Exelixis, Inc.

Good day, ladies and gentlemen, and welcome to the Exelixis fourth quarter and full year 2020 financial results conference call. My name is Lateef, and I will 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.

Thank you, Lateef, and thank you all for joining us for the Exalexa's fourth quarter and full year 2020 Financial Results Conference Call. Joining me on today's call are Mike Morsey, our President and CEO, Chris Senner, our Chief Financial Officer, Gisela Schwab, our Chief Medical Officer, and PJ Haley, our Executive Vice President of Commercial, who will together review our corporate, financial, development, and commercial progress for the fourth quarter 2020 and December 31, 2020. Peter Lamb, our Chief Scientific Officer, is also here and will join us for the question and answer session following our prepared remarks. During the call, 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 our reasons for using such non-GAAP measures, as well as tables deriving these measures from 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, product development, regulatory, commercial, financial, and strategic matters. Actual events or 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, including without limitation risks and uncertainties related to product commercial success, market completion, regulatory review and approval processes, conducting clinical trials, compliance with applicable regulatory requirements, our dependence on collaboration partners, and the level of costs associated with discovery, product development, business development, and commercialization activities. Now with that, I will turn the call over to Mike.

All right. Thank you, Susan, and thanks to everyone for joining us on the call today. Exalexis ended 2020 with a strong fourth quarter, hit the ground running in January as we strive to accelerate revenue growth in 2021 and beyond with the Cabo Nevo launch and first-line RCC and a variety of mission-critical development and regulatory milestones. Please see our press release that was issued an hour ago for our fourth quarter and full-year 2020 financial results and an extensive list of key corporate accomplishments. We'll keep our prepared remarks short today as we had a full update recently at the J.P. Morgan Healthcare Conference, including providing 2021 financial guidance. Obviously, we're thrilled with the recent approval for the Cabo Nevo combination and first-line RCC based on the positive results from the Checkmate 9ER pivotal trial. We believe we have significant momentum heading into the launch and anticipate a near doubling of Cabo RCC revenues by the end of 2022 when we expect to exit with a $1.5 billion annualized run rate in the U.S. if our assumptions and modeling are correct. This week will be busy for us as we share a number of important clinical updates for Cabo Xanthinib at ASCO GU, both as a single agent and ICI combination partner. In addition, over the course of 2021, we foresee a broad slate of important discovery, clinical, and regulatory milestones, including first, three potential SMDA submissions, second, up to two additional INDs, third, advancing the cabozantinib cosmic and contact clinical trials, fourth, building the XL092 full development program, fifth, the early evaluation of our new clinical stage molecules XL102 and XB002, and finally, sixth, advancing a deep bench of exciting discovery programs toward development candidate status. It goes without saying that 2021 will be an action-packed year for the ExFlexus team, and we're working as one to maximize our chance of success across the range of milestones ahead of us. I'm incredibly proud of the commitment and focus displayed by the entire team in 2020, and excited for the future as we drive our business forward during these challenging times. So with that, I'll turn the call over to Chris, who will provide an update on our fourth quarter and full year 2020 financial results.

Thanks, Mike. For the fourth quarter of 2020, the company reported total revenues of $270.1 million. Total revenues for the quarter included Cabo Zanted and Franchise Net Product revenues of $200.4 million. Net product revenues in the fourth quarter of 2020 were positively impacted by higher demand and by an increase in wholesaler inventory. Cabo Medics' wholesaler inventory increased from approximately 2.8 weeks on hand to approximately 3.1 weeks on hand. Total revenues also included $69.7 million in collaboration revenues from Ipsen, Takeda, and Genentech. Our operating expenses for the fourth quarter of 2020 were $245.8 million. compared to $273.7 million in the third quarter of 2020. R&D expense was the primary driver of the decline in operating expenses, which declined by approximately $27.9 million and was primarily related to declines in stock-based compensation expense, clinical trial-related expenses, and licensing and milestone fees associated with existing and new business development activities. Benefit from income taxes for the fourth quarter of 2020 was $300,000, compared to $6 million for the third quarter of 2020. The company reported gap net income of $28.4 million, or $0.09 per share, on a fully diluted basis for the fourth quarter of 2020. The company also reported non-gap net income of $43.2 million, or $0.14 per share, on a fully diluted basis. Non-gap net income excludes the impact of approximately $15 million of stock-based compensation expense net of the related income tax effect. Cash and investments for the quarter ended December 31, 2020, was over $1.5 billion. Now turning to our financial guidance for the full year of 2021, which we previewed at the J.P. Morgan Conference in January. Total revenues are projected to be in the range of $1.15 and $1.25 billion. Net product revenues are projected to be in the range of $950 million and $1.05 billion. Cost of goods sold is projected to be between 5% and 6% of net product revenues. Research and development expenses projected to be in the range of $600 and $650 million and includes non-cash expenses related to stock-based compensation of approximately $45 million. Selling general administrative expenses projected to be in the range of $375 and $425 million and includes non-cash expenses related to stock-based compensation of approximately $60 million. Guidance for the effective tax rate in 2021 is between 20% and 22%. And finally, we are projecting cash investments to be in the range of $1.6 and $1.7 billion. The R&D expense and cash and investment guidance does not include the impact of any potential new business development activities. And with that, I'll turn the call over to Gisela.

Thank you, Chris. We've made great progress during the last few months of 2020 and are off to a great start in 2021. And I'm pleased to provide a brief update on our Kobzantinib regulatory and development program, highlight our progress for XL092 and new compounds moving towards clinical evaluation. And I'll focus on a preview of ASCO GU 2021 as the main topic today. Starting with Checkmate 9ER, just recently on January 22nd, we announced the approval by FDA for the cabozantinib and nivolumab combination for the first-line treatment of patients with advanced RCCs. The FDA reviewed the parallel filings of Exelixis and PMS under the RTOR, or Real-Time Oncology Review Program, that enables FDA to expedite its review of regulatory submissions for life-threatening conditions, and we are delighted that the approval was granted well ahead of the set PDUFA date of February 20, 2021. FDA's approval was based on demonstration of superiority for cabozantinib plus nivolumab compared with sunitinib for all three efficacy endpoints, progression-free survival, overall survival, and objective response rate. Additionally, the combination of cabozantinib at 40 mg QD and nivolumab was generally well-tolerated and associated with a low discontinuation rate. Detailed results of the study were presented for the first time by Dr. Tony Tureri at the recent virtual ESMO conference and the presidential symposium. The presentation also included a high-level analysis of health-related quality of life, or HRQOL. And despite the fact that the study enrolled a patient population with a higher proportion of intermediate and poor risk per IMDC, as well as a lower proportion of patients with nephrectomy compared to other first-line trials in RCC. The high-level quality of life results included in the primary analysis showed improved quality of life by functional assessment of cancer therapy kidney symptom index 19, or FIXI-19, for the combination of cabozantinib and nivolumab as compared to sunitinib. We look forward to the more detailed presentation of the HRQL results at ASCO-GU by Dr. David Scheller, as we think these results may provide important additional differentiation for the carbonebo duplet compared to other first-line TKI-IO options. Turning to the ongoing Phase III program for carbazantinib. We have continued our efficient execution of COSMIC 0 to 1, 311, 312, and 313 studies that have either completed or are nearing full enrollment on a global level. And we have either completed or are on track for top line results for these trials as previously shared. And I'll provide a brief summary on key highlights for the program. For COSMIC 311, and radioiodine refractory DTC patients who have received a prior VEGFR-targeted therapy, we announced in December 2020 that the trial met its primary endpoint of progression-free survival with cabozantinib highly significantly improving PFS versus placebo with a 78% reduction in the risk of disease progression or death resulting in a hazard ratio of 0.22 that was highly statistically significant with a p-value of less than 0.0001. We are working towards a supplemental NDA submission based on these strong results in a patient population with unmet medical need. COSMIC 312, our phase 3 trial of cabozantinib plus atezolizumab versus serafinib, where the first-line treatment of advanced HCC completed a cool in the global study in mid-2020. And we anticipate top-line results of the event-driven analysis of PFS and the concurrent interim analysis of overall survival in the first half of 2021. And COSMIC-313, comparing the triplet of cabozantinib, nivolumab, and epilimumab, versus nivolumab and ipilimumab in first-line RCC patients with intermediate or poor risk per IMDC is expected to reach its expanded accrual goal of 840 patients shortly. As a reminder, we had expanded enrollment in COSMIC 313 following presentation of updated long-term follow-up results from the Checkmate 214 study showing a longer median overall survival 48 months for the nivolumab and ipilimumab combination than originally assumed when we designed the COSMIC 313 trial. We look forward to the event-driven analyses for the study in 2022. For COSMIC 021, we look forward to final analysis of the objective response rate by independent radiology committee of cohort 6 in the metastatic CRPC setting in mid-2021. And we're planning for regulatory submissions of the results data providing. And importantly, we're happy to report that all three Phase III trials in our collaboration program with Roche, the Contact Phase III program, are actively enrolling patients globally. So looking back on this quarter, I am thrilled with the regulatory and clinical development progress with the carbazantinib program and the high level of execution by both our own teams and our clinical partners' teams. I'll now turn to the progress on our XL-092 program and our next new IND project. First, XL-092, our next generation MET, AXL, MER, and VEGFR tyrosine kinase inhibitor with a shorter pharmacokinetic half-life is advancing quickly and we are in the midst of evaluating the combination with atezolizumab in a parallel Phase Ib part of the study while completing the single-agent dose range study. As discussed on the third quarter call, our XL092 development plan includes a broad and comprehensive program across various tumor indications, lines of therapy, and settings of broad therapeutic interest. We intend to pursue the comprehensive evaluation of XL092 in combination with various established checkpoint inhibitors and potential new combinations, including promising new checkpoint inhibitor duplets, as well as other combination partners. But the goal to potentially start late stage trials as soon as 2021 We are focusing on advancing the phase 1B dose ranging in combination with checkpoint inhibitors rapidly to move into expansion cohorts that may support data-driven late-stage development options across a variety of tumor types. And secondly, we are excited to initiate studies with our latest IND candidates in 2021. We have recently announced initiation of the XL102 phase 1 trial, and we plan to file an IND for XP002, an antibody drug conjugate, or ADC, targeting tissue factor, shortly following completion of product release assays. For both new IND compounds, phase 1 trials are designed as efficient dose escalation trials with disease-specific expansion cohorts, to allow for early assessment of initial anti-tumor activity. And I look forward to updating you on progress on our clinical pipeline in the future. And lastly, as the virtual ASCO-GU conference is starting this week, I'd like to provide a brief overview of some key presentations for carbazantinib at the conference. We look forward to the presentation by Dr. Mozart of updated results with a longer follow-up for the Checkmate 9ER trial. As you've seen in the abstracts that are now online and also in our own press release, the efficacy results are consistent with the earlier presentation and demonstrate sustained efficacy across all key endpoints of overall survival, progression-free survival, and objective response rate. including an increase in the CR rate with further follow-up. Additionally, patients with sarcomatid histology, a traditionally difficult-to-treat patient population, derived significant and consistent benefit from the combination of cabozantinib and nivolumab. As mentioned earlier, we will also see a detailed presentation by Dr. David Scheller of the patient-reported outcomes on health-reported quality of life from Checkmate 9-ER. At a high level, the combination of cabozantinib and nivolumab resulted in improved quality of life as compared to sunitinib, with a reduction in disease-related symptoms and a significantly extended time to confirmed deterioration of quality of life. Further, final results of the Phase 1b trial of cabozantinib plus nivolumab alone or nivolumab and ipilimumab in patients with advanced genitourinary malignancies will be presented in a rapid oral presentation by Dr. Apollo. This Phase 1b study laid the foundation for the dose selection of cabozantinib of 40 mg daily for the combination with nivolumab and for the triplet combination including also ipilimumab. High response rates were seen in RCC and in urothelial cancer and also in rare GU malignancies. Durable responses and an encouraging median overall survival of 15.9 months were seen in this Phase I trial, including heavily pretreated patients with various GU malignancies. Importantly, we will also see the first presentation of the NCIC-TIP-sponsored PAPMED or SWOG 1500 trial results in papillary RCC by Dr. Samantha Paul as part of the oral presentation session on February 13. He will present the results of a forearm randomized trial comparing each of three experimental arms of cabozantinib, sabolitinib, and crizotinib versus zonitinib, the guideline recommended therapy for papillary RCC. While both sabolitinib and crizotinib arms were discontinued as a result of planned futility analyses, cabozantinib demonstrated superior PFS over sunitinib in this randomized Phase II trial. And lastly, there will be an intriguing retrospective analysis of cabozantinib's effect in RCC patients with brain metastases, presented by Dr. Laura Hirsch and Dr. Tony Tueri. showing an encouraging high intracranial and systemic response rate in this patient population with difficult-to-treat disease. We are very much looking forward to these presentations and to all the new results of ASCU-GU21 and hope that you will be able to join us for our investor briefing on February 13 at 5.30 p.m. Eastern, to hear renowned RCC experts, Dr. Tony Tureri, Dr. Daniel George, Dr. Samantha Paul, and Dr. Raina McKay discuss the most recent important trial results in RCC that will be presented at the conference and provide their expert opinion and further context on implications for the clinical management of patients with advanced RCC. And with that, I will hand the call over to PJ.

Thank you, Gisela. I'm pleased to discuss the CaboMedics business with regards to Q4 2020, and importantly, to discuss the first combination approval for CaboMedics. CaboMedics received approval for use in first-line RCC in combination with Nivolumab on January 22nd, and the team immediately began promotion. The strong 9ER data and recent approval position the CaboZancin franchise to return to significant revenue growth. CaboMedics ended the year with a strong Q4, and we expect the launch of 9ER to build on that momentum. Additionally, potential growth could be further driven by data readouts and other important indications as the robust Cabo development program continues to generate data. I will discuss the opportunity that 9ER provides Exelixis looking forward as we continue to build upon the foundation in RCC where we remain. the number one prescribed single-agent TKI. Before turning to 9ER, I will highlight a few of the key metrics from Q4. NRX volume for Cobometics increased by 8% in Q4 relative to Q3, while the overall NRX market volume was stable. This translated to an increase of NRX share from 30% to 32% for Cobometics. The increase of prescriptions in Q4 was primarily driven by growth in second-line RCC new patient market share as more ICI-experienced patients have progressed to the second-line setting. Turning to the first line, the ICI combination opportunity is large, with 15,000 RCC patients in the U.S. eligible for treatment, with ICI combination therapy consisting of approximately 80% of that market. According to this brand impact data, ICI TKI combinations constitute about 50% of the first-line share and are widely used across clinical risk groups, demonstrating the broad potential for Cobometics with NEVO in the first-line setting. Cobometics was approved in RCC over four years ago. During this time, it has developed very strong brand equity and is viewed as the best-in-class TKI in RCC. The Excellences team has significant experience in RCC with two prior successful launches, and we look forward to this opportunity to educate physicians on the 90-yard data so that more patients can benefit from cabo medics therapy in the first line. The strength of the 90-yard data speaks for itself. A doubling of median progression pre-survival and ORR and superior overall survival versus Importantly, clinical benefits were observed in the vast majority of patients in the trial, resulting in a low rate of primary progression, regardless of IMDC risk status or patient subtype, supporting broad use in the marketplace. In addition, the optimized CAVO combination starting dose of 40 milligrams daily yielded a compelling safety and tolerability profile along with a low treatment discontinuation rate and favorable quality of life, all of which has been notable with physicians in our research and discussions. The 90-hour data are particularly impressive when considered in the context of the challenging patient population enrolled in the study, which had more IMDC, porous patients, and fewer patients with nephrectomies than other Phase III studies in first-line RCC. Taken together, the combination of a best-in-class TKI like Cabo with a well-established immune checkpoint inhibitor like nivolumab in RCC, supported by strong efficacy and safety data from Checkmate 9ER, presents Exelixis with the opportunity to share a compelling and highly motivating story to our customers and to enable broad positioning across all clinical risk groups in first-line RCC. Feedback on the Checkmate 90R data with both academic and community oncologists has been positive, and we believe we can leverage the success and prescriber familiarity of both Cabo and Nevo to gain traction quickly in the combination setting. There's a great deal to be excited about as we think about the totality of the CaboMedics RCC business looking forward. With regards to the launch of 9ER, we are extremely pleased with the rapid execution of our experienced team, which was well prepared and is deeply experienced in the RCC market, and started reaching out to customers immediately the afternoon of approval. We have received positive feedback on the label and data, and prescribers have generally expressed enthusiasm for the combination. Many of our digital promotional tactics went live the day of approval, and the team is fully enabled to detail customers virtually or, where appropriate, in person. Additionally, we've already executed numerous speaker programs, including a national broadcast. While it is early to discuss any metrics from the launch, I can say that we are very pleased with the energy and execution of the launch thus far and continue to be optimistic on 9ER based on our initial customer feedback. Beyond 9ER, we are very excited by the cabozantinib development program as it moves forward broadly across multiple indications and with different combination partners. We look forward to building on this momentum in RCC, HCC, DTC, and other potential future indications, such as prostate and lung, as our development program evaluating cabozantinib in combination with immune checkpoint inhibitors advances. Our team remains highly focused and motivated to compete every day to bring the benefit of CaboMedix to all eligible patients as we continue to build the franchise and maximize its clinical and commercial potential. And with that, I'll turn the call back over to Mike.

All right. Thanks, PJ. As we outlined at J.P. Morgan a few weeks ago, 2021 has the potential to be a transformational year for Exalexis as we launch the CaboNiva combination and first-line RCC. and set the stage to pursue numerous additional indications with new data readouts and potential SNDA filings, all while building a diversified portfolio of assets that provide significant growth opportunities. I'm excited for ASCO GU this weekend and hope everyone can join us for our virtual investor meeting on Saturday afternoon at 2.30 p.m. Pacific Time, 5.30 p.m. Eastern Time. I'll close by thanking everyone at ExoLexus for their efforts in 2020 under what were obviously extremely challenging conditions. While we may be starting to see the light at the end of the COVID tunnel, we continue to acknowledge the potential risks to all of us and of course to our business should the vaccine rollout stall. I'm incredibly proud to say that the entire ExoLexus team continues to work as one with great teamwork, expertise, and energy in making everyday count as we discover, develop, and commercialize the next generation of our medicines for cancer patients in need of better and more effective therapies. We look forward to updating you on our progress in the future. Thank you for your continued support and interest in Exalexis, and we're happy to now open the call for questions.

Thank you. To ask a question, you will need to press star one on your touchtone telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question comes from the line of Ashtika, Gunawar Dean of Tourist Securities. Your line is open.

Hi, guys. Thanks for taking my questions, and congratulations on a well-executed 2020. I've got a quick question for PJ. Just curious on the rebound on scripts that we're seeing in 4Q. Could you give us a sense of what proportion of that 200 basis points growth and share was from second line. I've got a quick financial question for Chris. What's the expectation for the SG&A for the next few quarters? Are we expected to sort of stay in line with 4Q? Thanks.

Yeah. Hi, Ashika. This is PJ. Thanks for the question. With regards to Q4 and the scripts, I mean, we certainly had a strong quarter closing the year, as we discussed in the In the remarks, and really, well, I'm not going to go into sort of specific details of the proportion of that, you know, driven by various market segments. Clearly, the second-line market share growth that we experienced in RCC was strong and, you know, driving a lot of that, so I won't go into detail beyond that. But what I will say is we did see strength across all the segments, a bit of momentum also in second-line HCC segments. as that market evolves as well. So we're pleased with that and, you know, look forward to building on that momentum as we go forward here in 2021, particularly with the 9ER launch.

I stick with Chris. So I guess your question on SG&A was, is it going to be relatively the same as Q4, Q3 and Q4? You know, we did give guidance of $375 to $425 million, you know, that which would If you look at that on just an average basis, you know, if you look to the midpoint, that's $400 million. So the run rate there is in that, you know, we'd be in the $100 million range. So, you know, that's what I'm not going to give you quarterly guidance, but that's kind of where we're looking at our SG&A growth going to. Great.

Thanks, guys, for the questions.

All right. Thank you, Jessica.

Thank you. Our next question comes from the line of Jason Gerberry of Bank of America. Your question, please.

Hey, guys. Thanks for taking my questions. To just on the early stage pipeline, just on XL092, can you talk a little bit about any key internal hurdles on the efficacy side as you think about when you ultimately evaluate the expansion cohorts and make your decisions to move XL092 into typical trials later this year? And then... You know, with numerous shots on goal emerging with the new to clinic pipeline, has the imperative to do biz dev lessened in any way, or does it ultimately remain unchanged in terms of thinking about perhaps a more advanced asset later along in development that could accompany Cabo in the portfolio? Thanks.

Yeah, Jason, thanks for the questions. Gisela, you want to take the first one, and then I'll loop back and get the second one.

Sure, happy to do so. Thank you for the question. So XL092 is making good progress, as I mentioned, in its Phase I study and also in the Phase Ib evaluation with atezolizumab, and we look forward to further combination approaches. And as we're making decisions based upon expansion cohorts and early observations, certainly we'll be looking at the continuum of safety, tolerability, as well as efficacy signals, and those will be very much dependent on the indication that we will take forward, of course, and the competitive environment. So it's a variety of factors that we will consider and certainly take into account the data that will be emerging from the expansion cohorts.

Fantastic. Thank you. On the BD side, look, obviously we're looking at a range of opportunities across the continuum of stages of assets. We've done a number of early-stage, you know, back-end loaded, small upfront deals, and there's certainly more of those to be done in the short to mid-term. We have a queue of those lined up, and we think that's a very important part of building our early-stage portfolio that complements our internal discovery efforts around small molecules, and I think that makes a lot of sense relative to building a pipeline for the future. We're looking at a variety of, I would say, mid- and late-stage assets as well. Obviously, different questions there in terms of the value proposition. And as I'm sure you're aware, things are pretty frothy right now out there, as well as the data that goes with those opportunities. So, you know, we're looking closely. And if we find the right asset, the right opportunity at the right cost, then we'll be inclined to move those forward. But again, we're not looking at the reality of overpaying for assets just because um, of the frothy market dynamics and, you know, people looking for a lot. So we're going to, you know, maintain a high level of discipline as we have in the past and, uh, and go for good science and good value at the same time.

All right. Thanks.

Thank you.

Thank you. Our next question comes from the line of Andy of William Blair. Your line is open. Okay.

Uh, thanks for taking my question. So, uh, First one, maybe Deepla, so I'm just wondering if you can frame expectations for us for the kind of mid-year update for cohort six. I know the company policy, you know, you want to have sufficient follow-up and basically a mature data set. So, you know, can we expect kind of the full 130 patients from that cohort around mid-year? Sure.

Sure. So what we're aiming for is the independent radiology review for cohort six. We had presented, as you know, last year at ASCO and ASCO-GU, the initial cohort of about 40 patients for cohort six, and we're very pleased with the outcome there with a response rate of 32%. and durable responses observed in this metastatic CRPC population with the combination, and that paired with a good tolerability profile. We have completed enrollment of the 130 patients, and we're looking to see the independently assist objective response rate. And so that's really what we're aiming for later in 2021.

Got it, that's very helpful. And maybe for T.J., if you look at slide number 31, you know, you have basically this frontline new patient share breakdown. And I think that's basically the same graph that you've shown on Q3. Just curious if there's any sort of material change as we exit at Q4 or maybe a little bit into Q1. about any sort of material change to that picture?

Yeah, hi, Andy. This is PJ. Thanks for the question. You know, what I'd say is we look at certainly a lot of different data sources with regards to market share and various data elements for the market. So I think regardless of what we look at, and over time these are, yeah, I'd say relatively in that ballpark, IO Combo share being, you know, 75% to 80%. and, you know, the majority of that being IoTKI. So I'd say that's roughly what we're looking at now, and we're very excited to really move Cabo Medics forward with Nevo into that IoTKI market. As I kind of mentioned, the team is really excited and working hard on the launch. We're getting a lot of great feedback and a heck of a lot of activity with that. So I think it'll be exciting to kind of move us forward in combination and first line.

Okay, thanks, that's helpful. So, last question, this is for Peter. So, as we think about, you know, the company kind of moving away from 265, you know, that asset really was asking about, you know, relevant clinical questions regarding the roles of the camp kindnesses. So, I'm just wondering if you are bringing forward any other lead candidates that could potentially fill in that void? or you're just basically kind of focusing on other, you know, early stage assets?

Yeah, I think, you know, what we learned from the XL265 experience was kind of helpful and I think felt relatively scientifically interesting. On the basis of that, we're going to be focusing on earlier stage programs for our internal discovery going forward. rather than an attempt to do a kind of do-over version of 265.

All right, great. Thanks for answering my question.

Okay, Annie, thank you.

Thank you. Our next question comes from Yaron Werber of Cohen. Your line is open.

Great. Thanks for taking my question, and congrats on the launch and a nice quarter of Maybe just a couple of questions. One, just any inventory changes can just remind us kind of where did you finish inventories in Q4. And then I have a question. When we look at the data, the Phase 1B data for Cabo Nivo, Cabo Nivo, IPI, this is patients remind us who they need to have failed one prior therapy. They obviously couldn't have failed the PD-1. So is this sort of a second-line therapy or The data is obviously better, obviously a very small sample, but better than Cabo alone in the mid-year. But when we're trying to compare it to a Cabo Nevo in first line, the response rate is higher. The median OS is slightly lower. But, again, the data looks pretty good, but is this sort of a second-line population? Just give us a little bit of sense how you think about it. Thank you.

Yeah, Jeroen, great questions. Why don't we start deep flow. Why don't you answer the last question first, and then Chris can cover the inventory questions.

Sure. I'm happy to. So regarding the NCI CTEP study, the first one B study that will be presented by Dr. Paul, this is a trial that was conducted in patients with advanced GU malignancies. And patients must have received at least one prior therapy, could have received multiple prior therapies. So it's a rather heavily pretreated patient population across the board. And so I would say, and answer the question, it's second and later line that we're looking at in the results that you will see in more detail explained at ASKGU.

Okay. You're on this, Chris. So on your inventory question, You know, as I mentioned in my prepared remarks, the Cobb Medics inventory weeks on hand increased from about 2.8 weeks on hand in Q3 to about 3.1 weeks on hand in Q4. And this is equal to approximately, you know, $7.5 million on the net revenue line.

Great. Thank you.

You're welcome, Jeroen. Thank you.

Thank you. Our next question comes from Michael Schmidt of Guggenheim. Your line is open.

Hey guys, congrats on the quarter and thanks for taking my questions. I had a few as well. I thought this brand impact data that you highlight on slide 30 was interesting. I guess with CheckMate 9ER, with the combination now approved, What market share do you ultimately think you might be able to achieve in the first-line RCC setting, and in what area do you expect to gain most share? Is it the monotherapy, the TKI combo, or the IOIO combos? Secondly, I thought the CNS data from ASK.GU looked quite interesting, and I was wondering to what degree it is known whether any of the other TKIs also cross the blood-brain barrier or whether that's a unique, you know, aspect of differentiation. And then lastly, on X102, your CDK7 inhibitor, I was wondering if you could just help us understand how that might, you know, fit in into the breast cancer space mechanistically relative to CDK4-6 inhibitors. Thanks so much.

Hey, thanks, Michael. Why don't we start there? Peter, do you want to take the 102 question first, and then Gisela can do the brain mets, and PJ can do the question about brain impact?

Sure. So if I caught the question, I think it was specifically around opportunity for CDK7 inhibitors and XL102 in breast cancer. And there were a number of questions very compelling pieces of preclinical data that support coming in with a CDK7 inhibitor in multiple settings, certainly in triple negative breast cancer. There's data showing that a lot of those cell lines are dependent upon CDK7 for growth, and some pretty compelling xenograft data there as well. In the ER-positive breast cancer, there's a direct connection between CDK7 and estrogen receptor, CDK7 actually phosphorylates the estrogen receptor and increases its transcriptional activation potential. So again, combinations there with ER antagonists of various types make a lot of sense. And then finally, and I think you alluded to this, CDK7 is upstream of CDK4 and 6, so it may well be an interesting place to go in terms of resistance to current CDK4, 6 inhibitors. So So at least those three kind of different flavors, if you like, are things that could be explored in the breast cancer setting.

Thanks, Peter. That's great. Isla, you want to do the brain met question?

Absolutely. Yeah, I'm happy to see the presentation at ASCO-GU on this retrospective analysis of patients with brain metastases from RCC and importantly this study assessed both patients with uncontrolled brain metastases at baseline and also patients with controlled disease at baseline and in both groups impressive responses, intracranial responses and also systemic responses were observed. And I'm highlighting that because patients with uncontrolled brain disease are usually excluded from clinical trials and certainly from large phase three trials because of potential complications that may occur in those patients. And usually they have to have controlled disease to be included, if at all, in larger studies. So in that vein it is a very important observation and certainly an understudied group of patients. That said, in terms of penetration of blood-brain barrier, we know that carbazantinib has the ability to penetrate the blood-brain barrier. We've seen that in very early evaluations in preclinical studies. In the context of brain metastases or brain involvement even with other histologies, sometimes the blood-brain barrier may be compromised and And so that is a feature that adds to, but it's not perhaps completely dependent on the penetration of the blood-brain barrier. But looking at the results at a high level that are being reported at ASCO-GU, we are very happy to see a high response rate in this very underserved patient population.

Great. Thanks, Michael. This is TJ. With regards to first-line uptake, I think I won't discuss specific numbers with regards to market share, but I think we have really the opportunity to gain share broadly in the market. And I mean that in a few different ways, whether we look at the competitive landscape with regards to ICI-TKI, ICI-ICI, or even expanding combinations into TKI monotherapy. You know, we certainly see that. We see broad potential across clinical risk groups, favorable, intermediate, and poor risk groups with the strength of our data overall. Certainly excited about the large body of data that will be presented at ASCO-GU this weekend to help kind of, you know, prescribers learn more about CAVO. And I think, you know, as we think about that, particularly with regards to the combination, we're really going to be helped by the experience that prescribers have with CaboMedix and RCC at this point. It is viewed as the best-in-class TKI according to our market research. And, you know, I think what we're going to see is the optimized dose of 40 milligrams and kind of the tolerability profile, low discontinuation rate with regards to the combination and really how that translated to Improved quality of life in 9ER, I think, is really going to help us drive utilization across all these different categories.

Super. Thank you.

You're welcome, Michael. Thank you.

Thank you. Our next question comes from Peter Lawson of Barclays. Please go ahead.

Thanks for taking questions. Just in first-line RCC, beyond that potential broad use of CARBO plus PD-1 What niches do you think are easier to penetrate? Is it things like patients with brain and bone mets?

Yeah, Peter, this is PJ. I'll talk about that. I mean, again, I think, you know, we do really see the broad potential here. And when we look at, you know, the current utilization of ICITKI, you know, on the market, we see it utilized broadly, particularly in the community setting. So I think... you know, will have the opportunity to, and prescribers really want to utilize it for a variety of their patients, particularly looking at that risk-benefit profile and the strong efficacy across subgroups and, you know, thinking about the tolerability profile and particularly the quality of life, which is just something not often seen in, you know, adding therapy, adding a second or third therapy, whatever it is, in a combination and seeing improved quality of life in oncology. So, we think that will give us really a broad opportunity.

Thank you. And then just on that first-line single-agent TKI segment, kind of your analysis of that, what kind of share do you think you have versus Lenbitnebo in Leiter?

You know, honestly, in the TKI monotherapy categories, where we do see, you know, in the last few quarters, historically, is more the legacy TKIs. If you look at the market share data, you know, that's where you see some significant usage, which, as Gisela mentioned, has kind of been the guideline-recommended therapy for non-clear cell. So you see Sutan and Botrien there, and I think with the data we have in 9ER, as well as the other data sets that Gisela described, whether that's PapMet looking at, you know, papillary RCC, where you see some of the monotherapy so i think the breadth of the data being presented will help us be more competitive there and you know historically that's really been more um uh more of votrian and student use um outside of you know certainly uh the cabo use that we have there do you think that's kind of a an easier area to penetrate that single agent first first line tki mono well I really think the combo is, you know, going to be just such a big opportunity, and our data is so strong that that should be, you know, really probably where we see rapid uptake, and it will be more of a dynamic, you know, certainly possibly a more dynamic market as we launch into that, because that's certainly what we're going to be focused on.

Okay. Thanks so much. Thanks, Vika.

You bet, Peter.

Thank you. Our next question comes from Jay Olson of Oppenheimer. Your line is open.

Hey, Jay, are you with us?

Yep. Can you hear me?

Yes, you sure can now.

Oh, great. Congrats on all the progress and thank you so much for taking the questions. Since you've rapidly grown the top line to billion dollars in just a few short years, What do you consider the key steps and timeline for growing to $2 billion in revenue? And then I had a question about your adaging collaboration where you recently added another ADC to your portfolio. What are the key points of differentiation you're looking for in your ADCs versus competitors? And is there a rationale to combine an ADC with Cabo or 092?

Yeah, Jay, it's Mike. Great questions. Peter, why don't you start there, and then I'll finish up.

Yeah, so as you've seen, we've done a number of ADC-related deals and partnerships over the last six months or so, and they are intended to work well together. Essentially, the way we're setting up, building a pipeline of ADCs is to have folks, particularly our Venra collaboration, who are the ones who can go out and find antibodies and binders. They're then the raw material, if you like, for actually making the ADCs. The deals we did late last year with Catalan and with NBE then give us access to contemporary site-specific conjugation technologies, which are believed to be increasingly important in terms of advancing high-quality ADCs into the clinic. And it also gave us access to a range of pretty interesting payloads. And obviously, we can pick which payloads we're going to do based on which tumor types we ultimately want to target. So with respect to where AllerGene fits into this, they have a very interesting antibody masking technology, which essentially is a small peptide, if you like, that sits in the binding domain of the antibody. really reduces its ability to bind to the target antigen, but it's released in a tumor-specific fashion. So it actually depends on greatly increased protease activity of the tumor surface, which then clips this peptide off. So it's really intended to increase the therapeutic index, if you like, for any on-target side effects that may occur due to binding to target normal tissue versus the target in the tumor. We think from an overall profile point of view, that's a very attractive technology to have. And as an aside, I'll also point out it actually broadens out potentially the target space in the ADC field as well. With the mask technology, you can start looking at targets which you maybe wouldn't want to pursue if you didn't have some kind of tumor-specific activation going on. So, you know, I think if you put those things together, Hopefully you can start to see where we think our point of differentiation is going to come here. It's from using, I think, having access to some of the most modern conjugation technologies that really enable you to get a homogeneous product. Some of the issues that people have seen with ADCs over the years really stem from them being mixtures of things. They can create manufacturing issues as well ultimately as contributing to toxicity. So that's the plan. That's definitely the plan from the ADC space. There's probably more to do there. And, you know, obviously we have our first ADC, XB002, which will enter the clinic in the not-too-distant future.

Fantastic, Peter. Thanks for that deep dive into the overall ADC approach. I'm certainly excited about having adagene collaboration in place now to be able to move that forward too. Jay, in terms of your first question, look, we're all about growing top-line revenue. Obviously, that is incumbent upon good clinical trial data, successful regulatory outcomes, and then obviously very, very strong commercial execution. We've seen that over the last few years in terms of our renal and liver programs, and obviously there's a lot going on right now in terms of you know, the commercial launch based on 9ER for first-line renal with Cabo Nevo. So that's a big driver for us in the immediate to short term. As I mentioned and as Gisela mentioned, we have a number of potential SNDA filings this year, top-line data results for first-line liver, prostate, thyroid, got lung trials going. So all in all, probably nine or ten pivotal trials ongoing right now with Cabo and various IOPs. and certainly with the opportunity to do more going forward, the next wave or even two coming beyond that with 092. So our focus is really on top-line growth, and our focus is making sure that we are executing extremely well across that clinical, regulatory, commercial framework so that we can meet our aspirations for success. Super helpful. Thanks for sharing that vision with us.

You bet. Thank you.

Yeah, thanks, Jay.

Thank you. Our next question comes from the line of Kenneth McKay of RBC Capital Markets.

Please go ahead. Hi. Thanks for taking the question, and congrats on the progress, and what a year. Thank you. Maybe for Chris or PJ, can you help a little bit more with the metrics behind the Cabo Q4 results, the – The pre-announced print was an awesome surprise, but I'm sort of having a hard time justifying demand versus gross to net versus the inventory changes you mentioned. So if there is anything you can comment around demand after you back out inventory and gross to net, that would be hugely helpful. And lastly, this was discussed a little bit, but I'd really love to hear the team's perspective once more on sort of the small bit of detail We've heard from the competitive Lendima-Ketruda combo in the CLEAR trial. Obviously, impressive median PFS and hazard ratio there, but that can obviously be defined by baseline demographics. Thanks so much.

It's Mike. Thanks for those questions. And certainly, they're both really important questions. Why don't we start with PJ, give you a quick... update on that conundrum, if you will, and then we'll move over to Gisela to chat about CABO and other competitive programs.

Yeah, hi, Kenan. It's PJ. Thanks for the question. So, you know, with regards to the prescription data and kind of demand in Q4 and our revenue, I don't know that I'm going to be able to solve the conundrum, so to speak, but, you know, certainly... What we would say is we see, I don't want to comment on any methodologies or the way, you know, capture rates, et cetera, of the third-party prescription data providers, but we do see variation in that, you know, quarter to quarter with our products, with other products in the market basket. So I think that's just kind of, for better or for worse, part and parcel of that over time. You know, one thing I could even point out with regards to Q4 is If you look at the TRX data for Exitinib, for example, I think they were up about 6%, whereas their Q over Q U.S. revenue was up 23%. So you just see some discrepancies there, some variability. You know, I think as we look at it, you know, certainly it's indicative of the strong momentum we had closing the year and really just setting us up well for you know, for Q1 and the launch that's ongoing.

Awesome. Gisela, you want to say a few words about the competitive situation?

Absolutely, yes. So with respect to the LEN PEM data, we've seen, as everyone on the call has seen, the abstract. for ASCO-GU for the CLEAR study and certainly you've seen the efficacy data and see a positive study here which is good news for patients always. I think the abstract is a little sparse on the description of the patient population and I think that is the key that we'll be looking at when more detail are available later in the week when the full data are being presented. In terms of the data that we can glean from the abstract, we've been focusing on the comparator arm with sunitinib that has been used in other studies as well, in our own Checkmate 9ER study and in the Keynote 426 trial. And when looking at the results here for the sunitinib arm in the CLEAR study, we see that a performance that's a little bit more akin to the Keynote 426 trial with a high response rate for sunitinib of 36% and an overall survival that has not been reached after 27-month median follow-up. And that, of course, indicates that the population may be a population of less high... favorable risk population patients when we look at the TECMED9ER data where the median OS had been reached after a 24-month follow-up with sunitinib showing a 29-month median OS. So we'll be curious and looking for more detailed descriptions. of the patient population, and in particular, we'll be looking at the distribution of the patient population by risk category, favorable versus intermediate or poor risk, number of patients with nephrectomy versus not, which may, of course, affect objective response and CR rates, and then also other variables such as patients' metastatic spread to two or more organs, with metastatic disease, patients with bone or brain metastases or liver metastases, all negative prognostic factors in their own right. And perhaps as a measure of tumor burden, the sum of target lesion diameters, if that is being presented. So there's a lot to learn for sure in this data set, and those are the variables we'll be looking at in the patient population. And just to finish off, in terms of safety and quality of life, we'll be looking for those data sets as well. That was not going into depth, certainly on the safety side, and there was no mention of quality of life in the abstract. So we look forward to all the detailed presentations, and also, of course, we are holding the investor event on Saturday, with a number of key experts in RCC, Dr. Troy, George, Cal, and McKay, who will discuss the new information coming out of ASCO-GU and we'll hope that you'll be able to join us for that event.

Absolutely. Thanks so much.

Great, Kenna. Thank you.

Thank you. Our next question comes from the line of Stephen Willey of Stiefel.

Your question, please. Yeah, good afternoon. Thanks for taking the question. Maybe just to follow up on the 4Q dynamic question. So I know that there was, I think there was a large phase three trial using CABO as a comparator arm that initiated in the fourth quarter of last year. So I guess, can you just speak to what extent that trials apply to that study? may have impacted product revenue in the fourth quarter, if at all? And I guess if not, how does that get accounted for?

Steve, thanks. It's Chris. Yeah, I'm not going to comment about the other trials and what's going on out there. If there was revenue in the future, you would account for that as normal revenue.

Okay. Maybe just to follow up on Gisela's comments regarding the potential incidence rate of favorable risk patients in the CLEAR trial. So I guess I understand the notion that a higher cognitive response rate would imply a greater proportion of favorable risk patients, perhaps in CLEAR. But I know that these favorable risk patients are also a headwind on the event-driven data with respect to PFS and OS because those patients inherently do better on sunitinib. So I was just wondering if you can somehow extrapolate those two things for me, or do you think the differences here will be more driven by some of the other baseline variables that you talked about, like nephrectomy status and visceral meds, et cetera?

Yeah, Steve, it's Mike. Yeah, there's a lot of open questions about the data because it hasn't been presented yet. So our recommendation is before we get too much into the weeds, let's see the data, and let's talk about it on Saturday.

All right. Lastly, on the XL092 Phase 1 data, I think I noticed that you've specified hormone receptor positive breast cancer as a target indication both for monotherapy and for combination with the TEZO and was just curious if you can maybe provide some of the rationale there, just kind of given some of the underwhelming PD-1, L1 data that we've seen there thus far. Thank you. Sure.

Gisela, Peter, want to comment on that? Sure.

Sure, and I'm happy to comment on the Phase I expansion cohort. So we have built those expansion cohorts based upon observations, of course, and learnings from the carbazantinib program, single-agent experience as well as IST and CTEF studies in that space, either in single-agent carbazantinib or combinations, and This is an indication where we've seen some activity for cabozantinib as a single agent and are curious about the combination with a checkpoint inhibitor given the cooperative activity that we are assuming here between the two pathways. Peter, if you wanted to comment further, please.

No, I would just add that mechanistically, we think that the rationale for combining O9-2 with checkpoint inhibitors is very broad and is applicable to multiple different tumor types. Some of the individual targets of O9-2, like MET, for example, are certainly upregulated and overexpressed in breast cancer as well. So there's potential for direct tumoricidal effects from the drug itself, but It's really around the breadth of the changes that we've seen with CABO and now seeing preclinically with O92 on different components of the immune system.

Thank you for taking the questions.

Thank you. Our next question comes from Paul Choi of Goldman Sachs. Your question, please.

Thank you. Good afternoon, and thank you for taking our questions. I have one commercial question for either Chris or PJ, and that's with respect to the gross-to-net trends. Can you maybe just comment on, you know, how that progressed over the course of 4Q versus 3Q? And as you're promoting the frontline combination here, how we should think about the gross-to-net progression over the course of 2021 relative to 2020? Thanks, Bob.

So, yeah, I mean, gross net was slightly down in Q4 versus Q3. And, you know, we did have a higher proportion of commercial patients in the quarter. So, you know, that did impact our gross net. And from a 2021 perspective, you know, we're looking at gross net as we, you know, based on our guidance that we put forward, you know, $950 million to $1,050,000,000. revenue guidance number. We're looking at gross to net in that 25 to 26% range for 2021.

Okay, that's very helpful. Thanks. Appreciate the details. And then my follow-up question on the clinical side is with respect to the X0092 program, can you maybe for Gisela, can you maybe just comment on your level of visibility with respect to the efficacy and safety profile for the monotherapy and the combinations? I ask this with regard to, you know, your comment in the PR and earlier comments just that you plan to, you know, proceed into pivotals by year-end here. So just, you know, the level of confidence and visibility that gives you, you know, a sense for being able to move into the pivotal trials by year-end here.

Yeah, happy to address that question. The XL192 single agent phase one study has been ongoing for a little bit. It's a dose escalation study, and as we escalate to higher doses and get towards identification of the MTD, we obviously have followed up patients for quite some time and will be looking forward to presenting data at a scientific meeting to present both safety and efficacy across the study and across the dose ranging. But the data that we're seeing thus far is consistent with how we set out in terms of constructing the molecule and the pharmacokinetic profile has borne out as hoped for, as was mentioned. earlier on in the call and so we see the program to a large degree de-risked given that XL092 is very similar in its target profile as cabozantinib and we certainly have many, many years of experience with cabozantinib as a single agent and in combination. So that is the backdrop from which we are making the comment of hoping to initiate pivotal studies in 2021.

So maybe just a quick follow-up. So is the correct inference here that you'll be just advancing the monotherapy into pivotal trials, or do you think you'll also be able to advance the combination?

I think that is something we'd be addressing as we move forward and accumulate data and then ultimately initiate pivotal trials.

Okay. Thank you very much.

Thank you. At this time, I'd like to turn the call back over to today's host, Susan Hubbard, for closing remarks.

Thank you. I want to thank you all for joining us today. We are running quite a bit over on time, so we'll need to wrap up the call, but I want to thank you for joining us and certainly welcome your calls with any follow-up questions.

Ladies and gentlemen that does conclude today's call. Thank you for your participation. You may disconnect your lines at this time. Have a great day.