Exelixis - Q4 2020

Transcript

Operator (participant)

Good day, ladies and gentlemen, and welcome to the Exelixis Fourth Quarter and Full Year 2020 Financial Results Conference Call. My name is Latif, 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.

Susan Hubbard (EVP of Public Affairs and Investor Relations)

Thank you, Latif, and thank you all for joining us for the Exelixis Fourth Quarter and Full Year 2020 Financial Results Conference Call. Joining me on today's call are Mike Morrissey, our President and CEO, Chris Senner, our Chief Financial Officer, Gisela Schwab, our Chief Medical Officer, and P.J. Haley, our Executive Vice President of Commercial, who will together review our corporate financial development and commercial progress for the Fourth Quarter 2020 ended 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 competition, regulatory review and approval processes, conducting clinical trials, compliance with applicable regulatory requirements, our dependence on collaboration partners, and the level of cost associated with discovery, product development, business development, and commercialization activities, and with that, I will turn the call over to Mike.

Michael Morrissey (President and CEO)

All right. Thank you, Susan, and thanks to everyone for joining us on the call today. Exelixis ended 2020 with a strong fourth quarter and hit the ground running in January as we strive to accelerate revenue growth in 2021 and beyond with the Cabo + Nivo launch and first-line RCC and a variety of mission-critical developments 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 + Nivo 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 cabozantinib 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 sNDA submissions, second, up to two additional INDs, third, advancing the cabozantinib COSMIC and CONTACT clinical trials, fourth, building the XL-092 full development program, fifth, the early evaluation of our new clinical stage molecules XL-102 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 Exelixis 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.

Chris Senner (CFO)

Thanks, Mike. For the Fourth Quarter 2020, the company reported total revenues of $270.1 million. Total revenues for the quarter included Cabometyx cabozantinib franchise net product revenues of $200.4 million. Net product revenues in the Fourth Quarter 2020 were positively impacted by higher demand and by an increase in wholesale inventory. Cabometyx wholesale 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 2020 were $245.8 million, compared to $273.7 million in the Third Quarter 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 2020 was $300,000, compared to $6 million for the Third Quarter 2020. The company reported GAAP net income of $28.4 million, or $0.09 per share, on a fully diluted basis for the Fourth Quarter 2020. The company also reported non-GAAP net income of $43.2 million, or $0.14 per share, on a fully diluted basis. Non-GAAP 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-ending December 31, 2020, was over $1.5 billion. Now, turning to our financial guidance for the full year 2021, which we previewed at the J.P. Morgan Conference in January, total revenues are projected to be in the range of $1.15-$1.25 billion. Net product revenues are projected to be in the range of $950 million-$1.05 billion.

Cost of goods sold is projected to be between 5% and 6% of net product revenues. Research and development expenses are projected to be in the range of $600-$650 million and include non-cash expenses related to stock-based compensation of approximately $45 million. Selling, general, and administrative expenses are projected to be in the range of $375-$425 million and include 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're projecting cash and investments to be in the range of $1.6-$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.

Gisela Schwab (CMO)

Thank you, Chris. We've made great progress during the last few months of 2020 and are off to a great start in 2021. I'm pleased to provide a brief update on our cabozantinib regulatory and development program, highlight our progress for XL-092 and new compounds moving towards clinical evaluation. Our focus is on a preview of ASCO GU 2021 as the main topic today. Starting with CheckMate 9ER, just recently, on January 22, we announced the approval by FDA for the cabozantinib and nivolumab combination for the first-line treatment of patients with advanced RCC. The FDA reviewed the parallel filings of Exelixis and BMS under the RTOR, or Real-Time Oncology Review Program, that enables FDA to expedite its review of regulatory submissions for life-threatening conditions. 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 milligrams q.d. 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. Toni Choueiri 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.

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 FKSI-19, for the combination of cabozantinib and nivolumab as compared to sunitinib. We look forward to the more detailed presentation of the HRQOL results at ASCO GU by Dr. David Cella, as we think these results may provide important additional differentiation for the cabozantinib-nivolumab douplet compared to other first-line TKI/IO options.

Turning to the ongoing phase III program for cabozantinib, we have continued our efficient execution of COSMIC-021, -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 III trial of cabozantinib plus atezolizumab versus sorafenib for the first-line treatment of advanced HCC, completed accrual 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 ipilimumab 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 of 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 the 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.

Looking back on this quarter, I am thrilled with the regulatory and clinical development progress for the Cabozantinib 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 new IND projects. First, XL-092, our next-generation MET inhibitor and VEGFR tyrosine kinase inhibitor with a shorter pharmacokinetic half-life, is advancing quickly. We are in the midst of evaluating the combination with atezolizumab in a parallel phase 1b part of the study while completing the single-agent dose range study. As discussed on the third quarter call, our XL-092 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 XL-092 in combination with various established checkpoint inhibitors and potential new combinations, including promising new checkpoint inhibitor duplets, as well as other combination partners. With the goal to potentially start late-stage trials as soon as 2021, we are focusing on advancing the phase I B 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. Secondly, we are excited to initiate studies with our latest IND candidates in 2021. We have recently announced the initiation of the XL-102 phase I trial. We plan to file an IND for XB002, an antibody-drug conjugate, or ADC targeting tissue factor, shortly following completion of product release assays.

For both new IND compounds, phase I 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. Lastly, as the virtual ASCO GU Conference is starting this week, I'd like to provide a brief overview of some key presentations for cabozantinib at the conference. We look forward to the presentation by Dr. Motzer 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 sarcomatoid 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 Cella of the patient-reported outcomes on health-related quality of life from CheckMate 9ER. 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 I B 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. Sumanta Pal.

This phase I B study laid the foundation for the dose selection of cabozantinib 40 milligrams 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 PAPMET or SWOG 1500 trial results in papillary RCC by Dr. Sumanta Pal as part of the oral presentation session on February 13. He will present the results of a four-arm randomized trial comparing each of three experimental arms of cabozantinib, savolitinib, and crizotinib versus sunitinib, the guideline-recommended therapy for papillary RCC.

While both savolitinib and crizotinib arms were discontinued as a result of planned futility analyses, cabozantinib demonstrated superior PFS over sunitinib in this randomized phase II trial. Lastly, there will be an intriguing retrospective analysis of cabozantinib's effect in RCC patients with brain metastases presented by Dr. Laure Hirsch and Dr. Toni Choueiri 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 ASCO GU 21 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. Toni Choueiri, Dr. Daniel George, Dr. Sumanta Pal, and Dr.

Rana 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. With that, I will hand the call over to P.J.

Patrick Haley (EVP of Commercial)

Thank you, Gisela. I'm pleased to discuss the Cabometyx business with regards to Q4 2020 and, importantly, to discuss the first combination approval for Cabometyx. Cabometyx received approval for use in first-line RCC in combination with nivolumab on January 22, and the team immediately began promotion. The strong 9ER data and recent approval position the Cabozantinib franchise to return to significant revenue growth. Cabometyx 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 Cabometyx 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%-32% for Cabometyx. The increase in 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 Cabometyx with nivo in the first-line setting. Cabometyx was approved in RCC over four years ago and is viewed as the best-in-class TKI in RCC. The Exelixis team has significant experience in RCC with two prior successful launches, and we look forward to this opportunity to educate physicians on the 9ER data so that more patients can benefit from Cabometyx therapy in the first line. The strength of the 9ER data speaks for itself: the doubling of median progression-free survival and ORR and superior overall survival versus sunitinib.

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 Cabo 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 9ER data are particularly impressive when considered in the context of the challenging patient population enrolled in the study, which had more IMDC, poorest patients, and fewer patients with nephrectomies than any 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 9ER 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 Nivo 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 Cabometyx 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 Cabometyx 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.

Michael Morrissey (President and CEO)

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 Exelixis as we launch the Cabo/Nivo combination in 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 Exelixis 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 Exelixis team continues to work as one with great teamwork, expertise, and energy in 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. We look forward to updating you on our progress in the future. Thank you for your continued support and interest in Exelixis, and we're happy to now open the call for questions.

Operator (participant)

Thank you. To ask a question, you will need to press star one on your touch-tone 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 Asthika Goonewardene of Truist Securities. Your line is open.

Asthika Goonewardene (Analyst)

Hi, guys. Thanks for taking my questions and congratulations on well-executed 2020.

I've got a quick question for P.J. 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 in share was from second line? And then a quick financial question for Chris. What's your expectation for the SG&A for the next few quarters? Are we expected to sort of stay in line with 4Q? Thanks.

Patrick Haley (EVP of Commercial)

Yeah. Hi, Asthika. This is P.J. 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 remarks, and really, well, I'm not going to go into sort of specific details of the proportion of that driven by various market segments. Clearly, the second-line market share growth that we experienced in RCC was strong and 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 as that market evolves as well. So we're pleased with that and look forward to building on that momentum as we go forward here in 2021, particularly with the 9ER launch.

Chris Senner (CFO)

Over to Chris. So I guess your question on SG&A was, is it going to be relatively the same as Q4, Q3, and Q4? We did give guidance of $375-$425 million, which if you look at that on just an average basis, if you look to the midpoint, that's $400 million. So the run rate there would be in the $100 million range.

So 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.

Asthika Goonewardene (Analyst)

Great. Thanks, guys, for the questions.

Gisela Schwab (CMO)

All right. Thank you, Asthika.

Operator (participant)

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

Jason Gerbery (Analyst)

Hey, guys. Thanks for taking my questions. Quick, just on the early stage pipeline, just on XL-092, 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 XL-092 into pivotal trials later this year?

And then 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?

Michael Morrissey (President and CEO)

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.

Gisela Schwab (CMO)

Sure. Happy to do so. Thank you for the question. So XL-092 is making good progress, as I mentioned, in its phase I study and also in the phase I B 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.

Michael Morrissey (President and CEO)

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 back-end loaded small upfront deals, and there's certainly more of those to be done in the short to midterm.

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 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 of the frothy market dynamics and people looking for a lot.

So we're going to maintain a high level of discipline as we have in the past and go for good science and good value at the same time.

Jason Gerbery (Analyst)

All right. Thanks.

Michael Morrissey (President and CEO)

Thank you.

Operator (participant)

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

Andy Hsieh (Analyst)

Oh, great. Thanks for taking my question. So first one, maybe Gisela. So I'm just wondering if you can frame expectations for us for the kind of midyear update for cohort six. I know the company policy, you want to have sufficient follow-up and basically mature data sets. So can we expect kind of the full 130 patients from that cohort around midyear?

Gisela Schwab (CMO)

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 assessed objective response rate. And so that's really what we're aiming for later in 2021.

Andy Hsieh (Analyst)

Got it. That's very helpful. And maybe for P.J., if you look at slide number 31, you have basically the front line 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 Q4 or maybe a little bit into Q1 about any sort of material change to that picture.

Patrick Haley (EVP of Commercial)

Yeah. Hi, Andy. This is PJ. Thanks for the question. 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 75%-80% and 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 Cabometyx forward with nivo into that IOTKI market, and as I kind of mentioned, the team is really excited and working hard in 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.

Andy Hsieh (Analyst)

Okay. Thanks. That's helpful. So last question, this is for Peter. So as we think about the company kind of moving away from XL-265, that asset really was asking about relevant clinical questions regarding the roles of cAMP kinase. 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 early stage assets.

Peter Lamb (Chief Scientific Officer)

Yeah. I think what we learned from the XL-265 experience was kind of helpful and I think fairly 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.

Andy Hsieh (Analyst)

All right. Great. Thanks for answering my question.

Gisela Schwab (CMO)

Okay, Andy. Thank you.

Operator (participant)

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

Yaron Werber (Analyst)

Great. Thanks for taking my question and congrats on the launch in the nice quarter. Maybe just a couple of questions. One, just any inventory changes? Can you 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 CaboNivo, CaboNivo, 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? The data is obviously better, obviously a very small sample, but better than Cabo alone in the midyear. But when we're trying to compare it to a CaboNivo 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.

Michael Morrissey (President and CEO)

Yeah. You're on. Great questions. Why don't we start? Gisela, why don't you answer the last question first, and then Chris can cover the inventory question.

Gisela Schwab (CMO)

Sure. Happy to. So regarding the NCI CTEP study, the phase 1b study that will be presented by Dr. Pal, this is a trial that was conducted in patients with advanced GU malignancies.

Patients must have received at least one prior therapy, could have received multiple prior therapies. It's a rather heavily pretreated patient population across the board. 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 ASCO GU.

Michael Morrissey (President and CEO)

Okay. Your turn, Chris.

Chris Senner (CFO)

So on your inventory question, as I mentioned in my prepared remarks, the Cabometyx 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 $7.5 million on the net revenue line.

Yaron Werber (Analyst)

Great. Thank you.

Gisela Schwab (CMO)

You're welcome.

Operator (participant)

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

Michael Schmidt (Analyst)

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 IO-IO combos? Secondly, I thought the CNS data from ASCO 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 aspect of differentiation. And then lastly, on XL-102, your CDK7 inhibitor, I was wondering if you could just help us understand how that might fit into the breast cancer space mechanistically relative to CDK4/6 inhibitors. Thanks so much.

Michael Morrissey (President and CEO)

Hey. Thanks, Michael.

Why don't we start there? Peter, do you want to take the one or two question first, and then Gisela can do the brain mets, and PJ can do the question about brand impact?

Peter Lamb (Chief Scientific Officer)

Sure. So the question, I think it was specifically around opportunity for CDK7 inhibitors and XL-102 in breast cancer. And there were a number of 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 positive breast cancer, there's a direct connection between CDK7 and estrogen receptor, whereby CDK7 actually phosphorylates the estrogen receptor and increases its transcriptional activation potential. So again, combinations there with 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 there's at least those three kind of different flavors, if you like, of things that could be explored in the breast cancer setting.

Michael Morrissey (President and CEO)

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

Gisela Schwab (CMO)

Absolutely. Yeah. We're 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.

I'm highlighting that because patients with uncontrolled brain disease are usually excluded from clinical trials and certainly from large phase III trials because of potential complications that may occur in those patients. Usually, they have to have controlled disease to be included, if at all, in larger studies. 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 cabozantinib 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. So that is a feature that adds to but is 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.

Patrick Haley (EVP of Commercial)

Great. Thanks, Michael. This is P.J. 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. 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 prescribers learn more about Cabo.

I think 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 Cabometyx and RCC at this point. It is viewed as the best-in-class TKI according to our market research. And 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.

Michael Schmidt (Analyst)

Super. Thank you.

Gisela Schwab (CMO)

You're welcome, Michael. Thank you.

Operator (participant)

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

Peter Lawson (Analyst)

Thanks for the quarter and thanks for taking questions.

Just on first-line RCC, beyond that potential broad use of Cabo plus PD1, what niches do you think are easier to penetrate? Is it things like patients with brain and bone mets?

Patrick Haley (EVP of Commercial)

Yeah, Peter, this is PJ. I'll talk about that. I mean, again, I think we do really see the broad potential here, and when we look at the current utilization of ICI-TKI on the market, we see it utilized broadly, particularly in the community setting.

So, I think we'll 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 thinking about the tolerability profile and particularly the quality of life, which is just something not often seen in 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.

Peter Lawson (Analyst)

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 lenvatinib or Inlyta?

Michael Morrissey (President and CEO)

Honestly, in the TKI monotherapy categories where we do see in the last few quarters, historically, it's more the legacy TKIs.

If you look at the market share data, that's where you see some sunitinib usage, which, as Gisela mentioned, has kind of been the guideline recommended therapy for non-clear cell. So you see sunitinib and pazopanib 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 papillary RCC, that's 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 historically, that's really been more of pazopanib and sunitinib use outside of certainly the Cabo use that we have there.

Peter Lawson (Analyst)

Do you think that's kind of an easier area to penetrate, that single-agent first-line TKI mono?

Michael Morrissey (President and CEO)

Well, I really think the combo is going to be just such a big opportunity.

Our data is so strong that that should be really probably where we see rapid uptake. And it'll be more of a dynamic, certainly possibly a more dynamic market as we launch into that because that's certainly what we're going to be focused on.

Peter Lawson (Analyst)

Okay. Thanks so much.

Gisela Schwab (CMO)

Thanks, Vicki. Thanks for that, Peter.

Operator (participant)

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

Jay Olson (Analyst)

Hey, Jay, are you with us?

Gisela Schwab (CMO)

Yep. Can you hear me? Yes, you sure can now.

Jay Olson (Analyst)

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 $1 billion 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 Adagene 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 XL-092?

Michael Morrissey (President and CEO)

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

Peter Lamb (Chief Scientific Officer)

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 Invenra collaboration, who are the ones who can go out and find the 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 Catalent and with NBE then give us access to contemporary site-specific conjugation technologies, which I believe 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 Adagene fits into this, we 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 and 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 at 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. And 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 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 that can create manufacturing issues as well, ultimately 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 obviously, we have our first ADC, XB002, which will enter the clinic in the not too distant future.

Michael Morrissey (President and CEO)

Fantastic, Peter. Thanks for that deep dive into the overall ADC approach. And certainly, we're 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, yeah, good clinical trial data, successful regulatory outcomes, and then obviously very, very strong commercial execution. You'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 the commercial launch based on 9ER for first-line renal with CaboNevo. 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. We've got lung trials going. So all in all, probably nine or 10 pivotal trials ongoing right now with Cabo and various IO functionalities and certainly with the opportunity to do more going forward, the next wave or even two coming beyond that with O92.

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.

Jay Olson (Analyst)

It's super helpful. Thanks for sharing that vision with us.

Michael Morrissey (President and CEO)

You bet. Thank you.

Gisela Schwab (CMO)

Yeah. Thanks, Jay.

Operator (participant)

Thank you. Our next question comes from the line of Kennen MacKay of RBC Capital Markets. Please go ahead.

Kennen MacKay (Analyst)

Hi. Thanks for taking the question and congrats on the progress, and what a year. Thank you, Chris, or P.J. Can you help a little bit more with the metrics behind the Cabo Q4 results? 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'd 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 Lenvima-Keytruda combo in the CLEAR trial. Obviously, impressive median PFS and hazard ratio there, but that can obviously be defined by baseline demographics.

Michael Morrissey (President and CEO)

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.

Patrick Haley (EVP of Commercial)

Yeah. Hi, Kennen. It's PJ. Thanks for the question.

So 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 certainly, what we would say is we see. I don't want to comment on any methodologies or the way capture rates, etc., of the third-party prescription data providers, but we do see variation in that 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 with that over time. One thing I can even point out with regards to Q4, if you look at the TRX data for Exelixis, for example, I think they were up about 6%, whereas their Q over Q US revenue was up 23%. So you just see some discrepancies there, some variability.

I think as we look at it, certainly indicative of the strong momentum we had closing the year and really just setting us up well for Q1 and the launch that's ongoing.

Michael Morrissey (President and CEO)

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

Gisela Schwab (CMO)

Absolutely. Yes. So with respect to the Lenvima data, we've seen, as everyone on the call has seen, the abstract for ASCO GU for the CLEAR study. And certainly, we'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. I think that is the key that we'll be looking at when more detail is 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 and the CLEAR study, we see a performance that's a little bit more akin to the KEYNOTE-426 trial with a high response rate for sunitinib of 36% and then 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 favorable risk population patients. When we look at the CheckMate 9ER data where the median OS had been reached after 24-month follow-up with sunitinib showing a 29-month median OS.

So we'll be curious and looking for more detailed description 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 dataset. 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 datasets 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. Choueiri, Dr. George, and Dr. 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.

Kennen MacKay (Analyst)

Absolutely. Thanks so much.

Gisela Schwab (CMO)

Great, Kennen. Thank you.

Operator (participant)

Thank you. Our next question comes from the line of Stephen Willey of Stifel. Your question, please.

Stephen Willey (Analyst)

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 trial supply for 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?

Chris Senner (CFO)

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

Stephen Willey (Analyst)

Okay. And then maybe just to follow up on Gisela's comments regarding the potential incidence rate of favorable risk patients in the CLEAR trial.

I guess I understand the notion that a higher sunitinib 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 mets, etc.?

Michael Morrissey (President and CEO)

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.

Stephen Willey (Analyst)

All right.

Lastly, on the XL-092 phase 1, I think I noticed that you've specified hormone receptor positive breast cancer as a target indication both for monotherapy and for combination with Atezo, and was just curious if you can maybe provide some of the rationale there, just kind of given some of the underwhelming PD-1/PD-L1 data that we've seen there thus far. Thank you.

Michael Morrissey (President and CEO)

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

Gisela Schwab (CMO)

Sure, and I'm happy to comment on the phase 1 expansion cohort. So we have built those expansion cohorts based upon observations, of course, and learnings from the cabozantinib program, single-agent experience as well as IST and CTEP studies in that space, either in single-agent cabozantinib or combinations, and this is an indication where we've seen some activity for cabozantinib as a single-agent.

And we're curious about the combination with a checkpoint inhibitor given the cooperative activity that we are assuming here between the two pathways. And Peter, if you wanted to comment further, please.

Peter Lamb (Chief Scientific Officer)

No. I would just add that mechanistically, we think the rationale for combining XL-092 with checkpoint inhibitors is very broad and is applicable to multiple different tumor types. Some of the individual targets of XL-092, like MEK, for example, are certainly upregulated and overexpressed in breast cancer as well. So there's potential for kind of direct tumoricidal effects from the drug itself. But it's really around the breadth of the changes that we've seen with Cabo and are now seeing preclinically with XL-092 on different components of the immune system.

Stephen Willey (Analyst)

Okay. Thank you for taking the questions.

Gisela Schwab (CMO)

Thank you.

Operator (participant)

Next question comes from Paul Choi of Goldman Sachs. Your question, please.

Paul Choi (Analyst)

Thank you. Good afternoon.

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 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?

Peter Lamb (Chief Scientific Officer)

Thanks, Paul. Yeah, I mean, gross to net was slightly down in Q4 versus Q3. And we did have a higher proportion of commercial patients in the quarter. So that did impact our gross to net.

And from a 2021 perspective, we're looking at gross to net as we based on our guidance that we put forward, $950 million-$1.05 billion revenue guidance number, we're looking at gross to net in that 25%-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 XL-092 program, 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 asked this with regard to your comment in the PR and earlier comments just that you plan to proceed into pivotals by year-end here. So I was just the level of confidence and visibility that gives you a sense for being able to move into the pivotal trials by year-end here. Yeah.

Gisela Schwab (CMO)

Happy to address that question. The XL-092 single-agent phase 1 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 we'll 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 XL-092 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.

Paul Choi (Analyst)

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?

Gisela Schwab (CMO)

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

Paul Choi (Analyst)

Okay. Thank you very much.

Operator (participant)

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

Susan Hubbard (EVP of Public Affairs and Investor Relations)

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.

I want to thank you for joining us and certainly welcome your calls with any follow-up questions.