Turning Point Therapeutics, Inc.

Ladies and gentlemen, thank you for standing by and welcome to the Turning Point Therapeutic Fourth Quarter 2020 Conference Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during this session, you will need to press star one on your telephone. If you require any further assistance, please press star zero. I would now like to hand the conference over to your speaker today, Mr. Jim Bezola, Head of Investor Relations. Thank you, sir. Please go ahead.

Okay, thank you. Good afternoon, everyone. Following market close today, we filed our Form 10-K and issued a news release with a summary of our results for the fourth quarter and full year 2020. We also updated our investor presentation, and you may find these documents posted on the investor pages of tbtherapeutics.com. Leading the call today will be Turning Point's President and Chief Executive Officer, Dr. Athena Conturiatis, who will provide an overview and update of our business results. Athena's remarks will be followed by a review of our financials by our CFO, Yee Larson. We will take questions following our prepared remarks. The three of us are in separate locations today, so please bear with us as we manage the call remotely. Before Athena begins, I want to remind you that during this conference call, we will be making forward-looking statements. The company's actual results may differ materially from those expressed in or indicated by such forward-looking statements. And for a description of risk factors associated with investing in Turning Point Therapeutics, please refer to our recent filings with the Securities and Exchange Commission. Now, let me turn the update over to Athena.

Thank you, Jim, and good afternoon to everyone joining us on today's call. Today, I want to briefly recap our progress in 2020, share a number of updates across our programs, and focus on our goals for 2021. Overall, we continue to make progress in developing our four internally discovered next-generation tyrosine kinase inhibitors that target genetic drivers of cancer. In addition, we are investing in a discovery engine with the goal of establishing a pipeline for long-term growth. The progress and investments we have made are all directed toward advancing our vision to be the leader in precision oncology. Starting with our lead program, Repetrectinib, in 2020 and in January 2021, we reported encouraging preliminary data from our Registrational Phase 2 Trident 1 study. Repetrectinib is a next-generation ROS1 and TREC TKI with greater than 90-fold higher preclinical potency than crizotinib and greater than 50-fold higher preclinical potency than intractinib against wild-type ROS1. Reprotractinib has been granted several key regulatory designations, including breakthrough therapy designation in the United States for the treatment of patients with ROS1-positive TK-naive metastatic non-small cell lung cancer. To recap our clinical data updates, which we believe support a potential best-in-class profile, As of a December 31st, 2020 data cutoff date, in 15 ROS1-positive TKNAs advanced non-small cell lung cancer patients who had at least two post-baseline scans in phase two portion of the Trident One study, the confirmed objective response rate by physician assessment was 93%, or 14 of 15 patients, with a 95% confidence interval of 68 to 100. At the time of the data cutoff, the one non-responder remained on treatment with a 13% tumor reduction. In 22 patients pooled from the Phase I and Phase II portions of Trident 1, the confirmed overall response rate was 91%, with a 95% confidence interval of 71 to 99. For historical reference, both Zalkori and Rosletrek are approved in this patient population with confirmed overall response rates of 66% and 67% by blind and independent central review, respectively. Equally important is the duration of treatment, and in the pool phase one patients, the duration of treatment ranged from 10.9 to 37.3 months, with a median of 30.9 months, which we find encouraging, given it compares favorably to the published data for Zalcori, with a median duration of treatment of 22.4 months. Turning to the preliminary safety profile, as of an October 30th, 2020 data cutoff date, in a total of 185 patients in the phase one and phase two portions of the study, Reprotrectinib was generally well tolerated. In addition to the recent update from our ROS1-positive TKI-naive non-small cell lung cancer patients within TridentOne, last August in 2020, we reported early encouraging data from multiple other cohorts of the Phase II TRIDENT-1 study in TKI pre-treated patients with ROS1-positive non-small cell lung cancer or NTRK-positive solid tumors. We look forward to sharing more data from the ongoing TRIDENT-1 study in the second half of this year. I want to now share an enrollment update. First, we continue to be pleased with enrollment in patients with ROS1-positive TK-naive non-small cell lung cancer which is cohort one of the current study. In the second quarter, we now anticipate reaching 50 patients pooled from the phase one and phase two portions and plan to discuss next steps with the FDA during a type B meeting, which was requested based on our recent breakthrough therapy designation being granted. We hope to be in a position to discuss our path to potential registration following this meeting. As it relates to the other cohorts of the study, We continue to steadily enroll patients in the TKI pretreated, ROS1 positive, and NTRK positive cohorts, and it is our goal to provide an enrollment and clinical data update in other cohorts of the Trident 1 study in the second half of the year. In addition to our development of repotrectinib in the Trident 1 study, our team continues to make progress towards the planned initiation of the first cohort, of our multi-arm TRIDENT2 combination study in mid-2021. This planned phase 1B-2 study in KRAS mutant solid tumors is based on Repetrectinib's inhibition of JAK2, SARK, and FAK, which is believed to suppress STAT3 and AKT signaling, known mechanisms of oncogenic resistance. We will provide further details of the study design closer to initiation. and plan to present additional preclinical data highlighting Repetrectinib's combination potential in KRF mutant disease at an upcoming medical conference in the second quarter. Next in our pipeline is TPX0022, our MET, SARC, and CSF1R inhibitor, currently being studied in our ongoing Phase 1 Shield 1 study in patients with advanced solid tumors harboring genetic alterations in MET. MET-driven cancers represent a heterogeneous population across multiple tumor types, as was reflected in our early clinical data update last October. While there are now two therapies approved for MET exon 14 skipping non-small cell lung cancer, we continue to believe we have the potential to expand the development of O2-2 and focus on MET-amplified non-small cell lung cancer both as a single agent and in combinations. as well as GI tumors. Additionally, we believe there is room for improvement in the exon 14 space, given the limited duration of response and safety profile of the two approved agents. As a reminder, our preliminary data update last year showed objective responses across multiple tumor types with a generally well-tolerated safety profile in a heavily pretreated patient population. The Phase 1 study continues to enroll patients, including those with MET amplification and MET exon 14 skipping alterations. Similar to how we approached the Phase 2 dose for Repetrectamib, we are evaluating multiple doses and schedules for O2-2 to further characterize the pharmacokinetics, safety, and efficacy profile before determining a recommended Phase 2 dose. We are currently enrolling patients in the Phase 1 dose finding portion of SHIELD-1, with the goal of selecting the recommended phase two dose in the second quarter, after which we anticipate proceeding directly into the phase one dose expansion in multiple patient cohorts. The dose expansion will include select patient populations, including patients who are both TKI naive or TKI pretreated. We have multiple updates anticipated in the second half of this year in our O2-2 program, including an additional clinical data update from the Phase 1 dose-finding portion of SHIELD1, a planned discussion with the FDA to potentially modify the SHIELD1 study into a registrational Phase 1-2 design, initiation of the Phase 2 portion of the study pending FDA feedback, and finally, initiating our combination study with an EGFR-targeted therapy. Lastly, I want to highlight that in January, we signed our second licensing agreement with XyLab, similar to our licensing agreement for Repetrectinib, The latest agreement included rights for Zylab to develop and commercialize O2-2 in greater China. There is a significant unmet need in met amplified cancer in China, particularly in gastric cancer, where 40% of the world's cases are diagnosed and are often advanced at the time of diagnosis. Next in our pipeline is our RET inhibitor, TPX0046. 0046 has demonstrated preclinical potency against wild-type RET and RET solvent-front mutations. In the dose-finding portion of our ongoing study, we continue to evaluate multiple doses and schedules to further characterize the pharmacokinetics safety and efficacy profile. We plan to provide a preliminary data update in the second quarter, which will focus primarily on safety and any early signals of efficacy from initial patients. We anticipate approximately 15 to 20 patients across multiple doses in this data update. Lastly in our pipeline is TPX0131, our fourth drug candidate. Patients with ALK-positive disease comprise approximately 3 to 5 percent of non-small cell lung cancer, and sales of approved therapies were estimated to be approximately $2 billion globally in 2020. While there are several ALK inhibitors currently approved, we believe TPX0131 could have great potential initially in TKI pretreated patients. Lorbrenna is the current standard of care in this setting, yet O131 is considerably more potent preclinically against many clinically observed resistant mutations, including with sub-nanomolar potency against the most common G1202R solvent-front mutation, L1196M gatekeeper mutation, and multiple compound mutations. PBX0131 has been designed with a compact macrocyclic structure and in preclinical in vivo studies has shown significant brain tissue penetration after repeat oral dosing, supporting its potential to cross the blood-brain barrier in humans. We are excited to have already received approval by the Australian Ethics Committee and plan to submit our IND to the FDA later this month and anticipate initiating our Phase 1-2 clinical study in the second quarter. We also look forward to presenting additional preclinical data highlighting the profile of O131 at a medical conference in the second quarter. Now let me turn the call over to Yi for an update on our financial results.

Thank you, Athena. You will see in our press release and financial tables that operating expenses for the fourth quarter totaled $47.9 million compared to $23.1 million in the fourth quarter of 2019. The $25 million increase was driven by a $17 million increase in R&D expenses and an $8 million increase in G&A expenses. Increased expenses were attributable to the investments we made to develop our pipeline in earlier stage discovery and in personnel. For 2020, operating expenses totaled 186.8 million compared to 77.7 million in 2019. The 109 million increase was driven by a 55 million increase in R&D expenses and 54 million increase in G&A expenses. Excluding a one-time non-cash stock-based compensation charge from the first quarter of 2020, non-GAAP operating expenses increased by 78 million driven by investments made to develop our pipeline, in earlier stage discovery, and in personnel. Net cash used during the year totaled $82.8 million. Recall, we recorded $25 million in revenue during the third quarter from the Xilab licensing agreement for Repetrectinib in Greater China. This revenue partially offset cash used during the year. Cash, cash equivalents, and marketable securities at December 31st totaled $1.1 billion in compared to $409.2 million as of December 31, 2019. The increase was driven primarily by net proceeds from our two follow-on public stock offerings in May and October of $351.6 and $433.9 million, respectively, partially offset by cash used in operating activities. Looking ahead to 2021, We continue to expect expenses will increase during the year as we execute across now four pipeline programs, initiate three new clinical trials, and make investments in our earlier stage discovery efforts. We continue to project our cash position fund's current operations into 2024. Now I will turn the call back to Athena. Thank you, Yi.

To close, I will summarize our goals for 2021. Beginning this month with our anticipated submission of the IND for TPX0131, our novel ALK inhibitor. We have a busy second quarter expected with anticipated milestones including reaching enrollment of 50 patients in cohort one of the TRIDENT-1 study and discussing next steps towards registration in this population with the FDA. In addition, reporting early interim data for TPX0046, initiating the TPX0131 Phase 1-2 clinical study, and multiple pipeline presentations at a medical conference. Moving on to mid-year, we expect to initiate the first cohort of our Trident 2 combination study. And in the second half, we anticipate providing an enrollment and clinical data update in other cohorts of the Trident 1 study, providing a clinical data update from the Phase 1 portion of the Shield 1 study and initiating the Phase 2 portion of the study, initiating the Shield 2 combination study, And finally, outlining our research strategy, including our focus and anticipated timeline to development candidates. With that update, we are now ready to take your questions. Before we do, I want to close by thanking our great and growing Turning Point team for all they accomplished in 2020. We are looking forward to another great year in 2021. Operator, you may now open the line for questions.

Thank you, ma'am. As a reminder, to ask a question, you will need to press star 1 on your telephone keypad. To withdraw your questions, please press the hash key. Please stand by while we compile the Q&A roster. And, ma'am, we have your first question from Michael Smith of Guggenheim. Sir, please ask your question. Your line is now open.

Hey, guys. Thanks for taking my questions. Athena, I had one on repotraction there, but maybe more specifically around the ROS1 market. And maybe I was just wondering if you could maybe share – you know, from your experience enrolling a triad in one study, what are you seeing at the moment in terms of what percentage of patients is actually receiving an approved ROS1 TKI versus being treatment naive? It seems like your TKI naive cohort is enrolling pretty quickly here. I'm just wondering if you could comment on that and then add a follow-up as well.

Yeah. Hi, Michael. I'm happy to do so. So our belief is that the Rothman market remains at approximately 2% of non-small cell lung cancer. And I will say we've gone through, with the leadership of our chief commercial officer, a very large market research campaign internally to help prepare us for hopeful potential registration and commercial launch for Reprotrectinib. And it does appear that, at least in the United States, that Crizotinib is still the standard of care. There's been very little change in the annual sales for Crizotinib year over year. That said, you know, the uptake of BrazoTrack appears to have modestly improved, but I still would say that it's a modest launch, you know, at least a year now into its commercial opportunity. That said, as it relates to enrollment for our trial, definitely we are the most pleased in that our cohort one has exceeded our initial projections, despite the competition, obviously, that's in the commercial landscape. So that's why we've been very much focused there. Of course, we've gotten breakthrough therapy designation there. and now moving as quickly as we can to the type B meeting with the FDA.

Great, thanks. And then on TPX0046, your red inhibitor, you obviously have activity against solvent fraud mutations. And I was just wondering if there are any other characteristics that could potentially address potential shortcomings of currently approved red inhibitors and how investors should be thinking about the upcoming phase one update in terms of interpreting the data that will get there.

So as it relates to O46, what we've consistently shown is that it is equally potent to the other two molecules based on our preclinical studies in the wild type setting. And again, as to the point you mentioned on solvent-front mutations, that O46 is more potent specifically against certain solvent-front mutations. That said, we have very little limited information as it relates to the prevalence of those mutations, but clearly we have been enrolling patients who not only are TCAT pre-treated but also have solvent-prone mutations, as well as patients who are TCAT naive. The trial has essentially been enrolling for approximately a year on a standard 3x3 design. Where we are today is continuing to evaluate additional doses and schedules. We tried to guide today to anticipate similar to what we did with the MET program, of the mid-teens, and we estimated 15 to 20 patients in the initial update. But we've been consistent in saying that the first update really will focus predominantly on safety, as well as any early signals of efficacy across multiple doses.

Great. Thank you so much.

And ma'am, you have your next question from Paul Choi of Goldman Sachs. Sir, please ask your question. Your line is now open.

Hi, this is Corinne Chickens on for Paul. As you're thinking about combination studies of reprotractinib and KRAS, meat and solid tumors, can you just talk about where you see the clinical hurdle for combination programs, especially given there's a lot of development in that area these days?

Yeah, hi, Corinne, and please say hello to Paul for us. So the first thing I would say is we've been very pleased with the progress we've been making, not only within the combination preclinical data sets that we've been developing around Repetrectinib, but towards initiation of the trial. We gave a little bit more information today to highlight that this is going to be a multi-armed trial. We will initiate the first cohort in the middle of this year. Our goal, obviously, is to submit the IMD relatively soon to enable that. And we don't typically have too much guidance as it relates to trial design until our IMDs are submitted and ultimately filed. But we do have more data coming at a medical conference in the second quarter, and I'm sure you can anticipate which conference that is, to support this. And I think much of the data we've shown so far is in combination with AMG-510 in the G12C setting. We've also shown data with Trematinib in the G12D setting. So without trying to forerun too much on what we think the clinical hurdle will be, I think it will be important for us to show you the design as it relates to which combination partner we're using, and then we can start talking in terms of what we hope to anticipate showing as it relates to response rate, duration, and safety.

Okay, that's fair. And then as you think about the upcoming Type B meeting, could you just talk a little bit about the key questions you'd like to get answered and kind of where you'd like to be exiting that conversation?

Yeah, so, you know, of course, the Type B meeting is exclusively focused on Cohort 1, which is our ROS1-TK-Naive population, and that's because this meeting was requested in the context of Breakthrough Therapy designation. And while it's not a pre-NDA meeting, we do have an extensive briefing document that will outline our preliminary clinical pharmacology studies, our CMC plans, our companion diagnostic plans, and the patient population. And inevitably, I think the key component here is to try to get some guidance and potentially clarify regulatory paths for cohort one as it relates to number of patients and or follow-up. As you know, we designed the trial to mirror cruzotinib and intractinib, which had essentially 50 patients in their initial applications. And our current guidance is that we will have 50 patients in the second quarter. So there are quite a few questions we hope to get answered. I will say I've been trying to be conservative here in saying that this is the first meeting since having VCD. So it's a preliminary discussion. And you obviously don't have as much until you have the pre-NDA meeting. But I do think any additional information we can receive in terms of regulatory clarity will be very helpful at this point.

Great. Thank you.

Okay, next question, operator.

Yes, thank you, sir. Your next question from David Naringarten of Woodbush Securities. Sir, your line is open. Please ask your question.

Thanks for taking the question. It's a little bit of a follow-up to the previous one, which is when you think about potential combinations, you know, KRAS and AMG-510 as one. You mentioned Tremetinib. You know, kind of maybe if you wanted to elaborate a little bit on your strategy for expanding, um, you know, the, the reach of the potential reach here. I mean, are you, um, you know, kind of planning to, you know, have a kind of a multi-prong approach? Are you just looking at these first two and, and kind of, uh, progressing to approval eventually, and then looking at additional combinations. I'm just kind of curious as you think about sequencing potential combination studies, kind of what your priorities are and, you know, what that might look like over the medium term of, you know, let's say a couple of years from now. Thanks.

Yeah. Hi, David. So, let me just start with Repetrectinib, because obviously this is the year where we're going to initiate two combination studies. The first, teripatrectinib, again, is trying to take advantage of the fact that it also has strong potency against JAK2, SARC, and FAC, which, as I mentioned in the prepared remarks, do suppress FAS3 and AKT signaling. So the goal here is, in a KRAS pathway, to try to hit bypass resistance multiple ways. What we've shown publicly so far, and again, trying not to jump too much of a medical conference that's coming, we have more data coming in our combination strategy, but what we have shown previously is with AMG510 in the G12T setting and Trematinib. We do have more data with other G12T inhibitors. We do have more data with other MEK inhibitors. And so right now, all we are publicly guiding to is that the initiation of this trial will occur in the middle of 2021, pending FDA filing, and that it will be a multi-arm approach. And how many drugs will be a part of this trial is still to be determined. The trial will initially start in KRAS mutant solid tumors and then potentially narrow down into a non-small cell lung cancer and or colorectal or pancreatic cancer setting. But that's all still, again, to be determined. And I'm sorry, but I can't give too much more. That's just kind of against our standard practice.

That's fine. It's a competitive space, I know. Thanks.

And, ma'am, your next question from Matt Begler of Oppenheimer. Sir, your line is open. Your line... You may ask your question.

Hey, thanks for taking my questions. I had a question going back to the SHIELD trial's eligibility. It's one I get inbounds on. So for MET-amplified patients, did you exclude copy number low patients, I think similar to what we've seen in some of Kat Mattenib's recent data?

No, and thanks for the question, Matt. So just as a reminder, thanks for fielding questions, of course. The phase one SHIELD1 study essentially is a trial that's open to all MET alterations. And so this by far has the majority of patients with non-small cell lung cancer. But as you saw from our update last fall, we've enrolled multiple GI tumors, whether it's gastric cancer, hepatocellular, colorectal. I can tell you we're continuing to enroll other cancer types, including GYN tumors. And so it's open irrespective of gene copy number for MET amplification. It's open to exon 14 mutations, of course, and then it's also open right now to kinase domain fusion. As we move towards the recommended phase 2 dose, which we're anticipating now will be within the second quarter, and move directly into phase 1 dose expansion, this is where we'll narrow down the patient population into select cohorts. We may at that time change the criteria to have a cutoff to your point on gene copy number. We have not made that determination yet, but we will for sure decrease the amount of prior chemotherapy. For the lung cancer met amplified patients that were enrolled in the initial update that we gave last fall, the median was three prior therapies, but again, these patients had more like four or five rounds of prior chemo and or immunotherapy. So those are the patients that will now potentially be excluded from the expansion. But no is the answer to your question. We did not exclude patients based on gene copy number.

Great. That's really encouraging. Maybe just a quick follow up, if I may. Just something more on broad strategy here as you think about expanding the pipeline. Do you foresee focusing exclusively on macrocyclic scaffolds in the future, or are you thinking about being more agnostic to really any type of structure or type of TKI?

Thank you for the follow-up. I think the company, obviously, at this point is very well known for our four drug candidates that all came off of the initial macrocyclic scaffold. I can tell you our chief scientific officer, Siegfried, has been not only mining that, but also looking at other opportunities when he's evaluating targets for future development candidates. So right now I would say that we do plan on continuing to evaluate our current macrocyclic scaffolds, but I would also not be surprised if we were to go down a slightly different path, but with the same idea of trying to maintain low molecular weight as well as highly potent potentially best-in-class and or first-in-class drug candidates.

Thanks, Athena, and congrats on the progress.

Thank you very much, Matt.

And, ma'am, you have your next question from Nick Abbott of Wells Fargo. Sir, your line is open. Please ask your question.

Good afternoon, and thank you very much for a very robust update. Maybe just a quick question on 131. You indicated that this molecule has good brain penetration, and it looks like on the corporate deck that you're allowing patients in with asymptomatic brain metastases. Do you think you'll see more of those kinds of patients given the CNS penetration with this molecule than perhaps typical for a phase one trial?

Well, thanks for the question, Nick, and congratulations for you. I would say one thing. First of all, let me just start. You know, I'm excited about the ALK inhibitor because I think in many ways it mirrors Reprotrectinib the most when I look at our pipeline. It is not only very potent in the wild-type setting, and what you see on that corporate deck is somewhere between 10 and 30-fold more potent than the second-gen TKIs, which you would say Electinib is the standard of care. Equally, we're getting over 100-fold more potent for G1202R. So again, it's a similar story to what you saw with Rupotrectinib. And again, of course, Rupotrectinib has CNS penetration. So I don't know if the patient population will be skewed in that direction initially. What you see on the slide, we gave a little bit of information on the trial design. is that we will limit down the number of prior TKIs and chemotherapy. This is all up for FDA discussion still, of course, because the IND has not been submitted. But I don't know specifically which patients we will see in terms of CNS disease or not. I will say that we are hoping to go through dose escalation as quickly as possible. We didn't get too much guidance yet, but the goal is to try to use some type of a single patient dose escalation and go as fast as we can to get to NCD.

Okay. Thank you. And then maybe just a follow-up on that. So, you know, when you think about the Trident 2 combination study, I mean, how potent a JAK2 inhibitor is Reprotrectinib? And part of the question relates to the fact, you know, you do see anemia as a grade 3 treatment-related adverse event. Is that related to JAK2? And then the role of JAK2 in interferon gamma-mediated efficacy, and that's PD-1 resistance. So is there Is there a concern that it could be potent and interfere perhaps with potential PD-1 combinations?

Yeah, first of all, it's a fair question. Let me maybe backstep on the anemia component first, and then I can go to the potency. So one thing we've seen with the initial data set, and remember, for our safety profile, which we showed in January of 185 patients, about half of that was coming from the Phase I. And remember, of the Phase I, about a third came from heavily pretreated ALK patients. So the majority of patients that had anemia came in not only with some type of baseline low hemoglobin, but also were heavily pretreated ALK patients. When you look at the in vitro potency data we have, For ROS1, of course, we're sub-1 nanomolar, and for JAK2, we're about 1 nanomolar. So it is not as strong as a JAK2 inhibitor, obviously, as it is a ROS1 inhibitor, but still incredibly potent. So we'll have to see, in terms of the translation into the clinic, to your point of JAK2 inhibitors being, unfortunately, prone to anemia.

Okay. Thank you very much.

Thanks, Nick.

And, ma'am, you have your next question from Signe Jala of Ruth Travel Market Partner. Your line is open. Please ask your question.

Hi, guys. Thanks for taking my question. The updates have been really good. I wanted to start with a reproductive. I just kind of wanted to know how much data do you think you'll have at the time of your type B media? I know you talked about, you know, having data on 50 patients, but, you know, what would perhaps be the minimum duration of follow-up at the time of the meeting? And then are we likely to expect an NDA initially on Cohort 1 and then the other cohorts could probably be label expansions?

Hi, Zegba. Thanks for the question. So we're putting the briefing document together now, so I can't give too much information as it relates to the duration of follow-up. What I do feel comfortable saying is the FDA will be seeing slightly more data than what you've seen from World Lung. But again, the follow-up, to me, is not the more important component. It really is where we are with response rate, confidence interval, duration of response, and the overall safety profile, so the totality. The follow-up, of course, will be important as we get closer to NDA submission, which I think to your second question, at this point, we can't predict where we will be in terms of what indication we'll go in first because, to some extent, that will be dictated by the conversation we're going to have with the type B. for frontline, but we are pleased with the way that the other cohorts are enrolling as well. So more to come. Of course, the Type B meeting is in second quarter, and pending minutes, we will give guidance as to the outcome of that call.

The next question is just about, you know, how helpful has that been in terms of, you know, body treatment across Trident One? And then it does seem, from my perspective at least, that The partnership for OO2-2 did happen a little bit sooner, so we're just wondering, you know, are they going to be a lot more involved with the clinical development for that program?

My apologies, but it might be the Polycom on my side in the office here. I couldn't hear the first part. I heard the second part as related to OO2-2. Was there a first part of your question?

Yeah, the first part is just about, you know, how helpful has ZYBE been in terms of broad recruitment for Trident One so far?

Oh, okay. Understood. Thank you. So ZYLAB reported this morning, and they announced that they will be participating in Trident One in the first half. So where I would say that they've been incredibly helpful is not only helping us understand more the market in their region, which obviously they are the experts, in my opinion, in that region, and getting us prepared to initiate the trial within greater China That's what I could say as it relates to Repetractinib. You're right in that the O2-2, I think I heard your second part, you're right in that the O2-2 collaboration was signed earlier in that we had less patient data, but remembering that when we originally signed with Zylab, they did have a right of first negotiation for other assets within the pipeline. So it was always my thought that if the MET data was encouraging, especially given the prevalence of gastric cancer within China that that would be a collaboration that could benefit us both. So I was not surprised in any way that that one was signed with much less clinical data. And I think if you were to speak to Samantha, I think she would also say, I've been on calls with her recently, that it was also a testament to how she's seen the team deliver. So I don't know if I can predict too much in terms of faster pace of additional collaborations. Of course, we maintain worldwide rights for the other assets in the pipeline.

Thanks, Athena.

Thanks, Edgar.

And, ma'am, you have your next question from Sylvan Thurken of JPM Securities. Please ask your question. Your line is now open.

Hi. Thank you very much for taking my questions, and congrats on the quarter. I see that you talked about initiating SHIELD2, the combination study of TPX0022 with the EGFR in the second half of this year. Could you tell us if this could also become a multi-arm study similar with reprotractinib with Triton2, where you could actually add a couple more compounds to this? And also, what are your objectives for the EGFR combo in terms of the setting and tumor types you're looking for?

Well, first, thanks for the question. I know you're not at JPM, you're at JMP, so I'm sure that gets unfortunately done quite often. Sorry for you. You know, unfortunately, it's not our standard practice to give too much in terms of trial design prior to IND submission, and my approach is really until IND filing by the FDA. So I think you're right on track with our thoughts in terms of there are potentials for multiple EGFR inhibitors to whether they're bispecifics or TKIs to include in a MET combination. We just haven't given that guidance yet. And that, unfortunately, also segues to the second part of your question of whether we'll be using this in patients who have already progressed or frontline. We haven't given that guidance yet. But again, as the study gets closer to initiation and IND clearance, we will give more in terms of the study design.

Great. Thanks. And then maybe more of a hypothetical question for your KRAS strategy. What do you think is the best way these days to develop a KRAS combo? There are multiple companies out there with KRAS, and they have multiple combinations. Would you eventually want to have a firm strategy or partnership, or do you think it would just be development side by side with multiple KRAS compounds? What do you think is the best strategy?

Well, I would just speak to the data that we have currently, which, of course, is with one of the two G12C inhibitors. That's what we've shown publicly in the preclinical setting and one commercially available MEK inhibitor. Again, all I can say at this point is that we are already saying now that our trial will be multi-armed. so you know that there will be more than just one drug that we're combining Repetrectinib with. We're just not saying yet which. I do think that there's lessons to be learned with the SHIP-2s and others that are currently ahead of us, taking slightly a different approach potentially on a different pathway. Of course, we're not targeting SHIP-2 or targeting JAK2, Sark, and Saks, but really much more to say about this trial design once the IND is filed.

Okay, great. I think we have our last question now, operator.

Yes, sir. We have our last question from Eileen Lee of Canaccord. Ma'am, please ask your question. Your line is now open.

Hi, guys. Congrats on the progress. I had maybe a follow-up question on your FDA meeting. Considering you, I think FDA saw less than a dozen patients' worth of RAS1-naive patients when they granted the breakthrough designation. And now that you have 50, I'm curious what exactly are you looking for from their feedback? Or what gating do you think to filing? I know you want to be conservative ahead of chatting with them, but is there a durability question, do you think? Do you think you might need additional patients? And are those sites continuing to enroll naive patients? Thank you.

Let me make sure I heard the last part. What was your last part, Arlinda? I'm sorry, you were tailing off. Something about enrollment?

Yes. Are you continuing to enroll TKI naive patients? Okay.

Sure. So let me respond to the first part. I mean, first of all, looking at small sample sizes, of course, as each of the data updates have come, hopefully you've seen specifically from last August where we only had the seven patients to the most recent update, a tightening of the confidence interval and specifically the lower bound, and that's important. And so I think that's an important component to bring to the FDA. But also at the same time, just as a background, receiving breakthrough therapy designation in December of last year, the FDA asks us to have a Type B meeting within six months. And so this is really now the opportunity for us to discuss with the head of the division our overall path. And that includes, as I said, much more than just the number of patients. It's where we are with our clinical pharmacology studies, healthy volunteer studies, DDI studies, hepatic impairment studies, CMC, where we are with our formulations, where we are with our companion diagnostics. and, of course, where we are in terms of the patient data. So there is quite a bit to get initial feedback from because, remember, at this point we've had an end-of-phase one meeting with the agency, and we've had a type C meeting last August, which was focused more on the pretreated and follow-up and pooling of phase one and phase two patients. So this level of conversation that we're going to hopefully have is much more than we've had before. And so it's an important meeting for much more than just the number of patients or duration of response. As it relates, though, to the key question for NDA timeline, that's important just to really understand is there any difference from the prior guidance, which is the guidance they've given us to date is that approximately 50 patients with a minimum of 12 months of follow-up passed the last responder to support standard approval. That's a key question for us to try to understand if there's any difference there as well based on our emerging data. But it's a much bigger meeting than just discussing number of patients, duration of response, et cetera.

Great. That's super helpful. And then on the enrollment of continuing to enroll in my unit.

Apologies. Yes, I'm sorry. I didn't answer that. I'm sorry. So I mentioned in January we had approximately 40 patients. We have guided that in the second quarter we anticipate we will have 50 patients. And I've also recently said that even after we get to the 50 patients, We will continue to enroll TKI-naive patients, especially to help benefit our partner in XyLab, who obviously are coming into the trial at a time where we're getting close to enrollment completion within cohort one. So we will, yes, continue to enroll. And that's also important if you look at all of the precedents with the approved two RET inhibitors and the two approved MET inhibitors, as well as Rosletrex. All five of those approvals, there were more patients and more follow-up that the agency required in the context of their approval letters. And so that will be something we will also mirror.

Thank you very much.

Thanks, Arlinda.

And speakers, that would be our last question for this call. Turning back over to Ms. Ciccine.

Thank you very much, Operator. Thank you, everybody, for dialing in today and, of course, for your interest and support of Turning Point Therapeutics. I hope that all of you and your families remain safe and continue to stay well. I was incredibly happy to see many of the employees today in the office, and I will just say personally I can't wait to hopefully see all of you face-to-face in the near term. Operator, you may now close the call. Thank you very much.

Thank you. Ladies and gentlemen, this concludes today's conference call. Thank you all for joining. You may now disconnect.