-line setting kind of en masse. So I think at steady state -- and obviously, this is all data dependent, and we certainly need to see more of the 426 data this coming weekend at ASCO GU, but it wouldn't surprise if there is numerous different combinations that take up the bulk of the first-line setting. And that's -- as we talked about in our prepared remarks, that's fine by us and makes sense based upon the data, but it also provides, I think, pretty compelling opportunity for CABOMETYX as the potentially go-to standard of care for second line. And we're seeing some of that data emerge right now, as P.J. mentioned in his prepared remarks, and some of the data from BrandImpact Rx. So -- but it's a dynamic playing field, lots of moving pieces. We're certainly in that game with 9ER and excited about having what are arguably the 2 best known RCC agents in terms of nivo and cabo being combined, the only 2 that separately show overall survival by themselves. And certainly, then the opportunity to look at the triplet CaboNivoIpi as well. So exciting times for us in this indication, and we're certainly very committed to continuing to work with our partners and do additional work ourselves to continue to move the goalpost as high as we can going forward.

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Operator [23]

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Your next question comes from the line of Ted Tenthoff with Piper Jaffray.

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Edward Andrew Tenthoff, Piper Jaffray Companies, Research Division - MD & Senior Research Analyst [24]

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So 2 questions, if I may, firstly on the thyroid. I think you said that you're going to provide an overall response update on the first 100 patients. Would that be potentially registrational?

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Gisela M. Schwab, Exelixis, Inc. - President of Product Development & Medical Affairs and Chief Medical Officer [25]

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You heard me say that objective response rate and durability of response and PFS are co-primary endpoints and that the study is assessing the objective response rate in the first 100 enrolled patients with sufficient follow-up, and any regulatory steps would be obviously data dependent, but co-primary endpoint retailed positive, that could potentially support projection.

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Edward Andrew Tenthoff, Piper Jaffray Companies, Research Division - MD & Senior Research Analyst [26]

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And then with respect to some of the other updates from COSMIC-021, when could we expect data coming out from some of those other cohorts?

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Gisela M. Schwab, Exelixis, Inc. - President of Product Development & Medical Affairs and Chief Medical Officer [27]

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Thank you. Yes, as I said earlier, we definitely want to present mature and stable data from the expansion cohort, and we'll do so soon as we have those data and with sufficient follow-up. And so we will certainly keep everyone in the loop and communicate when such data are available and when they will be presented.

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Operator [28]

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Your next question comes from the line of Peter Lawson with SunTrust.

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Peter Richard Lawson, SunTrust Robinson Humphrey, Inc., Research Division - Director [29]

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Mike, just the only kind of puts and takes we should be thinking about 9ER and how it could stack up versus 426? Anything we should be thinking about and any color around the timing of 9ER?

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Michael M. Morrissey, Exelixis, Inc. - CEO, President & Director [30]

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Yes, thanks, Peter. So look, I don't want to speculate too much on an ongoing pivotal trial, just bad form, probably not something we should be doing. That being said, in my answer to Boris, I think the idea of combining 2 agents, which improve overall survival together in this indication, which is obviously sensitive to both, is very attractive. And we're doing that with 9ER with cabo and nivo. And we're looking forward to doing that with the triplet as well with CaboNivoIpi. So again, we have lots of interest in this space, a lot of momentum in this space. We feel like we understand not only the clinical pharmacology and the clinical activity of these agents, as you heard from Gisela today, but as Peter mentioned as well, we really have a fundamental understanding of how cabo is working and interacting with the -- in the tumor immune microenvironment. So we've got a lot of things going for us, and we have to just get it done now and get the data and then move forward with that data in hand. So...

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Peter Richard Lawson, SunTrust Robinson Humphrey, Inc., Research Division - Director [31]

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And what kind of feedback are you getting from physicians around the use of combinations versus sequencing the individual TKIs and I/Os? What's the preference?

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Michael M. Morrissey, Exelixis, Inc. - CEO, President & Director [32]

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Yes. P.J., you want to take that?

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Patrick J. Haley, Exelixis, Inc. - SVP of Commercial [33]

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Yes. I think -- I talked about it a little bit in our -- in my prepared remarks. What we've seen in terms of the landscape is that sequencing is still -- plays a large role. We do think that to an extent single-agent TKI will maintain some position in the first line, and as Mike kind of alluded to, certainly the combinations we've always thought would be big players in the first line. But importantly, looking at all the market research we've done regardless of whether it's a NivoIpi or PD-1 TKI, really the indication is that cabo will be the therapy of choice in the second line there. And that's really been borne out so far by the data we've seen in Q4, as I mentioned, approximately 90% of the patients progressing on NivoIpi went on to receive cabo. So we're pleased with that, and that's really a key part of our messaging. It aligns with our positioning in the NCCN guidelines and really the data in our label and the breadth and depth of both the METEOR and the CABOSUN studies. So we think the patient flow dynamics of those patients coming off the combination of NivoIpi, those patients will continue to increase in second line, and I think we're well positioned to capture those patients.

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Operator [34]

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Your next question comes from the line of Silvan Tuerkcan with Oppenheimer.

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Silvan Can Tuerkcan, Oppenheimer & Co. Inc., Research Division - Associate [35]

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Could you just tell me a little bit about maybe some details, if you can, about your BD strategy. I mean, you have $850 million in cash. And are you looking for an asset that kind of combines well with TKI? Are you looking for another TKI? I mean, you just put one into the clinic. Could you give us a little color there, please?

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Michael M. Morrissey, Exelixis, Inc. - CEO, President & Director [36]

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Yes, sure. It's Mike. I'm happy to say a few words there. So look, we have a very broad approach here looking for appropriately valued assets that span the range of opportunities from late preclinical to early clinical to late clinical to even commercial. So we've a pretty big appetite and I think a pretty good vision on where we could go with any of those kinds of assets. We did a number of early stage deals last year, while looking certainly much more broadly and much more deeply at a wide range of assets. So we're looking for the right compounds. We're agnostic to the modality. We're certainly -- we have interest in biologics as well, and our deal with Invenra, I think, underscores that. But looking for the right kinds of products, the right kinds of drugs that have good data, that would allow us to either develop them or pursue them in some strategy that would allow us to move them into the commercial setting as quickly and as efficiently as possible. So I would think broad, I would think deep. And as we again get traction on the next wave of deals, we'll be talking much more about that in great detail.

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Kennen B. MacKay, RBC Capital Markets, LLC, Research Division - Co-Head of Biotechnology Research [37]

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Great. And maybe could you also tell us a little about your internal estimates in terms of size and speed to peak of the HCC opportunity with respect to RCC? And since there is a lot of overlap in KOLs and prescribers, is there a way to maybe get some margin expansion by -- as the sales ramp up in HCC?

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Michael M. Morrissey, Exelixis, Inc. - CEO, President & Director [38]

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Well, as we talked about previously, we were able to -- and as P.J. has alluded to a few minutes ago, the fact that there is a good overlap between the HCC market and the RCC market has allowed us to use our existing commercial footprint with a few enhancements to be able to address both simultaneously. So the idea is that we don't need to invest a lot more to be able to really address this large underserved market opportunity with second-line HCC. That being said, I think we've been very consistent along the lines that this is a market that we have to help build or rebuild from the standpoint that with the -- with all the new therapies coming into the marketplace now on the TKI side, on the I/O side that we need to help kind of educate not only oncologists, but also hepatologists around the value that some of these drugs can bring and then help move them -- move their patients again towards the medical oncology sleeve that could be very productive for them and for us. So this is going to be a slower ramp. We've been very consistent in talking about that. We haven't given guidance on HCC, since there is many, many moving pieces that are certainly hard to model and hard to predict, both by us and by others. But that's fine. I think we're certainly very committed in terms of where we stand today commercially, and we're ready to go within literally minutes of getting the approval letter for second-line HCC a few weeks ago. But also, we are continuing to reinvest in this indication as well. The COSMIC-312 study, again, looking at cabo, atezo in the first-line HCC setting is just clearly a sign of that -- of our interest, the value of the market and the need, the large unmet medical need that these patients actually have. So a lot of -- again, a lot of work to do, but we're certainly excited to be in the mix here and looking forward to pushing it forward.

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Operator [39]

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Your next question comes from the line of Stephen Willey with Stifel.

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Stephen Douglas Willey, Stifel, Nicolaus & Company, Incorporated, Research Division - Director [40]

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Maybe just a question for P.J. to start. Do you happen to see any kind of noticeable difference just in terms of duration of therapy for those patients who are progressing off of an ipi/nivo regimen versus those patients who have progressed off of a prior TKI?

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Patrick J. Haley, Exelixis, Inc. - SVP of Commercial [41]

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Stephen, thanks for the question. With regards to duration, I think relatively early in the patient flow dynamic to really make any comment on that specific patient population. We've always said that the duration we're seeing is similar to what we've seen in the trials. So something we certainly track very carefully, and we're encouraged to see sort of many -- 90% of the second line NivoIpi progressors going onto CABOMETYX and certainly some data and metrics that we look forward to tracking in the future.

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Stephen Douglas Willey, Stifel, Nicolaus & Company, Incorporated, Research Division - Director [42]

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And then just with respect to that 90% of patients who are progressing, I guess, on ipi/nivo, so the updated CheckMate 214 abstract that was released yesterday, I thought, had an interesting data point in it in the sense that I think it suggested that only 55% of patients in that trial actually went on to receive systemic second-line therapy. And -- but there's still another 10% or 15% of patients that are still on study drug. But just curious if you think this dynamic is kind of specific to the trial environment that is CheckMate 214? Do you think that some of these novel front-line regimens might be somehow kind of changing the proportion of patients who subsequently see second-line therapy?

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Michael M. Morrissey, Exelixis, Inc. - CEO, President & Director [43]

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Yes, Steve, it's Mike. I'll take that one. It's probably a little early to comment there. Yes, we saw that data too and certainly looks interesting. A question that -- we asked the same question that you asked there, is that a consequence of having it be at clinical trial sites as opposed to the community, et cetera? So we're certainly pleased to see enteric trends improve relative to what's happening in Q1 and at the end of Q4 relative to what we think is patients coming on cabo from -- after progression with ipi/nivo. So that's all internally consistent with the timing of that launch and the PFS data that we saw with 214. So great question, early days. Certainly, we will be able to attract more as time goes on and we get more data, more patients, just more data and numbers, right? So stay tuned.

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Operator [44]

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Your next question comes from the line of Paul Choi with Goldman Sachs.

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Kyuwon Choi, Goldman Sachs Group Inc., Research Division - Equity Analyst [45]

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I was wondering if either Mike or P.J, if you could maybe comment on how you think about the volume price dynamic over, let's say, 2019 and 2020 in RCC, given the changing landscape? Correct me if I'm wrong, but I think by my math, volume contributed approximately 20% of your growth for cabo in 2018. So as you think about this sort of short to intermediate term, how do you think about maybe volume versus the price growth? And can the sort of price increases you've taken annually sort of -- is that sort of a reasonable proxy going forward here?

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Michael M. Morrissey, Exelixis, Inc. - CEO, President & Director [46]

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Yes, Paul. Great. Thanks for the question, fair question. You're venturing towards a question around guidance, or at least data that could drive that math. And I'm not sure we're comfortable sharing that with you. We've certainly grown and continue to grow in quarters like Q4 and Q3 of 2018 in the face of pretty significant competitive pressure. In fact, we're the only TKI that was growing in that timeframe, both 6% in Q4, 5% in Q3. We had a big quarter in Q1, obviously, when we launched based upon the first-line approval in 2018. So I guess, the question you're asking is certainly a key issue. Again, what we're looking at is the dynamic around what's happening in first line and the impact to what happens in first line and the consequence it has -- or the impact it has on second line. So time will tell. I think our theory, as we've outlined several times today and provided some supporting data, is that we will continue hopefully to grow in the second-line setting and that volume pickup will drive growth on top of everything else that we're doing in that regard. So many moving pieces. We acknowledge that. It's a complex dynamic, but it's one that we've got, again, great data, great team and a lot of momentum going into 2019 to be able to cover that.

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Kyuwon Choi, Goldman Sachs Group Inc., Research Division - Equity Analyst [47]

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Okay. And maybe one for Chris on the guidance and on the R&D component. I guess, with CheckMate 9ER coming towards the finish line here in the not-too-distant future, can you maybe understand or explain to us is it primarily the COSMIC-311 and 312 components of the R&D expense that are driving the year-over-year increase? And also, apart from that, is the -- will there be any completion of enrollment time frames that you're willing to share for either trial?

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Christopher J. Senner, Exelixis, Inc. - Executive VP & CFO [48]

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So I'll take the financial piece of that. So I would say that 9ER is a significant contributor to the expenses in 2019. And it just doesn't stop on data. The trial doesn't stop on data when data is read out or revealed. So that will continue beyond any point of readout. And then, 311 and 312 will be a big contributor from an incremental perspective, just because they were started later in -- or during 2018. And so there will be -- the incremental piece will be more significant, I guess, on 311 and 312 when you compare '18 versus '19. So...

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Gisela M. Schwab, Exelixis, Inc. - President of Product Development & Medical Affairs and Chief Medical Officer [49]

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Yes. In terms of the accrual, at this time, we're early in these trials and we don't provide guidance on the accrual dynamics at this point. I think I can refer you back to what we said earlier regarding the 9ER study, where Bristol-Myers in their quarter's call indicated that results could be expected in the second half of 2019.

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Operator [50]

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Your next question comes from the line of Jeff Hung with Morgan Stanley.

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Jeff Hung, Morgan Stanley, Research Division - Equity Analyst [51]

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Just wanted to clarify, the $3.3 million inventory build, that was on top of the leftover inventory build from 3Q, correct?

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Christopher J. Senner, Exelixis, Inc. - Executive VP & CFO [52]

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Yes. I mean, that's the way to look at it, yes. So as I said in my prepared remarks, we did see approximately a 700-unit increase in inventory during Q3 and Q4 in total. And as I said to Andy earlier, we did see in Q4 our weeks on hand go up from 2.5 to 2.9 weeks. But the real story here is the demand story. I mean, as P.J said, I said earlier, Mike said, this is a 6% demand growth in Q4, 5% demand growth in Q3. And overall, in 2018, when you compare it to 2017, I mean, demand grew almost 66%. So it is a demand story. We provide the inventory information, so there is clarity on where the growth comes from and transparency and really heavily focusing on the demand story.

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Jeff Hung, Morgan Stanley, Research Division - Equity Analyst [53]

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Great. And then you guys talked about PD and potential opportunities -- types of opportunities you guys are looking at. But I guess, in terms of capital allocation, how do you think about balancing profitability and acquiring additional assets?

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Michael M. Morrissey, Exelixis, Inc. - CEO, President & Director [54]

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Yes, Jeff, it's Mike. We've spoken to that extensively. There is both strategic and tactical reasons to be profitable and to stay profitable, and that's certainly an important part of our equation over the last few years and certainly going forward. But we certainly have a lot of room to maneuver in regard to the financial depth that we've built over the last few years to be able to add assets that we think have value and can generate value going forward. So it's certainly a balancing act, but it's one that I think we've got the experience, the depth, both clinically from an R&D point of view, commercially as well as financially to be able to manage pretty well.

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Operator [55]

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Your next question comes from the line of Asthika Goonewardene with Bloomberg.

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Asthika Goonewardene, Bloomberg Intelligence - Senior Biotech Analyst [56]

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First question on cabo. You have the first-line RCC approved for more than a year now. I was wondering with all the real-world data at hand, does the real-world data for PFS, is that consistent with what's on the label, the 8.6 on the label? And then I've got a couple more.

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Patrick J. Haley, Exelixis, Inc. - SVP of Commercial [57]

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Yes, this is P.J. As I mentioned a bit earlier, I think the duration is consistent with what we've seen in the trial. So it's certainly encouraging and gratifying that the patients are getting the benefit that we saw in the data.

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Asthika Goonewardene, Bloomberg Intelligence - Senior Biotech Analyst [58]

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Excellent. And then so far we've seen some interest -- some first-line RCC combo data with Keytruda, Bavencio, NivoIpi, et cetera, and with it, some SUTENT competitor arms. I was wondering if you could tell me that given what you know about the trial recruitment sites for these trials as well as 9ER, you could maybe tell us which one of them might be a better representation of 9ER's SUTENT arm.

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Michael M. Morrissey, Exelixis, Inc. - CEO, President & Director [59]

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Yes, Mike. Yes, fair question. I think it's one that is probably not wise for us to comment on. It's always challenging, and arguably, somewhat dangerous to make crosstalk comparisons either retrospectively or prospectively. So we don't really do that and would not want to give any insight or guidance there. Sorry.

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Asthika Goonewardene, Bloomberg Intelligence - Senior Biotech Analyst [60]

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All right. I'm 0 for 2. Let's try one more. On -- last one, on XL092, we've been trying to dig up the patent for this to see if we can get a little bit more color as to what exactly this is targeting beyond MET and VEGF. And we think we might have found it. It's the one ending in 342, which hits MET VEGF2, c-Kit, AXL, FLT3, et cetera, and also has some associated patents -- used patents in RCC and HCC. I have to ask you, is this the right one? And then could you maybe contrast 092 versus cabo in terms of potency on the targets, please?

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Michael M. Morrissey, Exelixis, Inc. - CEO, President & Director [61]

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Yes, Mike. So I can answer that question with an emphatic no, that's not it. The patent -- that application hasn't published yet. So I would stop looking at least in the short term. In terms of the preclinical profile, again, I'll defer that -- we'll defer that to a later date once we have some additional clinical momentum that would allow us to kind of put the full story in context. As you could imagine, this is a pretty competitive space right now, and there's no need for us to enable the competition with any early looks at the data. But again, we're excited about, a, having discovery back in action. I mean, that's in our DNA going back almost 20 years. So it's very gratifying to have Peter and crew back in the lab, cranking out new molecules and moving them forward into Gisela's world. And certainly, again as both Peter and I talked about today, we have just tons of information and knowledge from cabo that we're able to put into a next-generation potentially better molecule. And we're going to get some clinical data to see if our hypotheses are correct. So stay tuned.

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Andrew Ross Peters, Deutsche Bank AG, Research Division - Former Director [62]

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I look forward to more assets come out in the clinic this year.

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Operator [63]

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Your next question comes from the line of Tim Call with The Capital Management.

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Timothy Colin Call, The Capital Management Corporation - President, CIO & Chairman of the Investment Policy Group [64]

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You have 0 debt. If you find the right acquisition, what would be the optimal debt level for the company?

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Michael M. Morrissey, Exelixis, Inc. - CEO, President & Director [65]

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Yes, Tim, it's Mike. Thanks for the question. Glad you could join us today. Yes, it's a question that we probably don't want to speculate on in terms of how we might tactically put our capital to work, either cash that we have or debt that we might access. We certainly have done debt in the past. We had a convert that we used to help finance the company going back to 2012. So we have some experience there. Chris and his expertise back at -- his time back at Gilead, did a lot of debt work. So we have the depth of knowledge and experience from a capital perspective to be able to, I think, really ask the right questions, do the right analysis and then deploy the right level of capital in the right way to help us maximize value for the company. But it would be probably unwise to speculate on that prospectively.

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Timothy Colin Call, The Capital Management Corporation - President, CIO & Chairman of the Investment Policy Group [66]

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Because of your excessive free cash flow, your cash balances rose by 86% this year to around, I believe it's, yes, $2.73 per share. Would some of that -- should some of that be returned to shareholders to offset future stock option dilution by buying back shares?

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Michael M. Morrissey, Exelixis, Inc. - CEO, President & Director [67]

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Yes, that's a good question. Chris, do you want to start with that, and I'll provide some commentary.

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Christopher J. Senner, Exelixis, Inc. - Executive VP & CFO [68]

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Sure, thanks. I mean, at this point in our life as a company, to us, the most important driver of shareholder value is really around the deployment of capital and finding new assets and less so on a shareholder return around a buyback or a dividend. We think it's more important to really drive shareholder growth through the acquisition of assets and deploying that in BD, in acquisitions, in licensing. And that is the most important piece of what we're doing today. Now I'll never say never. I'll never -- I won't say that we won't do a share buyback or a dividend in the future, but that is less of a priority than actually driving company growth through acquisitions or through BD and licensing.

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Michael M. Morrissey, Exelixis, Inc. - CEO, President & Director [69]

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Yes. I would just reaffirm that. Look, we're focused on long-term value creation, sustainable growth over the long term. And I think as a company and where we've come from and where we're going, that seems to be the best way to build value. So -- but thanks for the question.

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Timothy Colin Call, The Capital Management Corporation - President, CIO & Chairman of the Investment Policy Group [70]

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Many of your partner contracts have embedded very attractive escalation clauses when you reach certain cumulative sales, product sales and reach those thresholds or exceed those thresholds, your percentage of future product revenue received as royalties or collaboration revenue goes up nicely. Did you reach any of those thresholds last year? And do you expect to reach any in 2019?

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Christopher J. Senner, Exelixis, Inc. - Executive VP & CFO [71]

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So yes, we did reach, I guess, 2 thresholds last year to think -- to talk about that. So there is one -- the first threshold was around the cumulative $150 million of revenue. And the first $100 million of that $150 million was at a 2% royalty rate, the next $50 million was at a 12%. After we got to that cumulative piece, we hit the -- our now minimum royalty of 22%. So on an annual basis, our minimum royalty will be 22% 2019 and beyond from the Ipsen perspective. And then the other one is when we hit a cumulative $100 million -- or Ipsen hit a cumulative $100 million over 4 quarters, we did receive a milestone during the -- earned that milestone during the second quarter, which we recorded during the second quarter. And then on a future basis, I'm not going to speculate on what the future potential for them to hit the next set of commercial milestones, but just know that the royalty rate is at a minimum now from Ipsen of 22%.

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Operator [72]

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And at this time, there are no further questions. So again, I will turn the call...

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Susan Hubbard, Exelixis, Inc. - EVP of Public Affairs & IR [73]

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Great. Thanks, Andrew. And thank you all for joining us today. We certainly welcome your follow-up calls if any questions we were unable to get to during today's call.

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Operator [74]

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