My name is Jason, and I will be your conference facilitator today for Amgen's conference call from the 2022 World Conference on Lung Cancer. All lines have been placed on mute to prevent any background noise. There will be a question and answer session at the conclusion of the last speaker's prepared remarks. In order to ensure that everyone has a chance to participate, we request that you limit yourself to asking one question during the Q&A session. To ask a question, please press star and then the number one on your telephone keypad. To withdraw your question, please press pound. I would now like to introduce Arvind Sood, Vice President of Investor Relations. Mr. Sood, you may now begin. Actually, Jason, this is David Reese, Head of Research and Development at Amgen. I'll be helping to host today's conference. We'll provide an oncology clinical update on some of our lung cancer programs based on data that were presented here in Vienna at the World Conference on Lung Cancer over the last couple days. We know there's a lot of interest in these data, and so we'll move into data summaries very quickly here. Can we advance the slide, please? Here is our safe harbor statement and today's agenda. After a very short remarks from me, Dr. Bob Li will present an update on the LUMAKRAS combination studies presented here, including both checkpoint inhibitor combinations as well as the SHP2 combination trial. Following that, Dr. Luis Paz-Ares will present data, very promising data, we believe, from tarlatamab, our DLL3 targeting BiTE, from the first in human study. That's followed by Dr. Jean-Charles Soria, our Head of Oncology Clinical Development, who will provide some concluding remarks, and then we'll move into the Q&A session. As I mentioned, we have quite a bit of data to cover today, and we know there'll be many questions. I'll turn things over now to Dr. Li to summarize the LUMAKRAS combination studies. Dr. Li. Thank you, Dave, for the introduction and the opportunity to share with you the two abstracts on the sotorasib combinations. First one is in combination with PD-1 or anti-PD-L1 immunotherapies. Next slide, please. Combining sotorasib with immunotherapy has been very encouraging in preclinical models, showing the potential synergy in increasing CD8+ T-cell infiltration in the tumor cells. In mouse models, it's led to dramatic tumor shrinkage and durable responses. This is the clinical trial that we've brought it into the clinic to see if this approach can help improve the care of patients. In this CodeBreaK 101 study, we've had a flexible dose finding design. We know that historically that combining targeted therapy and immunotherapy has been challenging. We allowed escalation, also de-escalation of sotorasib doses from 960 down to 120 milligrams as clinically appropriate. We also allowed the combination with the anti-PD-1 pembrolizumab or anti-PD-L1 atezolizumab both in the concurrent regimen when you just combine the two drugs together or using a lead-in regimen where you can give sotorasib for three weeks or for six weeks as a single agent and then followed by combination therapy with atezolizumab or pembrolizumab. We primarily looked at safety in this phase I study, but also secondary endpoints, including overall response rate, duration of response, disease control rate and so forth. This is an analysis of data after a long period of follow-up with a median of 12.8 months. Next slide, please. We treated a total of 58 patients, and in this study, more than two-thirds of patients had already undergone anti-PD-1 or PD-L1 immunotherapy prior to study entry. A lot of pre-treated patients. There were some immunotherapy naïve patients as well. As you can see, there was a median prior lines of therapy of one, but up to seven prior lines of therapy. The PD-L1 expression ranges are also detailed on this table. Next slide. First, we combined with the high doses of sotorasib at 720 and 960 milligrams. As you can see, there certainly was a high incidence of treatment-related adverse events, primarily asymptomatic elevations of liver enzymes, AST and ALT. These were reversible side effects with dose modification and corticosteroids. Certainly from a drug development point of view, this is not a tenable combination for further development. We dose reduced it down to 360 and down to 120. You can already see numerically a reduction of these elevated liver enzymes with lower doses. That was the first experience. Next slide, please. We looked at the lead-in versus the concurrent regimens. Whether it's atezolizumab or pembrolizumab, you can see that the lead-in regimen had a lower risk of treatment-related adverse events in Grade 3 and 4, especially the elevated liver enzymes. In this experience, we saw that these hepatotoxicity events occurred primarily outside of the dose-limiting toxicity window of the first three weeks of the combination. This actually happened on cycle 2 and cycle 3. It took time for that to happen, but 97% of those events were resolved with corticosteroids, treatment discontinuation modification. Those were largely asymptomatic elevations of liver enzymes. This occurred in patients with immunotherapy-naïve as well as immunotherapy pre-treated settings. Next slide, please. I want to also point out there were no treatment-related deaths, and there were no Grade 5 events throughout the whole study. Given this experience, we looked at the loading of sotorasib in lower doses in combination with pembrolizumab. As you can see here, this is a better toxicity profile compared to where we started. If you look at the sotorasib 240 mg dose, there was still about 20% rate of Grade 3 or more elevated liver enzymes, but certainly much better overall safety data and tolerability for patients. Next slide. This is the overall waterfall plot, but this is a mixed bag of different cohorts and sub-cohorts. Overall showing a response rate of 29%. Bear in mind, many of those patients were treated with earlier cohorts and had to discontinue the study drug, so didn't have enough time to get drug exposure. Overall, we saw a median depth of response of 51% and a disease control rate of 83%. If you look at the swim plot on the right-hand side. Of the 17 responders, the median duration of response was 17.9 months. This is encouraging as it's longer than what's reported with a single agent. Eight out of the 17 patients are still responding at the data cutoff. Those responses were similar in immunotherapy-naïve or pre-treated patients. Next slide, please. This is just a spider plot showing the cohort of patients with sotorasib leading and then combination with pembrolizumab. You can see deep durable responses were observed in this plot. Three patients who out of the seven who confirmed response is still going on at the time of the data cutoff and still having able to receive the combination of sotorasib and pembrolizumab. Those were tolerable and durable for these patients. Next slide. In conclusion, in this mostly immunotherapy pre-treated patient population, but also one-third of patients were immunotherapy-naïve, sotorasib in combination with atezolizumab or pembrolizumab led to a higher incidence of Grade 3-4 treatment-related adverse events compared to what we know from monotherapy experience. Now, those were primarily asymptomatic elevation of liver enzymes, and they occurred outside of dose-limiting toxicity window, so usually Cycle 2, Cycle 3. Nearly all of them were resolved with corticosteroid treatment modification and drug discontinuation. There were no Grade 5 toxicity, no treatment related deaths. We also learned that there are mitigating strategies that were effective, such as lead-in cohorts, lead-in sotorasib, especially at lower doses, that were then combined with the immunotherapy that led to durable clinical activity and deep responses, and some of them are still ongoing. The median duration of response of 17.9 months gives us a glimpse of encouraging future. Due to this experience, the low-dose sotorasib as lead-in, followed by combination with pembrolizumab, is now being further studied as a potential first-line treatment for these patients. Next slide. I will now turn your attention to the sotorasib and SHP2 combination experience. Next slide. The genomic alterations in RTK pathway have actually been identified as a putative mechanism of resistance to sotorasib. In the resistance study that I presented at ASCO just a couple of months ago, more than half of the acquired genomic alterations in sotorasib resistance actually belong to the RTK pathway. Also in mouse xenograft models, we saw that combination with sotorasib with a SHP2 inhibitor impaired RTK signaling to RAS. Basically, it also prevents the activation of the GTP loading of the KRAS protein and therefore shut down the signaling and enhance antitumor efficacy. Based on this science, we set out to do a phase I trial combining sotorasib with RMC-4630, which is a small molecule SHP2 inhibitor, and primarily focusing on non-small cell lung cancer. We cast a wide net looking at a variety of solid tumors. Next, slide. This is a study design. It's pretty simple. Those are patients who underwent approved treatment and generally anti PD-1, PD-L1 or platinum-based chemotherapy already. We even allowed prior KRAS G12C inhibitors. Sotorasib as a single agent, for example, and those who progressed after that were able to enter this study. This is a dose-finding study. We started with 100 milligrams of RMC-4630. Due to the longer half-life, the dosing is two days every week. Day one, day two, every seven days. Or you could do day one, day four, every seven days. We escalated to 140 milligram and 200 milligram as well for the RMC-4630. For sotorasib, we gave the FDA-approved dose of 960 milligram daily. In this study we looked at safety as a primary endpoint, but also secondary endpoints. Of course, very keen to look at our overall response rate, duration of response and so forth as an early look into potential efficacy. Next slide please. In this study, we treated a total of 27 patients, across a range of solid tumors. Eleven of those had non-small cell lung cancer that were KRAS G12C mutant. As you saw in the 11 patients, they were pretty heavily pretreated, three prior lines of therapy as a median, up to six prior lines. Five of the 11 had previously undergone KRAS G12C inhibitor therapy, so a lot of pretreated patients. Next slide. This is the safety profile. In terms of the treatment-related adverse events, there were no surprises. We know that edema and diarrhea were adverse effects of SHP2 inhibition, and that's primarily what we saw. Overall it's been well tolerated. None of them led to drug discontinuation. They were managed, some of them with dose reductions. Overall, there's no treatment-related deaths or anything unusual. Next slide. Looking at the efficacy in patients with non-small cell lung cancer, this is the 11 patients. In all the 11 patients, there were three partial responses, so that's a 27% response rate in this early cutoff. Looking at the KRAS inhibitor-naïve patients, all three actually belong to that group, so that's of six patients, three patients responded. Three out of six, so 50% in a very small subgroup. Disease control was achieved in seven of 11 patients. Certainly this suggests that in the KRAS G12C inhibitor-naïve settings, the effects were more pronounced and looking promising. Two of the three patients who had partial response is still having a response at the time of the data cutoff. Next slide. In conclusion, there's preclinical rationale and pre-existing mechanism of resistance supporting the combination of sotorasib with the SHP-2 inhibitor. This is the first-in-human study of sotorasib plus SHP-2 inhibitor RMC-4630 appearing safe, tolerable, in these patients heavily pretreated with chemotherapy, immunotherapy and many of them with prior G12C inhibitors. In this experience, no grade four and no fatal treatment-related adverse events were seen and there were very few treatment-related drug discontinuations. We saw promising and durable clinical activity in the KRAS G12C inhibitor-naïve setting in non-small cell lung cancer. Based on this finding, the phase II study of sotorasib in combination with RMC-4630 is now ongoing. We hope to see more data as time goes on. This is looking specifically at the G12C inhibitor-naïve patient population. I now turn the floor to Dr. Luis Paz-Ares, who will tell you more about the tarlatamab experience. Thank you. Okay. I'm Luis Paz-Ares, and I'll be happy to give you an update on the tarlatamab development. We can go to the next slide please. Small cell lung cancer is accounting for some 15% of the lung cancer and is one of the most aggressive solid tumors. That typically happens in patients with heavy smoking history and has a very aggressive biology. Indeed, some 70% of the patients are metastatic at the time of diagnosis. The disease is typically responsive to chemotherapy. That typically happens with tumors that are highly proliferative, as response to chemotherapy typically happens in cells that are replicating all the time. However, responses are short-lived, are very transient and therefore the prognosis on those cases is quite good. Let's say for those cases with extensive disease, which accounts almost 70% of the cases, as we said before, median survival is in the range of a year and survivorship at long-term is happening very rarely, very, very rarely. Importantly, have been very few advances in the treatment of small cell lung cancer over the last two or three decades. Now, first line we use chemotherapy, platinum plus etoposide, and a PD-L1 inhibitor. The PD-L1 inhibitor really improves survival, but truly very modestly. Median survival is improved by 2.5 months, and that impacts in about 10%-15% of the patients in the long term. In second line we have very few advances. We are still using mainly drugs that were approved more than 20 years ago. Recently, we have the approval, the conditional approval by FDA of a new drug, lurbinectedin, but there is no data that show a clear improvement in the outcome. It's mainly a safety benefit, I would say. If we go to the next slide, you will see here the basis for the use of BiTE. In that case, tarlatamab in the treatment of small cell lung cancer. BiTE molecules actually are molecules that engage the own T-cells of the host, of the patient to attack and eradicate the tumor cells. In that case, the tarlatamab has a how do I say? An anti-DLL3 that binds to DLL3, which is typically a ligand expressed in the cancer cells. In that case, most of the small cell lung cancer cells express in the surface of the cell this molecule DLL3, which is typically has very little expression in normal cells. When it happens, it doesn't happen typically in the surface. That makes that is a very nice target for this kind of approach. On the other hand, the tarlatamab molecule has a binding space for CD3 that is engaging the T-cell. By putting together the two cells, the T-cell gets activated and therefore inducing cell killing by engaging the tumor cells to get into apoptosis. Importantly, the tarlatamab has a Fc domain to improve the pharmacokinetic of the drug to extend the half-life. Go to the next, please. After the drug has been shown activity in preclinical models, we have started the first-in-human some time ago actually. We just presented at the World Conference on Lung Cancer the most updated data on more than 100 patients with a median follow-up of 8.5 months of this phase I trial. Phase I trial where we started with a very low dose of 0.003 milligrams, and we have gone into the highest dose of 100 milligrams. Actually we have an expansion cohort with 100 milligrams. As you may imagine, this is a phase I trial first-in-human. Primary objective was to evaluate the safety and tolerability in that particular tumor, the small cell lung cancer with this drug. Of course, to get an MTD and a recommended dose for further study in phase II trials. As a secondary objective, we have to characterize the pharmacokinetics and evaluate preliminarily the efficacy, the antitumor activity of the compound. Of course, we also like to evaluate immunogenicity of tarlatamab and assess biomarkers in that particular case. If we can go to the next slide, please. 106 patients I told you have been included. Inclusion criteria were patients with small cell lung cancer that had confirmed diagnosis and progressed to at least one line of therapy, including platinum or etoposide. In the case that when the patient is treated, the anti-PD-L1 was approved, the patients should have received as well the PD-L1 therapy. Indeed, 60% of the centers had not available that particular therapy at the time those patients were recruited. Patients should have good PS, 0-2, and have measurable disease. Patients were allowed to have brain metastases if they were asymptomatic or they had been treated. As you see here, no prior therapy had been permitted over the last four weeks, and the patients shouldn't have HIV or interstitial disease. Basic characteristics are typical for those type of trials in the relapsing setting. As you see here, median age of 64 years, good PS for most of the cases. Some half of the patients had two lines of therapy. Some one third of the patients had three or more prior lines of therapy. Some 50% of patients, actually 49, had not only chemotherapy, but also PD-L1 treatment, which you have found evidence here. As you see here, some 27% of the patients had brain metastases and 51% of the patients hepatic disease, hepatic metastases at the time of being included into this study. Go to the next, please. In terms of safety, I can tell you the profile is quite favorable as compared particularly to what is expected from BiTEs. Now we have some experience with BiTEs in hematological malignancies, but also in some other type of cancer. I would say the profile of this specific BiTE, tarlatamab, is pretty favorable. We have seen, of course, some side effects, but in terms of cytokine release syndrome, which is, let's say, one of the more, we could say, toxicities we were somehow nervous about. I would say half of the patients have had some side effects of that, but only one case was Grade 3 and no cases of G rade 4 or Grade 5. For most of the cases, cytokine release syndrome was fever, sometimes some mild hypotension, very responsive to antipyretics, some fluids sometimes, in some cases a dexamethasone or, let's say, steroids. Only eight patients were given tocilizumab, which is a specific therapy we will give for cases that are grade two or grade three of cytokine release syndrome. I would say pretty reasonable, and as I said, in most of the cases were restricted to day 1. In terms of neurological events, we have seen typically mild Grade 1 headache, dysgeusia in some 50% of the cases. Very few cases had Grade 3, and those typically happen in patients that have had prior irradiation to the brain. We have had some cases of neutropenia, including 9% Grade 3. We are not very clear on the mechanism. The only thing I can tell you, no patient have had fever, so we didn't see cases of the important clinically relevant complication, which is neutropenic fever. Go to the next, please. This is the activity we have seen, which I would say is pretty remarkable. We have responses confirmed in some 23% of the patients, two CRs, 22 PRs. 37% of the patients have had tumor shrink rate of at least 30% of the volume I could say. Disease control rate, which means responses plus disease stabilization, we're seeing in some 52% of the patients. I would say a reasonable and encouraging response rate in this setting that I said is in patients with heavily treatment before entering here. Go to the next, please. Duration of the response is pretty remarkable. Remember that some clinical patients had confirmed responses. That response was typically identified very shortly after treatment was started, less than two months. Median time to respond was 1.8 months, and median duration was some 13 months. Still of course we are following up those patients as some half of the patients are still responding. 11 patients are still responding at the time of the last data cutoff. Go to the next, please. More importantly, maybe, is also the impact on survival. You see here survival in this heavily pre-treated population is about 13.2 months median survival. Of course, this cohort should mature still on time. I would say the relevant duration of the response seems to impact on the survival of this patient cohort. Go to the next, please. Just let me to finalize, to conclude. I think this first DLL3 target immune therapy, the first DLL3 BiTE that shows clinical evaluation is tarlatamab but has shown promising activity with remarkable responses duration. 23% of the patients responding with a median duration of 13 months, and importantly, impacting on survival 13.2 months. We have seen over the last decade a number of drugs with responses in the range of 20-30, even 35%, 40% in some cases, but median survival always in this relapsing setting had been in the range of 8-9 months, and that is the more remarkable data for me, the impact on survival. Of course, that is my personal view. The safety profile is pretty acceptable, particularly taking into account the nature of this immunological type of drug. Potential registration of H2 studies are already undergoing in the second-line setting basically for small cell lung cancer. I think that's my last slide. I will be happy to take any questions you may have later. I'm just passing the microphone to Dr. Soria. Thank you very much, Luis Paz-Ares. If I can have the next slide. We remain confident on LUMAKRAS future. This is the KRAS G12C inhibitor with the largest and broadest clinical program. We're exploring LUMAKRAS in combination with over 10 different partners, as well as in various tumor types, including non-small cell lung cancer, colorectal, and pancreatic cancer. We are currently discussing different potential paths to first-line non-small cell lung cancer with the LUMAKRAS. Next slide. I would like here to highlight our excitement and confidence on tarlatamab as a potentially transformative therapy for small cell lung cancer as well as other tumor types, including neuroendocrine prostate cancer. If we reflect on small cell lung cancer, this is truly a disease that while chemosensitive, as highlighted by Dr. Paz-Ares, remains a disease with very poor survival. Very few patients survive beyond one year. It's a significant number of patients, up to 70,000 patients in first line and relapse who could be addressable and treated and benefit from this T-cell engager. Put into context, the data we have shared to you is truly transformative. I mean, patients who are in third line small cell lung cancer usually have median survival of five months and response rate is below two digits. Here we have a confirmed response rate of 23%, sustained with a median duration of 13 months and a median overall survival of 13.2 months. This is why we are now exploring the activity of this compound even outside of small cell lung cancer and notably in neuroendocrine prostate cancer, which, you know, is the phenotype that usually appears on patients who develop resistance to hormonal therapies and chemotherapies. these two molecules, sotorasib and tarlatamab, give us confidence on our oncology thoracic portfolio. With that, I pass the mic to David Reese. Thanks, Jean-Charles, and thanks to all of our presenters. I know we have a lot of interest. Jason, could you remind everyone how to ask questions and then we'll go ahead and open up the line. If you would like to ask a question, please press star followed by one on your cell phone keypad. If for any reason you'd like to remove that question, please press Star followed by two. Again, to ask a question, press star one. Our first question comes from Matthew Harrison with Morgan Stanley. Your line is now open. Great. Good afternoon. Thanks for taking the question. I guess it would be helpful to understand with sotorasib in combination, I guess two parts. First, why you're expecting or what kind of efficacy benefit you're expecting to see when you move into a true frontline population who hasn't been exposed to prior G12C inhibitors. Then secondly, why you're confident that the lower dose with the lead-in wouldn't degrade maybe that efficacy advantage. Thanks very much. Thanks, Matt. You know, I'll ask Bob to weigh in here in a minute. You know, I think, you know, Dr. Li noted in his presentation, you know, one of the keys is determining whether there is a clear therapeutic window with the lead-in low dose approach. If there is, and then if you're able to get the combination in, you know, we would expect, you know, enhanced efficacy based on what we've seen. That, you know, that I think is the hypothesis we need to test going forward. You know, Dr. Li, it'd be great to get your perspective here as well. Thanks, Dave. I agree. We hope to do better for patients. In the first-line setting, we hope to really maximize the duration of benefit with these targeted drugs. In the first-line setting with standard treatment with chemotherapy or chemoimmunotherapy, it's just not good enough. You know, the median progression-free survival being, you know, nine months, approximately that. With KRAS G12C-mutant patients still being an unmet need, and this was still highlighted at the recent FDA presentation at ASCO, we hope to really improve the duration of benefit. That's in progression-free survival, duration of response endpoints. We are seeing a glimmer of hope in this phase I study of this combination, seeing a longer duration of clinical benefit in some patients. We highlighted in the World Conference on Lung Cancer presentation, one of my patients who's had a CR going on more than two years, and she still continues. She had a lot of initial liver toxicity with the infiltration of immune cells into the liver. In the long run, she's doing well. We really hope to translate that benefit in the first line setting. You raise a very good question. How confident are we that the toxicity is not gonna impede on the response, on the durability of response that we did see in the initial cohort experience? That certainly was not a no-go with the high doses. We did see numerically a dramatic reduction of grade three or four treatment-related toxicity with liver transaminitis in the lead-in cohorts. I suppose I don't have that crystal ball on a larger population of patients on the trial with cohort expansion. What are we gonna? Is that gonna translate to a much better first-line treatment for the patient? We certainly hope so, but we have to do the trial, and that's what we're doing with the current expansion. Great. Thank you. Next question, please. Our next question comes from Michael Yee with Jefferies. Your line is now open. Hi. Thanks, and thanks for hosting this call. We had a follow-up question. Of course, the former question was on efficacy and then also on safety, how you feel about the onset of the liver tox? If you look at that case study, there's liver tox early on, but then later on at five and six months, there's another sort of spike. I was just wondering if you could comment on either the mechanism or the time of onset. I know, does it matter if it's sequential or not? And I know you had some data on that at, I think 50-70 days. So maybe just talk about the onset and maybe the mechanism upon when it comes on. Thank you. Yeah. Dr. Li to comment on that again in just a moment. Yeah. Clearly, you know, one of the things that's quite clear is that, you know, the onset typically was outside of the dose-limiting toxicity window in the large majority of cases, and in some case could be late onset, perhaps due to some sort of immune timing. The mechanism remains unclear to us right now. You know, this is why, you know, I think adequate numbers of patients followed for an adequate duration is really essential to understand the profile of these regimens. You know, Bob Li, it'd be great to get your perspective here as well. Yeah. Thanks, Dave. I agree. This actually came as a surprise, 'cause, you know, when you do phase I trials, we set a dose-limiting toxicity window for a purpose because that's when you're gonna see the adverse events happen. If they pass that window, you're fine. The next cohort of patients can enroll. In this case, we didn't see any dose-limiting toxicities. The DLT window was completely fine. The patient went through it maybe with grade one liver enzyme elevation that we saw with the single agent. By the time we get to dose number two, cycle two and cycle three, that's when things went off with The case report that you alluded to in the presentation, it happened after the second dose and then the third dose, and then it just went sky high with the transaminitis. It's important not to just call it a day at the end of the DLT window and say, "Look, it's a safe combination." We really have to have long follow-up period in this study, and that's why we are only presenting the data after a median of 12 months of follow-up. You know, it's not good enough to just say, "Okay, DLT, we passed, we're safe." That's not good enough. It's the immune infiltration and the immune toxicities are somewhat mysterious, and we need to do the trial to prove it. We saw grade one in the DLT in that case, and then by the second dose it went to grade three. We had to immediately stop the drug, gave steroids. It reversed back to normal, completely normal. Okay, so we thought, "Okay, maybe we can just re-challenge." Re-challenge with a slightly lower dose, you know, 960 going down to 720, and then it went up again. The liver enzyme went straight up as you saw in the graph that you alluded to, and then we have to back off again. We went down, and eventually 240, and the patient's still taking 240. This is more than two years on with the CR. This is a learning experience for all of us, and we have to really do the due diligence and do the trial, expand it, and to observe carefully and take care of these patients so then we can confidently say what is the right strategy for first line. Great. Thank you. It is worth pointing out that this is not the first time that delayed toxicity has been reported for, you know, checkpoint inhibitor combinations, particularly with targeted therapies. A lot to learn here and we're going to really explore these things in the ongoing and the dose expansion. Next question, please. Our next question comes from Jay Olson with Oppenheimer. Your line is now open. Oh, hey. Thank you for providing this update and for taking the questions. Maybe for David Reese, if you could please talk about the feedback that you've received from KOLs on these data presentations at World Lung? Specifically for tarlatamab, given the results you presented today in the context of the poor prognosis and limited treatment options available for patients with small cell lung cancer, can you talk about the regulatory pathway and where the bar is set for an accelerated approval? Thank you. Yeah, sure. Thanks, Jay. Yeah, I mean, in terms of the feedback, you know, I think in the LUMAKRAS combination with checkpoint, you know, the sense is that we've seen this before with multiple targeted therapies combining with checkpoint inhibitors. The mechanisms remain poorly understood. I think there's a general sense it's worth you know attempting the lead in lower dose, you know, followed by then the sequential use of a checkpoint inhibitor. You know, I think the general sense is that it's an open question. In terms of tarlatamab, I've had a chance to talk to quite a number of investigators and of course we have Dr. Luis Paz-Ares here as well, very very enthusiastic. In fact, you know, our sites are, you know, they're looking for more slots on the trial. You know, many of the investigators are proposing investigator-sponsored studies. You know, there's just, I think, you know, some real excitement here and the general notion that this drug has a real shot at changing the natural history of this disease. You know, this is a molecule that we're very keen on. As Luis Paz-Ares presented, the safety profile has been you know, quite nice so far. We're moving forward. In terms of the regulatory pathway, we have a potentially registrational phase II ongoing right now. Then we've got trials open in both the second line and in the first line with standard of care therapy. Our goal is to attempt to develop this drug across lines of therapy again, and really change the natural history. Luis, I don't know if you wanna add anything to that. I think I was just telling that. I can hear that, I mean, the enthusiasm is pretty clear. I mean, I see in everyone in this, in the context of small cell lung cancer really like to do trial with this drug in the relapse setting, first line setting. They are of course, you know, like, cooperative groups, academic groups, we are thinking about different proposals to maybe try to convince Amgen to get there or to help us to get there. Secondly, it's not only doctors, it's also patients. I'm telling you my experience. I was the only center in the country. I was receiving patients with small cell lung cancers from everywhere in Spain. Every week in our teleconference, doctors were fighting for slots to include their patients because there was really excitement because of the early data that had been released over the last two years in the different cycles. Also, the patients and their advocacy groups, they are really enthusiastic about having a drug in a setting where is so desperately needed, such as small cell lung cancer disease with terrible prognosis, where the improvements over the last two or three decades has not been as good as in non-small cell lung cancer. I think here doctors and patients are on the same page in terms of really having high hopes with that particular drug. Great. Thank you. Next question, please. Our next question comes from Salveen Richter with Goldman Sachs. Your line is now open. Good afternoon. Thanks for taking my question. You're planning to initiate a phase III study of LUMAKRAS chemo in frontline PD-L1 negative non-small cell lung cancer, and then working on approaches for PD-L1 high and low expressers as well. Can you just discuss what you've seen here and give us a sketch of your strategy? Yeah. Thanks, Salveen. It's a very good question. You know, one thing that we like to do is think of, you know, patients, you know, according to their molecular tumor profile with non-small cell lung cancer, you know, for these purposes in kind of three big buckets. Those who have PD-L1 negative tumors, those that are PD-L1 low to intermediate, and those that are PD-L1 high. We've generated what we think is very interesting, preliminary data, in, using LUMAKRAS in combination with standard chemotherapy. As you know, we'll be moving forward with a phase III study, in patients with PD-L1 negative tumors, where the addition of checkpoint inhibitors provides a benefit, but it's fairly modest. We will provide, you know, guidance, you know, as the year goes on in terms of specifics of that study design, and, you know, the launch timing and expected data timing. We've had very good discussions with regulators regarding that trial. For the remaining patients who have some PD-L1 expression, of course, we're going to pursue the LUMAKRAS checkpoint inhibitor combination as described today. The question is whether some of the other combinations as we generate experience such as the SHP2 combination generates, you know, the sort of efficacy data that would indicate that that is worth exploring in the first line as well. You know, I think many avenues, but it's very likely the therapies are going to be customized according to the tumor profile. Thanks. Why don't we go to the next question? Our next question comes from Evan Seigerman with BMO Capital Markets. Your line is now open. Hey, guys. Hi, all. Thank you so much for taking my questions and congrats on the data update. While we, you know, have data on IO -naïve and IO experienced patients in the trial that you presented, do you have any data kind of looking at the difference in TPS? I'm specifically talking about those with greater than 50% and those with 1%-49%. And then was there any noticeable differences between, you know, PD-1 inhibition and PD-L1 inhibition? Thank you. Yeah. I'll ask Bob again to comment here in a minute. I would say, Evan, that you know it you know once we start subsetting the data the numbers become very very small. So I you know I think I would be hesitant to draw conclusions about distinct differences between the immunotherapy naïve versus exposed population. You know Bob why don't we get your perspective here? But you know to me it's just a little hard to say right now. I agree with Dave. It's subgroup of subgroup analysis. We're coming to sort of comparing one of two versus two of three, you know, so really, no way of making any statistical comparison. We need to just expand the trial and do a proper analysis with bigger sample size. Thanks. Great. All right. Thank you. Next question. Our next question comes from Umair Rafique with Evercore ISI. Your line is now open. Hi, guys. Thanks for taking my question, and candidly, I'm a little confused today, so I'll ask two, if I may. First, at the very start of the presentation, it says median durational follow-up is 12.8 months. When I look at the slide on how long was the median duration on the combination, it's only 0.7-2.5 months. Even the median duration of sotorasib is like, I don't know, 3-5 months, depending on which one you look at. I was really confused, sort of the 12.8 months of follow-up versus the duration of combination. Then secondly, as I think about sort of the reason to do this IO plus KRAS combination is ideally for, perhaps moving upstream, but also for incremental efficacy reasons. I know the ORR at your lower doses from phase I data was tracking right around 25%-30% based on the early disclosures that were done as of 2020. It's kind of in the same ballpark as what was reported for this data set here. I'm just trying to figure out how to interpret those two. Thank you very much. Yeah. Thanks, Umair. Yeah, I'll ask Bob to comment here on, you know, the first part of your question where, you know, he's taken, you know, quite a bit of time to look at these data. You know, in addition to response rate, and many of the patients came off, you know, study drug quite early. So that's one thing to keep in mind. You know, of those who are able to continue, you know, the duration of response is one thing that we're looking at, as Dr. Li highlighted, in his presentation. I think that's one of the key things that we will look at, in the expansion. You know, Bob, do you wanna go ahead and provide some perspective here? Yeah, I agree. This is the point that I believe affected the overall response because we followed up patients for more than a year, but many of them had to discontinue the drug 'cause we hit them with very high doses initially, and they discontinued. Up close to 40% of patients had to come off study because of toxicity, so they didn't really have time to get a response, a chance to have the study drugs long enough. The follow-up is still 12.8 months 'cause we have to report more, at least a mature set of data to you, so we can learn together to move it forward. That's the discrepancy between median follow-up and median duration of treatment. Certainly with the mitigation strategies, with lower doses in leading, we hope to get longer duration of treatment, so that these patients can benefit longer. That's at the moment it's still if you slice and dice for too long and you hit a 20% there, 50% there, it's really hard to compare. You know, if you look at, if this were vastly, what about the frontline treatment naïve leading, low dose 360, what's the response? I've got 2 patients, one responded, one had a stable disease, so why now 250? You can't draw a conclusion from that. Then what about the leading with 42 days with leading versus 21-day leading? You know, Okay, we got five patients with the 42-day leading, three responded to 60% response rate. Is that any meaningful data? I don't think so. Not at this sort of cutoff, but we need to do the expansion. Thank you. Great. Thank you. Next question. Our next question comes from Geoff Meacham with Bank of America. Your line is now open. Hey, guys. Thanks for the question. I just had a few maybe for Dave. The first one is, you know, as you move to other tumor types and different combos, you know, would you have to do a study to optimize dose and also help mitigate liver tox, just as you move forward, you know, to larger scale, you know, combo studies? And if so, what do you think that would look like in terms of size and scale? And then the second question, you know, kind of related to some, to a recent one, if you look at IO -naïve versus IO -pretreated patients, you know, would you guys expect to see a big difference in how fast you get to a response rate? I'm just trying to think of, you know, the best metrics here to kind of judge as you move forward in other combinations. Thanks. Yeah. Great. I will, I'll take the first part. I'll ask Bob again to comment on the, you know, the kinetics of response that you might expect between immunotherapy naïve versus pretreated. You know, for other combinations, all of those studies are designed so that we can do appropriate dose finding. It depends on the arm in each one of those arms is designed so that we can have an expansion where we can actually treat a fair number of patients to get, once we have target dose, and preliminary evidence of efficacy and safety, to get a better, more fulsome look at efficacy and safety. So, you know, we'll present those cohorts as data mature, you know, over, you know, the coming months, and year. I think the master protocol design is really quite flexible and allows us to, you know, to expand and really ask the questions that we need to ask based on what we're seeing for each combination. That, of course, will, you know, also vary across indications, lines of therapy. You know, so there's not going to be a generic answer. Bob, do you wanna comment on the IO naïve versus pretreated, kinetics and response question? Thank you. We did not see any significant difference at a glance, but it's small numbers, both in the response rate and also the kinetics. You saw in the spider plot, many of the responses sort of came gradually, and some of them are PI initially, and they got really deep as we go. My patient went into CI, you know, after many months. This is consistent with the immune effects on tumor. That's what we hope. Well, that's what we are hoping, that by leveraging the immune response and combining the drugs in the right way, we can mount a really fulsome immune response for lasting benefit. You know, my patient said back in 2019 when she came to the trial, she drove all the way from Florida and said, "Look, I'm gonna get onto this trial. I'm gonna take an AMG, like an aspirin, and I'm just gonna get on with my life." She did. Now it's three years on, and she's just doing that. Whether the immune, in our biopsy-derived, you know, we saw a lot of immune infiltrates. Whether that had anything to do with this durable response, I think we still have to prove it and have to do more studies. That's the hope. Great. Thank you. Next question, please. Our next question comes from Yaron Werber with Cowen. Your line is now open. Great. David, I got a couple also. The first one is the data with atezo looks better tolerated, or at least less AEs than with pembro. I know Tecentriq obviously is a minor player, but why not also do a study with Tecentriq? Secondly, when we're calculating, we're getting to an ORR of 42% in first line. As you think about and obviously, those patients are earlier, so they're sort of tracking the experienced population so far in terms of durability. I think only one progressed or died. What are you thinking as you go into first line? Is PFS the right benchmark? Can you get approved if you have a lower ORR there? I'm talking about the intermediate to high population. Thank you. Yeah. Great. Thanks, Yaron. You know, I'll take the first part and again ask Bob to comment on both parts here. You know, again, when we look at the numbers and they become small, I don't think you can conclude that there's any real difference in the profiles between the PD-1 versus PD-L1 inhibitors. So we elected to move forward with you know, the more commonly used in the first-line setting. You know, Bob, you may wanna comment on that and then the you know, appropriate endpoint for you know, first line and what you would be looking for. Yeah. This is more about practice patterns, and pembrolizumab just has such a dominant role in first line setting. We're trying to move the drug into first line, so that was a natural fit. I have no opposition to studying atezolizumab or nivolumab or any other PD-1, PD-L1, you know, from a scientific standpoint. This is a pretty practical choice. We really hope to stretch out by leveraging immune response, stretch out the durability of benefits. I personally believe PFS is a great primary endpoint. Of course, you have to look at the totality of data, the overall survival duration response rate as well. But you know, in my mind, PFS is a bit weak with chemo IO first line, and we have to beat that. No one's beaten it before, but I think we have an obligation to do better. Great. Thank you. Next question. Our next question comes from Mohit Bansal with Wells Fargo. Your line is now open. Great. Thanks for taking my question, and thanks for the detailed presentation. Maybe a question for you, David. Trop2 inhibitors, Trop2 ADCs actually are showing a 20% or so response rates in monotherapy. And especially, they are also targeting the third bucket that you alluded to, which are like PD-1 negative sort of patients. Do you have any thoughts on combining Trop2 ADCs with LUMAKRAS? Because there is a part that Trop2s could actually replace chemo in long term. Would love to get your thoughts there. Yeah. No, thanks, Mohit. It's a good question. We've actually had a lot of active discussion on potentially combination with antibody drug conjugates, ADCs. You know, as you know, there's a real renaissance in that field right now, and there will be drugs advancing in lung cancer and other indications where these combinations may make sense. You know, I would say stay tuned, but that is an area of very, very active discussion right now. To me, going forward, at some point, those combinations, that absolutely makes sense. Thank you. Next question. Our next question comes from David Risinger from SVB Securities. Your line is now open. Yes, thanks very much. I was just hoping that you could characterize LUMAKRAS' liver toxicity profile as you see it, versus Mirati's adagrasib. Also comment on what you're gonna be focused on going forward as you further assess your competitive profile versus that agent and others that might be forthcoming. Thank you. Yeah. Thanks, David. You know, look, I don't wanna speculate on others' data, you know. I think we need to see again an adequate number of patients with adequate follow-up. And we'll let others speak to their own data. You know, moving forward, as Jean-Charles Soria presented, you know, we've got a very broad-based program. It's international. I very much like the position we're in and the clinical profile that we've seen with LUMAKRAS, and it's really full steam ahead on this program. You know, it's always worthwhile to me to also step back, you know, and every now and then pause. You know, it took 40 years to get inhibitors that actually work against this target. You know, we've only been in the clinic, you know, three years now, basically, and there's still an enormous amount to learn. It's very clear that the biology of this target is different than the biology of receptor tyrosine kinases, for example, where kinase inhibitors are used. You know, I'm quite confident in the profile. We are, you know, we're firing on all cylinders across indications now. Thank you. Why don't we go to our next question? Our next question comes from Michael Schmidt with Guggenheim. Your line is now open. Hey, thanks for taking my questions. David, could you update us on where you stand with the other cohorts within the CodeBreaK 101 study? I'm just thinking, you know, by the time you dial in the lead-in dosing cohorts with sufficient follow-up with the PD-1 combination, it's gonna take some time, and it's a competitive space, obviously. I'm just wondering how far along the other cohorts are and if you might be in a position to perhaps accelerate some of those activities while waiting for the lead-in dosing information. Yeah. No. The other cohorts, I mean, in general, we're enrolling quite well. And again, as we get datasets that we think are informative, we'll present those. You know, we will have, for example, updated data on the Vectibix LUMAKRAS combination in colorectal cancer at ESMO. That's in roughly a month or so. You know, the additional data will follow behind. You know, Michael, you know, we'll provide guidance there, but we're actually moving along pretty quickly right now. I certainly expect many of those data to emerge as we're now enrolling this expansion with the checkpoint inhibitor combination, as you note. Why don't we go to our next question? I think we've got one or two left. Our next question comes from Colin Bristow with UBS. Your line is now open. Hey, good afternoon, and thanks for taking the questions. I really just have a point of clarification. The go-forward strategy for LUMAKRAS -IO combo now is it purely focused on the lead-in regimens, or is there gonna be any further exploration at all of concurrent dosing? 'Cause it looks like at a minimum, that's where you had both of your complete responses. Just to dig into the data a little bit more, looking at the lead-in efficacy data, could you give us a little more detail around the number of responses per dose level on the lead-in data you provided? Thanks. Yeah. Thanks, Colin. Again, I'll ask, Bob to comment particularly on the second part of your question. To answer the first part, yeah, we are focusing on lead-in only based on the safety profile, going forward. That is what we will focus on in the expansion. We're not going to further evaluate at this time straight combination from the start of therapy. Bob, do you wanna add some comments here? Thank you. Scientifically, you saw from the preclinical models that if you prime the immune system with sotorasib for a period of time, it may respond to an immune checkpoint combination, you know, after that period of time. There is a scientific rationale to prime it first for a few weeks and then get onto it. Also, Dave pointed out the safety reasons, you know, to make sure that patients are tolerating it, even with monotherapy, liver's okay, and then you get onto the combo. That, that's our rationale for pursuing lead-in. Absolutely right, that is the path forward. We're not gonna go back to the concurrent, especially high doses. That's already proven this trial to be a no-go. In terms of response rates, I mean, this is really a handful, single-digit at each subgroup. If you just look at the sotorasib lead-in 42 days with pembrolizumab, we had five patients that were first-line treatment-naïve, and three of those had a PR. But that to me doesn't really mean much. I'm not gonna quote a response rate based on these sort of small numbers. We really need to do the expansion to give more answers. Great. Thank you. All right, I think, Jason, we have time for one more question. Our last question comes from Nicole Germino with Truist. Your line is now open. Thanks. This is Nicole on for Robin. I just wanted to ask about tarlatamab a little bit. Could you just talk a little bit more about the updated data and for, you know, small cell lung cancer, it looks like from your last update at ASCO, the duration response grew. Can you just talk a little bit more about what we'll see going forward with tarlatamab and what is, you know, the strategy going forward there? Thanks. Yeah. Thanks, Nicole. And again, I'll ask Luis to comment in just a moment here, but you know, I think you picked up on what we believe is a very important point. There's a duration of response. So as the data continue to mature, that has increased and median duration is now 13 months, which is pretty remarkable in a patient population where roughly 75%, three-quarters of the patients were on their third or greater line of therapy. So as I mentioned, we're enrolling the potentially registrational phase II trial now. That's actually enrolling quite briskly, as you might imagine, based on the data that investigators and patients have seen. And we're investigating tarlatamab across lines of therapy. To me, the end game here is to really change the natural history and improve overall survival in this disorder, which has not changed much, as Luis noted, in decades. Luis, wanna add some final brief comments here? Yes. Thank you, Dave. I mean, I think having mature data on this cohort is actually giving us some light on what is gonna be the meaning of this drug in small cell lung cancer. I mean, I think something, but if you look at the drugs that have been explored in small cell lung cancer over the last decade or two decades, you're having drugs that are getting responses in 20%-30%, even sometimes 40% of the patients, second or third line. But you never achieve median survival lot higher than 8 or 8.5 months. Here, we have seen it's 13.5 months with this maturity we are having today. But importantly, every time you see the data maturing, actually the duration of response, the median duration of response is improving. Actually that is translating in a further improvement in median survival. I would say the data are getting more mature, but they still are maybe not the final figure here. Those data are very encouraging. I would say it's very likely that the registrational trial may give us an answer. It's gonna also give us an answer of what is the best drug to use, 10 milligrams or 100 milligrams, which is a relevant question as well. Thirdly, it's gonna give us also hints of how to do next, let's say, what to do in terms of, is this drug ready to go into the first line setting? We have already started the phase I trial with a chemotherapy combo in combination with chemotherapy, and of course this could be a potential registrational trial, but that should be a bit more in the midterm rather than tomorrow. Great. Thank you. All right, well we're a little bit over, so I think we'll end the call here. I really wanna thank everyone. As always, the Investor Relations team