Erasca, Inc. (ERAS) Earnings Call Transcript & Summary

Good afternoon, and welcome to the Erasca Virtual Investor Event. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Erasca website following the conclusion of the event. I'd now like to turn the call over to your host, Jonathan Lim, Chairman and CEO of Erasca. Please go ahead, Jonathan.

Thank you. Good afternoon, everyone, and welcome to the Erasca Investor Presentation. Joining me today are David Chacko, our CFO and Chief Business Officer; and Shannon Morris, our Chief Medical Officer. Before I begin, I want to remind you that we'll be making forward-looking statements. Please visit our website at erasca.com to review our latest SEC filings and the associated risk factors. During today's presentation, we'll provide you with a development update on ERAS-007 as well as a portfolio update across the entire Erasca pipeline. We'll follow that with a Q&A session. As a reminder, ERK is the terminal node of the RAS/MAPK pathway and hence, a critical target. Inhibition of ERK is less susceptible to pathway reactivation compared to inhibition of MEK, which is one node above ERK. ERK activation is also implicated in acquired resistance to other in-pathway inhibitors, which is why we are testing multiple combo approaches, which we'll talk about in today's presentation. The ERAS-007 monotherapy data, which we have already shared previously, support efficacy signal-seeking assessments of multiple combinations across different tumor types. The preclinical profile shows that ERAS-007 is the most potent ERK inhibitor in development, with single-digit nanomolar potency in both biochemical and cell-based assays. This compound also has a uniquely long target residence time that is over 30x longer than comparator ERK inhibitors, and we believe that this will allow for longer intervals between doses in patients and allow for optimization of the risk-benefit profile for our ERK inhibitor. In addition, the molecule has demonstrated robust in-vitro and in-vivo data across multiple models. The clinical profile has shown multiple monotherapy responses with intermittent dosing across a variety of different tumor types and alterations. This has been encouraging to see because while we don't intend to pursue a monotherapy registration path for ERAS-007, the best combination agents are the ones that show single-agent activity. The recommended dose range for ERAS-007 in various combos is likely between 50 and 100 milligrams BID-QW and has been well tolerated. With respect to the PK profile, the approach has been to focus on the risk benefit profile of the molecule by optimizing the time above IC90, which drives tumor cell killing, and the time below IC50, which allows for normal cell recovery. ERAS-007's clinical development plan enables us to evaluate 3 key biological hypotheses: first, preventing in-pathway resistance; second, reversing in-pathway resistance; and third, targeting adjacent pathways. Looking at each of these in turn, preventing in-pathway resistance is being tested in HERKULES-3, where we are looking at the combo of ERAS-007 plus the approved doublet of encorafenib plus cetuximab or EC in BRAF V600E CRC in patients who are naive to encorafenib-cetuximab. The second hypothesis of reversing in-pathway resistance is being tested in HERKULES-3 in EC-treated BRAF V600E CRC patients as well as in HERKULES-2 in post-osimertinib EGFR-mutant non-small cell lung cancer patients. Hypothesis 3 is being tested in patients with KRAS and NRAS-mutated CRC as well as KRAS PDAC with a combo of ERAS-007 plus palbociclib. We'll focus first on the HERKULES-3 trial of ERAS-007 plus encorafenib-cetuximab in both the EC-naive and EC-treated settings. This slide lays out the opportunity for us to improve the standard of care in patients with BRAF-mutant CRC, which represents about 10% of all patients with colorectal cancer. In the middle column, you can see that in the second and third line setting in EC-naive patients, the standard of care currently is the doublet of encorafenib plus cetuximab, the so-called BEACON regimen, which was approved with an overall response rate of 20%, a median DOR of about 6 months and a median PFS of about 4 months. Once patients have progressed on EC, the standard of care of TAS-102 plus bevacizumab has a response rate in the single-digit percentage range. The scientific rationale for this trial is shown on this graphic. We're pursuing a triple blockade of BRAF, EGFR and ERK in BRAF-mutant CRC where this combined blockade is predicted to more effectively inhibit the RAS/MAPK pathway and prevent resistance in EC-naive patients and potentially overcome treatment-induced resistance in EC-treated patients. The take-home message, which Shannon will elaborate on, is that we are seeing a promising signal in EC-naive patients with 3 responses out of 6 patients, including 2 confirmed PRs and 1 unconfirmed PR. While this is a small data set, it's encouraging relative to the BEACON benchmark that I mentioned earlier of a 20% response rate. In-vitro data generated by one of our SAB members, show that 007 blocks MAP kinase pathway feedback reactivation, better than MEK or other ERK inhibitors. What you're seeing here are 2 different BRAF V600E CRC cell lines with a MEK combo of binimetinib plus encorafenib on the left and 3 different ERK combinations on the right, including ERAS-007, Lilly's compound and Genentech's compound. If you look at the phospho risk row, starting first with the MEK combo, you can see that there's in complete shutdown of the pathway, as evidenced by the band still present at the 4-hour mark. Then you can also see very strong reactivation of the pathway, as evidenced by the band coming back more strongly even as early as within 24 hours. You see a similar picture with the 2 other ERK combinations. However, when you look at 007, you see complete inhibition of the pathway with no visible band. So the pathway has been completely shut down at the 4-hour mark and there's no reactivation out to the semi 2-hour mark. Looking further at Erasca's in vivo data, you can see that 007 plus EC, compared to EC alone, showed robust in vivo activity in BRAF V600E CRC models. On the left is an EC-sensitive model, this would be akin to patients who are naive to encorafenib-cetuximab. On the right is an EC-resistant model, which would be akin to patients who have previously been treated with EC. On the left, you can see that, as you would expect, the EC regimen, which is shown in dark green, performs well. When 007 is on board, shown in the yellow and the purple lines, you see an even better tumor response, which is significant to a p-value of less than 0.01. On the right, you can see that EC in an EC resistance setting does not perform well as evidenced by the dark green line. However, when 007 is on board, in the yellow and the purple lines, you see a very good antitumor response. With that, I'll hand it over to Shannon to discuss the early data we've generated in our HERKULES trials.

Thank you, Jonathan. Before we dive into the data, I'd like to introduce key components of the HERKULES-3 trial design for reference. Dose escalation was initiated using the ERAS-007 QW schedule and then transition to the BID-QW schedule. BID-QW is twice a day on day 1 of each week. The highest evaluated dose was ERAS-007 100 milligrams, BID-QW in combination with the approved doses of EC. Once that dose was achieved in combination and cleared the safety evaluation, we then focused our efforts on signal-seeking opportunities in EC-naive patients with BRAF-mutant colorectal cancer. This slide also points out that evaluation of the combination in patients with EC-treated BRAF-mutant colorectal is gated by the results in EC-naive patients, an approach we feel is warranted given the higher biological hurdle to reversing resistance versus preventing resistance. ERAS-007 plus EC is generally well tolerated with primarily Grade 1 or 2 treatment-related adverse events. You can see in the table that there were very few grade 3 or higher TRAEs, or treatment-related adverse events. In fact, there were no grade 4 or 5 TRAEs. I think the other thing that's important to point out is that the observed treatment-related adverse events were all consistent with what one would expect from an ERK inhibitor. In other words, no new safety signals were identified in this combination. As mentioned on the prior slide, ERAS-007 at the 100-milligram BID-QW dose is being expanded in combination with approved doses of encorafenib-cetuximab to assess signals of efficacy in EC-naive patients. If you recall the ERAS-007 monotherapy PK curve that we shared last year as compared to the ERAS-007 PK curve from the combination shown here, you can see that they're generally comparable. These results indicate that there are no apparent drug-drug interactions for this combination. The triplet of encorafenib plus cetuximab plus ERAS-007 showed encouraging early efficacy in BRAF-mutant CRC patients. What you see here are the waterfall and swimmer plots of both EC-naive and EC-treated patients pooled together. Please note that this data set is updated relative to Erasca's press release from May 25 and today's poster presentation at ASCO. These figures now include updated data for all the patients, including one additional efficacy evaluable EC-naive patients with an unconfirmed partial response. In the efficacy of valuable patients in the pooled group, you see a 17% response rate, which is 3 out of 18 patients, and a 78% disease control rate, which is 14 out of 18 patients. All 3 responders were in the EC-naive patient population. You also see that approximately 1/3 of patients remain on treatment at the time of this data cut. More importantly, if you drill down and look specifically at patients who are naive to encorafenib-cetuximab, you see very encouraging early data that have led us to focus our initial efforts on this patient population. You can see at the highest dose tested, which was 100 milligrams BID-QW, we saw a 50% response rate, which was 3 out of 6 patients, including 2 confirmed partial responses and 1 unconfirmed partial response from the most recent patient enrolled at this dose. We're pleased to report that this patient with the unconfirmed partial response was still in response at the subsequent scan, which was conducted 25 days after the first scan. To count as a confirmed response by RECIST criteria, the second scan had to have been conducted 28 days after the first scan. But we are hopeful that this patient will still be in response at a future scan. As a reminder, the BEACON regimen of encorafenib-cetuximab was approved with an objective response rate of 20%. So we're seeing a nice improvement in the response rate in these initial patients. You also see that the duration of exposure for both responders as of the new data cutoff was over 40 weeks, and that 4 out of 6 patients were still on treatment as of the data cutoff. Now we'll move on to the HERKULES-2 update for ERAS-007 plus osimertinib in the post-osimertinib setting, where we were testing the ability of ERAS-007 to reverse osimertinib resistance, which is a high biological hurdle. The combination of ERAS-007 plus osimertinib had acceptable and manageable adverse events with no clinically relevant from drug-drug interactions observed. And similar to the EC combinations, no new safety signals were observed. This slide shows the waterfall and swimmer plot for the combination of ERAS-007 plus OC in patients who had previously failed osimertinib. As demonstrated here, the best response observed in a limited sample size of 16 patients with stable disease. Therefore, based on these data, we have elected not to move forward with continued evaluation of this combination. Now we'll move forward to the third hypothesis of targeting adjacent pathways with ERAS-007 plus palbociclib, where we have the opportunity to shut down both the RAS/MAP kinase pathway with terminal node ERK inhibition as well as the cell cycle with CDK4/6 inhibition. The combination of ERAS-007 plus palbociclib shows acceptable safety and tolerability with reversible and manageable treatment-related adverse events. Overall, you can see that there were very few grade 3 or higher TRAEs. There were 2 grade 5 treatment-emergent adverse events that were reported. One was an intracranial hemorrhage that was deemed to be unrelated to either ERAS-007 or palbociclib. While the investigator felt -- the other was bacteremia, which was deemed by the investigator to be related to 007 and palbociclib. While the investigator felt the event was related to both 007 and palbociclib, the clinical setting was confounded by the fact that, number one, the patient had diffuse bony mets resulting in compromised bone marrow function at baseline. Number two, palbociclib carries a black box warning for neutropenia, which increases the risk of infection. And three, the patient made the decision to focus on comfort care while hospitalized. In our opinion, we feel this was an event specifically related to palbociclib, particularly since monotherapy ERAS-007 has not been associated with neutropenia, even when dosed continuously. This slide shows the waterfall and swimmer plot for the combination of ERAS-007 plus palbociclib, the best response observed at a variety of doses in 34 patients who either had colorectal cancer or pancreatic cancer with stable disease. Although the preclinical rationale for pursuing a combination of ERK and CDK4/6 inhibition in these patient populations was compelling, we knew that these were difficult to treat patient populations and the thesis ultimately was not supported by the clinical data. Based on these data, we have elected not to pursue continued evaluation of this combination. Now we'd like to transition from the HERKULES-3 data and provide an update on the status of our HERKULES-1 trial as well as summarize the clinical take-home messages for ERAS-007. As a reminder, in HERKULES-1, we evaluated our first MAPKlamp, where we initiated dose escalation of ERAS-007 in combination with ERAS-601. Disappointingly, this combination has not been as well-tolerated as we would have hoped, and we have observed 2 dose-limiting toxicities in 6 DLT-evaluable patients in the first dosing cohort. Based on these data, we have elected not to continue further evaluation of this combination using the current dosing regimen. As we revisit the overall development plan for ERAS-007, it's important to focus on the learnings across the HERKULES trials, where we are setting 007 in combination with our own pipeline agents as well as with approved agents like encorafenib, cetuximab, osimertinib and palbociclib. As we've said before, these are signal-seeking studies where the early clinical data reinforce the combined ability of ERAS-007 and its potential as a backbone to treat patients with GI cancers, including patients with BRAF-mutant colorectal cancer. We'd like to leave you with 5 key learnings: number one, the targeted PK profile was achieved with adequate exposures and well-defined PK as a monotherapy and in combination; number two, there have been no clinically relevant drug-drug interactions observed with multiple approved agents; three, the molecule appears to be able to be safely combined with multiple approved agents; four, ERAS-007 has shown monotherapy efficacy with intermittent dosing. Recall, we're the only ERK inhibitor that we're aware of that is dosed intermittently, which we believe allows us to optimize the risk benefit profile of this compound; and finally, we are seeing early signals of combination efficacy as seen in the EC-naive BRAF-mutant colorectal cancer population, which is why we are focusing our evaluation of 007 with EC in EC-naive patients with BRAF-mutant colorectal cancer. And with that, I'll hand it back to Jonathan.

Thank you, Shannon. I'll now provide a portfolio update. As you can see from the clinical update that Shannon provided, we've been highly productive over the past couple of years in designing and successfully executing a number of clinical trials to generate data that can help inform timely go, no-go decisions across our portfolio. We've undertaken a data-driven prioritization process to focus resources on the areas where we believe we'll have the highest probability of success for patients. So on this slide, I'll talk about several actions that we're taking in light of data that have been generated internally by Erasca as well as external data. First, within HERKULES-3, we are expanding ERAS-007 plus EC in the EC-naive BRAF-mutant CRC patient population. This is based on the encouraging early efficacy data seen in this segment that we shared just now. We're excited that the most recent patient with EC-naive BRAF-mutant CRC enrolled subsequent to the ASCO data cutoff had an unconfirmed response, making it 3 responses out of 6 so far for patients treated with 100-milligram BID-QW dose of 007, and we're excited to explore this efficacy signal further in a larger number of patients to be treated at this dose in the expansion. Second, we are gating the evaluation of 007 plus EC in EC-treated patients, as Shannon mentioned, which means we will only explore this segment if efficacy data continue to be promising in the EC-naive patient population. Since EC-treated is a more challenging segment to show a treatment benefit compared to EC-naive, we think this is a wise use of our resources. Because the benefit is not demonstrated in the EC-naive setting, it is unlikely to be demonstrated in the EC-treated setting. We are deprioritizing ERAS-007 plus each of osimertinib, palbociclib and ERAS-601 and as well as ERAS-3490 in the AURORAS-1 trial, which has not enrolled any patients. Despite 3490's strong differentiation in terms of its CNS penetration profile, the G12C inhibitor landscape has become increasingly competitive for small and mid-cap biopharma companies and is less attractive now than it was when we first discovered this compound. In terms of our research programs, we are deprioritizing our SOS1 ERAS-9 program to focus on SHP2 as the key upstream RAS/MAPK pathway node due to the promise of our ERAS-601 compound. We are highly encouraged by the data that we have already generated with 601 showing promising tolerability as a monotherapy and in combination with cetuximab as well as being only the second SHP2 inhibitor reported to achieve a confirmed response as a monotherapy. We are deprioritizing our ERAS-11 MYC program and our ERAS2/3 RAS Switch-II groove targeting program and are pursuing other research approaches to target RAS mutations beyond G12C that we believe are quite promising. These collective moves are a testament to Erasca's data-driven decisive approach to concentrating resources, focus and attention on indications and opportunities that have the highest potential to move the needle for patients. Our model has been to conduct efficient, signal-seeking studies in multiple indications with the goal of identifying those opportunities that hold the most promise for patients. In this regard, we are pleased to see promising early efficacy signals in EC-naive BRAF-mutant CRC. In addition to the promising proof-of-concept data that we've seen with naporafenib in NRAS-mutant melanoma and early efficacy signals in RAS Q61X solid tumors. To support our renewed focus on those opportunities that offer high value for patients, our revised pipeline is shown on this slide. In addition to the promising indications I mentioned for naporafenib and ERAS-007, we also are excited to explore the promise of 601 in combination with cetuximab in various solid tumors, including HPV-negative head and neck cancer as well as ERAS-801 as a monotherapy in EGFR-altered glioblastoma. This slide lays out our anticipated key milestones and clinical trial readouts. We believe that our previous guidance for these milestones remains on track. For naporafenib, this is multiple SEACRAFT trials. SEACRAFT-1 is our RAS Q61X tissue-agnostic solid tumor trial where we are combining with trametinib. We are on track for first patient dosing in the second half of this year, with the data readout expected between Q2 and Q4 of next year. This readout will be combo signal-seeking efficacy data in relevant tumor types. SEACRAFT-2 is our planned pivotal trial in patients with NRAS-mutant melanoma combining naporafenib plus trametinib, and we are on track for a first half of 2024 first patient dosing in this trial. For HERKULES-3, considering the data that we shared today, we are moving forward with the EC-naive BRAF-mutant CRC population, and we'll be sharing combination dose expansion data between second half of this year and first half of next year. For 601, our SHP2 inhibitor in the FLAGSHP-1 trial where we're combining with cetuximab, we are on track for a Phase Ib combo dose expansion data readout in relevant patient populations, including HPV-negative head and neck cancer in the first half of 2024. And for ERAS-801, our CNS-penetrant EGFR inhibitor, we are on track for a Phase I monotherapy dose escalation data readout in recurrent GBM patients, which will be focused primarily on safety and PK. In summary, with the compelling data presented and data-driven portfolio moves that we announced today, coupled with our strong balance sheet of $390 million of cash and runway into H2 2025, Erasca is in a strong position to advance the most promising trials forward for the benefit of patients in multiple segments of the RAS/MAPK pathway. We have several meaningful catalysts for each of our 4 clinical-stage programs anticipated within the next 6 to 18 months. With that, we'll conclude our formal remarks, and I really want to thank all of you for joining us on this call. And we'll turn the call back to the operator for Q&A. Operator?

[Operator Instructions] Our first question comes from Priyanka Grover at JPMorgan.

This is Priyanka on for Anupam Rama. Just a couple of questions regarding the data readouts that are upcoming, especially THUNDERBOLT-1. Will you be releasing the data in a medical conference or are you going to do press releases? And similar question for the other data readouts that are upcoming.

Yes. Thanks, Priyanka. Basically, we take an approach where if the data set is ready and mature and ready for a scientific audience, then it would be in the context of a scientific conference but you don't always hit that window. And so we also are open to an R&D Day type of event.

Our next question comes from Alec Stranahan at Bank of America.

Alec, your sound is not coming through.

We'll move to the next analyst question then. Our next question comes from Yige Guo at Guggenheim.

Yige, you may be on mute.

Sorry about that. This is Yige, on for Michael. I guess 2 quick ones from us. Number one, how should we think of the contribution of 007 to the ORR observed in the EC-naive setting? And do we have a hypothesis on why 007's contribution to efficacy is much more significantly in naive setting, but less clear on the EC-progressed patients? Is there sort of synergy specific in the naive setting?

Yes. Thank you, Yige. Great questions. So on the first one, that's a question that all companies in drug development have to address when they're adding a compound to standard of care in a population that's known to be responsive. So for us, we think the key is to continue to set a high bar in terms of exploring it. Certainly, 3 out of 6 patients responding. It's a small data set, but at the 100-milligram BID-QW dose, that certainly is very encouraging. And it's one of the reasons we want to expand it so that when there's a more meaningful number of patients, we can better understand what that triplet is doing. And of course, we also have the historical BEACON data of the 20% ORR, but cross-trial comparisons are really not appropriate. And so we're using that as a benchmark. We certainly want to beat that significantly. And I would say that if the data continue to hold the promise that they do in this small data set, and that will be very exciting. In terms of your other question, I would say that preventing resistance versus reversing resistance are just different bars. And so it's hard to say in this context -- just the fact that we are seeing promising activity in the EC-naive setting, it's certainly worth exploring that further, but we do know that biologically, reversing resistance just tends to be a little more difficult, and that's why we're gaining that indication. We enrolled all comers in the dose escalation to make sure that we could move as quickly as possible. And I think had we seen in this small set of patients some responses in that EC-treated population, then we might have pursued that further sooner. But at this point, we want to be basically more sequential in how we explore this. And I'll just pause there and see if Shannon, whether you have anything to add?

No, I don't really have anything to add. The only thing I'd speak to in terms of sort of preventing resistance versus reversing resistance, a lot of times, the resistance mechanisms to these targeted agents are genetic -- changes in the genetic material, right, is genetic mutations. And once those are in place, you really can't reverse them. So it certainly makes sense biologically and scientifically is if you can prevent the onset of those mutations, you're certainly going to be in a better place.

Our next question comes from Chris Shibutani at Goldman Sachs. Chris, you may unmute your line and ask your question. Okay, I think this concludes the verbal portion of the question-and-answer session. I'll now turn it over to Alex Folias from LifeSci Advisors to read any written questions that may have come in from the audience. Please go ahead, Alex.

Thank you, Pauline. The next question comes from Josh Schimmer at Evercore. "Thanks for the update. What do you think a registration-enabling trial for 007 will look like in terms of patient numbers and comparator arm, if any? And what additional data do you need to generate before starting a registration-enabling 007 study? Thank you."

Yes. Great question. So we're really focused on that additional data, which is to expand the EC-naive population and see whether the signal holds in a larger data set and then assuming that it does, then have appropriate conversations with regulatory agencies. I think the key though is that because we're adding to a known standard of care of EC, we certainly want to be able to look at both responses as well as stable disease and be in a situation where it's possible that we may want to explore that in a randomized setting, but it's too early to tell at this point until we see whether this signal continues to persist in a larger number of patients, which is what we're focused on at this time. Shannon, anything to add?

Nothing to add for me.

The next question is from Jeff Hung at Morgan Stanley. "Can you talk about the grade 3 macular edema? How long did it take to resolve? And does this impact how you're thinking about dosing?

Yes. Thanks, Jeff, and I will have Shannon chime in on that one.

So this is a patient who had, like I said, a grade 3 macular edema, it results spontaneously within less than, I think, approximately 1 week. The patient went on to continue to get multiple additional doses without recurrence. I think the key take-home message here is that this is certainly a common toxicity seen with inhibitors of this pathway, both MEK inhibitors and ERK inhibitors. And the good news is it's reversible and manageable.

Thanks, Shannon.

The next question is also from Jeff Hung at Morgan Stanley. "Has the data update changed your prior thinking on the optimal dose range? Any ability to narrow the range?"

No, it's actually -- that's a good question. It's actually confirmed our thinking on the optimal dose range, which is for combinations of 007 with other agents. We think the sweet spot is within 50 milligrams to 100 milligrams BID-QW. And what we're seeing is very promising activity at the 100-milligram BID-QW dose with the potential to dose-reduce to 75 as needed. And so that seemed to be in a good range at this point and is pretty tight.

The next question is from Chris Shibutani at Goldman Sachs. "What do we know about the HERKULES-3 EC-naive patient dose at 100 milligrams that have strong disease progression? Any insight that might enrich for the responses population?"

Shannon, do you want to share your thoughts about that?

Sure. I certainly appreciate the thought process, right? Is there a way to sort of have learnings from our patient population, and it's something we're constantly doing. I don't think there was anything particularly special about that patient. We certainly know that there's going to be a percentage of patients who don't get benefit. I think what's really exciting here though is that we had an increase, right? If you look at our benchmark of 20%, we're seeing 3 of 6 patients here, a 50% response rate. So I think that's really where we're focusing on now. But as we go forward, as we increase that sample size, we'll certainly be looking for other markers to -- for further enrichment if needed.

The next question comes from Jerry Gong at Mizuho. "Can you speak to the deprioritization of 007 and 601 due to dose escalation safety data? I believe the previous data showed largely nonoverlapping safety profiles."

Yes. And let me clarify this. So we're not deprioritizing 007 and 601 in terms of the concept of combining them, that's still a concept that we are very excited about. And to your point, they largely have non-overlapping safety profiles. Within HERKULES-1, this was a very specific hypothesis that we're testing, which is if you keep 601 at its monotherapy dose MTD and you keep that constant and then you dose-escalate 007, can they coexist? Or can they be safe and tolerated in that paradigm? And I think we got a clear answer in HERKULES-1 that allows us to make an informed deprioritization decision on that dose and schedule, or basically, broadly speaking, that regimen. Now what we are looking at in -- largely in the nonclinical realm as well as PK modeling realm is if you go lower on the 601 dose because the DLTs did seem to be largely within the class of SHP2 observations, is there a different regimen that could be explored? And so that's what we're looking at non-clinically. And then we also are looking at combos of each of those agents with other programs in our pipeline such as naporafenib. So stay tuned on that, but it's really a deprioritization of the HERKULES-1 question that we were asking. And so that came back with informative info for us to make that decision. But the concept of combining 601 with 007 with other agents is still very much on our radar and being explored.

The next question comes from Jerry Gong at Mizuho. "Was the DLT seen in the EC-naive or pre-treated patient group? And which AEs led to a dose discontinuation?"

Shannon?

The DLT was observed in an EC-naive patient, and the adverse events leading to dose discontinuation were worsening creatinine and worsening anemia.

Okay. And then the next question comes from Jerry Gong at Mizuho. "Can you give additional color to the rationale of testing a 125-milligram ERAS-007 dose in the palbociclib study and not in the EC combination study?"

Yes. So I'll take a first cut at that, and then, Shannon, feel free to chime in if I miss anything. But these are 2 different studies with different standard of care or investigational agents that we're combining 007 with. So each of them had their own particular dose escalation scheme. So in the case of palbo, we were able to basically dose-escalate 007 in a different way from with the EC combo. Now the reason why -- I mean we could have dose-escalated in the EC combo to 125 BID-QW, but because we started to see promising activity at the 100-milligram BID-QW dose, we chose to start expanding that to very quickly generate efficacy data. Now in the future to really identify a recommended Phase II dose, we will have a conversation with FDA and other regulatory agencies to see if more -- if it's worthwhile exploring higher doses. But in this case, we really wanted to see if there's a signal -- a real signal at the 100 dose. Shannon, anything to add there?

I think you summarized it really well. As you said, there are 2 different backbones here. And I think the key observation, as you said, is that we certainly have the ability to go to 125 milligrams. But with the EC combination, we know and feel that sweet spot is going to be sort of in that 50 to 100, and we definitely have seen activity there. And so our goal is to really optimize that risk-benefit profile for our patients and give them maximal efficacy, but really a tolerable regimen, and we think we've accomplished that at that 100-milligram dose with EC. On the palbociclib side, obviously, we were not seeing the same level of activity there. And so there was certainly a conversation with our investigators about whether we needed to sort of push that dose a little bit higher to see if that was -- could it change the situation. So I think you've really got 2 different clinical scenarios here.

The next question comes from Jerry Gong at Mizuho. "Do you think you would have seen any different results in HERKULES-2 with a different EGFR partner, i.e., possibly with Gilotrif knowing that it has some activity in a post-Tagrisso setting?"

Yes, Jerry, it's hard to say. I mean we did generate pre-clinical data with osimertinib, and that tends to be the EGFR inhibitor of choice in the naive setting. Of course, when there's resistance, it's a pretty high bar to reverse that. So the initial clinical experiment, if you will, to explore, made a lot of sense to partner with OC. I think based on the data, other EGFR partners could be explored, but that's probably not the highest priority on our list at this point.

The next question comes from Jerry Gong at Mizuho. "I'm curious if any trends can be drawn about time to response at this early data cut."

Hard to say. Well, Shannon, do you have -- I mean it's basically 3 patients that seem to respond fairly early in the EC-naive setting, but -- do you want to comment on this, Shannon?

Sure. It is very early. I think that's definitely the take-home message here. But I also think that if you think through targeted therapies, in general, as a class, you do tend to see responses relatively early. Certainly, as we expand at that 100-milligram dose and hopefully are able to continue to see this level of activity, we'll be able to do a more intensive analysis.

The next question comes from Mara Goldstein at Mizuho. "Can you draw any conclusions or trends regarding dynamics of response in the EC-naive patients for ERAS-007?"

Yes, I think we just answered that so we can move to Mara's next one.

Okay. So the next question is, "From a financial perspective, does the prioritization pipeline and discontinuation of clinical programs have an impact on cash runway?"

Yes. I'll turn it to David.

Yes, great question. While we're always looking at ways to extend our runway, especially in this macro environment, our public guidance of 2025 2nd half still stands, and these prioritization measures will certainly help offset our burn.

And the next question is from Alec Stranahan from Bank of America. "One question on the pipeline reprioritization. You've deprioritized your G12C asset, but you also have ERAS-4, which is a G12D inhibitor, as well as the G12V/D asset as well. How are you thinking about these assets as it relates to the competitive landscape as well as KRAS as a target more broadly? And could we see now an increased focus on accelerating these assets to the clinic?"

Yes. Thanks, Alec. So we are pushing forward with ERAS-4, which is targeting G12D. And then in partnership with Affini-T, we're excited about the TCR approach that they're taking to G12V and D, as you alluded to in your question. So the competitive landscape, it's still less crowded in these areas than in G12C. We're monitoring that because it does evolve. But because we have a very high degree of focus on ERAS-4, if focus translates into acceleration, then that's great. But sometimes with drug discovery, you can't always plan that. So we're really working intensively on that, and we'll keep you updated as progress is made.

Thank you, everyone. This concludes the question-and-answer session.

And this concludes today's call. Thank you, everyone, for tuning in.