HUTCHMED (China) Limited (HCM) Earnings Call Transcript & Summary

Okay. So I think we're live now. So welcome, everybody, to the Hutchison China MediTech conference call today to talk about ASCO and some of the other things that are going on in our business. My name is Christian Hogg. I'm the CEO of Chi-Med. I have also on the line Dr. Wei-Guo Su, our Chief Scientific Officer; and Dr. Marek Kania, our Chief Medical Officer, for our international operations based out of New Jersey. Today, if you go to Page #3 on the presentation, we'll be covering a few subjects. First of all, savolitinib Exon 14 skipping non-small cell lung cancer, the presentation of the registration study data that was presented or that was published today in full on the virtual ASCO site. Second, Wei-Guo will also take you through the data from the SAVOIR study, the papillary renal cell carcinoma study of savolitinib. And then Marek will take you through the international data, the U.S. data on surufatinib and also give an update on the announcement that we made today around our plan to proceed to NDA submission on surufatinib in the United States later this year -- starting later this year. Then we'll finish with Q&A. And what I plan to do or what we plan to do is try to keep the prepared comments to maybe 30 minutes and then leave 30 minutes for questions at the end. So we'll move quite quickly through the slides. Moving to Page #4. The pipeline -- the portfolio really continues to expand and progress. You can see on the far right-hand side of Page #4, we'll be talking today about savolitinib Exon 14. We have submitted now the NDA in China. That was last week. And that's our third NDA filing as a company of -- for novel oncology drugs. So obviously fruquintinib in colorectal, surufatinib in neuroendocrine tumors and now savolitinib in non-small cell lung cancer. So that's our third, and we're very excited to talk about that today. Moving back, there are 2 boxes in the registration intent area that we'll talk about today. The first is the SAVOIR data for savolitinib in papillary renal cell carcinoma. And then 4 rows down from the top, you can see surufatinib NET. Now the red box there, which is global development is now moving towards NDA as a result of our pre-NDA meeting with the U.S. FDA. So those are the 3 areas we'll talk about today: Exon 14, papillary renal cell carcinoma and surufatinib global NET. Moving to Page 5. This summarizes our overall approach. Today, as I said, PRCC and Exon 14 is our focus. We won't talk about our combination studies with Tagrisso and the PD-L1. That's for later this year with the interim analysis on the SAVANNAH study coming up midyear. But today, we'll just talk about the monotherapy programs. Moving on to Page #6, just the pie chart that we all know very well. As far as Exon 14 is concerned, the way it's represented on the pie charts on Page #6 is the -- in the treatment-naive setting, the red section, 6% MET positive patients in that first-line setting. It's actually Exon 14 is not restricted only to first-line patients, of course. But in this diagram, that's how we represent it. We think it's a reasonably large potential market size globally. Obviously, if you refer to ALK fusion patients, you can see that's well over USD 1 billion in sales there. So MET Exon 14 deletion and also c-MET gene amplification, which behaves in the same way in the monotherapy space. These are important patient populations with major unmet medical need. Moving on to Page #7, papillary renal cell carcinoma. This is a chart we've shown for several years now. But just to remind everybody, the patient population that was treated in SAVOIR, that Wei-Guo will talk about later, are MET-positive papillary renal cell carcinoma. So on the far right-hand side of this chart, you can see the top section. About 8% of all renal cell carcinoma are MET-positive papillary renal cell carcinoma and these are patients that genuinely today have very few treatment options. Moving on to the next page, Page 8. Again, for surufatinib, we'll be focusing on the monotherapy section of this chart. So the global net registration, the fast track designation that we received recently in the United States and our dialogue with the EU and Japanese regulatory authorities. So Marek will update you on that. Page 9. You can see where we sit with regards to the neuroendocrine tumor landscape very much in this grade 1/2 advanced NET space, where you see a median overall survival of about 8.3 years and moderately differentiated tumors. So that's the unmet medical need that surufatinib is going after. Finally, on Page #10, before I let Wei-Guo take over. You can see a chart that we've shown before, which shows the NET treatment landscape. And on the far right-hand column, you can see surufatinib, while not yet approved, the SANET-ep and the SANET-p studies have covered all of those NET patient subtypes. So really, the broadest positive clinical -- Phase III clinical study readouts across all NET. So that's what gives us a lot of excitement around the broad applicability of surufatinib in neuroendocrine tumors across the entire spectrum. So now moving on to Wei-Guo to take us through the Exon 14 skipping data on Page #12. Wei-Guo?

Thank you very much, Christian. I'll cover savolitinib Exon 14 study first. Just moving on to Page 12, the ASCO abstract, the 9519. So on Page 12, this is just the study design. This, obviously, was an open-label Phase II registration study in patients with PSC or non-small cell lung harboring MET Exon 14 skipping mutations. The primary end point is the IRC-assessed overall response rate. And the patient population, PSC, non-small cell lung primarily failed the first-line chemo or those who are medically unfit for chemo and with a group of patients who are older and with a poor performance status and they have to be naive to MET inhibitor treatment. As of March 31 this year, 50 out of 70 patients have progressed or have discontinued treatment. 20 patients were still on treatment. Page 13 is just the patient demographics for the 70 patients studied. Of note, there was a high proportion of PSC patients, 35.7%. And this is a very rare type of non-small cell lung cancer called pulmonary sarcomatoid carcinoma. It's probably 1% of the entire lung cancer. And with MET Exon 14 skipping mutations with these patients, this is a very aggressive disease and also tends to happen in elderly patient population. So if you look at the table, median age, so we have 25 PSC, 45 the other types of non-small cell lung, median age 69 versus 68, so overall 68.7 years of age. And I think it's also -- the rest are very similar comparing to other studies, a bit more male over female. And looking at the status -- performance status, the great majority were ECOG 1 over 80%; for PSC, almost 90%, ECOG 1 or higher. About 24% of the patients had baseline brain mets. And if you look at naive patients versus previous treated, you can see a higher proportion of naive patients in the PSC subgroup. So these are patients -- not they are just old. They have a very aggressive disease. They have poor performance status and they're not fit for standard of chemo, so they ended up in our study. Moving on to Page 14 right on to the -- our primary end point of the study, the IRC-assessed overall response rate. So we have 2 different sets here. The efficacy evaluable set, 61 patients out of the 70 for the IRC and 62 for the investigator assessor group. The difference is 1 patient that in the investigator assessor group with a tumor lesion size of 15 millimeters right at the border line for a target to qualify as a target lesion. But in IRC, 2 out of the 3 members measured, the tumor lesion was 14 millimeters. So this patient was disqualified as a patient with a targeted lesion. So that was the difference. And if you look at the IRC-assessed ORR, the confirmed OR was 49.2%; and stable disease, 44.3%; and very low level of disease progression, 6.6%. So add the lot, have the disease control rate of 93.4% and an interim duration of response, obviously, this is still ongoing, as you can see, the upper end is not reached yet, but median was 9.6 months. So we clearly demonstrate savolitinib activity in this particular patient population. On the right-hand side, you see the full data set. That's the intent-to-treat patient population. That's the entire 70 patients, including 9 -- or 8 or 9 patients that did not have any post [ baseline ] tumor assessment. In other words, those patients who dropped off early. And within the intent-to-treat, confirmed PR, confirmed ORR was 42.9%. And the disease control rate all the way down to the bottom was 82.9% and the duration of response 9.6 months as well. Now if you look at different subgroups, as we talked about, we had a higher proportion of PSC patients. And if you look at the response versus PFS in the next slide is that you can see, this is on Page 15, the upper-left table, is comparing PSC versus other non-small cell lung by the IRC. You can see the response rate were very similar, 50% versus 48.8% and the DCR was 90% versus 95.1%, and the duration of response not reached for PSC as a data cutoff, 9.6 months for other non-small cell lung. And here right, when we look at the first-line patient treatment versus second line and above, we had several patients in previous untreated. The ORR was 54.2% and the DCR was 95.8%, interim duration of response was 6.8 months. Now patients -- previous treated patients, the ORR was 46%, the DCR was 91.9% and the duration of response has yet to reach. I think the main difference here is in the previous untreated patients, these were patients, as I mentioned earlier, were deemed to be medically unfit patients and ended up a high proportion of PSC patients and also older patients at median age for this particular group was 75 -- almost 75 years of age. So this clearly had some impact on the efficacy, in particular, duration of response. Page 16, progression-free survival. By histology or by lines of therapies or prior lines of therapies, clearly, you can see here PSC 5.5 months versus non-small cell lung at 9.7, almost 10 months. And by prior treatment, naive 5.6. This will go against the grain because, as I mentioned, this previously untreated patients in our study had a much higher portion of PSC patients and this group also had a much higher median age, 75 -- close to 75. So comparing to previously treated patients, PFS was 13.8 months. Moving on to Page 17, safety. Safety was consistent with the profile reported earlier as a monotherapy in our older studies. You can see that the main grade 3 or higher AEs were either peripheral edema or the liver enzyme elevation. Everything else was mild-to-moderate grade 1/2 adverse events. So in summary, this study demonstrated savolitinib is a promising antitumor agent for non-small cell lung cancer with Exon 14 skipping mutations with an acceptable tolerability. That's all about the Exon 14 lung study. And as Christian pointed out, in China, the NDA has been submitted and that was accepted end of last month. So I'll just move on to next study, the SAVOIR study on Page 19. SAVOIR is a -- was meant to be a Phase III study in comparison to sunitinib in patients with MET-driven PRCC. Toni Choueiri was the -- at Dana-Farber was the leading investigator. Page 20, a quick intro. PRCC is about 15% of RCC. And the MET-driven was only a bit less than half of that. So it was estimated as 8%, as Christian earlier pointed out. And what we found was that in our Phase II study, this MET-driven group of PRCC patients were responsive to MET inhibitor, in our case, savolitinib. And the primary gene alteration in this group is -- actually obviously involves MET mutation, amplification, but the primary -- the highest frequency was chromosome 7 polysomy. I'll get to it when we look at the patient demographics. Page 21 was the study design. This is a line agnostic prior treatment -- no prior sunitinib treatment because this is a comparison to -- a study to compare sunitinib treatment. Patients were randomized 1:1 600 savo once-a-day versus sunitinib 50 milligrams QD. The primary end point is the PFS by BICR. So moving on to Page 22. A total of 254 patients screened, only 60 patients were randomized. And one of the reasons of this screen failure was obviously MET positivity. We -- in the previous studies, we found about 40% to 45% MET positive in this patient population. But in the Phase III study, looking at the MET failure, it was about -- the positivity was only about 30%. The 60 patients who were randomized into savo and sunitinib, 600 milligrams for savo, n equals 33 and 50 milligrams sunitinib 27 patients. The baseline, as you can see here, the majority were first line, meaning these were naive patients. And not surprising because the 60 patients, the majority of these patients came from the United States, where sunitinib is broadly used. Now if you look at the gene abnormality here, the MET-driven, MET amplification, HGF amplification and mutation, you can find them all at relatively low frequency, but chromosome 7 polysomy is primarily 90% above -- with the chromosome 7 polysomys. Efficacy, Page 24. You can see a clear separation around -- at the median. Savolitinib was 7.0, sunitinib 5.6, a hazard ratio of 0.71. Obviously, a very small sample size. And most encouraging was on Page 25, the overall survival of the 60-patient study, where you can see here, savolitinib was not reached. The median and sunitinib was 13.2 months, hazard ratio of highly positive at 0.51. Page 26, looking at the antitumor activity. The BICR-assessed overall response rate 27% for savo, 7% for sunitinib and it was statistically significant. And also, the duration of response was not mature, but you can look at the disease control rate at 6 months, 48% for savo and 37% for sunitinib; and at 12 months, 30% for savolitinib and only 22% for sunitinib. So there's a clear trend of -- in favor of savolitinib. Page 27, the waterfall chart for the 2 groups. As you can see, 29 patient: 9 PRs for savo, 27%; and 2 for sunitinib, 7%. Page 28, the safety profile. You can see here, grade 3 AE, 42% for savo and 81% for sunitinib. And the related grade 3, 24% for savo, 63% for sunitinib, so much lower frequency of these serious side effects for savolitinib. And if you -- going all the way down, you can look at -- the patients received post-discontinuation therapies much higher for savolitinib of 36% and only 19% for sunitinib, indicating patients coming off savolitinib is still relatively robust and able to receive additional therapies. Page 29, looking at the AEs in detail. You see a clear difference here. Just looking at it broadly, you can see sunitinib up and down, very broad while sunitinib -- while savolitinib focused on the bottom 3 or 4, and these are actually MET target-related toxicities or adverse events. Peripheral edema, you probably already heard that in the non-small cell lung cancer study as well as the liver enzyme elevation. So indicating very low off-target toxicities for savolitinib, as you can see anemia, nausea, everything is relatively infrequent in the none grade 3 or above. So indicating very highly selective MET inhibitor with MET-driven or MET-targeted base toxicity profile with very few off-target adverse events. Finally, Page 30. To sum it up, even though it was a very small sample size and limited duration of follow-up, savo demonstrated very encouraging efficacy in this particular patient population in comparison to sunitinib with the current standard of care for these patients. Secondly, as I mentioned, the patients receiving savolitinib experienced few grade 3 or above AEs. And these AEs were mostly concentrated on MET-target inhibition. These were peripheral edema and also liver enzyme elevation. As a result of the favorable safety profile, more patients coming out of -- coming off savo treatment were able to receive additional subsequent antitumor therapies. So overall, SAVOIR was early terminated Phase III study, 60 patients in total in comparison to sunitinib. In this study, savolitinib demonstrated a significantly higher overall response rate and a positive trend of PFS and OS.

Great. Thank you.

So this is it. Yes. The SAVOIR study has been just published on JAMA Oncology for those who are interested.

Great. Thanks, Wei-Guo. Okay. Let's hand it over to Marek to take us through the surufatinib U.S. data that's been presented at ASCO. Marek?

Great. Thank you, Christian, and good morning, good evening, everyone. At Slide 34, I will be discussing briefly a recent abstract presented by Dr. Dasari from MD Anderson over the weekend at ASCO meeting and also as Christian said, I will briefly update you on how the next steps on the regulatory front related to this program. Slide 35 quickly. Surufatinib is a novel, oral, targeted inhibitor of tyrosine kinases, inhibiting VEGFR-1, 2 and 3 as well as FGFR1 and CSF-1R. As you know, 2 randomized placebo controlled Phase III studies in advanced NET patients are completed. Both studies stopped at high bar efficacy, pre-planned interim analysis showing superior efficacy of surufatinib over placebo. SANET-ep, as reported during last year at ESMO, demonstrated superior efficacy in patients with advanced extra-pancreatic neuroendocrine tumors, with median progression-free survival of 9.2 for surufatinib versus 3.8 months for placebo arm with hazard ratio 0.334 and p-value 0.0001, highly statistically significant. As reported earlier this year, SANET-p demonstrated superior efficacy as well in patients with similarly high bar efficacy interim analysis and spot for meeting primary end point, and the results are pending at our upcoming scientific conference with press releases earlier this year. In this abstract, we reported data from ongoing case at U.S. trial in patients with NETs to demonstrate similar efficacy and safety in U.S. population. Slide #36, please. As you can see in this design, dose escalation and expansion study was conducted to evaluate and confirm efficacy and things which will help in U.S. patients. Dose escalation was completed and MTD reached with recommended Phase II dose with 300 milligram QD, which was equivalent to previous trials conducted in China. Primary objective of this study of the expansion cohort was to evaluate anticancer activity in patients with select indications in epNET and pNET study. Primary end point of this study was PFS and moderate secondary end points illustrated on this. We reported just first 2 cohorts on the upper boxes -- 2 boxes in the lower and as well in biliary as well as sarcoma in the long run. Slide 37. As of April 21, 32 patients with heavily pretreated progressive NETs had been evaluated with median prior lines of treatment 3 in the range of 1 to 8, as you can see highly pretreated population. 15 patients remain on active treatment, which is important detail to remember when you look at this efficacy data, 5 for pNET cohort 31% of the cohort and 10 patients in epNET representing 63% of this cohort. Objective response rate was 18.8% in pNET patients. So far, no objective epNET responders and confirmed PR that we have 1 unconfirmed PR. Again, highlight of that is still premature and follow-up on epNET cohort is still relatively short. What you can see on the table, I think it's important to see patients achieved significant clinical benefits with disease stabilization of 81% in pNET cohort and 100% in epNET with disease control rate of 100% in each cohort. Very promising median duration of treatment, 7.1 months in pNET cohort and 4.9 months in epNET cohort, but keep in mind that data will for surely change. Slide 38. As you can see on this graph, surufatinib shows clinical efficacy irrespective of prior lines of therapy, including everolimus and sunitinib with median prior lines in pNET 4 and epNET cohort 2 lines of therapy. And tumor growth control was observed in all NET patients. When we move to Slide 39, very colorful slide, but I think a very informative in a way. You can see how many lines of therapy patients have been treated with. In this pNET cohort, patients were required to be pretreated with everolimus and sunitinib. As you can see, many patients were treated with both and actually following some quite long duration of prior therapy on surufatinib or everolimus. Patient received PRs on surufatinib. All patients are benefiting clinically with a stabilization of PR, which is very encouraging. Moving on to Slide 40 on epNET cohort. Those patients were required to be pretreated by everolimus. And as you can see, still a vast majority of this cohort is still on ongoing treatment represented by green arrows and quite promise and duration of therapy. And again, very heavily pretreated population. Moving on to Slide 41, safety summary. The safety profile of surufatinib remains consistent with prior trials. No surprises here. 30 patients had reported at least 1 adverse event and 22 patients reported grade 3 or above AE. Most common adverse event -- grade 3 adverse events were hypertension in 9 patients, diarrhea in 4 patients and hematuria, proteinuria, respectively in 2 and 1 patients. Moving on to Slide 42 in conclusions. Surufatinib has demonstrated promising activity -- antitumor activity in U.S. patients population in progressive and heavily pretreated NETs. A manageable safety profile has been seen and is comparable with the larger pool of surufatinib safety study. As we reported also earlier at AACR meeting, the PK and dose exposure data has been performed and is consistent with collective pool of patients across both U.S. and China. As Christian mentioned at the beginning of this call, we reached an agreement with the U.S. FDA in our pre-NDA meeting, which is leading us to make a decision about NDA submission. We triggered that proprietary work and will be starting submission later this year by end of the year, which is very promising prospects for patients with neuroendocrine tumors. I will stop here. Christian, back to you.

Thank you, Marek, and thanks, Wei-Guo. So if we go to Page 44, very briefly, and then we'll open it up for questions because we've talked about a lot of stuff here today, a lot of work that's been going on over the last couple of years. So looking at Exon 14, a highly competitive efficacy despite having 36% PSC patients, and we enriched PSC patients initially because generally PSC patients have a higher degree, a higher proportion of Exon 14 deletion. So it wasn't by chance that we ended up with 36% PSC. We, of course, learned all about them during this process. But the NDA was accepted last week, and we're working very closely with AstraZeneca's lung cancer group around the launch of savolitinib, hopefully, early next year. As far as global development of Exon 14 -- savolitinib Exon 14 deletion non-small cell lung cancer, we're working very closely with AstraZeneca on that and plans are afoot to progress into global development there. With regards to savolitinib in PRCC, obviously, very encouraging efficacy, albeit, as Wei-Guo said, in 60 patients, so a relatively small sample size, but seeing 27% response versus sunitinib 7%, seeing the duration of those responses, one of the bullet points in the presentation showed that at data cutoff, none of the responders on the savolitinib arm had progressed, none out of the 9 responders. Whereas out of the 2 responders on sunitinib, 1 had already progressed. And so you see much more durable responses on savo. And obviously, the safety profile is terrific, 42% versus 81% grade 3 AEs and a trending overall survival with a hazard ratio of 0.51 that is -- was almost even at 60 patients was close to being statistically significant; and I think if we'd had another 20 patients, it probably would have been. So we're looking now working with AstraZeneca to evaluate the restart of global clinical development in PRCC, and that is something that we are very keen to progress on, and I believe we will shortly. Surufatinib, as Marek has just shown you, strong antitumor activity in U.S. NET patients; similar safety profile to what we've seen in China; PK and dose exposure consistent with U.S. -- in U.S. and Chinese patients. And that was the basis for our proposal to the U.S. FDA this week at our -- last week at our pre-NDA meeting. And fortunately, we were able to agree that our Phase III data from China, combined with the Phase II data in U.S. patients, is sufficient clinical data to support FDA -- NDA submission. So now we're working within the Fast Track rolling NDA submission framework to get that going later this year. So that's the summary. A lot of progress for the company. Now I will open it up for questions.

[Operator Instructions] Okay. So the first question we have is from Paul Choi from Goldman.

Congratulations on all the progress. I have 2 questions. So first, on surufatinib, could you maybe just speak to what remains to be done? And what are some of the gating factors to your U.S. FDA filing? I know you talked about the additional Phase II data from the U.S. patients. You've presented some of them over the weekend from the first 32 patients. But could you maybe speak to that? And then second, your partner, Astra, presented some data this weekend, showing Tagrisso in the adjuvant setting. Could you maybe comment on how you think about potential utilization of savo in that area? Is that something you're considering? And what would potentially be the next steps to consider, both the impact from Tagrisso use in the adjuvant setting and any potential development plans there?

Thanks, Paul. Maybe to answer the first question, surrogating for the FDA filing, I'll hand that back to Marek.

Yes. Thank you, Christian, and thank you for this question. So to answer directly your question, actually, our clinical packages is ready to go. It's just a matter of preparation of the full package, along with clinical, nonclinical. So if you're asking if there is any remaining clinical data to conduct or finish, actually, we'll conduct Phase II study and data cut appropriate with the timing of the clinical module. So we are ready to go on the clinical side. It's just a matter of pulling and submission and package altogether. And as Christian said, we'll be rolling submission module by module. We also reached a agreement with the CMC division. So CMC package is as well under preparation. So I hope it answers your question.

Thanks, Marek. And then maybe Wei-Guo, talk about the potential for use of savolitinib in the adjuvant setting.

I think the -- I mean that's obviously a very good question, Paul. But the way we look at it and -- we and AstraZeneca, is that regardless of the line of therapy, whether it's adjuvant, first line or second line about -- when these patients progress or relapse, savolitinib/Tagrisso combo will probably treat 30-some percent those with MET gene amplification. So regardless of the previous line of treatment, whether it's adjuvant or first line or second line Tagrisso treatment, when these patients progress, we expect about 30% will be MET-driven.

I also think the -- Paul, just one additional comment on that is the adjuvant opportunity seems to be the -- not the last one, but lower down the list on priorities. Obviously, we're focusing on post-Tagrisso failure in both the second and third line settings as our primary pathway to registration for the savo/Tagrisso combo. But in the future, I'm sure AstraZeneca will be looking at a number of sort of exploratory and expansion opportunities.

Okay. Thanks, Paul. Next question from Alec at Bank of America.

Congrats on both the clinical and the regulatory progress. So first, obviously, it sounds like the pre-BLA meeting went well for surufatinib. I was wondering how does this sort of accelerated path change your approach ex China. And how quickly do you think you'd be able to begin commercialization following approval? And would you seek to partner for the ex China launch? And then secondly, I'd be interested to hear your thoughts on whether it's appropriate to compare savolitinib to Novartis' Tabrecta in MET Exon 14 non-small cell lung, given there might be some differences between the baseline patient characteristics.

Thank you, Alec. Maybe I'll answer the first question on the -- how does this pre-NDA meeting change our ex China strategy. I mean I think what you're getting here is the sort of -- the kind of coming of age of our focus on bringing our innovations out to the global market. Marek and the team in New Jersey have really been building up a presence over the last 2-plus years to a point now that we can have these engagements and interactions with the U.S. FDA and make progress on our programs. But you're seeing surufatinib making that progress, and now hopefully moving towards the NDA submission late this year. You're seeing fruquintinib global Phase III in colorectal cancer kicking off in the next month or 2 in 100 sites across North America, Europe and Japan. And you're seeing on savolitinib, the expansion of a global study potentially in Exon 14 deletion, you're seeing the progress of savo/Tagrisso globally, you're seeing savolitinib in PRCC progressing as well globally now based on the SAVOIR data. So you're seeing on our lead assets, all of them moving aggressively in the global landscape or in the global setting. And that's really always been our strategy. We've never been a China-based company focusing on China alone. We've always designed our assets to have global potential. And I think now we start to see the value of that strategy and that investment over the last few years. So the next question is, how do we maximize the potential of surufatinib subject -- if the NDA is going in around the end of this year, we could be potentially considering launch maybe in the second half of next year. That is a challenge for the company to look at. Now it's not that we haven't been looking at it. We've been planning on this. And I think that we keep all options available and open at the moment, considering launching ourselves, building a team to do that. We will potentially talk to possible collaboration partners over the coming months. And so I think that we'll figure that out. But it's a step in the direction that we've been planning for the last 2 or 3 years. And actually, in the context of Wei-Guo and his team on the discovery side, we've been planning the global launch of our assets for many, many years. So it's an exciting time, and I think we'll be able to give you all more information about this as time goes by. On the comparison of savolitinib and capmatinib, I think you need to be very careful. I'll ask Wei-Guo to give some comments after. But I think you need to be very careful comparing study to study. I think the patient demographics are quite different. As we said, the capmatinib GEOMETRY study, which was their registration study in the U.S. for Exon 14, they had 5% PSC patients in that study versus the 36% that we had in our study PSC. And as Wei-Guo has said, these are quite fragile, difficult patients. So you've got to be careful looking -- comparing apples-to-oranges there. But I think we feel that, obviously, savolitinib with the NDA submission going in, has really met the requirements for providing real benefit to patients. I mean Wei-Guo, do you have any comments on that question? You might be on mute, Wei-Guo.

All right. Sorry, I was on mute. I was going to just add a point. I mean I guess these are -- actually including tepotinib as well, you're having 3 compounds getting NDA or approved launch stage. I think all 3 compounds in terms of the magnitude of efficacy, ORR or PFS, we believe they look very similar; ORR between 40% to 50% in that range; PFS around 9, 10 months. But no, we believe our study has really the most challenging patient population, not only 36% PSC, but also the age -- the median age around 70 years of age, really difficult to -- I mean the ECOG also as a performance status, almost 90% ECOG 1 or above. So I think this is a very tough patient population. So we are quite pleased to have this lot of efficacy.

Okay. Thanks, Alec. Next question from John Newman at Canaccord.

Just wondered in terms of the surufatinib pathway forward in neuroendocrine tumors in the United States. Christian, do you believe that you might be looking at possibly an accelerated approval pathway here? Or would you look at one of the more traditional paths to approval?

Maybe I'll let Marek answer that question.

Yes. Thank you, John, for this question. Well, I can share with you good news. The accelerated approval, as you know, is only reserved for pretty much package, which would be based on the surrogate end points or smaller package. In our case, it was the full approval. And the question only remaining, obviously after submission and validation and FDA decision, if this would be priority review or normal review. So we are out of that component. As you know, accelerated approval may sound farther, but then it goes with commitment of both approvals -- heavy-listings approval and your confirmatory study. So what we can say FDA is not expecting us to do any confirmatory study. That package would be -- can consist full package for full approval, but obviously caveat subject for review and the evaluation and so on. So I hope it clarifies. So we -- as far as if you are looking at timing, it's the question about priority review versus normal review, which is 2, 3 months difference.

Great. And then just had one question on the data in neuroendocrine tumors. The response rate is actually interesting. It seems, based on prior studies, you normally don't see a response rate outside of single digits. Just wondered -- just curious if you could comment on that. It's actually a very interesting finding.

Do you want me, Christian?

Yes, go ahead, Marek. Go ahead, go ahead. I'll add if I have.

Yes. So it's definitely one of the reasons why we had such a high level of engagement from top-notch institutions investigating surufatinib globally, both in Europe and U.S. We have presented MD Anderson as one of our leading institutions. And that's exactly why they are so interested and invested in this program because seeing response -- objective responses of any number after such a heavy pretreatment and long exposure of -- on everolimus and sunitinib and seeing significant clinical benefit even in such a highly pretreated population, that definitely shows us the -- that's something different than other pathways. So -- but again, I want to highlight our SANET-ep study, which has multiple subsets, including treatment-naive patients as well where [ benefit was on phases ]. So that's what keeps us going to bring that innovation as soon as possible to patients because there is definitely a high unmet medical need in this space.

Thanks, John. Okay. Next question from Tony of CLSA.

So yes, I wanted to ask about a cross-trial comparison against capmatinib and tepotinib again. Your competitors presented some data in patients with CNS metastasis, right? Could you also speak to -- about savo's data in CNS? I believe you guys recruited about 25% patients with CNS mets. And also, about the China PSC application. Any indication from the regulator in terms of time line of approval?

Yes. So on the CNS and the brain mets, as you say, 24% in our study of the patients had brain metastasis. We haven't -- we obviously haven't presented any specific data on brain mets. But clearly, when you're delivering a close to 40%, 50% response, and you've got 1/4 of the patients with brain mets, there's clearly activity there. We had published some ad hoc data from certain patients in the study with brain mets showing tumor shrinkage, some visuals in our corporate presentation. So clearly, there's activity in those patients. And obviously, savolitinib showing good blood-brain barrier penetration to enable to do that. Wei-Guo, do you have any other -- any comment on that?

Well, I think we presented some interim data before on that. As a matter of fact, throughout the study, we see total disease control, even responses in the CNS. We did not have a single disease progression due to CNS progression. So clearly very active in CNS. And that's why we're really interested in studying in the future. As you know, about 10% of glioblastoma -- the secondary glioblastoma carry the Exon 14 skipping mutations. So not just us, I think other companies, too, are starting to looking into how we can explore that indication as well.

Thanks, Wei-Guo. And on the China PSC application, well, the Exon 14 deletion non-small cell lung cancer NDA is not just for PSC, Tony. It's for all Exon 14 patients, so non-small cell lung cancer as well as PSC. Obviously, that NDA was submitted last week, and now we engage on the pathway of all of the post-submission inspections and engagement with the regulatory authorities. So that's going to take time now, probably over the next 6 to 12 months.

Thanks, Tony. Next question from Louise at Cantor.

So first one I have for you is, how do you think about the overall survival in PRCC for savolitinib, given your impressive hazard ratio of 0.51? And then people wanted me to clarify with you, if you will or will not need a Phase III study for the U.S. for surufatinib. I understand the way that you're filing it, but just curious of what cost studies you actually need. And then the last question is, are there any combos for savolitinib and surufatinib that you're particularly excited about in addition to your SAVANNAH trial?

Sure, thanks. Thanks, Louise. I'll answer the OS on PRCC, and then I'll pass the last 2 questions to Marek and to Wei-Guo. For overall survival in PRCC, obviously, you saw the hazard ratio of 0.51. How do we think about it is your question. The way that I think about it is that a MET inhibitor for those MET-driven PRCC patients is an absolutely critical therapeutic option. I think the reason you see such an extension in overall survival is because you've got a therapy that those patients -- that is providing a benefit of inhibiting c-MET gene amplification or inhibiting MET, that those patients otherwise wouldn't have. And that's a -- it's a new tool in the toolbox for treating this particular MET-driven disease. So from our standpoint, I think that's probably the biggest benefit is going to be the extension of life and extension of overall survival. And the -- while the OS data was not mature, the trend there really did show a very material increase. So addressing MET gene amplification in those patients is just absolutely critical, and you need a MET inhibitor to do it, and that's why you see such benefit. Passing over to Marek to talk about surufatinib, do we need a Phase III in America?

Yes, yes, yes. Thank you, Louise, for your question. The regulatory space is very complex. So let me clarify that if we would require additional study, we would not be announcing today that we are reaching now agreement with FDA for our filing. So our base for package was SANET-ep -- SANET studies, SANET-p, SANET-ep supported by our U.S. data. So that's the package. So FDA agreed that this could support our filing. There is no filing issues. So we are going full speed ahead with NDA and submission. So if, as I said, that we would be in need of additional study or repeating study, why we will be talking today about initiating of that filing of NDA? So I think that's all good news. I think one of the really few precedents that were in 2 Phase III studies will play a role as a pivotal study for the package for the U.S. FDA submission. So that's great news. Having said that, we'll continue clinical development of this important asset in a number of avenues, combining with other standard of care and basically looking at opportunity to combine with and continue on good signal combining with checkpoint inhibitors as those promising data come in from a number of investigations. So it will be all a continued effort. But on the NDA side, no, there's no requirement to do a repeat study.

Okay. Thanks, Marek. And then Wei-Guo, combinations for savo and suru, what, in your mind, are the most exciting areas?

Well, when you talk about combos, we start to -- I think data is emerging that a lot of MET amplification or MET mutations on that pathway activation plays an important role for resistance to target therapies similar to EGFR or TKI. So for instance, in a CRC Erbitux resistance, we're seeing a high level of MET amplification. Clearly, you can go there and do a combination with Erbitux. More recently, even HER2 antibodies, for instance, in gastric cancer and breast cancer, when patients start to relapse, MET amplification is also a -- is part of the -- one of the major resistance mechanisms there as well. So we can think of tumor types that are treated with targeted therapies. And when they become resistant, we're going to expect to see some level of MET amplification. So it's just a matter of getting the patient tested. And I'm sure, we'll need additional studies -- we'll need these studies to demonstrate the combination will work.

Thanks. And I mean...

And obviously, PD-1-IL combos, too. So we did a CALYPSO study AstraZeneca in renal cell carcinoma, but we are also interested in the same combination now with durvalumab in other tumor types, in other settings.

Great. Thanks, Wei-Guo. That's savolitinib. On surufatinib, I think combo opportunities, we presented some data recently at AACR on the surufatinib combination with Tuoyi, the PD-1 from Junshi, very exciting efficacy in grade 3 NET and neck patients. So that combination is -- the PD-1 combo for surufatinib is important. And just recently, last week, we partnered up also with BeiGene to explore both fruquintinib and surufatinib in combination with tislelizumab. So I think the PD-1 combos for surufatinib are very exciting as well.

Thanks, Louise. Next question from Jameel at Barclays.

Two for me. So my first one is, how are you looking to position surufatinib against Afinitor in the market? Do you feel that both of them could survive both with having a decent market share? Or do you feel that there's going to be some groups that migrates more to one or to the other? And then secondly, just if you could give us just a rundown of what you feel would be the key upcoming data points and data releases that you're going to have in the short-term that we should keep a lookout for. That would be very helpful.

Okay. Maybe Marek, if you'd like to talk about how to position surufatinib against in the NET space relative to Afinitor in the U.S.?

Yes. Thanks, Christian. Thanks, Jameel. Obviously, from a commercial perspective, everything will depend on the final label. However, as we are working based on the SANET-p and SANET-ep patient population, it's included in those 2 clinical studies, those were a consistent base for our package and future label and discussion. I'm not going to speculate on the final regulatory outcome of that. But what I will say is that both standard studies represented multi-cohort and multi kind of pretreatment aspects. 1/3 of patients were pretreated -- were treatment-naive and the remaining part were quite heavily pretreated. So I think what Christian and I was showing in one of the slides, as you can see, we have activity across multiple assets, actually, in majority of subtypes in epNET were represented in our studies. So I think that's one of the strengths of this data. And obviously, from efficacy point of view, it's highly comparable or with limitations to compare across studies. We studied its safety profile, definitely, it's very interesting and favorable. So all in all, what I'll say, surufatinib will play a very important role in treatment options within NET patients. Keep in mind, there's no, I would say, loyalty to line assigned treatment. It's actually one of the disease where lines do not matter as much, it's simply how you present clinically, and that's how patients -- physicians decide to apply treatment. There's no sequence data either with this growing number of treatment options. So I believe with the surufatinib profile, we will be very competitive based on what we see and what utilization of the other alternative is. As you may know, it's only 6% of currently used. Based on our real-world evidence data in the U.S., only 6% of patients are treated with approved option as a line of treatment. So there's a still vast majority of patients looking for options.

Okay. Thanks, Marek. Yes. I mean I think there's a lot of opportunity there for surufatinib to -- in particularly that chart that shows the treatment landscape. There's a lot of white space at the moment in NET, and we'll go after that. With regards to sort of catalysts or data points that are going to play out in the near term, I think, obviously, we've got the SAVANNAH interim analysis. The Tagrisso/savolitinib combination will reach its interim sometime in the middle of the year, probably June, July type time frame, so this month or next month. That will trigger a number of things, probably not announcement-driving outcomes, but it will trigger regulatory interactions, potential discussions about possible pathways to accelerated approval. It will trigger the savolitinib/Tagrisso combo potentially going into large global Phase III studies. Obviously, we hope that the SAVANNAH study can be used for registration. And any global Phase III would be confirmatory, but that all plays out over the second half of the year, and it's going to be very important because, obviously, the Tagrisso/savolitinib combo is probably the single biggest value driver for Chi-Med as a company. The second thing that plays out shortly is fruquintinib. As I said earlier, the colorectal cancer global Phase III kicking off. Marek and his team have already covered off the U.S. FDA, the European and Japanese regulatory authorities, all are now aligned with our Phase III strategy and protocol and that kicks off literally in the next few months in over 100 sites around the world. We also have an interim analysis on the FRUTIGA study, which is fruquintinib and paclitaxel, that interim should be happening shortly. And then we have the initiation of Phase I development of our IDH 1/2 dual inhibitor, that's going to kick off in China. But one of the things we're planning on doing more so in future, given the presence of the team now in New Jersey, is to do more parallel early development of our novel assets. So in China and the United States at the same time. So we expect our IDH 1/2 dual inhibitor will kick off Phase I in China shortly, but we'll follow quickly into early development in the U.S., hopefully later this year or before the end of the year, roughly. So those are the main things. We also have on our hematological malignancy assets, our PI3K delta and our Syk inhibitor, we are targeting to use the fairly substantial datasets from our Phase Ib exploratory studies to allow us to make some decisions as to what are the next steps on those assets, which indications are we going to go into late development on, and we hope that plays out over the balance of the year. So there's a lot going on, but the team is very focused on managing all of these NDAs. So you've got the surufatinib, SANET-ep NDA that's currently being processed towards, hopefully, an approval at the end of the year. And we're building out our commercial team in China on oncology. We're up to over 265 people on the ground. We're moving towards an objective of a commercial team of about 350 people by July, August to get ready for the launch of surufatinib, so that's going on. And the launch of suru late this year will be a big deal. But our team is working very closely on the NDA approval process led by Wei-Guo and all of our team in China. We are preparing the SANET-p NDA submission, so coming off of the positive Phase III study in January, the readout, we'll be submitting the SANET-p NDA sometime in the next few months. So that is also a lot of work. And then obviously, as we've discussed, the preparation for the submission of surufatinib's NDA in the U.S. is going to take up a lot of time over the next 6 months to get that ready. So all in all, a lot going on. And luckily, on savolitinib, we have AstraZeneca really stepping up and resourcing savolitinib to a level now to enable the start of global clinical studies in Exon 14 PRCC and the Tagrisso combo. So these are some pretty big studies that are all being lined up to be planned and hopefully executed around the end of this year. So it's going to be a very busy next 6 months, Jameel. But I think as time -- and there's a whole number of other things in there that I haven't mentioned. So I think that we always said 2020 was going to be a big year, and I think it will be.

Okay. Thanks, Jameel. Question from John at Edison.

I only have 1 question and that is how much data can we glean from the SAVOIR study? And going forward, is it likely that you will restart a Phase III trial in PRCC? And if so, can you maybe provide some details of what that would look like?

Well, John, the SAVOIR data, as we've said is, it's only 60 patients, but it's pretty compelling when you get a hazard ratio of 0.51 in overall survival compared to sunitinib. So I think everybody -- and I think the safety profile of savolitinib relative to sunitinib is very encouraging. So we are working closely with AstraZeneca at the moment to plan out and assess the restart of this Phase III. And our hope is that, that would happen in the near term, certainly over the second half of the year. Okay. Thanks. Okay. So I'm being told we've run over. It's quarter past the hour. So I think we'll cut it off there. But if there's any further questions, please feel free to reach out to us directly, we're always more than happy to engage. So thank you, everybody, for taking the time to listen to the presentation today, and we look forward to speaking to you all soon. Thank you.