Dr. Hope Rugo discusses Capivasertib FDA Approval based on CAPItello-291 Study

Unpacking Capivasertib FDA Approval and CAPItello-291 Study Hello everyone I am Rahul Ghosain. Speaker 2 And I'm Rohid Ghosain. Speaker 1 And we are the oncology brothers. In the year of 2023, we saw more than 40 new drug approvals or indications in oncology out of which three were in hormone receptor positive breast cancer, sacitizumab in refractory settings and then L assessment for ESR 1 mutation and CAPI resortib for PIG 3C, AA, KT1 and P Tina mutation. Previously we've covered LS Estrin with Doctor Kaak Lamani. Today we're joined by Doctor Hope Rugo again to unpack the data and to better understand the approval of Capu Lacerteb based off her study. Capitolo 291. Current Treatment Landscape for HR+ Metastatic Breast Cancer Doctor Rugo, thank you so much for joining us. Speaker 3 It's a pleasure to talk with you today. Speaker 2 Doctor Rugo, welcome. Just to set the stage where we stand today for hormone receptor metastatic breast cancer patients is we start off with endocrine therapy with AI. If there is progression then we tend to rely on PIC 3 CA mutation. If that is present, then L Pulseb plus fulvestrant is a choice. If ESR one mutation is present, then LSS Trent is a choice. If germline bracket mutation is present, then we tend to rely on olaparib. Now with PIC 3, CA mutation, AKT 1 mutation and P10 alteration, we have a choice of capiva assertive plus fulvestrant and that's what we are here to talk to Doctor Rugo about which led to the approval of capital sort of in November 2023. From Faction to CAPItello-291: Study Background Doctor Rugo, can you share a little background on how we got to Capitola 291 from Faction and then of course the study design? Speaker 3 Absolutely. And I will say that the one thing is that to add to your very nice sequencing is that we use CDK 46 inhibitors of course now in the first line setting. And there's a little bit of AI think a sort of intermediary time here where indeed if you have a PA3 kinase mutation or a mutation in the pathway, you have options to give patients in combination with fulvestrant and ESR one mutations play a role. But we're also waiting for data on whether or not giving AC DK46 inhibitor after progression on a C DK46 inhibitor with changing the endocrine therapy partner might be another effective strategy. So there are certainly a lot of things in the mix moment and we're exploring triplets of the agents that block the PI3 kinase pathway along with CDK 46 inhibitors in endocrine resistant disease. So Capitola 291 really developed out of data from a phase two study but also Kapiva Seritib came from the laboratory actually in the UK and was then developed by the Pharmaceutical industry after showing promise with an intermittent schedule given four days on, three days off with very tolerable safety. So an initial phase two randomized trial called faction where CAPIVA Seratib was added to fulvestrant compared to fulvestrant in a population where not everybody had CDK 46 inhibitors, but it was given in the second line setting after a progression on an aromatase inhibitor showed remarkable improvement in PFS and OS and this seemed to be regardless of the mutation status of the tumor. So we were very excited about that and the tolerability of the agent was quite good and that really led to the design of Capitello 291. Detailed Design of the CAPItello-291 Clinical Trial So the way Capitello 291 was designed was to enroll patients who had had progressive disease with hormone receptor positive, her two negative metastatic breast cancer after one or two lines of endocrine therapy. They were also allowed to have up to one line of chemotherapy for advanced disease, which not all of these studies have. And even with small numbers of patients who do tend to enroll a patient population with more resistant disease, patients were allowed to have prior CDK 46 inhibitors and at least 51% were required. That number is going up as CDK 46 inhibitors of course become more of a standard of care around the world. So that it's certainly somewhere in the 60 to 70% or higher range. Now in the newer studies that are being developed, you couldn't have had any agent of course that affected the PS3 kinase or AKT pathway and no prior SERD because the partner was fulvestrant. And then you could have recurred within 12 months of your or while on your adjuvant therapy, so-called primary and secondary endocrine resistance and that would have counted as one line of endocrine therapy because agents that target the PI3 kinase pathway as a pathway effect are known to affect glucose metabolism. We needed to have some kind of requirement for glucose control. But Kapiva Serativ in the earlier trials really hadn't resulted in much hyperglycemia. So we allowed patients with a hemoglobin A1C up to 7.9%. So patients could have had Frank type 2 diabetes or pre diabetes and those patients were allowed on the study which is not true of the other studies. Alpolosib had a slightly stricter control up to a hemoglobin A1C of 6.5%. In a recent study with a novel PI3 kinase inhibitor in a Volusib really had patients who did not have much abnormal glucose metabolism at all. They had pretty much all of the patients had a normal hemoglobin A1C. So that's important to keep in mind of course. CAPItello-291 Endpoints and Targeted Mutations First, the randomization was one to one slightly over 700 patients Capivis erative versus placebo with fulvestrant with the overall end point keeping in mind this prior data. So progression free survival overall, but also in the AKT pathway altered tumors defined similarly to faction. So you could have had a qualifying mutation in PIC 3C, AA, KT1 or P10 which is normally P10 loss that was evaluated in tissue because there aren't really well defined ways of evaluating P10 loss that are felt to be reproducible in the plasma looking at CTDNA and then but you could do CTDNA as well, but they they did require one of these to be abnormal in tissue and then overall survival and overall response rate. So that was the whole design of the study and it actually accrued fairly rapidly. So you could enroll whether or not you had a mutation in your tumor? Prevalence of AKT Pathway Mutations and Dosing Schedule Doctor Rogo, thank you for going over that. Before we even go any further, how prevalent is AKT 1 or PIG 3 CAP 10 mutations? Speaker 3 That's a great question. So any AKT pathway or PI3 kinase pathway alteration occurred in about 40% of patients in Capitello 291 and it was interesting the split you know any PIC 3 CA mutation or PIC 3 CA mutations only we're seeing just under 30%, about 28%. But if you looked at the combination of different mutations, looking at AKT one only, P10 only, which were in the 5 to 6% range and then combinations of mutations which are generally in 1% or less range altogether, it ended up being about 40%, which is what we would have expected. There were some patients where the tissue just wasn't adequate to look at 4 mutations and that occurred in 16% of patients in the CAPUA Sertiv arm and about 14% of patients in the control arm. And the plan in the future is to be able to look at blood, so CTDNA to define those pathway unknown alteration patients, but that hasn't been done yet mainly because of trying to validate the P10 analysis in blood. Speaker 1 Thank you again. Now 40% is not a trivial number. The other thing I want to re emphasize here, what you brought up was the dosing schedule. This medication was given four days on and three days off while we continued with Fulvesin Doctor Rugo, you have mentioned CTDNAI. Clinical Workflow for Mutation Testing with ctDNA Promise we will get to the results. But what is your workflow right now to look for these mutations? Speaker 3 So my workflow generally is to you know, if I know I'm giving AC DK46 inhibitor in the first line setting for a patient who doesn't have primary or secondary endocrine resistance, I won't check immediately. But if we have done a biopsy to establish metastatic disease will generally send NGS then it's covered within a month in California after the biopsy. That's one motivating factor. And then we do CTDNA when patients are suspected to beginning to have progressive disease and that makes a really big difference in terms of planning for patients looking for clinical trials and talking to them about next steps. As long as a patient has endocrine sensitive disease, I will check ACTDNA on progression just to see what other options I have. Of course, I'm also looking for somatic mutations in her two in bracha, other types of targetable mutations, although I have to say they're relatively limited in breast cancer. Speaker 1 Absolutely. Key Results of CAPItello-291 and FDA Approval Thank you. So now there is a potential mutation that we can target. What did this study show? Speaker 3 Well, of course we've been targeting PIC CCA mutations with alpellasib, but we've been really challenged with the toxicities of alpellasib and the fact that you know something like half of our population in the United States and in some countries even more have some abnormality and glucose metabolism. And then the there's also can be a significant rash that limits treatment and a long term diarrhea. So we are really excited to look for another agent that might have a different toxicity profile to see whether or not we could improve outcome. And in fact adding Kapiva serotype to fulvestrant improved progression free survival by almost doubling it from 3.6 to 7.2 months with a hazard ratio .6 and that was highly significant. But of course we looked at this 40% of patients who had alterations in the AKT or PI3 kinase pathway and there are the improvement in medium progression free survival was just a little bit better going from 3.1 to 7.3 months with a hazard ratio .5. So you see a little bit of improvement in hazard ratio. You can see that there's this, you know initial 20% of patients. If you look at the overall population you have some progression by the 1st scan that seems to be a little bit less when you focus on the pathway altered tumors, a little bit less of that early progression showing very immediate resistance to endocrine therapy which suggests that those patients may be benefiting even more than the patients in the with the AKT non altered or wild type tumors. We did look at and I think that this is important you know for the regulatory purposes and as an exploratory analysis we looked at the non altered population. We included that 15% or so of patients who have unknown mutations in that unknown population. Now some of them of course could have mutations but the PFS difference was very similar. They are going from 3.7 to 7.2 months, but we've gone down now in numbers of patients and so the hazard ratio is just .7 in that group of patients. So I think that that's what led to the FDA to say, you know until we have more information, we're going to just narrow the approval to patients who have alterations in AKT, PS3 kinase or P10. Sequencing Capivasertib with ESR1 Co-mutations But that's still pretty remarkable especially when not having the mutation and having such responsiveness. Now since you mentioned that having another option, especially when you talk about the hyperglycemia aspect of it, which we were dealing with L pelliceb, this is certainly a good option with no or less hyperglycemia concerns where diarrhea certainly stands major concern here. Now if ESR one mutation is present, then we have a choice of LSS trend. If we have a Co mutation of AKT pathway with ESR One, what do you really pick under those circumstances and exactly with the Co mutations? How often do you see that with ESR One? Speaker 3 Well, so I think there's two parts here. The safety, which we'll talk about in a little bit, but I think that's an important question too about how we assess safety. But then sequencing which of course has been a big issue, There's only maybe 20% of our patients are less above Co mutations in ESR one and pick three CA or AKT or P10 loss. And so it's not very frequent compared to when we see both of the mutations which occur over time and up to 40% with ESR one as I mentioned 40% for the Akt pathway. So I think that you know we are faced with that, but it's not as frequent as just seeing the individual mutations. I think that you know we obviously in the metastatic setting overall survival Trump's everything except for safety. But we don't have overall survival data from Ellis Estrin and we don't yet have the final overall survival or even protocol specified next overall survival analysis for Capitella 291. So that's not really going to be a driving consideration in this situation. I think it's going to be just side effects profile and how people, our patients are managing their treatment. So it's easier to take LS Estrin than to take a combination. So if all else is equal, I think with the combined mutation, generally we'd start with LS ESTRIN where there is data that it seems to be effective in patients who have them both mutations, although the numbers are very small in the Emerald trial. And then if you have just the PI3 kinase mutation, of course that's very straightforward. But you can sequence after giving LSS Trent and give Fulvestrant and Kapiva Ceratib. I think we're going to need real world data to really understand how effective this sequencing strategy is. But generally that's what people have been using. Speaker 1 Doctor Rugo, thank you for covering that. Managing Side Effects of Capivasertib in Clinic Rohit you and Doctor Rugo, you've mentioned about safety coming back to apolis of the uptake just in the community has been really low because of the safety there are hyperglycemia, diarrhea, rash and it looks whole lot better with KAPIV asserted. Can we take a few minutes to dive into some of the side effects? And Doctor Rugo, how to manage these side effects in our day-to-day clinic? Speaker 3 In Capitolo only about 9% of patients stopped due to toxicity, but remember it's four days on, three days off. So if you had a little bit of diarrhea then you could you know make sure a patient was taking an anti diarrheal agent, but then they have their three days off, so they get better. And we saw the same thing with rash where you know we just really didn't see rash being a big issue for the majority of patients even though you know overall about 9% of patients had grade 3 diarrhoea and about 12, 12% grade 3 rash. And then the, you know it's it's also interesting that dose reduction seem to have really played a big role, about 20% of patients dose reduced Kapiva Seritib compared to 2% for placebo. So that that actually helps too. Another factor that I think is important for us in clinic is how quickly you get these side effects. The median time to onset for diarrhea was about 8 days. The range went out to about 3 weeks and the rash about two weeks weeks with a very narrow range, interestingly 10 to 15 days. Now hyperglycemia also was, you know, something of big concern. As you mentioned, we only saw grade 3 hyperglycemia in seven patients out of the 355 who received Kapiva seratib and there was that same toxicity in one patient in the placebo arm, so very low percent, under 2%. If you subtract the placebo Group, One patient also had grade 4 hyperglycemia. That particular patient actually took did not stop her CAPIVA Sertip, which of course has resulted in a lot of interest in education and patients. But that was one patient and she just kept taking the CAPIVA Sertip for three weeks and had underlying glucose metabolism issues. So she recovered and actually went back on drug and tolerated it well. So the hyperglycemia overall any grade was only 17%. So that's very manageable in our patients, particularly given the fact that we allowed patients on who had significant issues with glucose metabolism. And then lastly, almost all of the drugs we give now these small molecules cause some degree of aptis ulcers similar to what we saw with everolimus, but generally at lower grade and steroid mouthwash makes them go away right away. And that those stomatitis occurred in about 14, 1/2% with the Cappy, but it actually occurred in 5% with placebo. So overall it's under 10% of patients who get any grade stomatitis and it's all mostly low grade. So very, very easy to manage. Prophylactic Strategies and Dose Management for Toxicity The most common adverse event that led to discontinuation is rash. So I think it's important to tell patients about the rash and diarrhoea and to help them with management before they start. So I start everybody because I did this with Alpella sib with a non sedating antihistamine agent and that works really well. I have them take it twice a day even though the label says once a day two and even three times a day is quite safe, not really just causing dry eyes and dry mouth. So they start up before they start the copy and then continue it. And depending on whether they get a rash or not, whether or not you need to dose reduce, you can actually just continue a lower dose of the antihistamine throughout the course and that works really well also. So you know we're you just have to sort of manage these individually with a patient and start out with good education. It's important you know patients who have significant side effects to dose reduce, you can always go back up again if you need, if you feel like you know you jumped again too quickly. But that works really well, both education, prophylactic strategies, management quickly and dose reduction as needed. Speaker 1 And again, we've brought up using low dose in certain patients that step down is 320 milligrams twice a day for four days and there's another step down which is 200 milligrams twice a day for four days and three days off. Utility of Starting Capivasertib at a Lower Dose Doctor Rugo, any utility in starting low upfront in a certain patient population? Speaker 3 You know, we have talked a lot about whether we should start low for some drugs in certain patients, for example in the truly elderly patients, you know over the age of 75 in in drugs that cause bone marrow suppression and we see more bone marrow suppression, we see more higher grade adverse events. So in that situation if you're starting a drug that has you know relatively narrow therapeutic index that certainly should be a consideration for Kapipa Serotube. We really just haven't seen that very much. So in a patient population, you know overall because you have you know four days on, three days off, I haven't dose reduced. I will say that maybe in a patient who had renal insufficiency or was elderly or had a lot of glucose control issues, you certainly could consider this in clinical practice. But I know I haven't done that quite as much as we have with some of our other agents and. Chemotherapy drugs and situations where we feel like there's concern about immediate toxicity. Recap: Capivasertib's Impact on HR+ Breast Cancer Thank you. Speaker 2 Certainly another option with better side effect profile or slightly different side effect profile. It's always a win win situation. To sum up, as Rahul mentioned in the beginning, in the community we need to know when and how to use these new novel agents and also get comfortable around managing these side effect profiles. Doctor Rugo, congratulations for this work which has led to the approval of Capu Assertive. Thank you so much for walking us through the study that has established a new treatment option for our patients for our listeners, let's recap in this discussion with Doctor Hope Rugo. We covered her study Capitolo 291, which led to the approval of CAPU assertive in hormone receptor positive breast cancer with AKT 1P10 and PIC three CA mutations which are seen in close to 40% cases. Speaker 1 We also got a chance to better appreciate where does Capilicertive fall in with all our treatment options that are available today. What are you going to use when you have Elysestrin or Capilicertive when you see a Co mutation with ESR One and AKT 1P10 or PIG 3 CA mutation? Speaker 2 Capilicertive got approved on November 16th, 2023 and is now part of our standard of care treatment option for metastatic hormone receptor positive breast cancer. Thank you for tuning in, Continue to follow us along for more practice changing data. We are the oncology brothers.