Good afternoon, everyone. Thank you for joining us. Oncology and hematology continues to be the largest therapeutic area in Roche. We focus on end-to-end diseases, largely in large opportunities where we currently have market leadership and where we also continue to unlock the next wave of innovations for the next wave. As you're thinking about in our Q1, within this Q1, we delivered CHF 5.9 billion in sales, that is about 40% of total Roche sales. This has also led to an 8% year-to-year growth. If you're looking at from a growth perspective, you can see that it's largely driven by breast, lung, malignant heme, as well as hemophilia. In breast cancer, obviously, we have our market leadership in HER2 breast cancer, and now we're expanding into the ER-positive.
In lung cancer, we continue to see market leadership in Tecentriq, returning back to growth and also growth opportunities with Alecensa. In malignant heme, as Bruno has highlighted, we continue to have market leadership in non-Hodgkin lymphoma and also in CLL with Venclexta, as well as in hemophilia with Hemlibra. Speaking more about our pipeline. We focus quite a bit in terms of rejuvenating our pipeline, primarily focus on A, how do we think about the right diseases, right anchors to innovate from? As you can see that since 2024, we delivered six positive phase III readouts. In additional with that, also three additional new molecular entities with phase III indications. Most importantly, most of these assets, over 70% of them are first-in-class and best-in-class.
In addition to the late-stage opportunities, we also have been investing quite a bit into the early stage, whereby in addition to our internal efforts, we've also brought in six new molecular entities into our pipeline through business development and as well as four platform deals in research and collaborations. All of these achievements are important because they reflect our ability to really compete in the marketplace and also our ability to really deliver the pipeline continuously. We look forward to speaking more about these innovations as we continue our sustained growth within the area. One of the key areas to think through in terms of thinking in terms of the next wave of innovations is investing into the right diversified portfolio of modalities and targets. Modalities and targets are important as we're thinking about investing into the end-to-end diseases.
As you can see into our portfolio, we have a diverse portfolio of modalities spanning from small molecules all the way to bispecific and multispecifics, ADCs, as well as cell therapies. Oral therapies continue to be important in our portfolio as we think about patients that are moving into earlier diseases, as well as in thinking about long-term treatments, especially in almost like in the chronic settings. As you can see in giredestrant, we're going to speak about that more later on. Equally, when we're thinking about bispecifics and multispecifics, as well as the next generation of ADCs, the importance of taking in not only thinking about the efficacy itself, but also thinking about how we continue to think about the patient journey with regards to tolerability, accessibility for patients in the community becomes key.
As you can see in some of the pipeline deals that we continue to bring in, this is an effort, not only are we thinking about this internally as well as externally. One of the example in terms of how we do this is with our RAS portfolio. Here you can see that we're building a pipeline of RAS mutative portfolio, not only in a single mechanism, but also across a variety of them. RAS is commonly seen, as you can see, that one in every four patients in stage IV has some type of RAS mutations, particularly primarily in lung, in colorectal, as well as pancreatic cancer. In non-small cell lung, it's about 12%-14%, primarily with G12C.
Thinking about the first generation of inhibitors right now, obviously, there have been great advances in bringing the clinical efficacy of these agents, but the liability of it in terms of toxicity, combinability, and also in resistance mechanism continue to prevail. This is why when we think about our portfolio, not only are we having a single mechanism of action, but we're bringing in best-in-class molecules in different mechanisms, allowing us to think about unique combinations, addressing the efficacy concerns, as well as tolerability and combinability across. We're excited to see some of the activities coming out with G12C with the divarasib and more to come in our portfolio. Speaking a little bit more about divarasib, we continue to see that this can be a potential best-in-class molecule for us within the G12C inhibitor arena.
When we look at preclinical models, we can see that both selectivity and potency, divarasib continues to be well compared versus sotorasib and adagrasib, with five to 20 times in potency and also 10- 20 times in selectivity. That data translates into the monotherapy data when we're thinking about second-line non-small cell lung cancer, whereby we continue to see that activity translates into median PFS, progression-free survival, about 15 months. As you may remember, comparing to sotorasib and adagrasib, that is about well over twice of what we see in terms of the progression-free survival as a single agent alone. With that, divarasib was awarded as a Breakthrough Designation, or BTD, with FDA, and that's how we actually got into the second-line phase III KRASCENDO- 1 trial, looking at head-to-head comparison versus sotorasib and adagrasib.
That data will be reading out at the end of this year. We look forward to sharing more. Translating from preclinical to monotherapy and now thinking about the combination, that consistency continues. When we're thinking about the KRASCENDO- 1 study data that we have presented at ASCO, we continue to see that best-in-class opportunity exists and confirmed with divarasib. As you can see, in terms of the PD-1 high expression population across, you can see that from the waterfall plot, the overall response rate with long follow-up continues to have about 73% with CR of over 10%. That consistency is also seen in the PD-L1 negative population, despite a short follow-up. From a toxicity profile, you can see that on the right, whereby the toxicity profile is well managed. It's expected from the class itself with a discontinuation rate of 13%.
Many of the adjustments when we're thinking about prophylaxis, adaptive dosing, side effect managements were incorporated progressively into 170. More importantly, those are included systematically into our phase II, and now phase III KRASCENDO- 2 program. That is important as we're thinking about the encouragement that we've seen from our principal investigators, from our patients in general, and also from the recruitment that we continuously see with KRASCENDO- 2. In summary, what I can say is that when you're looking at oncology as a whole, we continue to invest into large opportunities where we have market leadership today, where we have opportunities to unlock further with the next wave of innovations strategically, both internally and through external innovations.
In RAS, this is one of the example whereby we're thinking through and how do we think through from a tumor biology, how do we understand the modalities, and also in terms of what the patient considerations are as we're unlocking this next wave to serve more RAS patients. Equally, when we're thinking about breast cancer, with the best-in-class opportunity for giredestrant and also inavolisib, we continue to innovate within that. With that, let me introduce you to Aakanksha, who will share further in terms of our breast cancer portfolio. Over to you, Aakanksha.
Thank you. Perfect. Thank you so much. It's a pleasure to be with you this afternoon. Breast cancer franchise is one of the NCCN disease areas for Roche, and we've certainly built a very strong legacy in this franchise. As you know, breast cancer remains the largest oncology indication by revenue, but there remains a high unmet need and an opportunity to really optimize treatment. We've built a very strong legacy in the HER2-positive disease area within breast cancer, and we're now looking to expand leadership into the HR-positive space. We started this with Itovebi, as evidenced by the INAVO120 study, where we've seen stellar data, including positive OS data that continues to look strong. Now we're looking to further expand that with giredestrant, our next generation oral SERD inhibitor, which we believe will be an ET backbone.
We've been very intentional about the way we've been building out our breast cancer portfolio, looking at various nodes in the cell signaling pathway. For the HER2-positive node, we've been looking at ZN-1041. This is a highly selective brain-penetrant HER2 TKI, where we're looking to develop it in combination with other therapies and are also exploring monotherapy activity. For the PI3 kinase node, we have Itovebi, which you heard me allude to just now. It's a PI3 kinase inhibitor where we have a number of ongoing trials, and we have the positive INAVO120 results. For the ER-positive pathway, we have giredestrant, our next-generation oral SERD, which we believe has the potential to become the ET backbone treatment. On the CDK pathway, we have GDC-4198. This is a highly potent CDK4 inhibitor, but it also exhibits substantial activity against CDK2.
What we'll do now, we'll go through each of those four nodes. For HER2-positive, there's still a significant unmet need, despite how much the treatment landscape has evolved. The landscape is becoming increasingly fragmented as novel therapies and new regimens are approved. However, and despite this, in the early breast cancer setting, Phesgo and Kadcyla are expected to remain the standard of care and used in the majority of patients. In the metastatic breast cancer setting, the treatment strategy is really moving away from this one-size-fits-all approach to a more tailored approach anchored on disease biology and patient risk. Phesgo here is expected to remain a key treatment option, and we're looking at it in a variety of different frontline settings.
As you probably heard from past trials that were investor-initiated, such as PATINA and HER2CLIMB-05, the induction maintenance approach is gaining more ground, and we're truly trying to understand what is the best induction maintenance approach for HER2-positive breast cancer. We're continuing to look at this through the DEMETHER trial, which is an investigator-sponsored trial that is currently enrolling. We're also looking at novel combinations in the HER2-positive space with giredestrant. This is a phase III study called heredERA, which is giredestrant in combination with Phesgo, and with inavolisib, which is the INAVO122 trial, which is inavolisib in combination with giredestrant in combination with Phesgo. There's a lot of combinations across our portfolio, which is one of the secret sauces of our portfolio that we'll talk about.
However, the unfortunate reality in the HER2-positive space is that a number of these patients do go on to develop brain metastases. Almost half of the patients do. To address that, we have ZN-1041. This is our highly selective brain-penetrant HER2 TKI. The reason we feel that it's differentiated is because it has really high blood-brain barrier permeability, and it has unique CNS retention, and that's what's evidenced on the left-hand side of the slide. One of the things is that it's not a substrate for the efflux transporters. That's what gives it the strong CNS retention. We've also seen better preclinical activity than tucatinib. You may have seen the data in the past where we had very high response rates in a Chinese population, where we looked at ZN-1041 in combination with Xeloda and Herceptin.
Based on that, the results that were shared yesterday during the poster session are on the global patient population. That's what's evidenced on the right-hand side of the slide. This is a global patient population that's heavily pretreated that received different combinations of ZN-1041, either ZN-1041 in combination with T-DXd or ZN-1041 in combination with Phesgo. This data was meant to show combinability as well as tolerability, both of which it did well, we're very encouraged by the results that I'll see, and it enables further investigation of combination therapies. Various combinations with ZN-1041. We're also pleased to share that we have initiated the BREnnA trial. This is a phase II-III trial in the second line plus patient segment looking at ZN-1041 versus tucatinib in combination with trastuzumab and capecitabine. That one recently initiated and just had its first patient in.
We look forward to generating more data with this asset in the coming years. Now let's shift a little bit to ER-positive breast cancer. As you know, ER-positive breast cancer accounts for about 70% of the overall breast cancer landscape. Within that, the adjuvant setting is the largest segment. The adjuvant setting accounts for three times as many patients as the front-line metastatic setting. That's the setting that was unlocked by the lidERA trial. Also, the setting is expected to grow over the next several years. giredestrant is our next-generation oral SERD, which has the potential to become the standard of care backbone endocrine therapy. We've seen that it has a deep and sustained ER inhibition. What it does is it suppresses ER signaling through two routes, so ER immobilization and then subsequent degradation.
That ER immobilization is really important because that's been associated with what's really driving therapeutic potency. We feel that giredestrant is disrupting ER signaling at its core. You can see that in the middle of the graph, where you look at preclinical potency across a variety of different oral SERD molecules. What you can see here is that giredestrant has the highest preclinical potency compared to the other oral SERDs, and this data was just published a few weeks ago. We also see that giredestrant is a full ER antagonist and really achieves that deep and sustained ER inhibition. We've also seen very high target coverage compared to other SERDs. We've found it to be combinable with all CDK4/6 inhibitors that we've looked at, and we've found it to be well-tolerated at all doses, with no dose-limiting toxicities and no photopsia that's been observed.
As you know, we've had a number of phase III readouts for giredestrant, and giredestrant has shown positive results both in the adjuvant setting, as evidenced by lidERA, as well as in the metastatic setting, as evidenced by evERA. It is the first and only oral SERD to show positive phase III results in the adjuvant ER-positive breast cancer setting. Let's go into these three trials very briefly. The lidERA trial, which read out last year at SABCS, shows a 30% reduction in the risk of recurrence or death compared to standard of care. We saw a clear positive OS trend with a hazard ratio of 0.79x and lower discontinuation rates. You heard about the persevERA trial this morning, where unfortunately the primary endpoint was not met. However, we did observe a five-month improvement in PFS. We also saw a numerically longer duration of response.
The evERA trial was presented at ESMO last year, where we saw PFS improvement both in the ESR1 mutant population as well as in the ITT population. We also saw a clear OS trend favoring giredestrant. Across these trials, giredestrant has demonstrated that it is active from neoadjuvant to first-line and beyond. It has also been shown to be very well-tolerated. Let's dive a little bit into the adjuvant segment. We feel that giredestrant has the opportunity to become the standard of care across a broad risk spectrum in the adjuvant setting. You may have seen the press release this morning where we announced the file acceptance of lidERA with a PDUFA date of November 30th. evERA is already under review with the FDA with a PDUFA date of December 18th.
To dive a little bit into the adjuvant setting, we wanted to talk about risk groups. Risk groups can get a little bit tricky because everybody defines them a little bit differently, and it's based on the eligibility criteria of the different trials. As you can see here, we've broken it down into four different segments: low risk, intermediate risk, medium risk, and high risk. The medium and high-risk groups are where CDK4/6 inhibitors have been studied, but there's an opportunity beyond this where the lidERA trial was studied, which goes well beyond this and into what we're calling the intermediate risk group. We break this down even further. When we look here, if you look at the gray bars, that's the opportunity for giredestrant in the adjuvant setting. You can see here that the majority of the patients receive ET monotherapy.
Now we have provided an option where you have a safe and tolerable ET backbone. For some patients, they may need to receive a CDK4/6 inhibitor, and that's okay because we're also looking at how giredestrant can be combined with CDK4/6 inhibitors. I already shared with you from a tolerability perspective, we haven't seen any tolerability issues with the combination. We're looking to continue to establish giredestrant upfront as the monotherapy agent of choice, and we will continue to evaluate it in future studies in combination. Giredestrant has a large and still expanding clinical development program. There's a lot going on on this slide, so just bear with me. What you see on the right-hand side are the trials that have been announced or are ongoing for giredestrant in the order of earliest stage all the way going down to metastatic.
It starts with line of therapy moving down. On the left-hand side is where we expect to be in terms of patient segment. In green, you'll see the patient segments that have already been unlocked by positive trials. You see giredestrant in the adjuvant setting, that's the lidERA trial. Then you see giredestrant plus an mTOR inhibitor in the frontline and second-line setting, and that's the evERA trial. We also have several other trials ongoing, such as the pionERA trial that we're very excited about, and which is in a different setting than what persevERA was studied in. We also have the ongoing heredERA trial, which is giredestrant plus Phesgo. We have giredestrant plus GDC-4198, which I will talk about a little bit more in a moment. It's also my pleasure now to share with you that we have two new trials.
These two new trials, they're shown by numbers three and four here. They cut across all risk segments and they are looking at giredestrant use in different ways. Let's take a step back and we think about the early breast cancer setting. The best drugs are the drugs that patients can actually stay on so that they can derive the maximal clinical benefit. That's what these two trials are looking at. The first trial is a phase IIIb trial of 1,500 patients where we're looking at gire upfront and as well as switching for patients coming off of a CDK4/6 inhibitor and moving on to giredestrant monotherapy. It is across all risk subgroups, and we'll be looking at things such as adherence and understanding potential associations with tolerability, quality of life, patient-reported outcomes, and the like.
This trial I do want to mention is not yet public on clinicaltrials.gov, so it is yet to be initiated. The next trial, which is number four, is the novERA trial. This is live. It has been initiated, and you can find it on clinicaltrials.gov. It is similar in that it cuts across all risk segments, but it's looking at patients who are intolerant to aromatase inhibitors. As you know, aromatase inhibitors are associated with musculoskeletal toxicity and other reasons patients don't stay on therapy for the full duration. Through clinical trials and observational research, we see that approximately 1/3 of patients, if not more, come off of their aromatase inhibitor prior to the completion of their course of therapy.
This is looking at those patients that come off of their AI and move on to giredestrant monotherapy, and it's studying similar things as the trial that I just mentioned. These are two new to add to the overall clinical development program for giredestrant, which we're going to continue to expand in the coming months. I want to move a little bit and now talk about the CDK space. As you know, there are CDK4/6 inhibitors that are on the market. However, resistance to CDK4/6 inhibitors remains a challenge, and nearly all patients eventually progress on these inhibitors. There's data that suggests that CDK2 activity is a potential mechanism of resistance to CDK4/6 inhibitors, and that's where GDC-4198 comes in. GDC-4198 is a CDK4/2 inhibitor.
The reason why we call it a 4/2 inhibitor is because it's highly potent against CDK4, so it's a CDK4 inhibitor, but it also exhibits substantial activity against CDK2. We're also seeing that it has durable cell cycle arrest and actually more durable cell cycle arrest than the approved CDK4/6 inhibitors that are currently on the market. That's based on preclinical studies. We've looked at dose finding, and so the right-hand side waterfall is just a variety of different doses that we were looking at. However, we have an ongoing phase I-B/II MONRO study, which is looking at GDC-4198 in combination with giredestrant versus abemaciclib in combination with giredestrant. That's in the CDK4/6 inhibitor-experienced ER-positive patient population in the metastatic setting. Next, let's move over to our PI3K kinase inhibitor, Itovebi.
If we can get the lights back on, that would be great for this side of the room. Got a little dark up here. We're really excited about Itovebi and the data that we've demonstrated through INAVO120. This data just continues to get better. It's the first and only PI3 kinase with positive OS and a triplet blockade where we have strong data at the two-year mark. Where we're delaying chemotherapy utilization by at least two years. What you are seeing here is that in the longer-term follow-up, we see an OS hazard ratio of 0.67x and a PFS hazard ratio of 0.42x.
We also have a broad clinical development program for Itovebi, and we await the results of INAVO121. We're working to bring the benefit of the Itovebi triplet into earlier disease settings with INAVO123 in frontline ETS in the endocrine therapy sensitive population and with neoTOVE in the EBC population. We are also exploring further combinations with inavolisib and giredestrant. With that, I know Aditya Bardia is excited to talk to you and share a little bit about the giredestrant program, the three trials where we have reported data. Aditya Bardia?
Great. Thanks so much. I'll be presenting the results. We can go to the next slide. I'll start with the lidERA study, then I will talk about persevERA, and then I'll talk about evERA. Let's start with lidERA first. These are my disclosures. Go to the next slide. The lidERA study, as a reminder, looked at giredestrant versus endocrine therapy as adjuvant treatment for patients with ER-positive, HER2-negative early breast cancer. We presented these results at SABCS last year. Next slide. In terms of background, as was mentioned previously, giredestrant is a next-generation oral SERD. It binds to the estrogen receptor, and it degrades the estrogen receptor and is a potent blocker of ER signaling as well. As compared to other SERDs, it's been shown to be more potent.
We saw this in the coopERA study, where giredestrant in combination with the CDK4/6 inhibitor was superior to AI CDK4/6 inhibitor. That trial also had a two-week endpoint looking at Ki67, giredestrant was superior to aromatase inhibitor in terms of Ki67 suppression. We've also seen this in EMPRESS, where it was compared to tamoxifen, again, in terms of suppression, it was superior. lidERA study asked this question in the adjuvant setting with the primary endpoint being iDFS, it compared giredestrant head-to-head to AI and tamoxifen. Next slide. This was the study design. Patients with Stage 1 to Stage 3 ER-positive, HER2-negative early breast cancer, both pre or post-menopausal, were randomized to receive giredestrant versus standard of care endocrine therapy, which could be tamoxifen or any of the aromatase inhibitors.
Patients who were pre-menopausal, if they were randomized to giredestrant or AI, were required to have OFS. The primary endpoint was iDFS and a number of key secondary endpoints. In this trial, giredestrant was compared as a single agent to standard of care endocrine therapy. As was mentioned previously, giredestrant is also being evaluated in combination with abemaciclib in the sub-study of lidERA. Next slide. These are the primary results, as presented last year. The study met its primary endpoint. Giredestrant was superior to standard of care endocrine therapy. Three points to note related to these results. The first is the hazard ratio, .70. That's a 30% risk in terms of disease recurrence and/or death. Second is that the curves continue to separate over time. We see the results up to close to three years.
As you can see, the curves continue to separate, we'll have additional follow-up later on. Third is, if we compare giredestrant to AI, we see that even there, the hazard ratio is significant, 0.73x, and as compared to tamoxifen, it's close to 0.5x in terms of the hazard ratio. If you compare giredestrant even to aromatase inhibitor, it was found to be superior, as seen in the forest plot. Next slide. In terms of subgroups, all the subgroups derived benefit or at least was trending in the right direction in terms of giredestrant superiority. If we look at Stage 1, the confidence interval crosses one, but it partly could be because Stage 1 is also prognostic, meaning that patients have lower risk of recurrence. The number of events are few in Stage 1, and we'll need longer follow-up to look at this subgroup.
We look at risk, we look at region, we look at age groups in all the subgroups, the benefit with giredestrant was trending in the right direction. Next slide. In terms of overall survival, the results are not mature at this time. We need more follow-up. It was trending in the right direction with a hazard ratio 0.79x, this is immature at this time. We need more follow-up in terms of overall survival. Next slide. In terms of safety, that's where it's really important in the adjuvant setting, because compliance and adherence are key factors. giredestrant overall in terms of Grade 3, Grade 4 AEs was similar to standard of care endocrine therapy. We look at the number of deaths, those were lower in the giredestrant arm as compared to standard of care endocrine therapy arm.
If we look at discontinuation, it was also lower in giredestrant as compared to standard of care endocrine therapy. Next slide. If you look at specific type of AEs, overall arthralgias appeared to be similar between giredestrant and standard of care endocrine therapy. If we look at discontinuation because of arthralgias or musculoskeletal symptoms, those were lower with giredestrant as compared to standard of care endocrine therapy. The AE that was higher with giredestrant was bradycardia, which has been described previously. It's a side effect that's observed with this drug, predominantly Grade 1, so that's asymptomatic. Some patients had Grade 2 bradycardia as well. There were no serious AEs related to bradycardia seen. In terms of Grade 3 for bradycardia, that was zero. Finally, in terms of thromboembolic events, that was slightly higher in the standard of care endocrine therapy arm.
Could be because of tamoxifen, which is known to cause venous thromboembolic events. Next slide. Overall, the conclusions were that since the approval of aromatase inhibitors in 2000, more than 20 years later, now we have another endocrine agent, the first oral SERD, to demonstrate positive results in the adjuvant setting, improvement in iDFS, trend towards improvement in overall survival, as well as distant recurrence-free survival. A favorable safety profile. If anything, discontinuation rate was lower as compared to standard of care endocrine therapy. Potentially, it's a new standard for patients with ER-positive, HER2-negative early breast cancer. As mentioned, the sponsor has filed for approval with the PDUFA date of November of this year. Next slide. At ASCO today morning, we saw the results of the persevERA study. This is now in the metastatic setting. It's a different setting.
Here, the standard of care has been AI plus CDK4/6 inhibitor. This trial asked the question, can we look at giredestrant plus CDK4/6 inhibitor in the first-line setting? Next slide. This is the study design. First line setting, patients with metastatic or locally advanced disease who've not received any prior treatment for advanced disease. They could have received adjuvant, neoadjuvant treatment, but if they received neoadjuvant, adjuvant treatment, a disease-free interval of at least 12 months was required in this clinical trial. One-to-one randomization to giredestrant plus palbociclib versus AI plus palbociclib. Next slide. The primary endpoint was investigator-assessed PFS. After interim analysis, the P value boundary was 0.04. Primary analysis was planned after 620 investigator PFS events, and the study was designed to detect a hazard ratio of 0.77x with 89% power. Next slide. These are the baseline demographics. Overall, well-balanced in this study.
One point to note is the percentage of patients with visceral metastases in this clinical trial was 60%, and about 40% had non-visceral disease. Bone-only involvement was pretty low in this trial, in single digits, less than 10%. Majority of patients had received prior neoadjuvant or adjuvant treatment. Next slide. In terms of the study results, the primary endpoint was not met from a statistical perspective. There was a numerical improvement noted in investigator-assessed PFS, 33 versus 28 months, about a five-month difference in median PFS. This did not meet statistical significance. From a statistical perspective, the primary endpoint was not met. Next slide. In terms of subgroups, there are two subgroups that merit attention.
The first subgroup is if we look at patients who had prior TFI or no prior therapy, you could see that there was a trend in favor of giredestrant plus palbociclib that was noted. The other is the non-visceral subgroup. Here, you could see that the benefit appeared to be larger as compared to those with visceral subgroup. This was mentioned by the discussant as well today morning, and this is something previously that has been observed with another study that looked at fulvestrant versus aromatase inhibitor endocrine therapy in the first-line setting. Next slide. In terms of OS, pretty much no difference seen, not statistically significant as well between giredestrant-palbo versus letrozole-palbo. Next slide. In terms of other secondary endpoints, the overall response rate was similar between giredestrant-palbo versus letrozole-palbo.
If we look at the duration of response, that appeared to be slightly more with giredestrant plus palbo, 38.5 months versus 30 months with letrozole-palbociclib. If you look at the curves, you also see the separation in terms of duration of response. Next slide. In terms of safety, overall, no major differences between giredestrant-palbo, letrozole-palbo. I think the important point here is that there were no unexpected surprises with the combination. No new AE seen with the combination. The discontinuation was also comparable between the treatment arms. Next slide. In terms of AEs, again, no surprises. The AEs we've seen with palbociclib, which includes neutropenia or myelosuppression. AEs we've seen with giredestrant, which includes bradycardia. In terms of hepatotoxicity, that appeared to be similar between the arms. Next slide.
Overall, while there was a numerical improvement with giredestrant/palbo as compared to AI palbociclib, from a statistical perspective, the study did not meet the pre-specified threshold for statistical significance. The response rate was similar, but the duration of response was longer with giredestrant/palbo. OS results are mature this time. In terms of tolerability, it was well-tolerated. No surprising safety signal seen. Giredestrant is being evaluated in the pionERA study, which is also a first-line study. The difference being that that study allows patients who have disease progression on adjuvant endocrine therapy, so it's a slightly different population than this current persevERA study. The control arm in the trial is also thus different. It's fulvestrant in pionERA as opposed to AI in persevERA. Next slide.
The final study I'll mention, so we talked about adjuvant, we talked about first-line, now we'll talk about second-line plus, and that's the evERA study presented by Dr. Mayer at ESMO last year. Next slide. This study asked the question, giredestrant plus everolimus versus standard of care endocrine therapy plus everolimus in the second-line plus setting for patients with ER-positive, HER2-negative metastatic breast cancer. Exemestane everolimus, fulvestrant everolimus is considered the standard of care. This study asked the question, if we change the endocrine backbone to giredestrant but keep everolimus, would that result in superior outcomes? Next slide. The study had impressive improvement in investigator-assessed PFS in patients who had ESR1 mutations with a hazard ratio of 0.38x and close to doubling of median investigator-assessed PFS in patients with detectable ESR1 mutation.
If you look at the curves, you see early on there's a separation in favor of giredestrant, and that is maintained over time. Next slide. In the ITT population also, the results were positive, met statistical significance with a hazard ratio of 0.56x. The team also looked at exemestane versus fulvestrant in terms of the choice of standard of care endocrine therapy. In both the subgroups, there was benefit in favor of giredestrant. Next. The team looked at ESR1 mutation versus ESR1 mutation not detected, and it appeared that in patients who did not have ESR1 mutation that was detectable, the hazard ratio crossed one or did not meet statistical significance. It appears that the benefit is driven in the ESR1 mutant subgroup with giredestrant plus everolimus versus standard of care therapy was plus everolimus. Next slide.
If you look at chemotherapy-free survival, or we look at PFS2, again, you see that there's delay in the use of chemotherapy, or the chemotherapy-free survival is longer with giredestrant plus everolimus as compared to standard of care therapy plus everolimus. In this trial, patients had a chemotherapy-free survival in the ESR1 mutant subgroup of 12.5 months, so that's more than a year of delay in the use of chemotherapy with the combination of giredestrant plus everolimus, something that is clinically meaningful. Next slide. In terms of OS, trend appears to be favorable. If you again focus on the ESR1 mutant subgroup, we see that the trend is favorable in terms of OS with giredestrant plus everolimus versus standard of care therapy plus everolimus. Additional follow-up is ongoing to have more mature OS results. Next slide.
In terms of safety and no surprises, overall, the incidence of AEs were similar between the combination with giredestrant versus standard of care endocrine therapy, and we'll talk about specific AEs. Next slide. No major surprises in terms of AEs, and the conclusions were that the combination of giredestrant plus everolimus was superior, both in terms of statistical significance as well as clinically meaningful improvement in investigator-assessed PFS versus standard of care endocrine therapy plus everolimus. In the ESR1 mutant subgroup, we saw a hazard ratio of 0.38x. In ITT population 0.56x. The benefit was consistent in across all subgroups. At ASCO, as we saw, PFS2 Chemotherapy-free survival and a trend towards improvement in Overall Survival with giredestrant plus everolimus. The safety profile, no surprises. The usual side effects seen with everolimus, as well as with giredestrant was seen.
Giredestrant, everolimus might be a preferred or an effective option in the second line plus setting. That's the post-CDK4/6 setting for patients with ER-positive, HER2-negative advanced breast cancer, particularly in patients who have detectable ESR1 mutations.
Dr. Bardia, thank you for taking the time to walk us through the data for evERA, lidERA, and persevERA. Thank you, and I want to just bring it back to the Roche breast cancer portfolio, and I shared with you how we walk through the different signaling nodes and how we're looking at various pathways within the breast cancer disease area. One of the unique opportunities that we have is around combination therapies within our portfolio. We're very fortunate to have an endocrine therapy backbone because what this does is it enables us to look at innovative combination, both within our portfolio as well as combinations with partner agent outside of our portfolio. You'll see more of that coming in the future as well. With that, Bruno, back to you.
Very good. Yeah. I think we even have a few more minutes for Q&A. We have a first question I will read aloud because I think this is a question which will anyway come, and then we'll take questions from the room. This comes from James Quigley from Goldman Sachs. He's asking, in lidERA, how does the risk classification map to your epidemiology slides? He was basically asking, this classification we have seen with the intermediate patient segment, how does this match our results and our data, and what are future development plans for this segment? Also, I think we have to maybe define the definition of this intermediate patient segment.
Should I start?
Pablo, you want to start?
Pablo,
Yeah, I can start. If I stand correctly.
Maybe we can show the slide again.
Yeah.
Just go back to the slide where we have the-.
The design.
This is not-
I can start talking while we look at the slide. lidERA included patients with Stage 1 to Stage 3. The way we think about this medium or intermediate risk, there were patients with Stage 1 with certain features, biological or clinical features that were allowed in lidERA, were not allowed in the CDKI studies that were enrolled in lidERA. That's one key difference between lidERA and the other studies. There was also part of the question, if we plan to go further and expand. I kind of shared before we're starting two studies, phase IIIb studies, including patients who are lower risk of disease. We're looking forward to explore more giredestrant in the low-risk patient population as well. However, we know these patients do very well.
Some patients do not tolerate the current treatment options, and we believe giredestrant is well-positioned to serve these patients, although we have to investigate in further clinical trials.
Yeah.
Okay.
Maybe just to address the medium and high risk, we recognize that evidence generation is really needed in combination with CDKIs and really also in other patient segments. There's the HER2-positive segment and the PIK3CA mutant population. We are definitely working to bring forth other phase III studies in the early breast cancer setting.
Okay. We maybe Richard, your question, please.
Thank you very much. Maybe two questions, please. First question, just on persevERA. We obviously heard the level of ESR1 was low at the beginning of the trial, I think less than 5%. Did you test how that changed over time through the trial? We saw other trials at ASCO today showing the development of wider ctDNA and ESR1s over time. Did you monitor that, and how did that change across the trial? The second question, just back to KRASs. We obviously saw the data at the KRAS G12C. Just wanted to get your thoughts on pan-RAS inhibitors, what you have in development, what's your thoughts on pan-RAS inhibition and the promise or potential there. Thanks very much.
Maybe we start with Pablo.
The answer to the first question is yes. Unfortunately, we don't have the data yet. We have ctDNA at baseline. We have also ctDNA during treatment, and we have ctDNA at progression, and that we're going to be analyzing. Hopefully soon, we're going to be able to explore. Also, it's going to help us to understand some of the questions that we also have to better understand the results of persevERA. Hopefully, the data is going to be very helpful.
On the pan-RAS or the RAS opportunity, if I can address you from there, and I'll invite my colleague, Corey, to supplement as well. Thinking about overall, I think it's super exciting right now that we're seeing activity for PDAC with pan-RAS. We also have an opportunity in pan-RAS and also pan-KRAS in our pipeline. The key for me, if I think about it, is the combinability, right? What we've shown in PDAC, does that also translate to non-small cell lung and in colorectal in addition? The uniqueness of our portfolio is the diverse portfolio that we have, both in various different mechanisms, be it with an on/off, where we're looking at switch, pocket, single allele inhibitors, or we're thinking about tricyclics.
The orthogonal combinations allowing us to really think about the tumor biology across each of these diseases, and how do we unlock, not only from an efficacy perspective, but tolerability and duration. When we're thinking about targeted therapies, RAS-mutated patients have not really had the same benefit comparing to other targeted therapies that we've seen in the past. We believe that there's a lot of opportunities to innovate, and in our portfolio whereby we're introducing some of the modalities right now, and more to come when we're thinking about the next level of innovations with different modalities, as you can see in some of the innovations that we have today. Corey, anything else to add?
No, I think you summed it up really well. I think it's been very specific, if you look at our portfolio, that we're not going to go on one exact mechanism. We think it's really important to really push that best-in-class, and that best-in-class is not going to come from necessarily one modality or one platform. Just to reemphasize, combination therapy is really going to be the way that we're going to actually unlock further and further patients benefit, and that's not going to be able to tell you that it's going to be one or the other. It really has to be really developed altogether.
Richard, all questions answered?
Yeah.
Let's go on there. Mm-hmm.
Thank you. James Gordon from Barclays, thanks for taking the questions. Both into your giredestrant. One was on adjuvant. There was some mixed feedback on using a SERD already in adjuvant. On the Friday session, the discussant was saying like, where or when should you use a SERD, and maybe do we need longer follow-up data, or should you only use it after you've done a CDK because they're more established? Assuming you do get the approval in November, how will you change that perception or address that question? Do you think it could be a bit of a subdued launch because people need to change their mind about where this would be used? Or was that discussion a bit unusual? I spoke to one other KOL who also seemed a bit more cautious about initially going fast to start with.
That was the first question, please. The second question was just learning from persevERA. Quite a big difference between what lidERA showed and what persevERA showed. It sounds like it's not just about ESR1 and non-ESR1, there's something else to it as well. I think I heard a comment about you being excited about pionERA next year, but I think we're very excited, whereas I think a lot of people aren't that excited. Why should we be excited? It seems on the face of it like the ESR1 patients will do well in pionERA, but why will the other people do well when we've got quite different results between different studies?
Maybe I can start.
We'll start with the first one.
Then you can go with pionERA. In terms of when to use giredestrant. It's been shown to be very efficacious to the lidERA study, you'd want to use it upfront. Then there's going to be patients that will go on to receive other things. One of the things that we've seen with the lidERA study is if you look at the overall survival, it's immature right now, if you look at ours and where our results were compared to monarchE and NATALEE around the same time point, it's similar to the CDK4/6 inhibitor. We feel very confident in the ability to have a sustained response with giredestrant monotherapy right from the start. We recognize that, yeah, there will be some patients that might need something more or might need a combination.
It's a minority of the patients, but that's why we're doing additional studies.
Maybe just to add, Aakanksha already showed in the slide that adoption of the CDK4/6 inhibitors in the adjuvant setting, particularly in the medium risk, but also in the high risk, has been low.
Yeah. Do you want to talk about pionERA?
Yeah. Your second question. A couple of things on differences between pionERA and persevERA, first starting with persevERA itself. In persevERA, we see a signal, although, as it was discussed, the study did not meet significance. We see a numerical improvement in median PFS. The pionERA patient population is different. In a way, we're enriching for ESR1, that's one element. The other thing is these patients are recurring or relapsing on an aromatase inhibitor or shortly after an aromatase inhibitor, that would make that patient population potentially more susceptible to benefit of a SERD. Those patients, even if they don't have a detectable ESR1 mutation at baseline, those patients might be the ones that ESR1 becomes a clear mechanism of resistance shortly after. Results still to be seen. We expect that in 2027, we're tracking events.
The other key difference between pionERA and persevERA, which is not specific to your question, but pionERA combines with all CDKIs. In persevERA, we had only palbociclib, and in pionERA, we have palbociclib, ribociclib, and abemaciclib. Is that addressing your question?
Sorry. I think it addresses it, but I think there's still some people who aren't totally clear, what is it beyond ESR1 that makes someone susceptible or not susceptible to a therapy like this? What else would be in pionERA? It's the disparity between the studies.
Yeah. In the discussion today, there was some features about sort of the complexity of the tumor biology. There were other things that were mentioned, TP53s, when we think about endocrine sensitivity, ESR1 is a good surrogate, especially particularly as a surrogate of lack of efficacy for an AI. When we think about endocrine sensitivity, it's broader than that. I think that's the piece that's still to be investigated in the study. The fact that we are selecting patients who are not doing well and relapsing on an AI, that potentially makes that patient population more sensitive to a SERD, especially a better SERD. We know, and this we know already from the late line studies, that giredestrant or any of the other SERDs are significantly better compared to fulvestrant.
Okay.
Mm-hmm. Steve?
Thank you. Steve Scala from TD Cowen. I have three questions. First, on the persevERA slide of PFS by key subgroups, Western Europe looked like an outlier, and I'm wondering if there are any theories as to why. Secondly, given the fact that Roche has more perspective on the data itself as well as the underpinnings of the design of the trial, just to bring it back to basics, this is on persevERA, just to bring it back to basics, does Roche feel if the trial were merely larger, it would've been successful? Was it an issue of solely study size, or were there other things that were assumed? Lastly, since it was mentioned, I think twice, that hematology oncology is Roche's largest therapeutic category, Bruno, this is a question for you. In five and 10 years, do Roche forecasts assume that that's still the case? Thank you.
Do you want to start?
Sure. I take this one first.
Yeah.
Currently, I think there's a different dynamic with solid tumors, I would say projected, but you never know what happens down the road. I think definitely with the giredestrant win, I think we are set up for a big growth driver. I mentioned [Skylo] is a big one, but I would need a bit more then to be added on top.
Well.
Do the power one too.
The question really embedded the fact that you have other promising categories as well, but they will not rise up.
Yeah. There will be no shrinkage of hematology. I think both the segments are set up for growth. The question is which grows faster.
Totally agree. There's so much more room for us when we're thinking about the anchors that we have across the different diseases. I'm confident that we'll be able to continue this acceleration in terms of growth, thinking about where we're really investing in the anchors and the diseases, and where we continue to also replace those anchors as well. More to come.
To answer the question on Western Europe first. This is not an uncommon observation in some studies where you see a group that suddenly goes a bit to the right. The confidence interval crosses the one. We look very high level at the moment. We didn't see any obvious imbalance, and there's no obvious explanation, but sometimes it could be just a chance finding. There's no plausible explanation that we could find, and we believe generally inconsistent. Your question on the power, the study had an 89% power for the target hazard ratio, and our minimal detectable difference was 0.85x, and we typically power our studies for what we believe is a clinically meaningful difference. Would a much larger study turn the study positive potentially? We believe it had to be a significant sample size increase.
It starts getting into, is that a meaningful benefit for patients?
Should we continue over there? I think there were more hands. Nope. Additional questions? Richard, please.
Yeah, maybe one just on persevERA. Just to drill down on the EU subgroup and the Asian and North American subgroups. Was there any difference in tamoxifen use or the time from patient randomization to the last time they relapsed or anything like that, or visceral disease, just drilling down into those subgroups from what we can see in the others that might have affected those results. Maybe, just on the CDK4 too, you compared on the slide against abema and palbo, but not ribo, so just on the CDK4 potency or whatever. Just maybe you could just give us an idea how you see the performance versus ribo, because I think that is seen as the most potent of the CDK4/6s. Thanks.
I'll start with the first. I would say it's too early to answer the question. We kind of high level look at that. We haven't spotted any particular difference. What I must caveat is when we start looking into some of those things, the subgroup starts getting very small, so how much we can conclude of anything we find, but that is something we're definitely going to be looking at.
Maybe just to comment on the ribociclib. I don't think that it has any two as well. The exact numbers, maybe we could get back to you about that. In terms of potency, I don't think that ribociclib is really thought to be much more potent than abemaciclib. Abemaciclib actually was thought to have more heterogeneity in terms of what it could offer.
Yep. James, please.
Thank you. Just one more question, which was, so we need to see what pionERA shows, but depending what pionERA shows, might you try and do a new version of persevERA with some learnings from it, or are you sort of saying like that segment's just not going to be a SERD segment? Is it that that's pending and you're going to try and come up with a plan to address that segment as well?
I would say yes. I think that we have a lot of biospecimens that we hope to analyze from lidERA and persevERA. I think that there's a lot that we can learn from those trials, and we will absolutely leverage those learnings to better understand, is there a subpopulation in the first-line setting, either upfront or as a switch strategy, that might benefit?
Thank you. Let me take two questions from the emails coming in. One is from Graham Parry from Citi. He's asking on giredestrant. Firstly, in persevERA, thoughts on why did the de novo patients look worse than priorly treated patients, so the greater than 12 TFI patients. Wouldn't de novo be more endocrine sensitive? This is the first question. The second is on new adjuvant trials, switch trials. That's a big topic. Do you think needed for registration or could you get a switch label on the lidERA trial alone? I think there's a couple of further questions hidden here as well. First on all, maybe comments on how we design our additional studies, how switching exactly is designed there in the adjuvant setting, maybe switching differences, adjuvant versus first line. I think there's a couple of topics here. Yeah.
Okay. I'll try. The question on, I guess it's referring to the de novo versus the patients who are pretreated, treatment-free interval, more than less than 12 months. What we saw, again, with all the caveats that these are not pre-specified subgroups, we saw that the benefit trended more in the de novo patients and in the patients who had a treatment-free interval more than 12 months versus the patients who had a treatment-free interval of less than 12 months. There's several ways to think about this, although hopefully the biomarker data is going to help us to understand the endocrine sensitivity. The patients who had a shorter treatment-free interval, those were tamoxifen-only patients.
These were allowed very early in the study, and then with an amendment we limit this inclusion criteria, so these patients were not exposed to an AI, and these patients went to an AI, and they did very well on an AI. That's one of the hypotheses we know from persevERA, we know previously that AIs work very well, and particularly in patients who were not pre-exposed to an AI. The de novo might not be exposed to an AI, and these patients trended in favor of giredestrant with the caveats that I mentioned. These patients might have had a longer time to develop an ESR1, and then these patients could start to see a trend in favor of giredestrant. With all the caveats that these are the hypotheses. With these subgroups, it's harder to be very precise and very conclusive on any of these findings.
I hope this addresses. It's a breathing question. Then there was another question on lidERA.
Switch. That's basically about what do we want to do about what we think is needed for switching in the adjuvant setting, also having a look at our new studies to be initiated.
I can start.
Maybe start with the phase IIIb.
Yeah. I think there was also the question whether the lidERA data already, what you would expect then in the label, whether this would basically allow for switching.
The phase IIIb trials that we discussed will look actually at patients who are intolerant and also post CDK4/6. We really can't say much more about the label in terms of the switch strategy. What I can say is I think giving your best drug up front is important, and we will really focus our next wave of trials on really upfront use of giredestrant, and as we mentioned, potentially in various combinations. In some ways, that really answers the question. In terms of the label and switch, it's really something that we can't comment on. The phase IIIb studies will look at switch, but they are phase IIIb trials.
Again, really our main focus is going to be developing upfront use of giredestrant, putting our best foot forward, and looking at it in combination with CDK4/6 inhibitors and other things, and really other important subsets of breast cancer patients. We mentioned already the HER2 positive and the PIK3CA mutant. I don't know, Bruno, if you want me to take that a little bit further.
Yes, maybe I think this would be worthwhile. I think also we had the comments today from the discussant on switching studies in first line. What do you think in terms needed of the monitoring, the trial design? I don't know whether we can share already more details on the studies and the cohorts and how this would be then done in detail.
Do you feel comfortable you want to talk about?
Yeah
3B trials.
Sure
early breast cancer setting? I can talk about.
Yeah
the switching in metastatic disease.
Yeah. When we think about the adjuvant setting, as I kind of said before, this is a very large patient population, but also a very diverse one in terms of what they need and how we can better serve this patient population. A dogma in clinical oncology is to treat with your best therapy up front, and that's lidERA. As Maura mentioned, we're also looking to combine and see other options further. lidERA is very well-positioning us to be a potential partner for combinations as we start upfront. There's also patients who are already on endocrine therapy, and they've been on endocrine therapies for many years. If we think about their potential needs, they could not be feeling well on their current therapy.
These are the studies who are trying to address, if we switch them to a SERD, in this case, giredestrant, are they going to be feeling better? That specifically is the novERA study. As I mentioned before, on the upfront studies, or the cohort that include low-risk patients, is also trying to start to get a sense in the patients who currently are better served, the lower risk patient, they still have the unmet need of not tolerating the current therapy. We are starting with these phase IIIb efforts, but we're also thinking how can we additionally serve this patient population who we believe has an unmet need.
Maybe a comment on switching in later lines?
Yeah. Absolutely.
In metastatic setting.
The discussion raised some interesting points today. Do you give SERDs upfront, or do you sequence them or give them sequentially? ctDNA-guided studies really are probably our future in how we will potentially shape our landscape. I think that those trials need to be designed to answer a specific question, and I think that's something that the FDA has clearly pointed out. I do think that ctDNA-guided trials, both in the early breast cancer setting and in metastatic disease, will be important and something that we would like to unlock, and it's really all about the design.
Okay. Maybe one question here, which comes in from Emmanuel Papadakis from Deutsche Bank, and I think it just goes here in this direction. The question is, how precisely do you expect the FDA labeling and NCCN guidelines to reflect the enrolled study population, which was covered by lidERA?
We can't really comment on that right now.
Don't really comment. That's the answer. Okay. We go on, and I have a question from Luisa Hector Berenberg. She's asking, and maybe this also goes to our KL here, where do you think CDK4/6 belongs in the treatment paradigm, and how are you thinking about CDK4/2, adjuvant or metastatic? Yeah. Who wants to start?
Should we start by Aditya Bardia?
Yeah. Aditya Bardia.
Yeah, I think I can take this. In terms of CDK4/6 inhibitors, at this time, they will continue to remain in the first-line setting, endocrine therapy plus the CDK4/6 inhibitor. After persevERA, I think that'll remain. We will use CDK4/6 inhibitor in the first-line setting. Role of CDK4/2, as was mentioned previously, CDK2 inhibitors potentially could have a role in CDK4/6 resistance. In the second-line plus setting, CDK4/2 at the start, potentially will have a role, and we'll see the results of the [MORPHEUS] study, which is looking at that question. Eventually, maybe that'll move to earlier lines. In early breast cancer, I think that's where the role of CDK4/6 inhibitor is controversial.
The reason being that as we have superior endocrine therapy and better endocrine agents, and the tumor is dependent on the ER pathway, we could potentially reduce the use of CDK4/6 inhibitor, especially for patients who have medium risk disease, where there was already a hesitation in terms of use of CDK4/6 inhibitor. If you have a drug like giredestrant that showed superior activity with a very impressive hazard ratio, I think the use of CDK4/6 inhibitor in the adjuvant setting will decrease.
Maybe also this question to the team, I think as we are now getting closer to launch preparation. We have a PDUFA date set in November. How would you expect the initial uptakes, or what would be the patient populations where we would immediately make inroads? What is your latest thinking?
You want to start? Yeah. I don't think there's any question around. You can see here on this slide, you landed on the right slide, really. If you look at the gray bars in the intermediate, medium, high risk, those are areas where, without question, I think there's an opportunity to use giredestrant upfront right from the start. It is a very efficacious treatment. As we've heard, it's better to go in with your most efficacious treatment to try to delay progression than going on to other treatments where you might experience more toxicity or tolerability issues.
Yeah. Just to add, we still believe there's a role in combinations, and that is something we're going to continue to explore.
Yeah. Great.
As we think about the field evolving, we don't believe this question is fully addressed. With more studies, we might better understand what are the patients who might better benefit from a combination therapy, which may go also beyond CDK4/6 inhibitors. Who are the patients who are better suited for monotherapy.
If I understand you right, perhaps you talk also about PI3 kinase?
Correct
in an earlier setting, adjuvant setting.
That's something we are exploring. We have a neoadjuvant study. That is an area of interest, too.
Right. It's important to note that Itovebi can be given in combinations, so with the various CDK4/6 inhibitors. We have really developed a pipeline of drugs that can be given in combination and that are tolerable, and I think really unlocking, hitting the three important signaling pathways in hormone receptor-positive breast cancer.
Thank you. When we looked at persevERA, there was a 0.94 hazard ratio on visceral and 0.8 on non-visceral, biologically, why would there be the difference? Why does whether you got a visceral affect whether it works for you so well?
Yeah. I think the discussion put it better than what I going to say now. There was a specific slide, and this is something we've seen in prior trials. Bear with me, this is potentially a hypothesis, we don't have a concrete answer or we cannot fully address it. The patients with non-visceral disease tend to have a longer time on treatment, a longer PFS. The ability to develop an ESR1 mutation, it's higher compared to the patients with visceral disease that typically progress faster. Specifically, this was addressed during the discussion, which resonate on how we think about those potential findings.
Any other questions here in the room?
Hi, this is Ming Yu from Atlas Capital. I wanted to ask a question around the KRAS. There is a back-to-back presentation at ASCO this year, talking about quite some interesting data from monotherapy in KRAS G12C, I think molecule is elacestrant, then they also showed some data in first line combination in non-small cell lung cancer with pembrolizumab. I remember a discussion also talked about basically the question around whether to combo or not to combo given that there is basically marginal difference in terms of benefits in the combination of the KRAS G12C with pembrolizumab versus just the monotherapy in the first line, non-small cell lung cancer setting. In actually in the combo setting, you have a lot more side effects.
Basically the question would go around when and how you wanted to think about whether you use the combination versus not in combination. You mentioned a lot in terms of combinations, one of the key strategies with Roche, and just wondering how you look at their data versus divarasib, and how you think about the evolution of landscape.
I can start first, Corey, if you want. Certainly if you look at our data for divarasib, what I can say is that it's quite consistent. Right? The correlation from preclinical to clinical and monotherapy, and then now monotherapy and two combinations as a chemo-free option in front line, to me, that is exciting for front line non-small cell lung cancer. Having the ability to actually see the consistency in response rate and also in tolerability and discontinuation rate, to me, gives us that confidence that this can be the best-in-class opportunity for lung cancer patients with G12C mutations. The question is, what about others? How do you see in terms of their data versus ours?
I would think about maturity and consistency as we're thinking about the toxicity profile, the ability to actually combine, and seeing it across PD-L1 positive patients, negative patients, as well as the subgroup. I feel like we do have the leg up in terms of what the data have shown consistently across that sets us apart, and I look forward to sharing more from whether it's K2, or actually K1 first, coming up at the end of this year, more importantly than K2, where we believe that there's strong opportunity for us to have a better impact for patients in frontline. Maybe I'll add, Corey, anything else to add?
No, I really like that question because I think it's a really important question. It really is an unknown. Being able to answer it is going to be really critical as we go forward because we really want to focus on patients, right, and getting that right benefit risk profile, as well as making sure that we're pushing therapy to the right patients. I think what we've shown is we are just as efficacious in combination with pembro in PD-L1 negatives versus PD-L1 positives. That's across the board. I think that gives us really a little bit of excitement. In K170, we're exploring monotherapy. Right now, that's part of a contribution of components, which we want to make sure that we understand.
This is a question that we'll continue to answer, and as Wendy said, we are leading in this area, and we actually understand that this is a very important thing to do to this.
Maybe here two additional divarasib questions coming in from Graham Parry from Citi. The first question, does Roche CHF 1 billion-CHF 2 billion peak sales guidance only encompass second line and first line, so metastatic, or is also adjuvant included? I think the answer is that the up to CHF 2 billion, which we had announced before, is the metastatic setting primarily.
Correct.
Or is the metastatic not more. The second question is on the timeline we have shown on a slide, which I've pulled up here, that KRASCENDO- 1, the phase III and second line non-small cell lung cancer, where we really benchmark versus sotorasib and adagrasib, whether this is really reading out this year, and yes, that's the latest here. We expect data towards year-end for this study, which will, I think, be quite informative.
Maybe if I can make another comment, it's if you think about where sotorasib and adagrasib is right now, the evolution in sales and performance have been relatively stable, right? There's still a lot of room for patients that are from thinking about tolerability, duration of treatment, and the ability to actually get into frontline. I do think that the forecast that we currently are guided to is conservative. I do believe that we have a lot of opportunity there, especially in frontline as a first chemo-free treatment, thinking about the durability of actions that we can have, as seen as with the consistency of the data that we've shown. Not to mention in terms of the opportunity to unlock in the adjuvant setting.
I think we have to close now. Maybe one final question, then we have to close because we have to rush to the airport. Please.
Thank you. Thank you for squeezing me in. Wanted to ask one more on the phase IIIb studies that are planned for giredestrant in the adjuvant setting. Just wanted to confirm, are any of them planning to incorporate CDK4/6 as a combo partner or are they all monotherapy?
They're looking at monotherapy. We do have other trials that are ongoing that do incorporate CDK4/6 as a combo partner. We have a sub-study from lidERA. It is an abemaciclib combination, that's 100 patients, that's expected to read out towards the end of this year. We're also initiating one in combination with ribociclib, that'll be 300 patients.
I think as I mentioned, these are the first two of more studies to be initiated.
Yeah, stay tuned. There is probably more phase IIIs here to be initiated.
Yeah
This year, I would say for sure. Very good. I think with that, we are at the end of the event. Let me quickly close it and thank again our speakers for all their investments here and time and their efforts in exploring new treatments, options to serve patients. I also would like to thank the members of the IR team who have been preparing today's event, so to call out Rafal Pawlowski, Loren Kalm, and Alex Mora, and also Melanie Wolff for event organization. I hope the event was helpful. If there are questions, please reach out to the IR team anytime. We'll assist you, come back to you. With that, I think we close today's event, and wishing you a good evening. Bye-bye.
Thank you.
Thank you.
Thank you.