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

Good evening, afternoon, and morning. Welcome to HUTCHMED Conference Call and Webcast. [Operator Instructions] Please be advised that this call will be recorded. I'll turn the call over to your 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 III trial conference call. A couple of hours ago, we just presented the Phase III top line results at ESMO. I understand the presentation time was the most friendly for folks in the U.S. So 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. So 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 III 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 the behalf of the entire team. To recap, FRESCO-2 is a global randomized Phase III study of fruquintinib in patients with refractory metastatic colorectal cancer. These are my disclosures. As 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 1, 2 and 3. 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 2:1 to fruquintinib versus placebo dosed at 5 milligrams PO Q daily, 3 weeks on, 1 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 5 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 2-sided alpha of 0.05. There was an interim futility analysis at 1/3 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 2 arms, including age, region of enrollment and primary site of origin. With regards to prior therapy, specifically, the median lines of prior therapy were 5 and nearly 3/4 of the patients received more than 3 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 2 arms. Subgroup analysis of overall survival showed improvement in the prespecified 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 prespecified 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. And in addition of note, patients in the fruquintinib arm had tumor shrinkage despite the refractory setting as denoted in the waterfall plots on the right. Patients received over 90% dose intensity in both arms, and the median number of cycles were 3 versus 2 months in the fruquintinib versus placebo arms. Evaluation of the toxicity profile revealed that overall Grade 3 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 3 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 3 or higher were hypertension in 14% and asthenia in 8%. Of note, Grade 3 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 prespecified 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 those efforts it would not have been possible to complete a global study during the unprecedented pandemic that we all faced. Thank you very much.

Thank you. Next, we'll have a chance to hear thoughts from world-leading oncologists and Marek will modulate.

Yes. Hi, everyone. We are really privileged here to be joined by our distinguished panel. So 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 FRESCO to start 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. So I do 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. So a big thank you for believing in the concept and be a champion of that concept. Today with us, we have distinguished panel starting from [indiscernible], Professor Sobrero from Italy -- Genova, Italy. You've met Dr. Dasari from MD Anderson. We have Professor Cathy Eng from Vanderbilt, before MD Anderson, recently she [indiscernible]. And 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 relatively appreciate their contributions as well. So we'll kick 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, 3 years ago, we were conceptualizing this study, and we're a lot talking about unmet medical need in the 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. So I think it's really important to give a perspective, colorectal cancer still remains one of the leading causes of death and 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 IV disease, meaning they have metastatic disease. And if they can't undergo surgical resection due to their metastatic disease, the 5-year survival is estimated to be less than 15%. And in all the 20 years I've been practicing, it's basically only increased the 5-year survival from 9% to 14% for surgically unresectable patients. So we have several drugs that have been approved, but a lot of them are also very similar to each other, yet we have this unmet need. These patients still have not necessarily been cured, and we need to improve their overall survival. So 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. And 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. And honestly, we have not had any recent drug approvals for many years. And so this is an oral agent. It basically provides another option. And it really clearly fulfilled an unmet need because we enrolled patients despite COVID. And it was the only Phase III trial open internationally at that time, and we enrolled very quickly. And I'm 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, Cathy. Maybe moving on this journey of discussing results for those who are close to scientific evaluation of results, we speak hazard ratio and the results in a means -- medium 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, hazard ratio of 0.66 and medium observed both in OS and PFS.

We never mentioned hazard ratio to our patients. Hazard ratio is such a difficult concept to understand. So what this means to our patient is, number one, that we have a new player in this disease. And that's so good because, again, the story of the drug -- of this disease has been made by adding coaches of efficacy to the train of the overall clinical benefit. So back 25 years ago, we were stuck with 1 drug and the median survival was 12 to 14 months. Then the 2 other agents came up, and that was extended to 20 months. Then the biologics came and extended by another 6 months approximately. And then the third- and fourth-line agents came up, and they both extended by 1.5 months. Here, we have almost 3 months. And 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 3, 4 trials of between 2 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, I -- and I had to be completely honest, I'd say, no, we don't have anything more to offer to you before fruquintinib. And your median life expectancy is 5 months, 4.5 whatever, 4.8%, not even 5%, reflecting the fact that this is an even worse population than trifluridine and 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 regorafenib came up, you see -- actually a more general concept. When you speak of 2.6 months, you're speaking of nothing actually for the healthy person. But when you are desperate, well, life becomes more precious whenever so little is remaining. So again, being able -- so if I had to translate this to patients, I 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 4, 5 months, if you have not treated down to 25, 30, 35 months. Now we can have another chance. And 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 6, 8, 10 months, that's what those 2 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 late translation of PFS at 4 months. Here, you have twice as many those chances, 50% chances of not seeing the tumor progressing at 4 months. So again, to me, coming from the experience of seeing so many patients this is really a very good new player for patients.

Thank you, Professor Sobrero, very well said when we always remind ourselves 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 2 positive studies, FRESCO, which led to approval in China where now thousands of patients are benefiting from this therapy in much less pretreated situation. We have robustly positive results, FRESCO-2 in heavily pretreated. Can you put this in a perspective, what it means in this continuum of therapy?

Yes. That's really great to think about this as the kind of the combination of the development program. I always view kind of the highest standard is 2 well-controlled clinical trials. And here, you really do have FRESCO and FRESCO-2 showing robust benefit across refractory colorectal cancer in 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 and Arvind. Arvind, you concluded in your last slide, and we had a number of online reactions and commentary at the discussion [indiscernible] practice-changing results. Maybe you can team tag between Cathy and yourself and just share your thoughts why people are using this term, practice-changing, what it really means.

So firstly, 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. So 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. And 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. And the last thing I want to 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. So that, again, is a huge, huge win for our patients and providers alike.

Right. Cathy, anything to add?

Yes. I mean, as mentioned earlier, I think its 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. And although we shouldn't be doing cross-trial comparisons, it's very clear that it is significantly better, though, versus some of their competitors. And once again, I think the fact that it's tolerated extremely well with, I mean, a class effect of hypertension, which is not unexpected, I think it's just another great option for patients. The schedule is easy, 3 weeks on, 1 week off, which means that you can -- you only probably need to be in the doctor's office once a month, which is also an added convenience for patients. And also, this PFS is also quite impressive -- progression-free survival, sorry, is quite impressive for our patient population. So 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 are exposed to every single FDA-approved line of therapy. And this was a heavily pretreated patient population, median 5 lines of therapy, which is unheard of in most trials.

Whenever a new weapon, a new player comes in, we always evaluate its benefit under 3 prospects, 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. And here again, we have an excellent player. And number 3 is what technically is called external validity that is on how many patients can I apply this. And this is a very strong point, as you mentioned, essentially, because every patient can be proposed and advised to get it. It's -- there is no restriction. So 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 specificity, you can paint the picture of the best patients fitting to potential highest benefit of this option?

Whenever we have a new drug that available to patients. Obviously, we still want to evaluate the patient in a standard fashion for any medical oncologists 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 0 and 1. But regardless, these are patients that we see in our clinic. These long-standing patients are the ones that have fairly good performance status. And honestly, with the fact that there's so little toxicities, I think it's going to be, once again, as Alberto stated earlier, very applicable to the majority of our patients. And 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.

So maybe switching Dr. Yao to you. I'll put this slide in front. We always discuss about geographic differences and multiple factors playing into results. Can you put that in the perspective of consistency of results in this study, but also in the context of overall metastatic colorectal cancer, any other factors playing and how you interpret this data for, obviously, application across the globe for regulatory approvals and clinical practice.

Yes, 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 add -- take essentially the statistical robustness into another league where you have 2 well-controlled trials that are positive. And yet you still have quite consistent results across the other items, but also across third-line, fourth-line and fifth-line to therapy, third-line in Fresco and fourth and fifth line here in FRESCO-2. So I think it gives us high confidence in the drug that is going to work in North America, Europe and not surprisingly also in Asia. And I think it's going to globally bring benefit to colorectal cancer patients.

All right. Thank you.

Can I also mention something? I think we've been talking about the -- 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 with -- in other clinical trials with other agents. I think that's really important to keep in mind, unlike some of the other drugs...

[indiscernible] continue on this. I thought that was exactly one of the discussion points. Given the results, obviously, HUTCHMED and entire team will continue working across the globe to approach regulatory agencies to approve single agent based on this robust package. At the same time, we have a number of studies ongoing in the proof of concept. Where -- actually, I opened this to anyone. Where would you see this next step developing this, given this strong single-agent activity. And as you said, good profile combining with a number of options.

I'll let Alberto open it up because a European perspective for clinical trials, development is a little bit different.

Well, again, this is going to be registered in my opinion, for beyond trifluridine and/or regorafenib However, cross-trial comparison would suggest that to ask clinician moving it earlier for clinical use. So I don't know what will be happening in clinical practice because here the benefit is larger, again, with the limitation of cross-trial comparison. And the price to pay is less. So certainly, a major issue is once you are resistant to FOLFOX and FOLFIRI, what's going to be your choice, and these are the best data available. In terms of clinical trial, I'd certainly look for moving this agent earlier, looking for a wider use earlier. One observation may be important, there was, I think, the [ TRC 301 ] study investigated another Anti angiogenic alone in third and fourth line and there was 0 effect, 0. And that's the reason why we do not use bevacizumab beyond the 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 move it first line, I'd go with the trial.

And keep in mind, he mentioned bevacizumab, but we would never use bevacizumab as a single agent, right? And that's given intravenously. And we've been using it for years.

Arvind, any other thoughts?

So in 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 disruptive earlier lines of therapy, I think would be very exciting and areas to look into. And Marek, as we discussed the other day and potential for evaluating this drug in other malignancies as well.

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 with other targeted agents. So I think there's multiple possibilities moving forward from my perspective, sorry.

Dr. Yao?

Yes, absolutely. I think this drug, I think Cathy mentioned earlier, not much side effect. I think my interpretation is not very much off-target side effects. Hypertension [indiscernible] there, but it's a clean VEGF inhibitor that's having on-target side effects, which is what you want. And this allows you to combine with other agents and move it to the earlier lines of therapy and potentially explore other diseases where VEGF inhibitors has proven the role.

Right. Great. So we are not covering here more complicated, obviously, regulatory strategy discussion, we may address some of the questions when we move to Q&A. But 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 discussions 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 efficacy in third-line so called space, while you will have to do it in a head-to-head comparison, can you comment on James or Cathy on this? Given 2 Phase III studies and the package we have?

Yes, 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. And frankly, I think we're better off using that number of patients 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.

Cathy?

Yes. I actually agree fully with James here in regards to this. I think it would be a disservice honestly, to our patients to 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 [indiscernible] is extremely strong. And I think that basically we just as you mentioned earlier, FRESCO has 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, that is really necessary. And once again, I would rather utilize those funds for a clinical trial that would be quite different and no need to repeat.

Dr. Sobrero, do you concur?

You may -- we have a commitment to advance science in general and not to speculate on whether less than 1 month difference between one agent and the other much better spent money on advancement.

We're only 25%, 20% of patients are treated with remaining options [indiscernible] actually less investigated options. So... Thank you very much for this good discussion. Weiguo, anything from your side maybe to add?

Yes. I mean I hope that for audience, hopefully, this is helpful to you. Certainly, we have seen how great the unmet medical need is for these patients and how fruquintinib can help with the success of the FRESCO-2 study [indiscernible] help these patients. The next step, obviously, for HUTCHMED is we are working very hard trying to submit the NDA across different regions and territories to hopefully bring fruquintinib to patients as soon as possible. I would like to -- also like to thank the panel here and the -- 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'm also thinking of the very nice classification of how good a new agent is by Bruce Chabner -- ex -- former Head of NCI, who said, whenever you have a new agent, this may fall into the group of superstars, incrementalist or outcast and I struggled over the -- where to put this new agent. Certainly, it's not just to -- certainly -- well, certainly not an [ outcast ]. Of course, it's a positive trial, come on and strongly positive. But 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. So immuno-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 high, okay? That's the superstar. So this aligns with the other game changer incrementalist that have made the history of advanced colon 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 impactful. These are game changers, practice changing. Unfortunately, we have to work hard.

Well, yes. And I think I would add to this. Obviously, as the physicians, you're dealing with the most difficult setting where physicians and patients are running out of options. And unfortunately, as you said, ideal player would be biology changer, but obviously, we're striving every day in the discovery and development and I had an exciting industry to do it, but...

[indiscernible] comment just for a second. Just for the lay audience that may not be familiar with the term MSI high. So MSI high and immuno-oncology is definitely a superior game changer per se, but that's less than 5% of our patient population in metastatic colorectal cancer. So I just want to make sure for the audience that may not be familiar with that, it's not common. And so for those select patients, immunotherapy, obviously, it has been significant for them. But for the general patient population, this is a very good -- these are excellent results.

Thank you, Cathy. So I think we are ready to open this for Q&A.

[Operator Instructions] Our first question comes from the line of Alec Stranahan from Bank of America.

I want to offer my congrats on the data. Two 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 and TAS-102. And I guess along those lines, I'm talking about comparisons, the majority of patients in FRESCO-2 had received either TAS-102, regorafenib or both. How do you think this may be influenced the data when we're comparing results to say, CORRECT or RECOURSE? And the second question maybe for Weiguo. How do you feel about this randomized MRCT study from a regulatory perspective in the context of your experience now [ post surufatinib review ] in the U.S.?

So Cathy or Arvind, maybe you can take the first question.

So with regards to the survival of the placebo arm, we had assumed during the statistical design of about 5 months or 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 pretreated, have received more treatments. So likely have more advanced disease and more resistant disease. And 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. And these are actually better than what we saw with TAS-102 and regorafenib that actually enrolled patients that were less heavily pretreated.

I just want to tag on to that. I mean the median number of prior lines of therapy for correct and the RECOURSE study was 4. And here our median lines of therapy is five. So these are, as Dr. Dasari mentioned, extremely heavily pretreated patients. So once again, these results are quite remarkable for this setting.

And Alec, just to add to this, this study met exactly, well, short of 2 weeks estimation of placebo OS performance. And [indiscernible] has been said, obviously, in much more heavily pretreated population. It was challenging actually 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. And so kudos to this team and obviously large team behind in planning.

Weiguo, do you want me to address the other one.

Yes, I think for the second question regarding the regulatory, so obviously, surufatinib, CRL from FDA. But the main reason there is that yes, we did 2 Phase III registration studies, but both were in Chinese patients only. And so the main issue there is the representative patient population, so called. But this FRESCO-2, as you're aware, right, it was around a truly global multi-regional clinical trial. We did this in 14 countries, over 150 sites. So we are very confident that this will address the key issue regarding representative patient population. So we are extremely happy with the results and very confident. Now we also communicated previously with the U.S. FDA, we had a 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. And for other territories, we will be engaged with the regulatory agencies to discuss these specifics. [indiscernible] you have anything else to add to...

I would, just Alec, add for full clarity, 2 cases of surufatinib case and this case is like apples and oranges comparison, totally different. And as Weiguo said and before Dr. Dasari, this design was fully aligned and weathered through FDA, PMDA in Japan as well as MAA through regulatory submission strategy and as multiple times said, FDA agreed if FRESCO-2 is positive, both FRESCO and FRESCO-2 will support third-line indication application. And the other aspect, I think, important to keep in mind, surufatinib had 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. So I think as Weiguo said, we are very confident that we met exactly. And actually, I would say we exceeded our expectations in our regulatory strategies. So we remain very confident. And I would say, what I'm hearing from the panel life, I think they will concur with us as a company from clinical assessment perspective as they are equal experts in the regulatory environment if this would not meet expectations, nothing [indiscernible] correct with this level of magnitude of benefit.

Yes, another very strong point is the internal consistency of the results. meaning that you extend the life, you prolong PFS. And you also have a certain degree of tumor shrinkage, much more pronounced than with the other 2 compounds. So 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 down with adjective. This is boring because this goes without saying, it's all fitting.

I translate for the audience. boring means noncontroversial results in a highly meaningful way. More questions?

[Operator Instructions] Our next question comes from the line of Louise Chen from Cantor Fitzgerald.

This is [indiscernible] for Louise. Congrats on the data. So I had a few for you. The first one will be a follow-up. So have you heard any updates from the FDA yet? I'm just wondering if these results are in line with their expectations. And then second question I have for you was on the fruquintinib application progress in the U.S. and Japan. Given the strong results from FRESCO-2, what is the time in terms of potential approval there?

I'll actually ask Marek maybe to get you an update.

Yes. So regarding U.S. strategy, we are in the process of preparation for pre-NDA meeting. Having said that, and it will be happening in October time frame, we had 3 formal meetings in the past end of Phase II meeting, prior starting FRESCO-2 as well as Type C meeting before, each time we are consistent with the agency. Obviously, this one will be -- 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 are on a good path of that. Regarding -- I think your second question was regarding the progress of Japan and other territories that will cover equally on an 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 3 different regions. So we'll be optimizing all that heavy lifting work and approaching our respective agencies following a respective process. So again, pre-NDA meeting with Japan and EMA. All that will be happening through next several months. So 2023 will be very busy for all of us, and we are anticipating U.S. will be likely first approval followed by either simultaneous EMA and Japan approval. And we are also now just working on those 3 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'll just add one more point that in the U.S., we have 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.

And Fast Track designation gives us rolling submission opportunity. We are not going to speculate at this point what designation, what priority -- what review type will have priority or normal, I feel very confident that this would not priority review, but we're not going to speculate for the agency. This will come with submission, validation and acceptance early next year.

Congrats again on the data.

Next question comes [indiscernible] from Jefferies.

This is [indiscernible]. 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 prespecified statistical significance. So based on this new information, could you talk about fruquintinib, your next development strategy, specifically for ongoing combination strategy with PD-1, maybe stratified by a market in China versus the market outside China.

Okay. So just briefly, though, we think we have already published extensively on fruquintinib/PD-1 combos, particularly with [ sintilimab ]. So obviously, in a very encouraging efficacy and more importantly, well tolerated. I think that it's really, really important, I think. The lenvatinib/Pembro combo, the confirmatory trial failed about perhaps tolerability, how patients can stay on the treatment really all contribute to the primary endpoint, we believe. So specifically with HCC, obviously, this failure or inability to confirm will open up a window of opportunity, I assume. But we are still making plans. We are still discussing with KOLs in China, how we proceed at the moment.

Maybe do you want to comment on the difference of your drug versus lenvatinib, that might be helpful?

So maybe you can do it [indiscernible] I think the obviously, fruquintinib is a potent and highly selective kinase inhibitor while lenvatinib is more of a multi-kinase inhibitor and with very difficult to manage off-target toxicities. So 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 for us. So we are quite encouraged by the data we have so far. Fruquintinib -- in combination with fruquintinib, we already have over 200 patients dosed and some of the patients already on the drug for over 1 year, maybe 1.5 year now. So 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 III registration trial in RCC. So there are a couple of other indications on the radar screen right now, including colorectal cancer and HCC as well. So I think ultimately, not just efficacy but also safety is really, really important.

Our next question comes from line of Yang Huang from Credit Suisse.

Yes. This is Yang from Credit Suisse. I have 2 questions. The first one is for the panel. The second one will be for company management. So my first question for the panel is, assuming fruquintinib is going to be approved in the U.S. and the EU for the third-line CRC. So when you have a patient come in, so how are you going to decide? Are you going to use -- or based on what kind of criteria are you going to choose between [indiscernible]?

Cathy, can you start?

Yes, I'm happy to answer this question. I think as what Dr. Sobrero alluded to earlier, my #1 recommendation is it would likely be a patient that has already received irinotecan-based or an oxaliplatin-based treatment regimen because those are the first 2 standard chemotherapy regimens. So they may have progressed or be intolerant to those regimens. But 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, moving -- utilizing it earlier. So if I have those capabilities, I would prefer to utilize it likely before considering TAS-102 or Lonsurf. That would be my preference.

Alberto?

And 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 80% -- 85% of cases and they prescribe regorafenib 15% of the times. Why is that? A, the [ data and ] efficacy, 1.8 gain in median survival for trifluridine, 1.4 for regorafenib. B, and the most important is the toxicity profile. Now here, we have an agent that overcomes these figures under both directions. So 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 5 months come on, blood pressure is not a threat.

James, anything to add?

Yes. No, I think it's been very well stated. It's going to be based on, one, the regulatory approval. And second, safety and efficacy profile and also, again, patient profile. This patient have [ recent bleed ] or pulmonary emboli and hypertension or are they safe [ to foresee ].

And I do want to comment for the gentleman from Credit Suisse that may not be aware. So TAS-102 results in significant neutropenia or significant drop in white blood cell count. And if you utilize the current schedule that's recommended based upon the FDA insert. And a lot of those patients end up requiring Neulasta on top of that all, which is to help boost their white blood cell count. So 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 for this addition. What was your second question for us?

Yang, [Operator Instructions]

Can you hear me?

Yes, we can hear you now. You had a second question for us. Yes?

Okay. Sorry. Yes, my second question for management. So basically, I want to understand the commercial strategy for the company if company is going to successfully get approval of fruquintinib in U.S. EU and all other overseas markets outside China?

Yes. So we are flexible on this, and we -- we're building our own commercial organization in the U.S., but in parallel, we are also open for discussion with potential global partnership in commercialization as well as future clinical development. And really, it's all about how we can bring fruquintinib to patients worldwide as broadly as possible and as quickly as possible. We think with a global partner, we may be able to best achieve this objective.

And congrats for the success.

Thank you very much. Are there any more questions?

We have a final question [indiscernible]. He's asking, what's your plan for filings for doctors? Can you comment [indiscernible] 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?

Can you repeat the beginning of your question, we had some static on the line? Do you mind to repeat your...?

Number one question [indiscernible] filings.

If you were 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 [indiscernible] profile.

So 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. And 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 and 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 anymore question? That's it. So I think this concludes our Q&A session. Weiguo, do you want to close?

No, I think other than to say, just to reiterate that we are working very hard on the regulatory side. I hope to initiate submission as soon as possible and really want to bring fruquintinib to patients as soon as possible worldwide. And again, thank you all very much for participation here but also for the trial and congratulations, too. Thank you.

Thank you.

Thank you.