Puma Biotechnology Inc (PBYI) 2020 Q4 法說會逐字稿

Good afternoon. My name is Donna, and I will be your conference operator today. Welcome to the Puma Biotechnology conference call. (Operator Instructions) And as a reminder, this conference is being recorded.

I would now like to turn the conference over to Ms. Mariann Ohanesian, Senior Director of IR for Puma Biotechnologies. Thank you. Please go ahead.

Thank you, Donna. Good afternoon and welcome to Puma's conference call to discuss our financial results for the fourth quarter of 2020.

Joining me on the call today are Alan Auerbach, Chief Executive Officer, President and Chairman of the Board of Puma Biotechnology; Maximo Nougues, Chief Financial Officer; and Jeff Ludwig, Chief Commercial Officer.

After market closed today, Puma issued a news release detailing fourth quarter 2020 financial results. That news release, the slides that Jeff will refer to and a webcast of this call are accessible via the homepage and Investors sections of our website at pumabiotechnology.com. The webcast and presentation slides will be archived on our website and available for replay for the next 90 days.

Today's conference call will include statements about the company's future expectations, plans and prospects that constitute forward-looking statements for purposes of federal securities laws. Such statements are subject to risks and uncertainties, and actual events and results may differ from those expressed in these forward-looking statements. For a full discussion of these risks and uncertainties, please review our periodic and current reports filed with the SEC for time to time, including, once filed, our annual report on Form 10-K for the year ended December 31, 2020. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this live conference call, February 25, 2021. The company undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call, except as required by law.

During today's call, we may also refer to certain non-GAAP financial measures that involve adjustments to our GAAP figures. We believe these non-GAAP metrics may be useful to investors as a supplement to, but not a substitute for, our GAAP financial measures. Please refer to our fourth quarter 2020 news release for a reconciliation of our GAAP to non-GAAP results.

I will now turn the call over to Alan.

Thank you, Mariann, and thank you all for joining our call today.

Today, Puma reported total revenue for the fourth quarter of 2020 of $52.6 million. Total revenue includes net U.S. NERLYNX sales as well as royalty fees from our sublicensees . Net NERLYNX sales were $50 million in the fourth quarter of 2020, representing a slight increase from the $49.3 million in net sales reported in the third quarter of 2020 and a decrease from the $58.7 million reported in Q4 of 2019. Our fourth quarter results also include royalty revenue of $2.6 million versus $200,000 in Q4 of 2019. During the fourth quarter of 2020, we continued to experience challenges brought on as a result of the COVID-19 pandemic.

I will begin with a review of some of the highlights of the quarter, and then Jeff Ludwig will provide more details on NERLYNX commercial activities. Maximo Nougues will follow with highlights of the key components of our financial statements for the fourth quarter of 2020.

During the fourth quarter of 2020, there were several clinical updates for the company that were meaningful for investors. In early October, we announced that efficacy results of neratinib in HER2-positive, HR-positive, early-stage breast cancer from our Phase III ExteNET clinical trial were published in the journal, Clinical Breast Cancer. We believe that this publication will also increase awareness of NERLYNX and its benefit in this patient population.

We also presented updated data from the ExteNET trial and from our ongoing CONTROL trial, which is investigating ways to reduce the side effects of NERLYNX and improve the tolerability of the drug at the San Antonio Breast Cancer Symposium in December.

As investors are also aware, Puma has an ongoing basket trial of neratinib in HER2-mutated cancers referred to as the SUMMIT trial. The SUMMIT trial was modified in early 2020, such that ER-positive, HER2-negative breast cancer patients who have a HER2 mutation were randomized to receive either fulvestrant alone, fulvestrant plus trastuzumab or the combination of neratinib plus fulvestrant plus trastuzumab.

Under the initial Simon 2-stage design, each arm of the amended study will enroll 7 patients during stage 1. And if no patient in a given arm responds, that arm will be closed for further enrollment. If in the first stage, one or more patients respond, the arm will be expanded up to 18 patients. If less than 4 patients in the expanded arm respond, that arm will be closed to further enrollment. If more than 4 patients respond, the arm will be expanded and additional patients will be enrolled.

Enrollment in this trial is continuing in 2021, and our current estimate is that we will reach the initial enrollment of 21 patients, which would be 7 patients per arm, in early Q2 of 2021. The timing of this enrollment may be impacted by COVID-19 or the recent weather conditions in certain parts of the U.S. Once enrollment in this trial is complete, we would look forward to being able to perform a top line analysis of the response data, which would determine whether or not to expand their respective arms under the Simon 2-stage design that was previously described.

The timing of this is obviously dependent on enrollment and whether or not patients in a given arm responds. We would expect to have this top line analysis completed somewhere between mid-2021 and late 2021. As we have noted previously, we would further anticipate that this top line analysis would form the basis for a pre-NDA meeting with the FDA to discuss the potential for accelerated approval.

As investors are also aware, in November, we announced interim data from another cohort from the SUMMIT trial and, more specifically, the cohort of patients with metastatic non-small cell lung cancer with epidermal growth factor, or EGFR, exon 18 mutations who have been previously treated with an EGFR tyrosine kinase inhibitor. In late January 2021, we presented additional data from this cohort of patients in an oral discussion at the World Conference on Lung Cancer presented by the International Association for the Study of Lung Cancer. We are continuing to enroll this cohort of patients and anticipate that we will have additional data from this cohort to report in the second half of 2021.

Moving on to other developments in the fourth quarter. We were pleased to announce that Puma prevailed in the final appeal proceedings brought against its licensed European patent, EP patent 1848414, which covers the use of irreversible EGFR inhibitors in treating gefitinib and/or erlotinib-resistant cancer and cancer with a T790M EGFR mutation. The European Board of Appeal announced its decision at a final hearing on December 1, concluding that the opposition of the patent initiated by a Boehringer Ingelheim entity was inadmissible and reversing the European opposition decision issued in 2014, thereby upholding the patent as originally granted.

In addition, today, after the close, Puma announced that Puma and Pierre Fabre have agreed to extend the terms of their existing licensing agreement to include granting Pierre Fabre commercialization rights for NERLYNX to Greater China, which includes Mainland China, Taiwan, Hong Kong and Macau. Under the terms of the agreement, Puma will receive an upfront payment of $50 million as well as additional regulatory and sales-based milestone payments that could add up to an additional $240 million. These milestones will be based solely on regulatory and sales achievements in Greater China. In addition, Puma will receive significant double-digit tiered royalties on the sales of NERLYNX in Greater China.

In addition, Puma and CANbridge Pharmaceuticals have mutually agreed to terminate their license agreement to commercialize NERLYNX in Greater China. Puma has agreed to pay CANbridge a onetime fee of $20 million in return to -- to return all rights to neratinib in Greater China back to Puma.

We are pleased to extend our relationship with Pierre Fabre into the Greater China region. Pierre Fabre currently markets the drug Navelbine, also known as vinorelbine, which is one of the common chemotherapy drugs used in the treatment of breast cancer in China and is, therefore, well equipped with an existing commercial infrastructure in China to make NERLYNX a success in Mainland China. We anticipate that Pierre Fabre plans to make NERLYNX available to breast cancer patients in Mainland China in the second quarter of this year.

I will now turn the call over to Jeff Ludwig, Puma's Chief Commercial Officer, for a review of our commercial performance during the quarter.

Thanks, Alan. Appreciate it and thanks to everyone for joining our fourth quarter earnings call.

The commercial organization continues to work very hard to reposition NERLYNX with the goal of strengthening the risk-benefit perception, increasing our promotional interactions with customers and deploying resources in an innovative and efficient manner. We believe that NERLYNX can play an important role in the treatment of metastatic breast cancer, but our focus is on extended adjuvant with the goal of preventing patients from becoming metastatic. This market is significantly underpenetrated and more must be done to help patients and their families in this battle with early-stage breast cancer. I am pleased with the foundational work that has been put in place, and we are increasing our emphasis around focus and execution moving forward.

Before I move into the commercial review, just a reminder that I will be making forward-looking statements.

As you may recall, we have 2 channels that provide NERLYNX to patients. We refer to these as our specialty pharmacy channel and our specialty distributor channel or in-office dispensing channel. The majority of our business flows through the specialty pharmacy channel. More specifically in Q4, approximately 79% of our business went through this channel with the remaining 21% flowing through the specialty distributor channel. This is in line with what we reported during our Q3 earnings call as well.

Now later in the call, Maximo will review the full financial results, but I will now provide you with the current U.S. sales results. Slide 4 shows U.S. quarterly net sales of NERLYNX since FDA approval. As Alan noted, our net U.S. product sales were $50 million in the fourth quarter of 2020. This is a slight increase over the $49.3 million we reported in Q3 of 2020.

As mentioned on prior Q4 earnings calls, we tend to see a decline in new patient starts in the fourth quarter each year as some patients decide not to initiate new therapies around the Thanksgiving, Christmas and New Year's holidays. In addition, these results continue to be impacted by the COVID-19 pandemic.

As you are likely aware, COVID-19 infection rates and deaths increased significantly in the fourth quarter to levels not seen previously, and we have only recently begun to see these decline. These spikes have caused continued challenges with live face-to-face interactions with customers and virtual interactions remain the norm.

The field team is working very hard to adapt to this new environment, and we have increased our nonpersonal promotional efforts. With that said, overall promotional interactions remain below our pre-COVID baseline. In addition, these spikes can cause a disruption in overall patient flow, and this is more likely to occur in the early-stage breast cancer setting. Combining the Q4 holidays along with the significant increase in COVID-19 infections, we did see some softening in both the specialty pharmacy channel and the specialty distributor channel in Q4.

Now Slide 5 shows the bottles of NERLYNX sold by quarter since launch. We sold 3,585 bottles of NERLYNX in Q4 2020, which is a very slight decrease from our Q3 2020 bottle sales of 3,611. The focus of the commercial organization is to grow NERLYNX quarter-over-quarter, which did not happen in Q4.

With that said, I mentioned previously that I am happy with some of the foundational work that has been put in place to change the risk-benefit perception of NERLYNX. Key elements of this strategy include the following: first, the publication of the interim results of the CONTROL study in the September edition of Annals of Oncology. This was important because it highlighted that anti-diarrheal strategies, including dose escalation, can significantly reduce the incidence of grade 3 diarrhea and improve overall tolerability of NERLYNX.

The second key element was the publication of the final efficacy results from the ExteNET trial in the October edition of clinical breast cancer. This was important because it highlighted the benefits seen in a descriptive analysis of patients at heightened risk of disease recurrence. These patients were HER2-positive, HR-positive with residual disease receiving NERLYNX within 1 year following their trastuzumab-based therapy. This descriptive analysis demonstrated a consistent benefit in invasive disease-free survival, overall survival and CNS events. We believe that NERLYNX can play an expanded role in the broader extended adjuvant setting, but it's important to note that there remains significant opportunity even in this high-risk group.

And finally, good representation of NERLYNX during December San Antonio's Breast Cancer Symposium with 10 accepted posters, including a spotlight poster on the ExteNET OS data and a poster highlighting the benefits of dose escalation from the CONTROL study. We believe that this information, combined with additional supporting initiatives, can play an important role in changing the perception of the risk-benefit profile of NERLYNX going forward.

An early indicator of the impact of the CONTROL publication can be seen on Slide 6, which shows that in Q4, approximately 38% of all new patient starts were initiated at a reduced dose. This is an increase over the 33% we reported in Q3. As a reminder, this is very important since the CONTROL data showed that utilizing a dose escalation strategy in the extended adjuvant setting, coupled with prn loperamide, showed a greater than 60% reduction in grade 3 diarrhea, a 60% reduction in median cumulative days of grade 3 diarrhea and an approximate 80% reduction in discontinuation.

We believe that the increasing adoption of dose escalation will improve the overall tolerability of NERLYNX and increase the average length of therapy with the end result benefiting more patients battling breast cancer.

Slide 7 highlights the strategic collaborations we have formed across the globe with the goal of making NERLYNX available to more patients around the world. Key highlights in Q4 include the launch of NERLYNX in Finland and Switzerland as well as the most recent metastatic approval in Argentina that occurred in January of 2021.

In addition, as Alan highlighted in his opening remarks, we have extended our partnership with Pierre Fabre to Greater China, which will now include Mainland China, Taiwan, Hong Kong and Macau. We are continuing to work closely with our partners and look forward to the potential for NERLYNX to be approved in additional countries in Europe, Latin America, Asia and the Middle East.

In summary, I'm proud of the foundational work that has been done by the team and believe that we are well positioned to increase the impact we are having on patients battling HER2-positive breast cancer.

I will now turn the call over to Maximo for a review of our financial results. Maximo?

Thanks, Jeff.

I will begin with a brief summary of our financial results for the fourth quarter of 2020. Please note that I will make comparisons to Q3 and Q2 2020, which we believe are better indications of our progress as a commercial company than year-over-year comparisons. For more information, I recommend that you refer to our 10-K, which will be filed in early March and includes our consolidated financial statements.

For the fourth quarter of 2020, we reported a net loss based on GAAP of $15 million or $0.38 per share. Our GAAP net loss for Q3 2020 was $31.5 million and our GAAP net income for Q2 2020 was $3.4 million. On a non-GAAP basis, which is adjusted to remove the impact of stock-based compensation, we reported a net loss of $5.5 million or $0.14 per share for the fourth quarter of 2020.

Gross revenue from NERLYNX sales was $60.1 million in Q4 2020 versus $58.6 million in Q3. As Alan mentioned, net revenue from NERLYNX sales was $50 million, a slight increase from net sales of $49.3 million in the third quarter of 2020. In Q4 2020, we also recognized $2.6 million in royalty revenue from our global partners versus $1.5 million in Q3.

Our gross-to-net adjustment in Q4 was about 16.8%, an increase from the 5 -- 15.8% gross-to-net adjustment in Q3. The increase was driven mostly by higher rebates due to our price increase in August.

Cost of sales for the fourth quarter was $10.9 million, which included the amortization of intangible assets related to our license of neratinib of approximately $2 million. Going forward, we will continue to recognize amortization of the milestone payments to the licensor of about $2 million per quarter as cost of sales.

For fiscal year 2021, Puma anticipates that NERLYNX net sales will be in the range of $205 million to $210 million. We also anticipate that our gross-to-net adjustment in 2021 will be between 18.5% and 19.5%. Furthermore, for fiscal year 2021, we anticipate receiving royalties from our partners around the world in the range of $16 million to $17 million and potential license revenue in the range of $30 million to $32 million.

We recognize there is a great deal of uncertainty regarding the impact of COVID-19, and this may continue to negatively impact our sales, royalties and license revenue. Historically, the first quarter represent the lowest net product sales quarter of the year due to a number of factors, including the decline in new patients starting NERLYNX during the holidays in the fourth quarter of the prior year, which carries over to bottles sold in Q1. Also, the recent weather conditions in certain parts of the U.S. created some disruptions to our shipment and enrollment. We are tracking the recovery closely.

We anticipate that Q1 2021 NERLYNX net sales will be in the range of $42 million to $43 million, royalty revenues will be in the range of $2 million to $3 million and license revenue will be $30 million. Also, we anticipate that the gross to net in Q1 2021 will be approximately 20% to 21%.

SG&A expenses were $28.8 million in the fourth quarter of 2020 compared to $29.6 million and $29.4 million for Q3 and Q2 2020, respectively. SG&A expenses included noncash charges for stock-based compensation of $4.3 million for the fourth quarter of 2020 compared to $4.1 million for Q3 and $4.7 million for Q2. Research and development expenses were $24.2 million in the fourth quarter compared to $23.3 million and $24.7 million for Q3 and Q2 2020, respectively. R&D expenses included noncash charges for stock-based compensation of $5.3 million in Q4 compared to $3.5 million and $5.9 million for Q3 and Q2 2020, respectively.

In the fourth quarter of 2020, Puma reported cash burn of $15.6 million, which included a $10.1 million milestone payment to Pfizer compared to cash earned of $1.8 million in Q3 and $6.2 million in Q2 2020. For the full fiscal year, our cash burn was $19.3 million, which included $20.6 million of payment to the licensor of neratinib.

We ended the fourth quarter of 2020 with $93.4 million in cash, cash equivalents and marketable securities. Our accounts receivables balance at December 31 was $25.5 million. Our accounts receivables turn range is between 10 and 68 days while our days sales outstandings are about 46 days. We estimate that as of year-end 2020, our distribution network maintained approximately 3 weeks of inventory.

Overall, we continue to deploy our financial resources to focus on the advances of neratinib through ongoing clinical trials and the commercialization of NERLYNX.

Thanks, Maximo.

We continue to recognize that we need to improve NERLYNX sales growth and that the COVID-19 pandemic is presenting challenges to us with respect to achieving that growth. Puma's senior management, in cooperation with the Board of Directors, continues to remain focused on NERLYNX revenue and sales growth in 2021 and beyond. We are continuing to adapt to the virtual environment that we have needed to pivot toward due to the COVID-19 pandemic. And we are hopeful that changes to our commercial infrastructure will make a positive contribution to NERLYNX sales growth. We look forward to updating investors on this in the future.

There continues to be a significant unmet need for women battling breast cancer. We at Puma are committed and passionate about finding more effective ways at helping these patients during their journey, and we will continue to strive to achieve that goal.

This concludes today's presentation. We will now turn the floor back to the operator for Q&A. Operator?

(Operator Instructions) Our first question today is coming from Kennen McKay of RBC Capital Markets.

Maybe a twofold question. I'm wondering, first off, sort of next steps on the ongoing litigation on T790M on your IP in the EU. And then beyond that, as it relates to sales of NERLYNX, just wondering in the metastatic setting what the feedback has been from reps around competition with Tukysa in HER2-positive space, again, metastatic setting.

Thank you for the question, Kennen. So with regard to our T790M patents, as I'm sure you can imagine, that topic is one that's a very sensitive legal matter. And so therefore, there's not much comment we can provide on it.

On your second question with regard to the metastatic. Jeff, if you'd like to take that?

Sure. Happy to. So Kennen, as I mentioned in the opening remarks, we are excited that NERLYNX was approved in the metastatic setting in February. As you mentioned, Tukysa was approved soon thereafter in April, and we feel very good. And quite honestly, another agent was approved in late December. So that's very good for patients in a metastatic setting where there's many more options.

We are still watching to see how that sequencing plays out. But I can tell you that our focus is really in extended adjuvant, trying to do everything we can to prevent patients from becoming metastatic. In the metastatic setting, we expect to see some sequencing of agents as, unfortunately, patients progress. But in the extended adjuvant setting, we do not see the same type of competitive environment. And we believe that market is significantly underpenetrated. So our focus is really in the earlier lines of therapy.

Yes. And Kennen, I can add to that. Look, in the metastatic setting, and especially kind of that third line and beyond, there's been 4 drugs approved within 2020 time frame. You had -- in HER2, Tukysa, NERLYNX and then Margenza. And as Jeff said, from a commercial standpoint, that's an extremely competitive area.

So it's much wiser for us to maintain our focus on the extended adjuvant where there is no competition for us when a new drug is approved. And so that tends to be where we have the very large majority of our focus.

Our next question is coming from Kenneth Atkins of Cowen.

As we look forward to the update in the second half, could you remind us what you think the bar for success is in EGFR exon 18 lung cancer? What profile do you think you need to achieve there to be successful?

Thanks for that question. That is a good question. I don't know the answer to "what the bar is to be successful," if you will. We are focusing on patients who have an EGFR exon 18 mutation and specifically, those who've already been treated with EGFR TKI. The only data that's out there in that space would be the data with afatinib, which showed a roughly 10-ish percent response rate. So using that as a bar, using that as kind of a comp, if you will, that's where I think the bar is.

Obviously, I can't answer that from a regulatory standpoint until we've actually had a discussion with them. But from our perspective, our interim data showed a 40% response rate. We think that compares very, very favorably to the data with afatinib. I think the best comp I can give and the only one that's out there for that niche, if you will, is the afatinib data. So that's the best barometer I can give you.

Got it. Okay. And then just one question on the guidance. What kind of assumptions are built into the guidance for NERLYNX sales in 2021 in terms of what happens with the pandemic? And how should we think about trend through the year?

Jeff, would you like to take that?

In terms of guidance for NERLYNX, especially focused on the U.S., we are thinking about the COVID pandemic. Obviously, you're aware of what's happening here. We believe a lot of folks are beginning to get vaccinated. And ultimately, we believe the second half of 2021 will be very different than the first half of 2021 from a commercial promotional perspective as we start to see hopefully, knock on wood, offices begin to open up, travel resume in a little bit more normal fashion. And ultimately, from NERLYNX commercial standpoint, this is a very promotionally sensitive product. And we obviously have some very good data that came out in the latter half of 2020.

And so having those channels open up for more promotional activity should allow us to build growth quarter-over-quarter moving forward.

(Operator Instructions) Our next question is coming from Cory Kasimov of JPMorgan.

This is Turner on for Cory. So it sounds like the pre-NDA meeting to discuss accelerated approval of the HER2-mutated hormone-receptor positive breast cancer cohort of the SUMMIT trial will occur later this year. Can you just talk about the pushes and pulls of getting accelerated approval? And perhaps just what do you think you need to show in the data to achieve it?

Yes. Just to clarify, you're talking about the HER2 mutant breast, correct?

Yes. Correct. Yes.

Yes. Okay. So if you don't mind, I'll go into kind of a long-winded explanation here. When we started the SUMMIT trial, we were first treating with neratinib as a single agent in that study. So these were patients who were HER2-negative, ER-positive and had a HER2 mutation. We treated with neratinib. We were getting responses, but the duration of them was very short. And what we found was, looking at pre- and post-treatment biopsies, we were finding that when you gave neratinib to inhibit the mutation, the estrogen receptor transcription was upregulated, quite high. So it was clear that the mechanism of escape there was the estrogen receptor.

So we then moved forward with combining neratinib with fulvestrant, so that we are hitting the HER2 mutation and hitting the estrogen receptor. We were getting a higher response rate. We were getting a longer duration of response, but it wasn't kind of that 9-, 10-month types of durations we were looking for. We again did pre- and post-treatment biopsies and what we found was, although we were hitting the estrogen receptor and we were hitting the mutation and the tumor was HER2-negative, the mechanism of escape was it was upregulating the HER2 receptor, so it's flipping from being HER2-negative to HER2-positive.

So we then gave neratinib to hit the mutation. We gave fulvestrant to hit the estrogen receptor. And then we were getting Herceptin, trastuzumab to prevent the tumor from trying to go to become HER2-positive. That's when we started getting much higher response rates, longer durations.

We went to the FDA, and we had a meeting with them to discuss the path forward. And they acknowledged that the science was very well thought out, and they even acknowledged to us that they have had a lot of meetings with companies where were some involving kind of smaller targeted populations or you needed more than one drug to try to treat -- effectively treat the tumor. What they asked us to do was to try to isolate the contribution of neratinib to that triplet, to the neratinib, Herceptin, fulvestrant triplets. And that's where Simon 2-stage came in, which was the triplet in one arm; Herceptin, fulvestrant in the other; fulvestrant alone in the other.

It's going to really depend on what we see in that data. I mean if you see what you would hope to see, which is the clear advantage of the triplet over the others, I'm hopeful that will be what the FDA was looking for. Now we obviously have a very large body of data on the triplet on neratinib, Herceptin, fulvestrant, and that would obviously form a very significant basis of an accelerated approval filing. But we're hopeful, if you see that clean separation, that's exactly the question the FDA would like answered.

So I can't kind of give you any metrics or numbers. All I can say is that appears to be what they have asked us to do, that's what we are doing. And so we will know more after we've seen the data and had a discussion with the FDA.

Our next question is coming from Geoff Meacham of Bank of America.

This is Alec on for Geoff. I think Jeff touched on this a little bit, but on your new partnership with Pierre Fabre in Asia, how do you view the market for neratinib in these geographies versus what you've seen in the U.S.? And I guess what is your sense as to Pierre Fabre's commitment to pushing neratinib in these markets versus your prior partner?

And secondly, I guess related to that, what will be your go-to-market strategy in additional geographies, whether we could expect additional partnerships announced over the course of '21?

Okay. So to talk about Pierre Fab. Pierre Fabre has been a great partner to us in Europe. We expanded the partnership once to include some other countries in addition to Europe, and this is the second expansion of it. Their execution has been excellent in Europe, and they've been a wonderful partner to us. One of the things that's very attractive about them is the fact that they have been selling the drug navelbine, which is vinorelbine, which is one of the main chemotherapy drugs used in breast cancer. So there is an existing channel that's in place to breast cancer physicians in their territories.

In terms of in China, there -- train -- they've already been training their people, and we're scheduled to launch the drug in China in the second quarter, so in a few months. They have a very large commercial infrastructure there. It's on par with the other companies in the area. So we have a very optimistic view of it.

In terms of the actual dollar amounts, I would say that the U.S. is probably the biggest market for the drug. Europe is probably second. And I would say China is close behind in that second place, and it may actually be a tie between Europe and China. So I think it's going to be a very significant opportunity for us, and we're looking forward to their launch there.

Now in terms of your question on other territories. As Jeff went over in his slide, we've got pretty much partnerships across the board. I think there's a few more countries out there, but the main ones, which is obviously now Europe, the Middle East, Northwest Africa, South Africa, Latin America, Canada, Israel, Australia, they -- we all -- we partnered those.

So we've got -- I think the main large country that we still haven't partnered is Japan. And then I think there's a few smaller ones as well.

Our next question is coming from Paul Choi of Goldman Sachs.

This is Charlie on for Paul. So I've just got a quick question. It's great to see the uptake of the dose titration increase with the Q4 patients that you showed there. I'm just wondering or we're just wondering, what is being done in terms of expanding, making sure that patients continue that uptake of this dose titration regimen from the CONTROL study? In addition to publication of the CONTROL study results, what's being done to promote this sort of regimen to increase NERLYNX uptake?

Yes. No. I appreciate it. Very good question. We believe that is a very important foundational part of our strategy is as we believe the embedding or operationalizing of dose escalation can change the profile of risk benefit and tolerability. So clearly, a significant message for the field force commercially, both directly as well as nonpersonal promotion, is to highlight the benefits of the CONTROL study.

We have also submitted the CONTROL study to the FDA for a label update, a potential label update coming forward. And we are working with many of the pathways and guidelines committees as well to ensure that this becomes embedded as part of the standard of care for extended adjuvant patients there as well.

One other piece that we're moving forward with is, we have actually received approval for a new bottle size. That is a 133-count bottle size that supports the adoption of dose escalation for the first month of therapy. That bottle size obviously supports the 3 pills per week, 4 pills per week and then 6 pills for the remaining 2 weeks. So that will also be launched in the foreseeable future as well to further embed dose escalation.

Our next question is coming from Gena Wang of Barclays.

This is Sheldon on for Gena. The first, could you comment on your current revenue breakdown from the extended adjuvant setting versus metastatic and also, your expectation about this breakdown -- the evolution of this breakdown going forward? Can we assume that, that majority will still come from extended adjuvant?

And second is on the EGFR exon 18 mutated non-small cell lung cancer. Do you have any idea about the current penetration of genetic testing for these specific mutation? Is it bundled in the EGFR testing already?

Okay. On your first question, Jeff, you'd like to handle that?

Yes.

I believe what they're asking is the breakdown of metastatic versus extended adjuvants.

Yes. We estimate currently, let's say, in the fourth quarter, about 6% of our new patient starts are in the metastatic setting. And I would suggest that, that expectation or breakout will be consistent for at least the next several quarters.

As I mentioned before, our focus is really heavily on the extended adjuvant in early-stage breast cancer where there's an awful lot of patients that are not being treated there. And we think we can make a bigger impact on patients' lives and -- with the goal of preventing them or hopefully helping them prevent recurrence in the metastatic setting.

And then on your second question, which is on the EGFR exon 18. In lung cancer, they're very good about doing mutation screening. I would venture to guess that it's pretty much done for every patient. And the EGFR exon 18 mutation is already on the lung cancer panel that everybody runs. So there's no special test that anyone has to run. It's being picked up on the existing panels.

At this time, I'd like to turn the floor back over to Mariann for closing comments.

Thank you for your interest in Puma Biotechnology. As a reminder, this call may be accessed via replay of the webcast at pumabiotechnology.com beginning later today. Have a good evening.

Ladies and gentlemen, thank you for your participation and interest in Puma Biotechnologies. You may disconnect your lines at this time and have a wonderful day.