Good evening, afternoon, and morning. Welcome to HUTCHMED conference call and webcast. At this time, all participants are in a listen-only mode. After speaker's presentation, there will be question and answer session. Please be advised that this call will be recorded. I'll turn the call over to our first speaker today, Dr. Weiguo Su, Chief Executive Officer and Chief Scientific Officer of HUTCHMED. Please go ahead, sir. Thank you. Welcome everyone. This is the FRESCO-2 phase 3 trial conference call. A couple of hours ago, we just presented the phase 3 top line results at ESMO. Understand the pre-presentation time was the most friendly for folks in the U.S. We are privileged today to have the steering committee of the study members on the call to give another presentation and also a panel discussion. Following that, we'll have the Q&A. On the screen is the HUTCHMED development portfolio. HUTCHMED is dedicated to innovation and bringing our innovations to patients worldwide. Today's focus is fruquintinib, and specifically our global FRESCO-2 phase 3 trial results. Without further ado, I'll turn it to Dr. Dasari to walk you through the top-line results. Thank you very much for the introduction and for this opportunity to present on behalf of the entire team. To recap, FRESCO-2 is a global randomized phase 3 study of fruquintinib in patients with refractory metastatic colorectal cancer. These are my disclosures. By way of background, the VEGF pathway is a key mediator of angiogenesis necessary for tumor growth and metastasis. Fruquintinib is a highly selective and potent oral tyrosine kinase inhibitor of VEGF receptors one, two, and three. It was approved in China in 2018 for patients with metastatic colorectal cancer in third line and beyond based on the placebo-controlled FRESCO trial that showed an improvement in the primary endpoint of overall survival with a hazard ratio of 0.65 and progression-free survival with a hazard ratio of 0.26. However, the standard of care in China at that time differed from current practices. For instance, only 30% of the patients received prior anti-VEGF antibody, and none received TAS-102 and/or regorafenib. Acknowledging these differences from the current global practices and the huge unmet need for effective treatment options in the refractory setting for metastatic colorectal cancer, FRESCO-2 was conducted as a global phase III study to evaluate the efficacy and safety of fruquintinib in more heavily pretreated patients. This is the study design. Eligible patients were required to have prior treatment with all standard cytotoxic chemotherapy agents, an anti-VEGF antibody, and targeted therapies as appropriate. In addition, they were also required to have prior TAS-102 and/or regorafenib. Eligible patients were randomized two to one to fruquintinib versus placebo, dosed at 5 mg PO q daily, three weeks on, one week off, and also received best supportive care in both arms. Stratification factors included prior therapy that is TAS-102 versus regorafenib versus both RAS mutation status and the duration of metastatic disease. For alignment with ongoing clinical practice, the proportion of patients with prior regorafenib was capped at 50%. The study was designed with the primary objective of overall survival, and progression-free survival was a key secondary endpoint. Other secondary endpoints that were discussed included objective response rate, disease control rate, and safety. Assuming a median overall survival of five months in the placebo arm, with an improvement by 1.8 months to 6.8 months in the experimental arm, corresponding to a hazard ratio of 0.73, 687 patients contributing towards 480 events were required to provide 90% power with a two-sided alpha of 0.05. There was an interim futility analysis at one-third of the events, and safety was monitored by an independent data monitoring committee. These are the patient demographics. 691 patients were enrolled between September 2020 and December 2021 globally through the height of the COVID pandemic. This reflects the huge unmet need of the setting globally. Patients and disease characteristics were generally well-balanced between the two arms, including age, region of enrollment, and primary site of origin. With regards to prior therapy specifically, the median lines of prior therapy were five, and nearly three-fourths of the patients received more than three lines of therapy. These included a VEGF antibody in nearly all the patients. In addition, prior TAS-102 was in 90% of the patients, and prior regorafenib was in 50% of the patients. The study was positive and met its primary endpoint of overall survival with a hazard ratio of 0.662. That is a 34% reduction in the risk of death. This corresponds to an improvement in median overall survival from 4.8 months in the placebo arm to 7.4 months in the fruquintinib arm. That is a difference of 2.6 months with a P value that is highly statistically significant at less than 0.001. The Kaplan-Meier curve, as you can see here, shows that the arms separate early and remain distinct throughout the duration of the study. Subsequent therapies after the trial were well-balanced between the two arms. Subgroup analysis of overall survival showed improvement in the pre-specified subgroups. These include demographics such as age and region of enrollment. Importantly, with regards to prior therapy, there was benefit irrespective of prior treatment lines, prior VEGF exposure, and prior regorafenib, TAS-102 or both. There was also a significant improvement in the key secondary endpoint of progression-free survival with a hazard ratio of 0.321, with improvement in median PFS from 1.8 months in the placebo arm to 3.7 months in the fruquintinib arm, corresponding to a difference of 1.9 months. Looking at the subgroup analysis for PFS, this also showed benefit across all the pre-specified subgroups similar to the overall survival analysis. Disease control rate was significantly higher in the fruquintinib arm at 56% versus 16% in the placebo arm. The objective response rate was 1.5% in the fruquintinib arm. In addition of note, patients in the fruquintinib arm had tumor shrinkage that is despite the refractory setting as denoted in the waterfall plot on the right. Patients received over 90% dose intensity in both arms, and the median number of cycles were three versus two months in the fruquintinib versus placebo arms. Evaluation of the toxicity profile revealed that overall, grade three or higher treatment-emergent AEs were noted in 63% of the patients in the fruquintinib arm versus 50% in the placebo arm, while treatment-related grade three AEs were 36% versus 11%. Dose interruption was in 54% versus 30%, reduction in 24% versus 4%, and discontinuation was in 20% versus 21%, respectively. The most common AEs that were grade three or higher were hypertension in 14% and asthenia in 8%. Of note, grade three or higher hand-foot syndrome, proteinuria, and LFT changes were all 6% or lower. In summary, FRESCO-2 met its primary endpoint of overall survival with a hazard ratio of 0.66, corresponding to an improvement of 2.6 months. There was also an improvement in the key secondary endpoint of progression-free survival with hazard ratio of 0.32 corresponding to an improvement of 1.9 months. Both these were clinically and statistically significant and consistent across all pre-specified subgroups. Fruquintinib was also well-tolerated and consistent with prior established safety profile. Overall, these results validate those noted by FRESCO and support a new, potentially practice-changing global oral treatment option for metastatic colorectal cancer patients, enriching the treatment continuum for these patients. I'd like to gratefully acknowledge all the patients who participated in this trial and their families. A huge thank you to the entire team at all the sites, without whose efforts it would not have been possible to complete a global study during the unprecedented pandemic that we all face. Thank you very much. Thank you. Next, we'll have a chance to hear thoughts from world-leading oncologists, and Marek will moderate. Yeah. Hi, everyone. Good evening, good morning, good afternoon. We are really privileged here to be joined by our distinguished panel. I'm going to go back to our agenda because I do want to introduce them. We have only select members of our steering committee who joined leadership of the FRESCO study early on. It's always easy to celebrate great results, as Dr. Dasari presented. It's not so easy to join on the concept early on and rally around it. I would like to express my great gratitude on behalf of, first of all, patients, families, investigators, but also on our behalf of the company leadership, as well as board members joining us today. Big thank you for believing in the concept and being a champion of that concept. With us, we have a distinguished panel starting from the left side, Professor Sobrero from Italy, Genoa, in Italy. We've met Dr. Cathy Eng, Professor Ng from Vanderbilt before MD Anderson. Recently, she changed allegiance. Well-known Professor James Yao, the chair of GI department at MD Anderson. We don't have with us Professor Tabernero and Professor Yoshino due to conflicts, but we greatly appreciate their contributions as well. We'll take a little bit interactive discussion here just to keep discussion going, and we'll open this session for Q&A for the audience on this call. Starting with the beginning of the concept, I will ask Professor Eng, Cathy, you know, three years ago, we were conceptualizing this study, and we were talking a lot about unmet medical need in this space of colorectal space. If you can take a few minutes and simply share with the audience why you were so excited to join this effort, why we designed this study this way, and how this meets the outcome in this space. Thank you for the question. I think it's really important to give a perspective. Colorectal cancer still remains one of the leading, causes of death, not only in the United States. It's the second leading cause of cancer death, but it's also a very common malignancy worldwide. It is rising in incidence in early onset or young onset colorectal cancer patients as well. We know for our patients that do not undergo surgical resection with stage four disease, meaning they have metastatic disease, and if they can't undergo surgical resection due to their metastatic disease, the five-year survival is estimated to be less than 15%. In all the 20 years I've been practicing, it's basically only increased the five-year survival from 9% to 14% for surgically unresectable patients. We have several drugs that have been approved, but a lot of these patients still have not necessarily been cured, and we need to improve their overall survival. I was delighted to participate in this, and thank you for inviting me to help lead this effort with this wonderful group here, because this is such an unmet need for our patients. The reality is that all of our patients have to be maintained on some type of treatment, usually historically standard chemotherapy, in order to improve their overall survival. Honestly, we have not had any recent drug approvals for many years. This is an oral agent. It basically provides another option, and it really clearly fulfilled an unmet need 'cause we enrolled patients despite COVID. It was the only phase three trial open internationally at that time, and we enrolled very quickly. I am delighted to see these results, and I think I'm very, very hopeful that this will get approved, because this really will help so many patients to improve their overall survival. Thank you. Thank you, Cathy. Maybe moving on this journey of discussion, discussing results, you know, for those who are close to scientific evaluation of results, you know, we speak hazard ratio and the results in the means, median difference and so on. I would like to ask Professor Sobrero really translate this to more lay audience. What does it mean to your conversations with patients, you know, hazard ratio 0.66 and a median observed both in OS and in PFS? We never mention hazard ratio to our patients. Hazard ratio is such a difficult concept to understand. What this means to our patients, number one, they have a new barrier in this disease, and that g ood, because again, some of the progress in the treatment of this disease has been made by adding doses of efficacy to the treatment of the overall clinical benefit. Back 25 years ago, we were stuck with one drug, and the median survival was 12-14 months. The two other agents came up, and that was extended to 20 months. The biologics came and extended by another six months, approximately. The third to fourth line agents came up, and they both extended by 1.5 months. Here we have almost three months. As you were representing, actually this is the 100th time I listened to this presentation, but came to my mind the fact that irinotecan and oxaliplatin actually were approved for an overall benefit out of the three to four trials of between two and 3.5 months gain in median survival. Here we are under prohibitive condition that is end of life. Look at the control. The control arm, if I had to tell a patient in this condition, and I had to be completely honest, I'd say, "Now, we don't have anything more to offer to you before fruquintinib, and your median life expectancy is five months, 4.8, not even five." Reflecting the fact that this is an even worse population than the trifluridine and the regorafenib trials. If you get this drug, well, you get 2.6 months gain in median. Again, that's not common under these conditions. Now, your question was, how do I translate this to patients? Well, when the regorafenib came up. Actually, a more general concept. When you speak of 2.6 months, you're speaking of nothing actually for the healthy person. When you're desperate, well, life becomes more precious whenever so little is remaining. Again, say, if I had to translate this to patients, I would tell them, "Well, you may get nothing because you may be tired of coming to the hospital, of combating this disease. However, we have a new drug now that on top of all the other drugs that have extended your life on average from four or five months, if you are not treated, down to 25, 30, 35 months, now we can have another chance. If you don't get it, that's your life expectancy. If you get it, you extend by 50% the chances of being alive at six, eight, 10 months. That's what those two curves say, aside from hazard ratio. Again, when I had to see how well or bad was regorafenib perceived, I used the expression, if you get rego, you have 24, 25% chances of not seeing your tumor progressing, which is the lay translation of PFS at four months. Here, you have twice as many those chances, 50% chances of not seeing the tumor progressing at four months. Again, to me, coming from the experience of seeing so many patients, this is really a very good new player for patients. Thank you. Thank you, Professor Sobrero. Very well said. When we always remind ourselves about that one single patient we have at the time versus statistical analysis, that's very useful. Moving on, maybe I'll ask, Professor Yao. Now we have two positive studies, FRESCO, which led to approval in China, where now thousands of patients are benefiting from this therapy in much less pre-treated situation. We have robustly positive results, FRESCO-2 in the heavily pre-treated. Can you put this into perspective, what it means in this continuum of therapy? Yeah. That's really great to think about this as the kinda the combination of the development program. You know, I always view kind of the highest standard is two well-controlled clinical trials. Here you really do have FRESCO and FRESCO-2 showing robust benefit across refractory colorectal cancer and the consistency across the different trial, different regions of the world, in the different prior treatment. It really gives you high confidence that the treatment is benefiting our patients. I think that's really my take-home from this. That's great. Maybe I will go back between Cathy Eng and Arvind Dasari. Arvind Dasari, you concluded in your last slide, and we had number of online reactions, and commentary at the discussion phase, this practice-changing result. Maybe you can tag team between Cathy Eng and yourself and just share your thoughts why people are using this term practice-changing, what it really means. First, as Dr. Sobrero mentioned, the setting in which this drug was developed, heavily pretreated patients who progressed through multiple lines of therapy and no other options are available, this is an effective drug. A new treatment option that in itself I think is practice changing. Equally important is the fact that this is a well-tolerated drug because quality of life is very important for these patients towards the end of their journey. Given the very favorable toxicity profile, I think this would be a great addition and indeed practice changing for patients. The way I would look at it, as an oncologist taking care of colorectal cancer patients would be, this is a drug that works well, and it's an oral drug, so patients can take it at home without needing to go back and forth between hospital and home, and it's well-tolerated. The last thing I wanna mention and really emphasize is that this is a drug that would work in every patient with metastatic colorectal cancer. That is, it's not selected based on a biomarker or limited to a small proportion of patients. That, again, is a huge, huge win for patients and providers alike. Right. Cathy, anything to add? I mean, as mentioned earlier, I think it's truthfully practice changing just because what it provides to patients. As mentioned by Dr. Sobrero, the change in overall survival versus the control arm is significantly better. Although we shouldn't be doing cross-trial comparisons, it's very clear that it is significantly better though versus some of their competitors. Once again, I think the fact that it's tolerated extremely well with, I mean, a class-effective hypertension, which is not unexpected, I think it's just another great option for patients. The schedule's easy, three weeks on, one week off, which means that you only probably need to be in the doctor's office once a month, which is also an added convenience for patients. This PFS is also quite impressive or progression-free survival, sorry, is quite impressive for our patient population. Across the board, this is such a new option for patients. I truthfully believe it should be viewed that way, and also because we've also seen the benefit in patients that have been exposed to every single FDA-approved line of therapy. This was a heavily pretreated patient population, a median five lines of therapy, which is unheard of in most trials. Maybe, whenever a new weapon, a new player comes in, we always evaluate its benefit under three different prospects. Number one, efficacy, and we have discussed extensively about efficacy. Number two, the second component of clinical benefit. Clinical benefit is efficacy compared to toxicity. Here again, we have an excellent player. Number three is what technically is called external validity. That is, on how many patient can I apply this? This is a very strong point, as you mentioned, essentially, because every patient can be proposed and advised to get it. There is no restriction. Correct. Again, this is why I think this is a major improvement in the treatment of this disease. Fully agree. Cathy, just following on the more specifics, if you can paint the picture of the best patient, you know, fitting into potential, you know, highest benefit of this option. You know, whenever we have a new drug, that is, available to patients, obviously, we still want to evaluate the patient in a standard fashion for any medical oncologist in regards to performance status or their ability to complete their adult daily activities. This trial was specifically for patients with a performance status that was fairly good at between zero and one. Regardless, you know, these are patients that we see in our clinic. These long-standing patients are the ones that have fairly good performance status. Honestly, with the fact that there's so little toxicities, I think it's going to be, once again, as Alberto stated earlier, very, very applicable to the majority of our patients. Once again, I think it's, as mentioned earlier, you don't have to go through every single multiple line of therapy. You can simply just go through your couple of standard lines of treatment, and I think this would be an appropriate option, especially in our RAS mutant patient, RAS mutant tumors, for our patients, just because they don't have a lot of treatment options nowadays unless they have specifically that G12C tumor type. This is just another great option for our patients, and I don't feel that I'm inhibited in any way. Thank you. Maybe switching, Dr. Yao to you. You know, I put a slide in front. We always discuss about geographic differences in multiple factors playing into results. Can you put that in a perspective of consistency of results in this study, but also in the context of overall metastatic colorectal cancer, you know, any other factors playing and how you interpret this data, for obviously application across the globe for regulatory approvals and clinical practice? Yeah, absolutely. Going back again to looking at the context of FRESCO and FRESCO-2, you really not only add all the things that's been discussed, but you take essentially the statistical robustness into another league where you have two well-controlled trial that are positive, and yet you still have, you know, quite, you know, consistent results. You know, across the other items, but also across third line, fourth line, and fifth line to therapy. Third line in FRESCO, in fourth and fifth line here in FRESCO too. I think it give us high confidence in the drug, in that it's gonna work in North America, Europe, and not surprisingly, also in Asia. I think it's gonna globally bring benefit to colorectal cancer patients. Right. Thank you. Can I also mention something? I think, you know, we've been talking about really, the lack of side effects for this agent, and I think it's really also important to highlight because of that. I look forward to combining it in other clinical trials with other agents. I think that's really important to keep in mind, unlike some of the other drugs. Continue on this thought. That was exactly one of the discussion points. Given the results, obviously, Hashmat and entire team will continue working across the globe to approach the regulatory agencies to approve single agent based on this robust package. At the same time, we have number of studies ongoing in the proof of concept. Actually I open this to anyone. Where would you see this next step developing this, given this, you know, strong single agent activity and as you said, good profile combining with a number of options? I'll let Alberto open it up because European perspective for clinical trials development is a little bit different. Well, again, this is going to be registered, in my opinion, for beyond refractory beyond trifluridine and/or regorafenib. However, cross trial comparison would suggest to ask clinician moving it earlier for clinical use. I don't know what will be happening in the clinical practice because here the benefit is larger, again, with the limitation of cross trial comparison, and the price to pay is less. Certainly a major issue is once you are resistant to FOLFOX and FOLFIRI, what's going to be your choice? These are the best data available. In terms of clinical trial, I would certainly look for moving this agent earlier, looking for a wider use earlier. One observation may be important. There was, I think the TRC-0301 study investigated another anti-angiogenic alone in third or fourth line, and there was zero effect. That's the reason why we do not use bevacizumab beyond second line. We may in practice, but in general it's not recommended and there is no scientific proof. Here you have an anti-angiogenic compound that by itself, under the most stressful and negative condition, gives you a size of benefit that is of the same size of those obtained by toxic chemo in first line. I'd move it first line. I'd go with the trial. Keep in mind, he mentioned bevacizumab, but we would never use bevacizumab as a single agent, right? That's given intravenously. Yeah. We've been using it for years. Yeah. Yeah. Amit, any other thoughts? The immediate future, as Dr. Sobrero mentioned, getting this drug as a single agent to patients because it meets a huge unmet need globally. Building on the really exciting results that we've seen with this trial and reflecting its activity and good tolerance, looking at combination studies in metastatic colorectal cancer in the refractory setting, and perhaps moving this drug to earlier lines of therapy, I think would be very exciting and areas to look into. Marek, as we discussed the other day, and potential for evaluating this drug in other malignancies as well. Great. Great. I would just say that because this is an anti-angiogenic agent that blocks multiple receptors, obviously, I think it just gives us a lot of opportunity to develop it not only with cytotoxic chemotherapy, but with other targeted agents. I think there's multiple possibilities moving forward from my perspective. Sorry. Riccardo? Yeah, absolutely. I think you know this drug. I think Cathy mentioned earlier, not much side effects. I think my interpretation is not very much off target side effects. Hypertension, it does, is there, but it's a clean VEGF inhibitor that's having on target side effects, which is what you want. This allows us to combine with other agent and move it to the earlier lines of therapy and potentially explore other diseases where VEGF inhibitors has proven a role. Right. We are not covering here more complicated, obviously, regulatory strategy discussion. We may address some of the questions, you know, when we move to Q&A. Just briefly, I think Professor Sobrero mentioned approval, potential approval line. I would like to refer maybe to one of the comments which was made by discussant at the podium, who definitely agreed with conclusions of Dr. Dasari about practice changing, but he did make one comment about in order to define the efficacy in the third line so-called space, while you will have to do it in a head-to-head comparison. Any comments, James or Cathy, on this? Given two phase 3 studies and the package we have. Yeah, I'd be happy to start. I mean, I think we have already shown FRESCO and FRESCO-2 robust benefit, consistent benefit. I don't really see a particular need to do a head-to-head study because such studies will require a very large number of patients. Frankly, I think we're better off, you know, using that number of patient to advance the field, to come up with new treatments, either in earlier line or in combination. I think that will be more meaningful benefit to our patients into the field. Okay. Yes. I actually agree fully with James here in regards to this. I think it would be a disservice, honestly, to our patients if we have to duplicate those exact same efforts and compare it to either TAS-102 or regorafenib. I don't think it's necessary. I think the data is extremely strong, and I think that basically we just, as you mentioned earlier, you know, FRESCO's already been completed, and it was a very positive study, and here we have FRESCO-2. It's a large patient population. It's an international study. I don't think that is really necessary. Once again, I would rather utilize those funds for a clinical trial that would be quite different and no need to repeat. Professor Sobrero, do you concur? We have a commitment to advance the science in general and not to speculate on whether less than one month difference between one agent and the other. Much better spent money on advancement. Where only 20-25% of patients are treated with remaining options. Correct? Everyone else is treated by actually less investigated options. Thank you very much for this good discussion. Weiguo, anything from your side maybe to add? Yeah. I mean, I hope that for audience, you know, hopefully this is helpful to you. Certainly, we are, you know, we have seen how great the medical need is for these patients and how fruquintinib can help, you know, with the success of the FRESCO-2 study, you know, how fruquintinib can help these patients. The next step, obviously, for HUTCHMED is, you know, we are working very hard trying to submit the NDA across different regions and territories to hopefully bring, you know, fruquintinib to patients as soon as possible. I would like to also thank the panel here. I mean, you know, they also happen to be the steering committee members, and without your efforts and your dedication, the FRESCO-2 wouldn't be possible, and really, thank you very much. I think we will open up for Q&A. Professor Sobrero may have some comments. I was just thinking of the very nice classification of how good a new agent is by Bruce Chabner, former head of NCI, who said whenever you have a new agent, this may fall into the group of superstars, incrementalist or outcast. I struggled over where to put this new agent. Certainly not an outcast. Of course, it's a positive trial. Come on, it's strongly positive. Again, to put these data into a broader perspective in oncology and for honesty, say, "Okay, this cannot qualify for a superstar." The reason for that is that you call superstar something that alters the very long-term life of patients. Biology of disease. Change the biology. Immune oncology in such a way has the characteristics of being a superstar. Nevertheless, I cannot find a single agent active and registered in this disease who can be qualified as a superstar, except for the immuno checkpoint inhibitor in the very small category of advanced colorectal cancer patients who are MSI-H. Okay, that's the superstar. This aligns with the other game changer incrementalist that have made the history of advanced colorectal cancer treatment. I think this is just for honesty and for balance. Otherwise, I don't want to be too triumphalistic in presenting these data. These are excellent data. These are, in fact, impactful. These are game changer, practice changing. Unfortunately, we have to work hard. Well, yeah. I think I would add to this. Obviously, as physicians, you're dealing with the most difficult setting where physicians and patients are running out of options. Unfortunately, as you said, ideal player would be biology changer that obviously we are striving every day in the discovery and development in academic setting industry to do it. But. Do you mind if I come in just for a second? Just for the lay audience that may not be familiar with the term MSI-H. MSI-H in immuno-oncology is definitely a superior game changer per se, but that's less than 5% of our patient population in metastatic colorectal cancer. I just wanna make sure for the audience that may not be familiar with that, it's not common. For those select patients, immunotherapy obviously has been significant for them. For the general patient population, these are excellent results. Thank you, Cathy. I think we are ready to open, yes, for Q&A. Yep. Thank you. To ask a question, you will need to press star one one on your telephone. That's after I will compile the question and answer. Our first question comes from the line of Alec Stranahan from Bank of America. Please ask your question. Hi. Thanks for taking our questions and wanna offer my congrats on the data. Few questions from us. First maybe for the panel, could you touch on the OS of placebo? I think it was maybe slightly lower than studies for regorafenib in TAS-102. I guess along those lines, talking about the comparisons, the majority of patients in FRESCO-2 had received either TAS-102 regorafenib or both. How do you think this maybe influenced the data when we're comparing results to say CORRECT or RECOURSE? The second question may be for Weiguo. How do you feel about this randomized MRCT study from a regulatory perspective in the context of your experience now post thorough review in the US? Thanks. Cathy or Arvind, maybe you can take first question. With regards to the survival of the placebo arm, we had assumed during the statistical design of about five months, close enough at 4.8 months. In comparison to other trials, within the limitations of doing that, it's not surprising given that these patients are more heavily pre-treated, have received more treatments, likely have more advanced disease and more resistant disease. Keeping those factors in mind, that makes these results even more remarkable in that we saw this efficacy with a hazard ratio of 0.66 for progression-free survival, that is about 2.6 months improvement, and a hazard ratio of 0.32 for progression-free survival with improvement of 1.9 months. These are actually better than what we saw with TAS-102 and regorafenib that actually enrolled patients that were less heavily pretreated. I just wanna tack on to that. I mean, the median number of prior lines of therapy for CORRECT and the RECOURSE study was four, and here our median lines of therapy is five. These are, as Dr. Dasari mentioned, extremely heavily pretreated patients. Once again, these results are quite remarkable for this setting. Alec, just to add to this study met exactly, well, short of two weeks estimation of placebo OS performance, and, you know, as has been said, obviously in much more heavily pretreated population. It was challenging actually, you know, historically, we can add now how smart we are, how accurate we are in planning, but we were agonizing on this, because there was no reference point at that time, really, which we could have hard evidence. Kudos to this team and obviously large team behind in planning. Weiguo, do you want me to address the other one? Yeah. I think, you know, for the second question regarding the regulatory, so obviously surufatinib, CRL from the FDA. The main reason there is that, yes, we did 2 phase 3 registration studies, but both were in Chinese patients only. The main issue there is the representative patient population, so-called. This FRESCO-2, as you're aware, right, was a truly global multi-regional clinical trial. We did this in 14 countries, over 150 sites. We are very confident that this will address the key issue regarding representative patient population. You know, we are extremely happy with the results and very confident. Now, we also communicated previously with the U.S. FDA. We had prior communication that our plan is going to combine FRESCO and FRESCO-2 to support registration in the U.S. for third line and above. For other territories, we will be engaged with the regulatory agencies to discuss these specifics. I wonder if you have anything else to add to it. Yeah. I would just, Alec, add, you know, for full clarity. You know, two cases of surufatinib case and this case is like apples and oranges comparison. Totally different. As Weiguo Su said and before Dr. Dasari, this design was fully aligned and vetted through FDA, PMDA in Japan as well as MAA through regulatory submission strategy. As multiple times said, FDA agreed if FRESCO-2 is positive, both FRESCO and FRESCO-2 will support third line indication application. The other aspect I think important to keep in mind, surufatinib had a PFS as a primary endpoint, which obviously is always a little bit more problematic. In here, you have gold standard endpoint, regulatory and clinically meaningful. I think as Weiguo Su said, we are very confident that we met exactly, and actually I would say we exceeded our expectations in our regulatory strategies. We remain very confident. I would say what I'm hearing from the panel, I think they would concur with us as a company that from clinical assessment perspective as they are equal experts in the regulatory environment. If this would not meet expectations, nothing would, correct? With this level of magnitude of benefit. Another very strong point is the internal consistency of the results, meaning that you extend the life, you prolong the PFS, and you also have a certain degree of tumor shrinkage, much more pronounced than with the other two compounds. Again, that's another aspect that is unusual in clinical trial. We are accustomed to discussing uncertain aspects of clinical trials. Here, we actually, during the discussion, we came up with the adjective, this is boring, because this goes without saying. It's all fitting. I translate for the audience, boring means non-controversial results in a highly meaningful way. More questions? Thank you. Our next question comes from the line of Louise Chen from Cantor Fitzgerald. Please ask your question, Louise. Hi, this is Wayne Wu for Louise Chen. Congrats on the data, and thanks for taking our question here. I had a few for you. The first one will be a follow-up. Have you heard any updates from the FDA yet? I'm just wondering if these results are in line with their expectations. Then second question I had for you was on the fruquintinib application progressing in the U.S. and Japan. Given the strong results from FRESCO-2, what is the time in terms of potential approval there? Thank you. Okay. Thank you. I'll actually ask Marek maybe to get you an update. Hi, Weiguo. So, regarding U.S. strategy, we are in process of preparation for pre-NDA meeting. Having said that, it will be happening in October timeframe. We had three formal meetings in the past, pre-IND and the end-of-phase 2 meeting prior starting FRESCO-2, as well as type C meeting before. At each time, we are consistent with the agency. Obviously, purpose of this will be obviously sharing results of this study along with entire package. So we are working towards that, and we are progressing aggressively as planned, and we're on a good path of that. Regarding, I think your second question was regarding progress of Japan, and other territories that we cover equally, on aggressive path. We'll be optimizing overall submission, heavy lifting work just for those who are not close enough. We are talking about 3.5 million pages of submissions across three different regions. We'll be optimizing all that, heavy lifting work, and approaching respective agencies, following a respective, you know, process. Again, prep and the meeting with Japan and EMA. All that will be happening through next several month. 2023 will be very busy for all of us, and we are anticipating, you know, US will be likely first approval, followed by, either simultaneous EMA and Japan approval. We are also not just working on those three main regions. We are focusing really heavily through partnerships and all efforts to make this option available for other regions and patients around the world. Maybe I just add one more point that in the U.S., we have a Fast Track designation for fruquintinib, and so we actually are targeting initial submission before end of this year and a complete submission early next year in the U.S. Fast Track designation gives us rolling submission opportunity. We are not going to speculate at this point what designation, what review type will have priority or normal. I feel very confident that this would match priority review, but we're not going to speculate for the agency. This will come with submission validation and acceptance early next year. Thank you. Congrats again on the data. Thank you. Thank you. Next question. Right. Thank you. Our next question comes from the line of Chi-Wen from Jefferies. Please state your question, Chi-Wen. Hi, thanks for taking my question. This is Chi-Wen at Jefferies for Kali Shoe. Just a quick question from me. At ESMO, we have seen LEAP-002, the study for lenvatinib plus pembrolizumab in first-line HCC did not meet the pre-specified statistical significance. Based on this new information, could you talk about for fruquintinib, your next development strategy, specifically for ongoing combination strategy with PD-1, maybe stratified by market in China versus the market outside China? Thank you. Okay. Just briefly though, we think we have already published extensively on fruquintinib with PD-1 combos, particularly with sintilimab. Obviously, you know, very encouraging efficacy and more importantly, well tolerated. I think that is really, really important. I think you know, the lenvatinib pembro combo, the confirmatory trial failed, but perhaps, you know, tolerability, how patients can stay on the treatment, really all contribute to the primary endpoint, we believe. Specifically with HCC, obviously this failure or inability to confirm will open up, you know, a window of opportunity, I assume. We are still making plans. We're still discussing with KOLs in China how we proceed at the moment. I mean, maybe do you wanna comment on the difference of your drug versus lenvatinib? That might be helpful. Maybe you can do it. I mean, you're the. I think obviously fruquintinib is a potent and highly selective kinase inhibitor, while lenvatinib is more of a multikinase inhibitor and with very difficult to manage off-target toxicities. I think a lot of combinations have the experience with lenvatinib and even as a monotherapy, it's quite difficult to manage. When combined with pembro, it's even more difficult. We are quite encouraged by the data we have so far. Fruquintinib in combination with pembro, we already have over 200 patients dosed and some of the patients already on the drug for over one year, maybe one half year now. We are quite encouraged with the proof of concept data, and we are already in registration study in endometrial cancer in China, and also just started a phase 3 registration trial in RCC. There are a couple of other indications on the radar screen right now, including colorectal cancer and HCC as well. I think ultimately, not just the efficacy, but also safety is really, really important. Thank you. Next question. Next question comes from Yang Huang from Credit Suisse. Please state your question, Yang. Yes, thank you. Yes. Thank you. This is Yang from Credit Suisse. I have two questions. The first one is for the panel, the second one will be for company management. My first question for the panel is, assuming fruquintinib is going to be approved, let's say in the US and the EU for the third-line CRC. When you have a patient come in, how are you going to decide? Are you going to use, or based on what kind of criteria, how do you going to choose between TAS-102, regorafenib, and the fruquintinib? Cathy, could you start? Yes, I'm happy to answer this question. I think as what Dr. Sobrero alluded to earlier, you know, my number one recommendation is it would likely be a patient that has already received an irinotecan-based or an oxaliplatin-based treatment regimen, 'cause those are the first two standard chemotherapy regimens. They may have progressed or be intolerant to those regimens. Then if I had to make a decision between fruquintinib and TAS 102 or regorafenib, given these findings from our heavily pretreated patient population, I suspect this will also result in better benefit, as once again, as Dr. Sobrero mentioned earlier, utilizing it earlier. If I had those capabilities, I would prefer to utilize it likely before considering TAS 102 or LONSURF. That'd be my preference. Roberto. Actually, there are marketing data supporting what Cathy Eng just said. That is, see what happened with the competition between regorafenib and trifluridine. Doctors are prescribing trifluridine 85% of cases, and they prescribe regorafenib 15% of the times. Why is that? A, the delta in efficacy, 1.8 gain in median survival for trifluridine, 1.4 for regorafenib. B, and most important is the toxicity profile. Now, here we have an agent that overcomes these figures under both directions. Again, I would not have any hesitation. I may find the occasional patient. Who is very hypertensive, although that is never a rate-limiting condition. In cancer patients with a life expectancy of five months, come on, blood pressure is not a threat. Great. Arvind, anything to add? Yeah, no, I think it's been very well stated. It's gonna be based on, one, the regulatory approval, and second, you know, safety and efficacy profile. also, again, patient profile. You know, does the patient have, you know, recent bleed or pulmonary emboli and hypertension or are they safe to proceed. Right. I do wanna comment for the gentleman from Credit Suisse that may not be aware. TAS-102 results in significant neutropenia or significant drop in white blood cell count. If you utilize the current schedule that's recommended based upon the FDA insert. A lot of those patients end up requiring Neulasta on top of that all, which is to help boost their white blood cell count. Once again, that is the limitation regarding toxicity of TAS-102, and that's why we're mentioning this in regards to side effect profile. Thank you. Thank you for this addition. What was your second question for us? Yang, can you please press star one one again? Line is open. Please state your question. Hello, can you hear me? Yeah. Yeah, we can hear you now. Yes, we can. Your second question for us. Yes. Okay, yeah, sorry. Yeah, my second question is for management. Basically, I want to understand the commercial strategy for the company if company is going to, you know, successfully get approval for fruquintinib in U.S., E.U. and other, you know, overseas markets outside China. Thanks. Yeah. You know, we are flexible on this, and we were building our own commercial organization in the US, but you know, in parallel, we are also open for discussion with potential global partnership in commercialization, as well as future clinical development. It's all about how we can bring through fruquintinib to patients worldwide, as broadly as possible and as quickly as possible. We think with a global partner, we may be able to you know, best achieve this objective. Thank you. Okay. Yeah, thanks again and congrats for the success. Thank you very much. Are there any more questions? Thank you. We have a final question from Paul Choi from Goldman Sachs. He's asking: What's your plan for filings for FDA? Can you comment on your potential clinical practice using fruquintinib? Example, is it possible to move to earlier lines, quality of life? And secondly, considering AEs, how you manage those AEs typically, example, hypertension. Thank you. Can you repeat the beginning of your question? We had some static in the line. Do you mind to repeat your- Thank you. Again. Number one question, what are your filings? Filing strategy. Oh, filing. Maybe. Regulatory filing? Right. Yeah. Will you? Maybe you can ask Arvind. Yeah. Sorry. Okay. Maybe she missed it. Second- You know, if you are asking about filing strategy, I think we addressed that in the prior answer, so we will skip that. I think it will be on our recorded line. I will let maybe Cathy or Arvind to address the clinical part of your question. AE management. AE management. AE. Hypertension profile. Yeah. As was mentioned earlier by Dr. Yao, the side effect profile that we're seeing with fruquintinib is a class effect, that is inhibition of VEGF, which is the target of this drug. The most common side effect that we noted was hypertension, which is easily manageable and really not an issue in terms of maintaining therapy and maintaining dose intensity. All the other side effects are relatively rare. With regards to this class of drugs, especially those that have broader activity against other tyrosine kinase inhibitors, we tend to see other side effects such as hand-foot syndrome, proteinuria, and liver toxicities that often limit the use of those agents. The incidence of such side effects in FRESCO-2 and FRESCO were minimal, all reflecting the good tolerability of this drug, built on the very selective profile. Thank you, Arvind. Do we have one more question or is that it? No. I think this concludes our Q&A session. Weiguo, do you want to close, please? No, I think it, you know, other than to say, just reiterate that we are working very hard on the regulatory side. Hope to initiate submission as soon as possible and you know, really wanna bring fruquintinib to patients as soon as possible worldwide. Again, thank you all very much for participation here, but also for the trial, and congratulations too. Thanks. Congratulations. Thank you. Thank you. Thank you.