Turning Point Therapeutics, Inc.
Q2 2021 Earnings Call Transcript

Published: 9 Aug 2021

[Operator:]

Thank you all for standing by, and welcome to the Turning Point Therapeutics Second Quarter 2021 Conference Call. At this time, all participants are in a listen-only mode. After the speakers' remarks, there will be a question-and-answer session. . I would now like to hand the conference over to your speaker today, Jim Mazzola, Head of Investor Relations. Please go ahead.

[Jim Mazzola:]

Okay. Thank you. And good afternoon, everyone. Following market close today, we filed our Form 10-Q and issued a news release with a summary of our results for the second quarter of 2021. We also updated our investor presentation. You may find these documents posted on the Investor pages of tptherapeutics.com. Leading the call today will be Turning Point's President and Chief Executive Officer, Dr. Athena Countouriotis, who will provide an overview and update of our business results, before turning the call over to Paolo Tombesi, our Chief Financial Officer, for a review of our financials. We will take questions following our prepared remarks. And we'll be joined by Mohammad Hirmand, our Chief Medical Officer. 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. 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.

[Athena Countouriotis:]

Thank you, Jim. And good afternoon to everyone joining us on today's call. I am pleased to be joined by Mohammad and our newly hired CFO, Paolo, who brings tremendous financial experience supporting commercial organizations, which is critical as we advance our current pipeline. Our growing Turning Point team of now more than 200 employees has continued to make excellent progress against many important milestones for 2021. Since our last quarterly update, we have received two regulatory designations from the FDA for TPX-0022 and began dosing in our FORGE-1 study of our fourth clinical candidate TPX-0131, bringing our total number of ongoing studies to five with two additional clinical trial initiations planned in the second half. Overall, we continue to advance our four clinical stage next generation tyrosine kinase inhibitors that target genetic drivers of cancer, and I look forward to sharing today initial information about our ongoing discovery work and our anticipated timelines to potentially new development candidates. As always, I will start with our lead program, repotrectinib, which is a next generation ROS1 and TRK TKI with three fast track designations for ROS1 TKI naïve and pretreated non-small cell lung cancer patients and NTRK positive TKI pretreated patients as well as breakthrough therapy designation for patients with ROS1 positive, TKI naïve non-small cell lung cancer. Repotrectinib is currently being studied in our ongoing multi-cohort registrational TRIDENT-1 study in patients with ROS1 positive advanced non-small cell lung cancer and NTRK positive advanced solid tumors. As of last week, we now have approximately 300 patients enrolled in the combined Phase I and II portions of the TRIDENT-1 study. This total includes approximately 200 patients in the Phase II portion of the study and more than 50 in the ROS1 positive TKI naïve advanced non-small cell lung cancer cohort, or EXP-1. We have continued steady enrollment across all five additional cohorts within TRIDENT-1 and we were pleased to see our partners Zai Lab dose initial patients in the study in China. This triggered milestones of $5 million, which we recognized in the second quarter. In June, we reached our target enrollment in EXP-1 and have continued to enroll patients in this cohort based on strong momentum and to provide continued treatment access to new patients. As we announced last quarter, based on feedback from a Type B meeting with the FDA, we plan to discuss the top line blinded independent central review results from EXP-1 with the FDA when responders have been followed for at least six months past onset of response, which we continue to anticipate in the first quarter of 2022. We plan to provide further guidance on the potential registration timeline upon completion of the FDA meeting. Turning to the second half TRIDENT-1 clinical data update, we currently anticipate providing updated efficacy data across multiple ROS1 and NTRK cohorts by physician assessment at AACR-NCI-EORTC annual conference in early October. We expect this update at the ANE meeting will also include safety data from approximately 300 patients. And at that time, we will be in a better position to provide next steps on other TRIDENT-1 cohorts beyond EXP-1. Our development plan for repotrectinib includes two additional studies beyond TRIDENT-1. The first is our Phase I/II CARE study in pediatric and young adult patients with advanced malignancies harboring ROS1, NTRK or ALK alterations. We are pleased that our first clinical data has been accepted for oral presentation at the International Society of Pediatric Oncology Conference this October. The second is our Phase Ib/II TRIDENT-2 combination study of repotrectinib and trametinib, which we plan to initiate in the third quarter. The TRIDENT-2 study will examine safety, tolerability, pharmacokinetics and any early signals of efficacy of the combination in patients with KRAS G12D mutated advanced solid tumors with the potential to add additional cohorts to the study over time. Next in our pipeline is TPX-0022, our MET, SRC and CSF1R inhibitor, currently being studied in our ongoing Phase I SHIELD-1 study in patients with advanced solid tumors harboring genetic alterations in MET. During the quarter, we received orphan drug designation for TPX-0022 for patients with gastric cancer, including gastroesophageal junction adenocarcinoma. In addition, just last week, we received fast track designation for TPX-0022 for patients with MET-amplified advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma after prior chemotherapy. As a reminder, there are no currently approved MET-targeted therapies in gastric cancer. We believe we have multiple opportunities to differentiate 022 including an exon 14 indications, as well as both MET-amplified gastric and non-small cell lung cancer. Last fall, our preliminary data for TPX-0022 in the first 21 patients treated showed objective responses across several tumor types with a generally well tolerated safety profile in a heavily pretreated patient population. Since then, we have continued enrollment across multiple different dosing cohorts. And based on the available PK, safety and preliminary efficacy data, we have selected our likely recommended Phase II dose and began dosing in the Phase I dose expansion. This is an important milestone for the program as the patient populations within SHIELD-1 will now be further refined, with less heavily pretreated patients enrolled into individual cohorts based on tumor type, including exon 14, and MET-amplified non-small cell lung cancer and MET-amplified gastric cancer. We are preparing for an end-of-Phase I meeting with the FDA this quarter. And pending FDA feedback including agreement on the recommended Phase II dose, our goal is to revise the study into a potentially registrational Phase I/II and proceed into the multi-cohort Phase II portion of the SHIELD-1 study. Our proposed Phase II study design is similar to the Phase I dose expansion, which is currently ongoing and focuses on four main patient populations, including MET, exon 14 skipping non-small cell lung cancer, both treatment naive and pretreated, and both MET-amplified non-small cell lung cancer and gastric cancer. We plan to share more details on the FDA feedback and the Phase II design after the end of Phase I meeting. In addition to our TRIDENT-1 data update at the ANE meeting in October, we also anticipate providing a clinical data update in patients with MET alterations across multiple tumor types from the Phase I dose finding portion of the SHIELD-1 study. This update will focus on PK, safety and preliminary efficacy data supporting our recommended Phase II dose. Last, for 022, we continue to anticipate initiation of our combination study with an EGFR targeted therapy later this year. We plan to provide guidance regarding the details of the study once the IND is filed. Next in our pipeline is TPX-0046, our RET inhibitor, currently being studied in our ongoing Phase I/II SWORD-1 study in patients with advanced solid tumors determined to be RET fusion or mutation positive. The Phase I dose finding portion of SWORD-1 continues to enroll patients where we are evaluating multiple doses and schedules to further characterize the pharmacokinetics, safety and efficacy profile before determining the recommended Phase II dose. We will outline plans for our next data update from this program in early 2022. Last in our pipeline is TPX-0131, our CNS-penetrant ALK inhibitor, where the Phase I/II FORGE-1 study is actively enrolling and we are currently opening additional sites in the US and Australia. We are excited to advance 0131 given the potency we have seen preclinically, which was recently published in Molecular Cancer Therapeutics. 0131 is a selective ALK inhibitor that is highly potent in a wide array of cellular and in vivo tumor models. Against the G1202R, L1196M compound mutation which harbors both solvent front and gatekeeper mutation, TPX-0131 had substantially higher cellular activity than approved ALK targeted therapies. In in vivo xenograft tumor studies, 0131 demonstrated complete tumor regression in an ALK dependent model, harboring the G1202R solvent front mutation and models harboring compound mutations. While there are several ALK inhibitors currently approved, we believe 0131 could have great potential initially in TKR pretreated patients who often develop single or compound ALK mutations. Shifting focus now, the progress and investments we continue to make in our discovery programs are all directed towards advancing our vision to be the leader in precision oncology. Since the company was founded, Turning Point's core discovery methodology has been anchored by deep structure based drug design expertise to deliver highly potent and differentiated small molecules. This approach has enabled us to successfully advance four candidates into clinical development, with our lead asset now in an ongoing registrational study. Moving forward, our goal is a research portfolio that can support at least one new IND every year beginning in 2023. Today, I will share two of the four discovery targets our team is pursuing and our potential timeline to future development candidates. Our focus in selecting new targets begins with the following criteria. First, addressing areas of high unmet medical need for patients. Second, leveraging our deep expertise in fragment and structure-based drug design. Third, the strength of the biology supporting the target. And finally, the potential market opportunity. Each of our four new programs have been established around targets that play large roles in an aberrant GTPase activity and signaling known to drive genomically defined cancers with significant unmet medical need. Each program is underpinned with a fully enabled structural platform, providing real time protein ligand cocrystal structures used to prospectively guide designs. We are focused both on validated targets, as well as novel first-in-class opportunities within oncology. Today, I will share initial information on the two most advanced programs. The first program targets KRAS G12D. Mutant KRAS is present in approximately 30% of all cancers and is an attractive therapeutic target for its role in modulating RAF/RAF/MET signaling pathways. While there is now an approved KRAS-G12C therapy in Lumakras, there have been very few advances in the G12D space. And it remains an area of high unmet medical need in multiple tumor types, including pancreatic, colon and non-small cell lung cancers. Our goal is to nominate a development candidate in the second half of 2022. Our second program targets the p21 activated kinase or the PAK family. This target represents a multi-tumor opportunity with a selective inhibitor of PAK1 and PAK4, which are key signaling nodes in subsets of breast and ovarian cancers, melanoma and non-small cell lung cancer. Our goal is to differentiate this program with dual inhibition of amplified PAK1 and PAK4, which we believe has potential as a single agent and in combination. We are also targeting a development candidate in the second half of 2022 for this program. Overall, we are excited by these early pipeline programs and look forward to sharing more detail in future investor and medical forums. Now let me turn the call over to Paolo to provide an update on our financial results.

[Paolo Tombesi:]

Thank you, Athena. I'm excited to join the company and look forward to meeting many of you in the coming months. You will see in our press release and financials tables that we generated $5.2 million in revenue during the quarter, mainly related to development milestones earned from Zai Lab under our licensing agreement for repotrectinib in Greater China. Operating expenses for the second quarter totaled $61.8 million compared to $32.7 million in the second quarter of 2020. The $29.1 million increase was driven by $20.5 million increase in R&D expenses and $8.6 million increase in G&A expenses. Operating expenses for the first half totaled $123.1 million compared to $95.4 million for the first half of 2020. Excluding a one-time, non-cash stock based compensation charge in the first quarter of 2020, operating expenses for the first half of 2021 increased by $59.1 million, driven by our increased investment in R&D and growth in G&A expenses. We continue to expect expenses will increase during the year as we execute across now five clinical trials, initiated two additional clinical trials and continue to invest in our discovery programs. Net cash used during the first half of 2021 totaled $44.7 million, with the revenue generated from the Zai Lab agreement partially offsetting the cash used. Cash, cash equivalents and marketable securities at June 30 totaled approximately $1.1 billion. We continue to project our cash position to fund current operations into 2024. Now, let me turn the call back to Athena.

[Athena Countouriotis:]

Thank you, Paolo. To close, I will summarize our goals for the second half of 2021. First, for repotrectinib, we look forward to providing updated TRIDENT-1 clinical data by physician assessment from multiple ROS1 and NTRK patient cohorts at the ANE conference in October. In addition, we plan to report initial clinical data from the ongoing Phase I/II CARE study in pediatric and young adult patients at the SIOP Congress in October. For TPX-0022, we also plan to provide a clinical data update at the ANE conference in patients with MET alterations across multiple tumor types from the Phase I dose finding portion of the SHIELD-1 study. We also plan to initiate the Phase II portion of the SHIELD-1 study pending FDA feedback and initiate the Phase Ib/II SHIELD-2 study of TPX-0022 in combination with an EGFR targeted therapies. We look forward to continuing progress across our additional clinical trials, including our SWORD-1 and FORGE-1 studies and our planned TRIDENT-2 study. And we'll outline plans for our next data updates from these studies in early 2022. And lastly, we are excited to continue the ongoing discovery work and look forward to sharing more in 2022 as we get closer to candidate nominations. With that update, we are now ready to take your questions. Operator, you may now open the line for questions.

[Operator:]

. We have our first question coming from the line of Paul Choi with Goldman Sachs.

[Paul Choi:]

Congrats on all the progress. Couple of questions on SHIELD-1. First, with regard to the dosing of TPX-0022, you mentioned in your press release that you are enrolling patients in the expansion portion here. But I was going to ask, are you only enrolling patients at what you think is the recommended Phase II dose? Or are you still enrolling patients across different dose levels and schedules here? I guess this is a measure of your confidence that you found the right dose here.

[Athena Countouriotis:]

Yeah, let me pass that question to Mohammad Hirmand.

[Mohammad Hirmand:]

For the Phase I expansion portion of the study, we are enrolling patients at the likely recommended Phase II dose. As Athena mentioned, we have an upcoming end-of-Phase I meeting with the agency where we plan to discuss our recommended Phase II dose with them to make sure that they're aligned prior to us initiating the Phase II portion of the study.

[Paul Choi:]

Just as a follow-up, with regard to your upcoming update from the program, can you maybe help us think about what the mix of tumor types you might have at the triple meeting? And will you be in a position to talk about gene amplification, copy numbers where it's appropriate?

[Mohammad Hirmand:]

Paul, I can also follow on that response as well. So, the data update in October at the ACR-NCI-EORTC meeting, again, in October is going to be from the Phase I dose finding portion. As you may recall, we enrolled patients across a number of tumor types and various MET genetic alterations across doses. So, that's the data we're going to be presenting. As Athena mentioned, the focus of that data is mostly going to be on PK, safety and primary efficacy supporting RP2D. But we'll try to bring as much data as we can right now. So, we just recently were notified of that acceptance. So, right now, we're in the planning stages in terms of putting the pieces together, so we can have the data delivered in time for that presentation.

[Operator:]

We have our next question coming from the line of Michael Schmidt with Guggenheim.

[Michael Schmidt:]

Congrats on the updates as well. I guess on 022, nice to hear that you're planning to potentially initiate these registration directed Phase II cohorts in a study following the FDA meeting. I guess, how should we think about the approval bar for those different indications, especially given that MET inhibitors are already on the market for exon 14 non-small cell lung cancer, but not any of the other cancers that you are enrolling or planning to enroll in the study?

[Athena Countouriotis:]

So, as you know, and you're referring to, of course, the first MET inhibitor that's approved in MET exon 14 in patients that have seen a platinum-based chemotherapy regimen or have had no therapy. As you know, we're exploring in the SHIELD-1 dose expansion right now multiple cohorts, happy that we've started dosing. And now this is where we refine down the patient populations to have slightly less therapy than what we allowed in dose finding. But it is very much focused on a few indications. Obviously, exon 14 as well as MET-amplified lung as well as gastric cancer. And as we said earlier, happy that we received our second designation. In terms of the approval bar, as you know, the one approved therapy has accelerated approval. So, it's not necessarily a benchmark to go against. But what we think about in terms of ways that we can differentiate, clearly, there's no approved gastric cancer, MET amplified targeted therapy. So, we would likely be benchmarked against chemotherapy. But these are the kinds of conversations we'll be looking forward to more feedback within the context of the end-of-Phase I meeting. And as Mohammad said, he's preparing for that now. And that meeting is now planned in the third quarter.

[Michael Schmidt:]

Just a quick follow-up on your upcoming update, as well on the TRIDENT-1 study. I think you mentioned 200 patients now enrolled in the Phase II portion. I guess, how are you tracking towards completing enrollment in those cohorts? And which cohorts will you provide data on? Will that include the cohort one as well at the triple meeting? Or is it more geared towards the other cohorts in this study?

[Mohammad Hirmand:]

I can take that question as well. Again, we have been quite pleased with how enrollment has been going in TRIDENT-1. We have seen steady enrollment across all the cohorts. As Athena mentioned in her opening remarks, we have now enrolled approximately 300 patients in total in the study, about 100 in Phase I, about 200 in the Phase II portion of the study. Regarding the data updates, in October, at the triple meeting, right now, we're anticipating to report data again by physician assessment on multiple ROS1 and TRK cohorts with the safety, again, coming from approximately 300 patients that we have enrolled in TRIDENT-1.

[Operator:]

We have our next question coming from the line of Matt Biegler with Oppenheimer.

[Matt Biegler:]

Don't want to jump the gun on the TRIDENT-1 update here, but 300 patients seems like a pretty substantial increase versus our last cut, which was, I think, at 185. Should we be expecting a larger focus on NTRK patients than we had before? Or just kind of how are you thinking about the breakdown amongst cohorts?

[Athena Countouriotis:]

Maybe let me take a second here to say how proud I am of the team. The team has done such an amazing job as it relates to enrollments against what I think has been a very difficult, challenging time, obviously, with the pandemic continuing with the TRIDENT-1 study. And as I've said, consistently we've been enrolling steadily across all of the cohorts. We actually just, I believe, had our strongest enrollment cohort. And so, again, I'm incredibly proud of the progress they've been making. That said, as Mohammad said, we don't normally front run our abstracts. And at the same time, it's premature for us to give too much in regards to what you'll see. But we did say today multiple ROS1 and NTRK cohorts. And it's been a while since the last update from last August. So, without going into more specifics, I would just say that we look forward to sharing the data. And of course, we were just informed last week.

[Michael Schmidt:]

Maybe I can just follow-up with a quick one on the SHIELD-1 trial. We thought it was really nice to see the activity amongst the MET amplified patients in the last readout. I just kind of wanted your thoughts on how that might portend to the EGFR mutant cohort that you're planning to explore or just whether those two diseases are too different to extrapolate meaningfully.

[Athena Countouriotis:]

They are similar in the sense that you've seen the data that has come in the EGFR setting, specifically, obviously, with an approved inhibitor and the combinations and the combination approaches that have been taken with MET targeted therapies. Our goal is to pursue both our lead asset, repotrectinib, as well as our second asset in 022 as both single agents and in combinations. And one of those combinations, as you highlighted, is the EGFR combination that we're planning. I think, one, for the data update that you'll see in the second half, while Mohammad didn't go into specifics, there are more lung cancer patients that we will hopefully have data for in that update. And in addition, we look forward to still initiating the EGFR combo prior to the end of the year when we would normally give more information as an IND is submitted and inevitably filed. And so, that's the plan right now for the EGFR combo.

[Operator:]

We have our next question coming from the line of David Nierengarten with Wedbush Securities.

[David Nierengarten:]

Just a couple quick ones. You've mentioned a couple of times physician assessments at the triple meeting for repotrectinib. I assume that means we will be waiting till next year for the blinded central review as part of the ongoing data collection there. And then, another question on repo, now that Lumakras is approved, I was just curious if you guys were planning any combo studies with that agent over time or focusing on the other combo that you have up and running?

[Athena Countouriotis:]

We've specifically said physician assessment because we didn't want anyone to think that we would have the blinded independent central review data, which we've not yet seen in time for the ANE presentations. We've consistently said that our goal for the FDA meeting in Q1 of next year is to discuss the data with the agency and then inevitably to come public with the information that we've had in the context of FDA feedback. So, that's what I can say, sorry, as relates to the BICR data at this point. And in regards to the approval for the first G12C inhibitor, yes, we are, as I said in the prepared remarks, anticipating the addition of more cohorts into our combination trial. I don't know specifically that will be Lumakras. I have said multiple times some of the current capsule burden with the combination based on how many capsules are required for Lumakras daily dosing currently is somewhat of a feasibility concern, at least from my side right now. And so, that trial may start in terms of a G12C arm into 2022. But we very much look forward to initiating the first arm with trametinib, of course, this quarter.

[Operator:]

We have our next question coming from the line of Andrew Berens with SVB Leerink.

[Andrew Berens:]

A couple on the MET agent. It sounds as if the dosing for 022 have a similar dose escalation portion to minimize dizziness like repo. Just wondering if you could give us some color on that. And then, you mentioned the combo with EGFR drugs, would that be small molecule or large molecules? And are you considering combination with other classes of drugs that MET is thought to be an escape mutation? And then lastly, what's the copy number you've chosen from MET amplification?

[Athena Countouriotis:]

Let me take as it relates to 033. So, we've taken an approach, as you saw, with repotrectinib in evaluating flat dosing as well as titrations. We did outline in our corporate presentation today, and I've said it consistently, that since the plenary session last year for the MET program, we have done additional titration cohorts, predominantly focused around 40 milligrams and 80 milligrams, whether you're using QD dosing or BID dosing. And we will wait at this point until we hear the FDA's feedback on our likely recommended Phase II dose to get more information there. But that is essentially why we've been exploring multiple doses, as you mentioned, in regards to managing safety, which I think is really much of a follow on to Paul's question in regards to our confidence in our dosing approach. The combination for EGFR, we have looked at quite a few potentials. And where we are today is, again, closer to initiation, but with the lens of – that we don't normally give too much information until an IND has been filed. And so, I would just say that we've been looking at inclusion of other tyrosine kinase inhibitors, including approved agents like Tagrisso and/or using collaborations that could include antibodies as well. And to your escape mutation question in gene copy number, at this point where we are with the program is we're continuing to evaluate both low gene copy number and high gene copy number in the ongoing SHIELD trial.

[Andrew Berens:]

Are you considering other programs, other than EGFR, KRAS or MET escape mutation?

[Athena Countouriotis:]

We were looking at initially, based on some preliminary data that we shared at AACR earlier this year, at an IO combo. And so, I would just say that the lifecycle planning for the 022 program is something that we're currently continuing to evaluate. And hopefully, we'll share more over time.

[Operator:]

We have our next question coming from the line of Zegbeh Jallah with ROTH Capital.

[Zegbeh Jallah:]

I just have a few follow-ups of a question that has been asked. I think the first is just about expectations for NTRK because we've been so focused on ROS1. So, just wondering how you're thinking about that opportunity, what the expectations are and you can probably do the same for the pediatric data as well.

[Athena Countouriotis:]

I think you said expectations, is that right, Zegbeh? Did you say expectations?

[Zegbeh Jallah:]

Exactly. And the market opportunity, how are you thinking about that?

[Athena Countouriotis:]

Let me just start with what we said today in regards to the second half updates. As Mohammad said, we're excited that we've heard now we have three clinical presentations coming in October. And for those that haven't already heard, the virtual meeting of ANE, unfortunately, is still a virtual meeting. And so, at this time, what we're looking forward to is at least a preliminary, I believe, five minutes video presentation for both TRIDENT-1 as well as SHIELD-1 and then an oral presentation for our pediatric program. Now, what we said for the TRIDENT-1 update to your NTRK question was that we would give multiple cohorts including ROS1 and TRK. So, we have committed to a TRK update. And in regards to expectations, I've consistently said we've been pleased with steady enrollment across TRIDENT-1. We always knew that the TRK naive cohorts may lag a little behind the pretreated cohort. Obviously, we also have fast track designation for TRK pretreated patients. But that said, with the recent addition of Zai Lab, we've actually been pleased with the way the enrollment has gone in the TRK naive population. And so, my expectations currently is that we'll share more data in the second half as it relates to NTRK. From a commercial perspective, our market opportunity, we have limited information as to how the current approved TRK inhibitor is doing. But I think, of course, we're continuing to monitor the clinical landscape in terms of the competition, as well as increasing testing rates with more tests, obviously, being approved potentially helping that as well.

[Zegbeh Jallah:]

Can you just comment on the pediatric data as well?

[Athena Countouriotis:]

The pediatric expectations, now just as a reminder, this trial allows patients in that are either ALK positive, ROS1 positive, of which certain tumor types, unfortunately, are known to be ROS1 driven in pediatric patients and NTRK. And so, it is a mix in regards to what to anticipate from that update. But again, pleased that this is our first clinical update and it was accepted for an oral presentation.

[Zegbeh Jallah:]

Just another follow-up here. I think I heard you mention additional cohorts for the KRAS combo, I'm just wondering what those cohorts might be, what are you looking for to initiate those cohorts?

[Athena Countouriotis:]

At this point, we've been focused initially on the G12D combination with trametinib, as well as G12C, again, as I mentioned, potentially in 2022 just simply right now based on pill burden because we've been very pleased with the preclinical data we've shown in the past with AMG-510. We haven't disclosed any additional arms in terms of the combination yet, so that would have to be more information to come.

[Zegbeh Jallah:]

Just two more here. The first is just regarding the MET program. Just wondering if you're going to meet with the FDA first before initiating the MET combo, or that is not even related?

[Jim Mazzola:]

Are going to meet with FDA before initiating that combination with EGFR target therapy in MET?

[Athena Countouriotis:]

Zegbeh, the EGFR combination, our current plan, just as we did with repotrectinib and trametinib, is to submit an IND because this is a combination with 022. Of course, our goal right now is focused on the end-of-Phase I meeting and our likely recommended Phase II dose. We would go right then into the IND submission to hopefully then disclose more information to you in regards to the IND being filed. So, not necessarily a meeting, but it would require a new IND submission.

[Zegbeh Jallah:]

Then the last one here, just because we're excited about combos and what that could do for patients and the market opportunity, so I was just wondering, as you're thinking about expanding the pipeline, you mentioned two programs. And I was just wondering, how important was the potential to do combos with that?

[Athena Countouriotis:]

One of the things I would say is just excitement, in general, of sharing now the progress we've made with the discovery group. Thank you for highlighting the opportunity within the combinations. We did specifically say for at least the p21 activated kinase, or PAK, the idea of combinations. And I believe it was Arlinda, on our last quarterly call, asked me about would we do a combination in the G12D space with a G12D inhibitor. So I would just say stay tuned. We look forward. This is just the first bit of information that we're sharing regards to our targets. But of course, now we've put out there that we have, hopefully, two new development candidates coming in the second half of 2022 with our goal of at least one new IND starting in 2023. And that may or may not include additional, not only just single arm trials in terms of single agents, but also combinations.

[Zegbeh Jallah:]

Congrats to you and your team on all the progress. I always am so pleased with you coming. Unfortunately, late in the queue and coming with so many questions. So thank you.

[Operator:]

. We have our next question coming from the line of Silvan Turkcan with JMP Securities.

[Silvan Turkcan:]

Congrats on the great quarter and the progress. Looking forward to all the data. I have a quick question. Could you please describe what hurdles there are regarding transforming SHIELD-1 into a potentially registrational study that you will discuss with the FDA, if there are any left.

[Mohammad Hirmand:]

I can take that one. Again, we have been quite excited regarding the progress we have made in the 022 program and look forward to the upcoming FDA meeting. So, during that end-of-Phase I meeting, what we would like to run by the FDA is a number of items. One of them is, obviously, making sure they're aligned with our recommended Phase II dose. We also want to talk to them regarding what the Phase II may look like. And one thing we would like to do is to basically modify our existing protocol from a Phase I study into a Phase I/II study, so that under that same protocol umbrella, we can actually move into the Phase II study as opposed to doing a separate trial, which obviously takes additional startup time. So, that's kind of conceptually how we're trying to approach it. And then, obviously, once we have the FDA meeting, with the minutes in hand, we will come back and share that with you.

[Silvan Turkcan:]

About your Phase I/II CARE study, congrats on the data presentation or the oral presentation. Could you tell us anything that is fundamentally different in these pediatric tumors that may alter the biology as a response of the KRAS or TRK targeting? Or is it more or less the same as tumors in adults?

[Athena Countouriotis:]

Interestingly enough, because I trained in pediatrics, I'll take that, Silvan. The one thing I would just say is children oftentimes have better tolerability of agents. Really, it's quite interesting, just thinking about less comorbidities, et cetera, than adults. And so, one of the things we've been very mindful of is dosing within the pediatric population using either a flat dose, like we have in the adult program, which is 116 mgs going to twice daily or more of a weight based approach. But with the exception of modifying dosing based on weight, obviously, because children get bigger, the biology component, what we see is some relatively frequent, unfortunate tumor types that are ROS1 driven. And then, as you can appreciate, especially from the prior TRK inhibitors, unfortunately, infantile fibrosarcomas are often TRK driven as well as glioblastomas. And so, there are, to some extent, more unique tumor types that you may not have seen in our adult program, which is much more focused at least in the ROS1 population, of course, in lung cancer. But looking forward to the data update. Again, as I said, this is the first clinical update we'll have from the program.

[Operator:]

We have our last question coming from the line of Arlinda Lee with Canaccord.

[Arlinda Lee:]

Congratulations on the progress. I had two. One, can you provide additional color on your earlier pipeline targets and the philosophy that you have and how you're looking at inhibiting these targets? Are you going to stick with the macrocyclic inhibitor? What's your philosophy on addressing emergence of resistance versus trying to target combinations? And then, secondly, can you talk about cash use or what you intend to do with $1.1 billion in cash. Your burn has been quite low. Obviously, it'll go up as you increase your combination studies in others. But just curious about how you're thinking about your cash situation.

[Athena Countouriotis:]

I'm excited to spend some time with you later this week as well at your conference. So, let me take the pipeline component first. One of the things I think you've seen from when you first met with me and when Turning Point was, obviously, still a private company is a top line investment in discovery. And specifically, from a headcount perspective, just further expertise within our chemistry department, our biology department, our scientific advisory board, our DMPK group, and this is now one of our largest components of our organization. The philosophy is really two ways, which is, first, to look at validated targets, such as what we said today in G12D, in ways that potentially we could develop best-in-class assets as we have, hopefully, with repotrectinib as well as the rest of our pipeline, and then potentially less validated where we could be first-in-class that might be a little bit more risky, but potentially a larger opportunity. So, those are the two approaches that the team have been taking. You know that the macrocyclic platform is the foundation of our current four clinical stage assets, of course, with repotrectinib in a registration trial, and there may be targets where that scaffold is more appropriate than others. And so, it's something that we're currently evaluating as we go further. As it relates to staying within treatment resistance, there are, clearly, assets within our current clinical stage pipeline that are more focused on treatment resistance and others that are more focused on potentially first line opportunities, such as, obviously, repotrectinib, but also even our MET program. And so, I can't say that we're focused in one area resistance versus combinations. But that's the general philosophy. And as I outlined in my prepared remarks, we're sticking to a target product profile that absolutely keeps on that medical need at a very clear point of view in our forefront in terms of our selection criteria, as well as the expertise that we have in-house, our biology and then, of course, the market opportunities. My apologies, Arlinda. In terms of the cash use. The cash use, of course, at $1.1 billion takes us into 2024. And as it relates to how we plan on using our cash, we're going to continue to use our cash as we have been, which is continuing to advance our critical stage assets, as well as pushing forward our discovery platform.

[Operator:]

Thank you. There are no further questions at this time. I will now turn the call back over to Dr. Athena Countouriotis for any closing comments.

[Athena Countouriotis:]

Thank you, operator. I think that was the best way an operator has ever said my name. So, thank you very much for that. Obviously, thank you for everybody that's dialed in today for your interest and, of course, your support for our company at Turning Point Therapeutics. As I said during the Q&A, I'm so incredibly proud of what the team has accomplished this quarter. And I want to close by thanking all of you. I know many of you always dial in to this call. Thank you for everything that you're doing every day for us as a company and, more importantly, for patients. Operator, you may now close the call. Thank you.

[Operator:]

This concludes today's conference call. Thank you for participating. You may now disconnect. Goodbye.