Welcome to our third IR call in 2024 here out of Chicago, focusing on our late-stage oncology pipeline. Could I have the first agenda slide, please? Next one, please. One more. Yeah, here we go. So let me quickly guide you through today's agenda. The event is scheduled for one hour. We will have 40 minutes for the presentation, followed by 20 minutes for Q&A. We have today with us Charles Fuchs, our Senior Vice President, Global Head of Oncology and Hematology Product Development, and Charles will provide us updates on our late-stage oncology pipelines, covering solid tumors as well as malignant hematology. Could I have the next slide, please? This slide, I think, most of you have seen already before.
It's what we define as our young on-market portfolio, which accounts currently for 55% of pharma revenues, and which is growing rapidly right now and is expected by itself to drive growth in coming years, at least until 2027. Of course, we are eager to keep our historic track record here as well of launching two-three drugs annually, which would come then on top. You can also see here that we have two drug launches scheduled already for 2024. There's crovalimab in PNH and inavolisib in hormone receptor-positive breast cancer. Charles will touch on in his presentation on a few drugs shown here, especially on inavolisib, our best-in-class PI3K inhibitor, which just got a breakthrough therapy designation by the FDA, and is undergoing an accelerated review and is expected to launch later this year.
In addition, we will touch on Lunsumio and Columvi, our CD20/CD3 bispecifics, which are developed in DLBCL and follicular lymphoma. Can I have the next slide, please? This slide summarizes our current growth drivers in oncology, which are on the market, and let me make a few remarks summarizing our current expectations. So on the solid tumor side, to start with Tecentriq, you have seen the latest Q1 numbers. We expect low single-digit growth for Tecentriq in 2024, with ex-U.S. growth compensating for the US decline, which we have recently seen. Peak sales, as you know, have come down now below CHF 5 billion, which is reasonable considering the remaining growth opportunities, such as, for example, Tecentriq subcutaneous or the opportunities outside the U.S.. However, if tiragolumab would play out, there would of course be immediate upside to the current expectations.
The second molecule shown here, Phesgo, I think is going very well. I will comment on this molecule on the following slide. Then Alecensa, I think, got launched in the U.S. in the adjuvant setting, has a positive CHMP opinion in Europe, is also set for additional growth, for more than CHF 0.5 billion in incremental sales. Then if we go down and have a look on the hematology side, to start with, Polivy has a very strong launch at first-line DLBCL. It's getting really established as the new standard of care in markets all around the world. We can confirm previous peak sales assumptions here for up to CHF 2 billion in this first-line indication, and Charles will tell you more about further development plans, now really building on Polivy in first-line DLBCL.
Columvi and Lunsumio, strong launches in third line plus DLBCL and third line plus follicular lymphoma. However, sales-wise, only a couple of hundred million CHF in later lines as the overall opportunity just is very small. It will be key to move these assets now into novel and unique combinations into earlier lines. The second line, for example, would be an opportunity of already up to CHF 2 billion, and a first line would of course be something significantly more. Let me please go to the next slide. So this is a slide I've felt might be helpful to quickly comment on our HER2 franchise and the outlook, and since this franchise is not really covered separately in the deck, and I know there are many questions.
On the left side, you see the current treatment landscape with the current standard of care, which will change in the future due to a variety of factors. There's competitor data and also the first Perjeta biosimilars in 2026, which could lead to a situation that the franchise will peak in 2026 before slowly declining over time in a more linear fashion. But clearly, we do not expect that there will be any cliff situations for a couple of reasons. There are, of course, still many unknowns, especially how competitor data will play out, and safety will be of relevance here. But it is also clear that there are patient segments in the early breast cancer setting, especially in the adjuvant setting, where Phesgo or Perjeta plus Herceptin will remain the standard of care.
For Phesgo, we see a really strong uptake everywhere, even in the hard-to-convert markets like, for example, the United States, where we now are close to a 25% conversion rate. We expect this momentum to continue, and by 2026, when first Perjeta biosimilars are expected, we expect to have converted more than 50% of our Perjeta sales. What is also noticeable is that Perjeta seems to drive further adoption in major markets, allowing for more women and men to become treated, which clearly shows the value proposition Phesgo brings, and also that there have been resource constraints all around. All this, we believe, bodes well for Phesgo remaining an important part in future treatment landscapes. As you can also see here on the bottom, we...
in the right, lower corner, we keep building on Phesgo in combination development with giredestrant or inavolisib. And let me quickly comment also on Kadcyla. We expect low single-digit growth in the next, two to three years due to ongoing geographic expansion. In the second-line setting, Kadcyla will keep a share of around 20%, and currently, we expect no biosimilars to enter the Western markets after the loss of exclusivity Then we also call out here that we keep investing in the metastatic setting with combination development, especially building opportunities around our brain-penetrant HER2 tyrosine kinase inhibitor. Next slide, please. I will remain short on this slide. So, for a 2024/2025 news flow perspective, today's event just will focus on late-stage oncology, what is here boxed in red.
The hematology assets are not listed here on this slide, as we have just focused on the NME opportunities. Previous IR events in 2024 had focused already on prasinezumab in Parkinson's disease and trontinemab in Alzheimer's disease. This was the IR call back in March, and two weeks ago, we just held a diagnostics day in London, covering the key news flow items on the right side. With that, let me go to my final slide. The next slide, please. With regards to upcoming IR events, so let me just give you here an update. For Sunday, June 16, we plan now to cover the hematology franchise more in depth, especially focusing on the phase III STARGLO results in second-line DLBCL, which will be presented at EHA.
Also a bit, we will provide you an update on the non-malignant hematology portfolio, and that's up front of ISTH. On July 23rd, we have an IR call covering then the ophthalmology franchise in more detail, covering also the latest follow-up data for Vabysmo, which will be presented at ASRS. And for the end of September, we will have our traditional Pharma Day in London. So this is the latest in terms of the event planning. There will be, of course, additional events in 2024 as data will get presented at medical conferences, and we will keep you posted. And with that, let me hand over to Charles for the late-stage oncology update, and Charles, please.
Thank you, Bruno, for the opportunity to share some key highlights of our oncology and hematology portfolio in advance of this week's ASCO meeting, if I can have the next slide. Roche and Genentech have a rich legacy in transforming the therapeutic landscape in oncology and hematology. We're leveraging a broad portfolio of molecules to advance best-in-class precision medicine, such as inavolisib and divarasib. We're focusing on accelerating novel therapies in early curative settings, such as the recent FDA approval of Alecensa in ALK-positive lung cancer and our ongoing work of giredestrant in HR-positive early breast cancer. We're developing next-generation immunotherapies, including tiragolumab in non-small cell lung cancer, and our next generation off-the-shelf allogeneic CAR T therapy in collaboration with Poseida Therapeutics.
We're committed to rational and high-impact combination regimens, including the addition of Columvi, our CD20/CD3 bispecific, to the newly established Pola-R-CHP regimen in DLBCL, and the combination of giredestrant and Phesgo in HER2-positive, HR-positive breast cancer. Next slide. Building on the deep science at Roche, we're advancing a broad set of innovative modalities across both solid tumors and hematologic malignancies, including new technologies with high potential to bring meaningful patient benefits such as cyclic peptides, protein glue degraders, cancer vaccines, next-generation costimulatory molecules and cytokines, and allogeneic CAR T therapies. Next slide. At Roche, we're privileged to develop one of the broadest and richest portfolios in oncology, leveraging a range of innovative mechanisms of action and technologies, including the ones that I just mentioned. Turning to the next slide, that impressive array of molecules. Thank you.
is equally true in hematology, spanning both malignant hematology and other blood disorders, which includes novel therapies for malignant indications, next-generation approaches for hemophilia, as well as other areas of unmet need. I won't be able to cover all of these agents in our oncology and hematology portfolio, but I'd like to highlight a few of our programs as key examples. For those programs I'm not able to address, Bruno and I look forward to answering any of your questions during the Q&A session. Turning to the next slide. As I mentioned, we have a rich history of launching targeted therapy for breast cancer, transforming the lives of patients with HER2-positive disease. In that vein, we are now equally committed to developing next-generation treatments for hormone receptor-positive breast cancer, the largest segment of breast cancer, representing 70% of all breast cancer worldwide.
While there have been important advances in the treatment of HR-positive disease, it really remains a high unmet need for new treatment options that improve both efficacy and tolerability. Novel treatments like giredestrant, are a selective estrogen receptor degrader, and inavolisib, our PI3K inhibitor, aim to address these critical unmet needs and improve the lives of patients. Endocrine therapy, on the next slide, remains the backbone of treatment for HR-positive, HER2-negative disease across both early and metastatic disease until resistance develops. Despite multiple available endocrine therapies, there are, as I mentioned, limitations with each, giving giredestrant potential to replace standard of care endocrine therapies across both adjuvant and metastatic settings. CDK4/6 inhibitor combinations are standard of care now in first-line metastatic disease and are emerging in the high-risk adjuvant setting with recent positive data.
As the CDK4/6 inhibitor landscape evolves, it is critical for new agents to tolerably combine with all CDK4/6 inhibitors, which we have demonstrated with giredestrant. Finally, targeted agents to date have been limited to late-line settings, largely due to the lack of combinability with endocrine therapy and CDK4/6 inhibitors. With inavolisib, we can combine with endocrine therapy and CDK4/6 inhibitors at full dose, giving inavolisib the potential to expand into earlier lines and benefit the 40% of patients with PIK3CA mutations. Turning to next slide. As I just mentioned, current options which target estrogen signaling have significant limitations, which could be overcome by giredestrant. In the adjuvant setting, up to 50% of patients discontinue or are not adherent to endocrine therapy, which has impacted outcomes for patients. Additionally, up to one-third of patients with early breast cancer eventually progress to metastatic disease.
giredestrant, in contrast, is well-tolerated at all doses, with no dose-limiting toxicities. In the metastatic setting, we've seen resistance to aromatase inhibitors, including development of ESR1 mutations. As an orally available SERD, giredestrant has the highest potency in preclinical studies as compared to other SERDs, including fulvestrant and the other competitive oral SERDs in development. Moreover, in contrast to other SERDs in development, giredestrant is combinable at full dose with all CDK4/6 inhibitors, specifically palbociclib, abemaciclib, as well as ribociclib. Next slide. Two studies across the early and late-line settings demonstrate the potential for giredestrant to drive benefit to patients over current standard of care endocrine therapies. First, in our neoadjuvant window of opportunity study, the coopERA trial, on the left, giredestrant demonstrated greater suppression of Ki-67 than anastrozole.
Moreover, coopERA demonstrated superiority both in the monotherapy comparison of giredestrant and anastrozole, as well as in comparison with both molecules were combined with a CDK4/6 inhibitor. As you're familiar, Ki-67 is a validated biomarker of proliferation in early HR-positive breast cancer, and therapeutic suppression of Ki-67 has been correlated with improved long-term efficacy. For instance, in previous trials of endocrine therapy, Ki-67 results in the neoadjuvant setting have been predictive of benefit in subsequent adjuvant trials. As you're also aware, in the phase II acelERA trial, in the second and third-line plus HR-positive metastatic breast cancer, giredestrant did not show a statistically significant benefit versus fulvestrant or an aromatase inhibitor. Although we now recognize that following multiple lines of endocrine therapy, these tumors are not being driven by the endocrine receptor, but by other oncogenic pathways, and therefore are insensitive to any estrogen-directed therapy.
One notable exception are those late-line tumors with ESR1 mutations, which remain dependent on estrogen receptor signaling, and in the acelERA trial, we saw a hazard ratio of 0.61 for giredestrant in patients with ESR1 mutations. To further understand this, in the right panel of this slide, we assessed ER dependence in patient tumors across a range of clinical settings. Specifically, in late-line ESR1 wild-type tumors, we saw gene expression profiles consistent with ER independence. Whereas in late-line ESR1 mutant tumors, we saw patterns consistent with continued estrogen receptor dependence. Moreover, when we looked at early breast cancer and first-line metastatic breast cancer, we also see ER dependency that is comparable to those late-line ESR1 mutant tumors, which clearly benefited from giredestrant. These results strengthen our confidence that in both the adjuvant and the first-line settings, all patients, regardless of mutation status, could benefit from giredestrant.
Next slide. Our development plan for giredestrant aims to replace standard of care endocrine therapies across early breast cancer and metastatic disease as the next-generation, best-in-class endocrine backbone. We expect first results from the phase III persevERA trial in first-line endocrine-sensitive patients in 2025. As well, we've initiated an additional trial in first-line endocrine-resistant disease, which allows physician choice of CDK4/6 inhibitors. Additionally, we are leading SERD trials in early disease with a head-to-head lidERA trial comparing giredestrant to an aromatase inhibitor in the adjuvant setting. We're also evaluating the combination of giredestrant in a CDK4/6 inhibitor as a sub-study in lidERA. PIK3CA is one of the most frequently mutated oncogenes, including up to 40% of patients with HR-positive breast cancer and 30% of patients with HER2-positive breast cancer.
Current PI3K inhibitors have been limited to late-line settings due to issues of limited efficacy, poor tolerability, and poor combinability with CDK4/6 inhibitors. inavolisib is differentiated, as a highly potent and selective inhibitor of the PI3K alpha subunit, which offers far greater tolerability when compared to previous PI3K inhibitors. Moreover, with inavolisib, we have the ability to combine with endocrine therapy and a CDK4/6 inhibitor at standard doses. Next slide. This past December, we shared the results of the INAVO120 trial, which demonstrated a strong clinical benefit when inavolisib was added to fulvestrant and a CDK4/6 inhibitor in the first-line endocrine-resistant setting. Based on the strength of these data, we are conducting additional trials in PIK3CA-mutated breast cancer, including INAVO123 in the first-line endocrine-sensitive setting, INAVO122 in HER2-positive disease, and multiple other tumor types in signal-seeking studies.
Additionally, we'll explore further development in early PIK3CA mutant breast cancer settings. Next slide. We previously presented the INAVO120 data, which showed a 57% improvement in progression-free survival when inavolisib was added to fulvestrant and palbociclib. Moreover, although survival remains immature, we saw a strong trend in overall survival with a hazard ratio of 0.64. Tomorrow at ASCO, we'll report data from the trial looking at time to next treatment, which shows clinically meaningful, sustained benefit, with fewer patients going on to receive subsequent therapy when inavolisib was added to their standard therapy. The INAVO120 data has been submitted to EMA and FDA for approval, with the FDA granting breakthrough designation and priority re-review underlying the strong clinical benefit. Next slide. Turning to our anti-TIGIT antibody, tiragolumab.
Earlier this year in the journal Nature, our scientists further documented the mechanism of action for tiragolumab and its ability to overcome resistance to to currently available checkpoint inhibitors, thereby providing additional supportive rationale for the benefit of TIGIT blockade to improve cancer patient outcomes. As you're aware, we have a broad portfolio of studies across of indications, a range of indications, as shown in this slide. And you know, we're anticipating final overall survival results from the SKYSCRAPER-01 trial later this year, which should be the first phase I trial readout of overall survival in the anti-TIGIT space. Next slide. Turning now to our KRAS G12C inhibitor, divarasib. In preclinical studies, divarasib demonstrated superior potency and selectivity when compared to the two other G12C inhibitors currently on the market, suggesting a best-in-class potential for divarasib.
Subsequently, we've shown strong overall response rates and progression-free survival results in the second-line setting of non-small cell lung cancer, with ORRs for divarasib of 53%, compared to 30%-40% for other approved agents, and a median progression-free survival of more than 13 months for Divorasib, compared to 5-6 months for the other approved molecules. Next slide. Based on those results, we're accelerating development of divarasib in non-small cell lung cancer. Specifically, in light of the strong evidence of superiority in the second-line setting, we're conducting a head-to-head comparison of divarasib to investigator choice of sotorasib or adagrasib. And concurrently, we're aggressively advancing first-line combinations with divarasib, with a plan to initiate a pivotal trial next year. Next slide. I'd now like to turn to our key programs in hematology, focusing on our work in non-Hodgkin lymphoma.
NHL accounts for nearly half of all hematologic malignancies, with DLBCL the most common form of aggressive lymphoma, and follicular lymphoma representing the most common indolent form of non-Hodgkin lymphoma. While there remains a significant unmet need, with 60,000 people diagnosed with aggressive and 30,000 with indolent in the US and the EU5 countries alone each year, let me call out the advances that have been made, especially by Roche and Genentech. Namely, as you're familiar, Rituxan, our anti-CD20 antibody, which was the first antibody to be approved for lymphoma and CLL. Gazyva, our humanized CD20 monoclonal antibody, engineered to create greater ADCC and directed cell death compared to Rituxan, now in use for CLL and follicular lymphoma. Polivy, our first-in-class antibody-drug conjugate, targeting CD79B and now being utilized in diffuse large B-cell lymphoma. And finally, our two anti-CD20/CD3 T-cell bispecifics, Lunsumio and Columvi.
Currently in use in both follicular and large cell lymphoma. Next slide. We, as Bruno mentioned, we've seen strong launches of our CD20/CD3 bispecific antibodies, Lunsumio and Columvi, in late-line settings of follicular and diffuse large B-cell lymphoma, respectively. Both assets are fixed duration, off the shelf, showing high complete response rates with durable responses and manageable safety. And with both molecules, we're uniquely positioned to provide CD20/CD3 bispecific antibody solutions that are tailored to the patient, the disease, physician, and the healthcare system. Lunsumio does not require mandatory hospitalization, with the potential to a broader use in the outpatient setting and across a broad range of indications and treatment lines. Columvi has the potential to offer best-in-class, best-in-class efficacy comparable to CAR T for patients with aggressive disease such as diffuse large cell or mantle cell lymphoma.
Beyond addressing the important unmet need of third-line therapy, as Bruno mentioned, we're accelerating development into earlier lines of therapy. Next slide. Despite the improvements in first-line therapies, 30%-40% of diffuse large B-cell lymphoma patients progress after first line and need additional treatments. Only half of these second-line patients are eligible for stem cell transplant, and out of those that get transplanted, only half will have a durable remission. Although there is no outright clear standard of care, R-GEMOX is a standard therapy for transplant-ineligible, relapsed, refractory DLBCL, although the benefit of R-GEMOX, among other regimens, has been modest. Clearly, these transplant-ineligible patients need more efficacious second-line treatments that can be administered without delay. We have two studies investigating our bispecific antibodies in the second-line setting of large cell lymphoma, STARGLO and SUNMO.
The first, our phase III STARGLO trial, examines the combination of Columvi and GEMOX as compared to R-GEMOX. We recently announced that STARGLO met its primary endpoint of overall survival, making it the first positive phase III study of a bispecific in combination with chemotherapy. While I can't go into detail today, as Bruno mentioned, these results will be presented in two weeks at the EHA meeting in Madrid. Next slide. Tomorrow at ASCO, we'll be presenting the phase Ib/II results for the combination of Lunsumio and Polivy in relapse refractory DLBCL patients who are unable to tolerate chemotherapy. In this difficult-to-treat patient population, this chemotherapy-free combination demonstrates durable, objective, and complete responses that are superior to historic standards and provides strong rationale for the ongoing phase III SUNMO trial, which is assessing this chemotherapy-free regimen in second-line transplant-ineligible DLBCL patients. We look forward to SUNMO results next year.
Next slide. For more than 20 years, the R-CHOP regimen, developed by Roche and Genentech, transformed the landscape of the first-line therapy for DLBCL. More recently, the Polarix trial demonstrated a statistically significant and clinically meaningful improvement in progression-free survival for the Polivy R-CHOP or Polivy R-CHOP regimen when compared to R-CHOP, making Polivy R-CHOP a new standard of care in the first-line setting of DLBCL, now being incorporated into the national treatment guidelines across the globe. We also see rapid adoption of Polivy R-CHOP in the clinic, which is reflected in the market share in key countries. About a quarter of US patients are treated with Polivy R-CHOP in first line since its approval just a year ago, and almost half of Japanese DLBCL patients are currently treated with Polivy R-CHOP in first line.
Importantly, improving progression-free survival in the first-line setting gives patients the best chance for cure and to live out the remainder of their life free from DLBCL issues. Additionally, greater efficacy in first line translates into substantial cost savings for healthcare systems and patients, and most importantly, improves quality of life for patients. In fact, in one abstract at this week's ASCO meeting, the cost of treating a progressing DLBCL patient is approximately four-fold higher than for patients who do not progress. This skyrockets to eighteen-fold higher for patients treated with current CAR T therapies. Next slide. Despite the improvement in progression-free survival and chance for cure brought by Polivy R-CHOP, there remains a need to further improve first-line DLBCL therapies. We recently reported on the combination of Columvi with Pola-R-CHOP and demonstrated an unprecedented 100% objective response rate with a 93% complete response rate.
Of note, these results appeared superior to the combination of Columvi with the historic R-CHOP regimen. These results led to the ongoing phase III SKYGLO trial, where Columvi is being added to the Pola-R-CHOP regimen, which we believe has the potential to define yet a new standard of care in the curative setting of DLBCL. Of note, this is the only trial adding a CD20/CD3 bispecific to the Pola or CHOP regimen, whereas another effort is combining an alternative CD20/CD3 bispecific with R-CHOP, which our results suggest may be an inferior combination as well as an inferior control arm. Next slide. Beyond DLBCL, we're looking at Columvi in another aggressive lymphoma, namely mantle cell lymphoma. Patients with relapsed refractory mantle cell lymphoma have a poor prognosis, especially those who progress after a BTK inhibitor.
At this week's ASCO, we're reporting updated data for Columvi monotherapy in heavily pre-treated, relapsed refractory mantle cell lymphoma patients, about half of whom were BTK refractory. Fixed-dose duration glofitamab continues to generate high objective, complete, and responses that are maintained well beyond end of treatment, with long-term durability observed in heavily pre-treated patients with relapsed refractory mantle cell lymphoma, including those with prior BTK inhibitor therapy. At the same time, safety was quite manageable, with cytokine release syndrome principally at low grade. On this basis, last year, we launched the phase III GLO-BRIT trial, comparing Columvi monotherapy to one of two standard of care therapies in patients with a relapsed refractory mantle cell lymphoma. Turning to the next slide. Before closing, I want to briefly cover our other CD20 bispecific, Lunsumio, currently approved for the third-line treatment of more indolent follicular lymphoma.
In third-line+ heavily pretreated patients with relapsed/refractory follicular lymphoma, we previously reported a 60% complete response rate and a 78% objective response rate. Moreover, with this fixed-duration therapy, we're seeing very durable remissions, with a median duration of response of 36 months and a three-year overall survival of 82%. Of note, this OS rate is comparable to the overall survival seen with CAR T therapy in the same setting. Moreover, therapy was delivered in an outpatient setting with a very manageable CRS rate, which was almost entirely low grade. With over 50 countries approving Lunsumio in third line, we're seeing a strong uptake in key markets, despite the limited third-line population. To further improve the patient experience and ease of administration, we're completing work to bring subcutaneous Lunsumio to patients. Moreover, we're accelerating development of Lunsumio into earlier lines of therapy.
On the next slide, the phase III CELESTIAL trial in follicular lymphoma builds on powerful data from our phase Ib/II trial of Lunsumio and lenalidomide in the second-line follicular lymphoma setting, providing a highly efficacious chemotherapy-free approach for patients who relapse after first-line therapy. At the same time, we're partnering with the SAKK to examine the combination of Lunsumio and lenalidomide in the first-line setting of high tumor burden follicular lymphoma, based on promising data from our phase Ib/II trial on the combination of Lunsumio and lenalidomide in the first-line setting of high tumor burden patients. The phase III MORNING SUN study will enroll almost 800 patients to explore this very promising chemotherapy-free treatment in this previously untreated patient population. This concludes my presentation. I thank you for your attention, and I'll turn it back to Bruno.
Thanks a lot, Charles, and with that, we will open the Q&A session. Let me also invite here Stefan Frings, our Deputy Chief Medical Officer, who's also here, part of the Q&A session, to take questions. The first question would then go to Richard Vosser from J.P. Morgan. Richard, please.
Thanks, Bruno. A couple of quick questions from me on giredestrant. Just, excuse me, Charles, given the confidence you exhibited on the analysis of giredestrant, that you displayed, you're thinking it's gonna work in all patients with tumors that are estrogen receptor responsive. So why have you decided to start at just an ESR1 first-line trial as well earlier this year, and just your thoughts there? And second question, you highlighted the correlation of the neoadjuvant Ki-67 data with outcomes in adjuvant. So there was about a 70% benefit, so how much of a disease-free survival benefit would you expect from that sort of benefit that you saw in the Window of Opportunity trial? Thanks.
Of course. So, with regard to your first question, I think you're referring to the recently opened pioneERA study, which is technically an effort to look at endocrine-resistant patients, because, as you recall, persevERA is in first-line endocrine-sensitive. We wanted to complement that with a study in first-line endocrine-resistant. Now, admittedly, I think as you point out, we are including patients with ESR1 mutants, but that is not the primary intent. The other thing I think worth pointing out about pioneERA is that in contrast to other studies, it allows physician choice of any of the three CDK inhibitors, so that we'll have data with all three with giredestrant.
With regard to the coopERA study or Coop or Window of Opportunity study, obviously that was what was intended to be an efficient effort to compare giredestrant to an aromatase inhibitor in a window of opportunity where Ki-67 is, has been a pretty reliable proxy for ultimate benefit in the adjuvant setting. I think clearly we saw a significant benefit when the monotherapy comparisons of giredestrant to anastrozole, and we also saw a significant increase in suppression even when the molecules were combined with a CDK inhibitor. In terms of how does that compare precisely with the magnitude of what we look for in disease-free survival, I think it's. Yeah, I wouldn't, you know, I think it'd be hard to speculate.
But I think what you can say, if you look across the literature, is those studies that use Ki-67 in the neoadjuvant setting as a marker of treatment benefit, have translated into benefit in the postoperative adjuvant setting.
Perfect. Thank you very much.
Mm-hmm. Okay, and we move on. Next one would be Harry Gillis from Berenberg.
Hi, yes. Thank you very much for taking the questions. So just thinking about the sort of shape of the overall oncology pipeline, ADCs and radiopharmaceuticals have obviously been a sort of very active area of development. Could you just discuss why Roche doesn't appear to be focusing on these areas in the solid tumor pipeline, and why that might be? And then just secondly, based on the divarasib preclinical data and the clinical trial data available so far, how confident are you that you'll be able to demonstrate a significant head-to-head benefit versus the approved KRAS G12C inhibitors? And what's the rationale of in initiating the second line trial, rather than just moving directly to the first line? Thank you very much.
Yeah. That's a great question. You know, I'll, I'll start with your second one first, but I'll, I'll come to your first question. So with regard to our confidence in the head-to-head comparison, which, as you point out, is our second-line study, in which divarasib is being compared to investigator's choice of the alternative molecule, sotorasib or adagrasib. I think the preclinical data suggests that our molecule is far more potent than the other currently commercially available molecules. Additionally, you know, I think if you look at cross-trial comparison, you know, we're seeing significantly, substantially better objective response rates. But more importantly, 'cause really, I think the real measure is progression-free survival, we're looking at more than 13 months as compared to 5-6 months for the other the other studies in, in comparable settings.
So I think given that magnitude of difference, even with ideas of progression toward the mean, we're quite confident in that head-to-head comparison. Now, you ask, "Well, why, why are we pursuing that study, and not a first-line study?" The fact is, we are pursuing a first-line study. As I mentioned, we're actively looking at first-line combinations with divarasib. I'm not at liberty to disclose those data, but we are looking to launch a pivotal study. And let me just say, I think with both the first-line data, which we have increasing confidence in, as well as our head-to-head comparison, I think we then provide a body of evidence for investigators to say that this is truly the best-in-class molecule in the G12C realm, and it offers a real benefit beyond second in first-line settings. And that's really the rationale for our investments on our...
in our look. And I think with regard to your first question, and I'll welcome Stefan and Bruno adding, you know, with regard to ADCs and radioligands, you know, we've made investment in radioligands with PeptiDream, and it's an area that we continue to monitor. With ADCs, I think this organization led that field with Kadcyla and Polivy. It has been a rocky road. I think, you know, if you look at, let's say, 2010, 2012, there wasn't the enthusiasm for antibody drug conjugates that we see today. This is an area we continue to monitor. We, you know, we made a recent partnership with MediLink and with the c-MET ADC, and this is an area we continue to look at. But I defer to my colleagues if there's anything they wanted to add.
Yeah, I mean, the only thing I would add, yes, I can just confirm ADCs, they are an area of interest, and we have a wealth of, you know, previous data, which we generated with, I think, at the peak, we had 16 molecules in the preclinical development. And I think we have been carefully looking at these data now in light of new data available, and I think this is still an area where we are thinking and we'll explore, and we will have a look what we do. Mm-hmm. Okay. Harry, did this answer all your questions?
Yes, absolutely. Thank you.
Okay. Then we move on, and, next one would be Sachin Jain from Bank of America. Sachin?
Hi there. Thanks for taking my question. Sachin Jain, Bank of America. A few questions on the SERD again, please, given persevERA next year. So firstly, is there any way of enriching this study for ER-sensitive patients outside of ESR1 mutation, just given that you've talked about ER sensitivity within that slide? The second question is a similar one to the adjuvant study that was asked earlier. Any commentary on persevERA powering as to what benefit you're looking for over AI? I've got a specific reason for the question: Your study is about two-thirds of the size of the equivalent ASTRA study. So just trying to get a sense of why that may be, and is there any risk from you running a smaller study? And then the final question is just on differentiation.
Could you remind me which SERDs you believe are not combinable or which have dose-limiting tox? Thank you.
Yeah. So, let me, I'll run through your three questions. With regard to the, I'm trying to remember, your first question on persevERA was Enriching for.
Yes. So, you know, that study is first line endocrine sensitive. We're not enriching in persevERA for ESR1 mutation, specifically because the data that I showed, the transcriptome data, suggested that if you compare ER dependency of ESR1 mutant patients in later lines, we see comparable ER dependence in the first line setting, as well as the early breast cancer setting. So that study is not enriching for ESR1. You, you also may be aware that the pioneERA study, which we recently opened, that I just mentioned, which is in the endocrine resistant, is looking at ESR1 patients, mutant patients, but not exclusively. They're just being incorporated actively into that study. With regard to the power of persevERA, you know, I- it's not-- I'm not in a place to discuss the statistical analysis plan, but let me just say, this study is designed for success.
I mean, clearly, we believe that persevERA has the ability to read out as the first SERD in the first-line setting, and we believe in the best-in-class potential for the molecule. But I probably can't say more about our power other than it was designed to give us the absolute highest chance for probability of success, given what we know about the molecule. And then, you know, in terms of discussing the other SERDs and their ability to combine at full dose for CDK4/6, as I mentioned, we can. I don't want to necessarily comment on any specific other molecules, but I think if you look, you'll see for some of the other molecules, they have not been able to combine at full dose.
If I may just add on the powering, we typically just design for clinically meaningfulness. We don't want to overpower, that we are even with the minimally detectable difference to just have an almost undifferentiated, clinical, negligible difference to comparator.
That's a great point. Thank you, Stefan.
Sachin, did we answer all your questions?
Yeah. Thank you very much, Bruno.
Yeah. Then, next one would be Richard Parkes from Exane BNP Paribas. Richard?
Thanks, Bruno. Yeah, Richard Parkes from Exane BNP Paribas. So I've got two questions. First, first one's also on giredestrant. If you look at the GI tolerability of giredestrant, it's a little bit worse than probably your closest kind of competitor in the oral SERD class. So can you help us put that in context? I'm just wondering if that could be a competitive disadvantage if in the adjuvant setting where even low-grade GI toxicity could be a disadvantage. And then also on giredestrant, the first-line study is in combination with palbo, which is obviously no longer the highest level of standard of care. So what's your confidence you can get a broad label irrespective of CDK4/6 background at the time of launch?
Yes.
Then second question is just on divarasib. And just expanding on what you talked about earlier on, we've seen Merck move their KRAS inhibitor straight to first-line in combination with Keytruda. I'm just wondering how you think divarasib compares to that compound, and is there any risk that Merck could leapfrog you by being more aggressive in moving to first-line combinations? Thank you.
Of course. So with regard to the tolerability of giredestrant, I think, yeah, bottom line is we're not seeing dose-limiting toxicities for the molecule. In terms of GI tox, it's it has not been an issue in terms of issues in terms of dosing, in terms of dose interruptions, or for that matter, in terms of discontinuation. You know, so it hasn't really been an issue clinically, and in fact, compared to some of the side effects that patients experience on aromatase inhibitors, we're seeing the potential for a better quality of life. With regard to the toxicity profiles of the various SERDs, you may be aware, others have toxicities, most notably ocular, which I think is a genuine concern when you're talking about long-term therapy, a toxicity we do not see with giredestrant.
With regard to the design of persevERA and our use of palbociclib, I think it's worth pointing out that, you know, you can choose any of the three C, CDK4/6 inhibitors. Palbo still remains the most commonly used CDK4/6 inhibitor in the first-line metastatic setting. But we recognize that we want to give physicians and patients a choice, which is why pioneERA is looking at all three, that is dealer's choice, for the CDK4/6 inhibitors. With regard to your question about, the G12C molecules, you know, I think what we have disclosed is our preclinical and clinical data suggesting that divarasib is decidedly superior, in my, in my view, compared to the currently commercially available molecules.
We are in the process, and we're not ready to disclose it, an effort to study divarasib beyond the data I've shown you in second line, in the first-line setting, that I think will establish divarasib as a real standard of care in the first line, leveraging what we already know are accepted practices in the first-line setting of non-small cell lung cancer. So it's a competitive field. I think the data we're generating for the molecule is best in class, in second line, and what you'll see, hopefully soon in first line, I think, position us for success.
... Thank you.
Okay. And we move on. Next one would be, Steve Scala from Cowen.
Oh, thank you very much. A few questions. How confident are you that inavolisib will demonstrate statistically significant and clinically meaningful OS benefit in the INAVO120 trial? And how do you see it being sequenced with capivasertib? Second question is, how do you anticipate Phesgo being treated under IRA? Does the subQ delivery provide its own 13-year exclusivity, and does the high hyaluronidase technology provide any unique treatment under IRA? And then the final question, it seems that the focus on giredestrant during the presentation was much greater today than in the past, and I'm just curious, what has changed? Was it some finding relative to giredestrant, or do you sense a change in the landscape that you now believe this asset has greater potential?
Of course. So I'll tell you what, I'm gonna answer questions one, two, and four, and I'm gonna defer to my colleagues, Bruno and Stefan, to answer the Phesgo question. So, you know, with regard to the, the data for overall survival for inavolisib, you saw obviously what is, I think, clinically meaningful, in benefits for progression-free survival, which is the primary endpoint, and certainly led to, I think, what has been a, a, a good discussion with health authorities. With regard to the OS data, the data are immature. The hazard ratio is 0.64, but if you look, the upper 95% confidence limit is not one, it's 0.97. So I think it gives us confidence in that overall survival signal.
As well, the data that we're showing at ASCO tomorrow look at what we think could be a proxy for OS, namely, you know, PFS2 or time to next treatment, showing that we really do sustain a long-term benefit, delaying any need for future therapy. So we're pretty confident in the OS benefit, even the data we have to date, which is immature. With regard to your second question on sequencing with the other available AKT inhibitor, you know, their data has been in the second or later line. Our data obviously is in first line, and, you know, we think that the data that we're showing with this molecule, we believe, has really the chance for best-in-class opportunity to inhibit, really globally, the PI3K AKT space in PIK3CA mutated patients.
And we're, you know, committed to, to really leveraging that obviously in first-line endocrine-resistant, endocrine-sensitive, obviously in the second-line head-to-head comparison, and, and in the HER2 space, as well as what we look to be, ultimately in the early breast cancer setting. And then in the fourth question, you know, why did I go into such great detail on our data for giredestrant? Our confidence has been really steadfast. It was really, you know, three years ago when I arrived. I think it's, it's, equally now, I think the... You know, the data that I was excited to share with you in terms of the transcriptome data and some of the preclinical data, really, I just wanted to explain, you know, our continued look at this to make sure that we're maximizing our investments in this molecule.
But really, the data that we were seeing three years ago and we continue to see today, I think just continue our confidence in this molecule as what ultimately will be the backbone endocrine therapy for patients across the globe. But let me, let me turn to my colleagues for your third question on Phesgo.
A question about Phesgo and how it's protected.
Oh, right. Yes.
Yeah. I think we have a belief that we, you know, have a solid protection here and a long lifetime ahead for Phesgo. It's a triple combination, as you know, two antibodies and then the hyaluronidase enzyme, and we expect it not to get negotiated under IRA, and also, you know, the patents go beyond 2030.
One more thought on the OS benefit, and you realize in inavolisib, the INAVO120 is a very special population because it's a high risk patient who relapse on adjuvant or within one year of adjuvant therapy. And the current overall survival data after, when you look at one-year rate, 25% already die on the control arm, which tells you in this setting, there is a really urgency to get those patients treated. And certainly you may refer to how overall survival is typically seen in the hormone space in breast cancer because patients get multiple lines of therapy, chemo comes later, and sequencing. I believe there's a strong indication with those one-year rate already that those patients deserve urgent treatment, and the PI3K inhibitor, inavolisib, is addressing this need.
Thank you.
Steve, all questions answered?
Yes, many thanks.
Mm-hmm. Then, next one is James Quigley from Goldman Sachs.
Thanks, Bruno. Thanks for taking my questions. I've got a couple, please. So on the first line, DLBCL trial, Columvi plus Polivy plus R-CHP, are there any toxicity considerations with the six-drug combination in the first-line setting, or is it more of a blast the tumor in order to increase the cure rate? Then secondly, on sub-Q development of Lunsumio, can you give us some details on the timing? And then for glofitamab as well, are you still pursuing sub-Q development here in the DLBCL setting as well? And then finally, one quick one as well.
Bruno, picking up on one of your comments from the intro, what population would you expect for Phesgo or vedotispocettin to remain standard of care in breast cancer? Thank you.
... Excellent. So, with regard to your first question about the combination of Columvi plus Pola-R-CHP, which is part of our ongoing first-line study in the curative setting, the tolerability has been excellent. I mean, I mentioned to you the 100% objective response rate and 93% complete response rate. And we're seeing in that, you know, that phase one B two data of highly durable responses. With regard to toxicity management, it's actually been excellent. What I think interesting is that when you combine, you know, the concerns that I think get raised, perhaps among health authorities, is the cytokine release syndrome you see with this class of bispecifics. When we look at it in combination with chemotherapy, like Pola-R-CHP, the CRS rates have actually been quite modest and almost exclusively low grade.
So, the tolerability has been excellent, and so we're really confident that this regimen, you know, you know, while we... You know, I think you used the word blast or something. You know, yes, I think it'll certainly be deleterious to the lymphoma cells, but our evidence is that it's, you know, very tolerable regimen and, you know, that is comparable to, I think, what patients otherwise experience in the first-line setting. With regard to subcu Lunsumio and subcu Columvi, I actually wanna make... I'm looking at Bruno because I just- I'm not sure what moment we're able to disclose in terms of those development timelines.
Sabine, maybe you can jump in quickly and,
Yeah, the Lunsumio subcu data, you know, will be early data, and we are actually envisioning to provide them together with the SUNMO data.
Yeah.
It's actually planned for the SUNMO launch because that makes the most sense.
Yes. Yeah, I wasn't sure what we were-
Glofitamab, where do we stand with the subcutaneous?
I think that's actually a little further out.
Yeah. A little further out, so we have no precise timeline here to offer. And maybe, Stefan, you want to jump in for the question, you know, of how much of the current neoadjuvant adjuvant space could still remain with Phesgo? I think it's tricky to predict because, of course, it will depend on the data and the details, especially the safety profile of an HER2. But I think, first of all, I think with all the studies ongoing, there's always, like, 50%-20% of the patients where there's not a complete overlap with the patient pool currently treated. And then I think also from the trials running, not the entire adjuvant space is covered. But maybe also, Stefan, you can give your perspective.
I mean, in the HER2 space, inhibition of HER2 is essential, and Phesgo has the Perjeta and the pertuzumab component, and Phesgo contains trastuzumab as well, but an ADC doesn't lend itself for long-term use. And I would even chime in first line, where we see with Phesgo, months and years, multiple years of treatment, where I believe what we hear back from the marketplace is that you would struggle to do this with an ADC from a toxicity perspective. Phesgo is super well established. The toxicity of pertuzumab and trastuzumab is very modest, and we have seen now a decade of long-term use in this space. Therefore, we will continue to see space for Phesgo in the future, and how substantial it is depends certainly on various factors, including how competition will be priced.
And that's what you're referring to as a maintenance setting, and also for Phesgo, which would remain in the adjuvant part. But then I think on top, even not, there will be a couple of a fraction of patients who will, from the beginning, remain on Phesgo.
Depending on the risk profile-
Yeah
... it wouldn't exclude even the first line setting.
Yeah.
Mm-hmm.
So it's probably difficult to give a number. I don't know, within 30%-40% probably is, could be something in that range. Absolutely. Yeah. James, did this help you? Mm-hmm.
That's perfect. Thank you very much.
Okay. Then, next one in a row is, Peter Welford from Jefferies. Peter?
Hi, thanks. Two big picture and a quick one. The quick one, first of all, just looking to the other SUNMO study. I think that was supposed to read out initially, potentially by the end of 2023, and now then 2024, and now it's 2025. Can you just update, is that because of interim analysis has passed, or is it that the events are just occurring more slowly? Then the two sort of bigger picture ones. Firstly, I guess related to the KRAS G12C, where we've seen, you know, a competitor to- today, or at least close today, that, you know, that they're discontinuing because they just don't see the sort of competitive environment being sufficient to justify investment. I guess from a Roche perspective, what...
Given what we're seeing with portfolio prioritization and the efforts to increase productivity, I guess, is this an example of an asset where you think the commercial potential is multi-blockbuster, you know, and is sufficient to justify? And I guess, what's the risk that this isn't an asset that in the end is developed and may even succeed, but just isn't really, you know, big enough in the scale of Roche to justify their taking forward, given what we've seen with the take-up so far of the current generation of KRAS G12Cs? And I guess a similar vein to some extent, but more related to ADCs, there aren't, at least I can see in solid tumors, any CAR TCR or similar sort of programs at the moment in the early-stage pipeline of Roche.
I guess, what are you internally, I guess, doing to potentially avoid the risk that perhaps has happened with ADCs, that you know, Roche is on top of what's going on in the TCR, CAR, et cetera, space for solid tumors and doesn't potentially miss a revolution that could perhaps be happening? Thank you.
... Yes. So, with regard to the SUNMO study, that's, you know, well, I'm not able to disclose the SAP. It's, it's driven just by events. And the trigger is not, is not influenced by any of us, but by, by when we hit the planned events as defined by the statistical analysis plan. And, you know, we're gonna keep you all updated as we learn. I think we're reasonably confident in the 2025 readout, and that is based simply on the, the, the rollout of events as we're seeing it. You saw obviously the data we're disclosing at ASCO this week, which give us considerable confidence in that combination for diffuse large B-cell lymphoma as a chemotherapy-free regimen. With regard to the news in G12C, yes, we too saw that announcement. You know, we are firmly committed to divarasib.
I think the data, the—you know, the preclinical data, I think are very compelling in terms of its greater potency, substantially greater potency. What I think is most compelling, frankly, is the clinical data, 'cause, I mean, how often do you see, with all the caveats of cross-trial comparison, more than a doubling of progression-free survival benefit? So I think our confidence in the molecule in this space of what is a competitive market is quite high. And then with regard to your point about our portfolio reviews, which are... You know, we are aggressively making sure that we're not... You know, we're investing in the best opportunities for patients and in terms of the long-term success of Roche. We think that the KRAS space is an important one. Obviously, non-small cell lung cancer is a priority for us.
It's one of the biggest markets in oncology, frankly, in biopharma, and we think tackling the G12C space with a best-in-class molecule is not only good for patients, but it's good for the long-term health for Roche. With regard to the issue of ADCs and TCRs, you know, I think we, you know, we have a number of ongoing investments, certainly in cancer immunotherapy. With regard to our investment with Poseida in terms of next-generation, off-the-shelf allogeneic CAR T, I think we've talked about our work in multiple myeloma and in diffuse large B-cell lymphoma.
In multiple myeloma, you know, that off-the-shelf technology, which can provide really, sort of immediate need for patients and, and overcome a lot of the limitations of CAR T therapy and, and ultimately democratize it, these are things that we are thinking about, how we can expand that technology, both in terms of the stem cells and the genetic engineering, to move into other disease areas. I think also with regard to ADCs, I think, you know, as we've answered, you know, we are monitoring the space. We've made a recent investment with, uh, MediLink, and we're continuing to do that. So to your question about is Roche committed to staying on top of what are the next-generation technologies? Absolutely. I think, you know, there is a lot of clamor about ADCs.
We're also following it, but we're investing in a broad array of MOAs and technologies that we think will position us well into the next decade. I don't know if my colleagues want to add anything.
Yeah. Okay. Peter, all covered?
Yeah, it's great. Thank you.
Mm-hmm. The final questions for today would go to Emily Field from Barclays.
Hi, thanks for taking my question. Just kind of asking some of the ones asked earlier in different ways, so hopefully that's okay. Just on the giredestrant adjuvant study, you know, I believe in lidERA you have an abemaciclib arm for combination with CDK4/6. You know, if ribociclib is approved with a wider label, would you expect to also study giredestrant on top of that as well? And then I know the capivasertib question was also asked, but I know they do have a first-line study expected to read out in the next few years. Mechanistically, regarding, you know, PI3K inhibition versus AKT inhibition, is there anything that, you know, aside from their molecule potentially addressing a wider population set in terms of mutations that could be advantageous versus inavolisib versus capivasertib? Thank you.
Yeah. So, with regard... You're absolutely right. The lidERA study includes a substudy of looking at giredestrant with abemaciclib, because we wanna make sure that the study and the data we generate are relevant as well for settings where physicians wanna use a CDK4/6 inhibitor, of which abemaciclib, if you're gonna use one, it's principally abemaciclib. The NATALEE data that you referred to, that is suggesting a benefit for ribo, is something we're monitoring. We have a body of evidence that our giredestrant can be safely combined in full dose with all three.
So we have data with all three CDK4/6 inhibitors, and we are committed, should, you know, as the space evolves with ribo, to be in a place to ensure that we can make continue to make our, our, SERD the backbone of choice in the endocrine space. With regard to the AKT inhibitor, you know, I think it. With all the danger of cross-trial comparisons, you know, I think the magnitude of benefit of our best-in-class PI3K inhibitor. I think potentially offers what is the greatest benefit in terms of various manipulations of the PI3K/AKT pathway, which could include AKT inhibition. Now, it's cross-trial. There is no head-to-head comparison, but I think you know, this could be that if you look at the data, this could be the opportunity for an intervention that's gonna have the greatest effect on this pathway.
Yes, I mean, obviously, the other molecule is a few years behind, attempting to get into the first-line. You know, we're looking forward to having a first-line label based on a pretty compelling result from the INAVO120, and given the fact that we think this has, really, the best-in-disease opportunity to hit the pathway, we're fully committed to covering all the potential ranges of indications. With regard to a broader label for AKT, I think right now, you know, the best evidence remains in tumors where you clearly see perturbations, mutations in the pathway. So I think really both AKT and PI3K interventions are gonna still rely on circumstances where you have a biomarker, that the pathway is principally activated.
I think that's what physicians managing HR-positive patients are gonna expect when they're being asked to choose those molecules for patient use.
Okay. Then I think we are at the end of the event. Let me thank you, Charles and Stefan, for joining, and let me also thank the IR colleagues who were working on the event. First of all, Sabine Borngräber, who had the overall lead for the event, and then also Richard Sahli, Lauren Kulm, Julia Royer, and Jan-Philipp Schwarzhans for working on the individual slide decks. And then last but not least, also Melanie Wolf, who was responsible for the event organization. I hope the event was helpful in providing the latest update on our oncology franchise, late-stage pipeline. If you have any remaining questions, then please reach out to the IR team, and with that, I wish you a good day, and talk to you soon. Bye.