Approval of Capivasertib for PIK3CA/AKT1/PTEN–Altered Breast Cancer With Jason Mouabbi, MD, and Carlos Doti, MD
Recently, the FDA granted approval to capivasertib in combination with fulvestrant for patients with hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN alterations. In this interview, Editorial Board member Dr. Jason Mouabbi speaks with Dr. Carlos Doti, Head of Medical Affairs, US Oncology at AstraZeneca, about the significance of the approval, its dosing schedule, AstraZeneca's approach towards patient education and adverse event management, and the future of capivasertib in different treatment settings.
Jason Mouabbi, MD: Good afternoon, everyone. I'm Dr. Jason Mouabbi. I'm a Breast Medical Oncologist in the Department of Breast Medical Oncology at MD Anderson Cancer Center, and I'm also one of the Editors of Oncology Data Advisor. I have the pleasure today to interview Dr. Carlos Doti, Head of Medical Affairs in the US at AstraZeneca. Welcome, Dr. Doti.
Carlos Doti, MD: Thank you very much for having me.
Dr. Mouabbi: This is very exciting. We heard recently about the FDA approval of capivasertib with a brand name called Truqap™—genius name, I really like it. We are here today to ask you a few questions to understand more about the study that led to the FDA approval and to understand more about the drug itself. The first question I have is, can you discuss the results of the CAPItello-291 trial that led to the FDA approval—especially the progression-free survival outcomes—and how they can support the efficacy of capivasertib in treating hormone receptor–positive, HER2-negative metastatic breast cancer that harbors a PIK3CA/AKT1/PTEN alteration?
Dr. Doti: Sure. By the way, just a disclaimer, you are the breast cancer specialist. I am just a hematologist working here, so I'll do my best not to embarrass myself in front of a specialist like yourself. Capivasertib, as you mentioned, is an inhibitor of the AKT pathway that includes PI3K, which is a target that has already been addressed by other molecules, but with a novel approach about also getting inhibition of AKT and PTEN alterations. The trial was designed for patients with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer after one or two lines of endocrine therapy.
The whole rationale behind this for patients having endocrine resistance was to delay or even avoid chemotherapy in the second line or beyond. The control arm was the standard of care when this started, which was fulvestrant. The arms were capivasertib plus fulvestrant versus fulvestrant plus placebo. The trial enrolled more than 700 patients, and 40% of them were altered in this pathway. The other 60, either we don't know or they were not altered. I'm mentioning this because the original design of the trial was for all-comers, with the power to identify differences between the subpopulations, but it was an all-comers trial.
The results in the altered population proved to reduce the risk of progression by half. The hazard ratio was 0.5, reducing the risk of progression by 50% in the patients that have any of these mutations. The toxicity profile, compared to what we expected from preclinical data, was better than what we've seen in other inhibitors in the same pathway. So, that is a summary of what we saw and what led to the approval that we received at the end of last year.
Dr. Mouabbi: Excellent, and very exciting for sure. Now, given the significant improvement in the progression-free survival that is observed in this special population with a PIK3CA/AKT1/PTEN alteration, how do you envision capivasertib changing the treatment landscape for patients with this type of breast cancer?
Dr. Doti: I think if you go back in time, the landscape in breast cancer started changing when HER2 was introduced, and that brought a completely different approach to patients with that specific mutation. Then there were some other advances, but everything changed when CDK4/6 inhibitors came to the market, establishing themselves as the first line of therapy, which is a great therapeutic area to have for these patients. Unfortunately, some of these patients will develop resistance to this. The only options that we have are very toxic regimens. If you have a PI3K mutation, you can go to an mTOR inhibitor, which is also very toxic, or you have to go to chemotherapy. That's why with these results, we are bringing a new opportunity for patients after that progression from CDK4/6 and continuing with the endocrine drive by including capivasertib with fulvestrant.
It's definitely a great opportunity to bring new therapies to these patients in this setting, but it's also setting the tone to ask, can we advance this into other areas, potentially earlier lines in the hormone receptor–positive space? Also, we have studies ongoing in triple-negative disease which have similar resistant pathways involving the PI3K/AKT1 pathway that has not been unlocked yet, and that's part of the future for this. The summary of all this is that we're very happy to bring this new opportunity. Also, up to 50% of the patients can have any of these mutations if they're diagnosed properly, and then moving into earlier lines can actually bring these better opportunities for even more patients than currently.
Dr. Mouabbi: Definitely, and it's very exciting that you're also going to be looking at it in triple-negative disease. You're right, this pathway is also altered and is observed in triple-negative.
Now, I always tell my patients, I can have the best drug on earth, but if you are not going to tolerate it and you're not going to take it, it's not going to help you. My next question to you is—you did observe that it's better tolerated than a lot of other drugs that target that pathway; however, we still see that the most common adverse reactions to capivasertib include diarrhea and some cutaneous reactions like rashes and changes in blood glucose level, mainly hyperglycemia. How is AstraZeneca planning to support health care providers and patients in managing these side effects?
Dr. Doti: Let me go one step back. When we started developing this molecule, we realized from the very beginning that you definitely need a certain therapeutic level to inhibit the whole pathway and get the efficacious part. However, continuous inhibition can also lead to more adverse events. That's why the schedule of how to take this drug is actually four days on and three days off. That maximizes the therapeutic effect and minimizes the risk of adverse events.
Now, that doesn't mean that they disappear, but it minimizes them and actually helps the patient stay on treatment longer. You still see a lot of diarrhea, rash, and hyperglycemia—not that much hyperglycemia, but definitely rash and diarrhea. But if you see in the trial, the number of patients who actually discontinue the drug because of this were very limited. So yes, there is a problem, but it is manageable depending on the efficacy that you're getting.
To answer your specific question about supporting patients and caregivers, every patient who starts on capivasertib also receives material to help them identify these adverse events early on—how to manage diarrhea, how to make sure that they are cognizant of the hyperglycemia that can happen, and how to recognize some early signs so they can contact the physicians if necessary. There is training about how to manage these adverse events and how to remain hydrated. There's more than just giving the patient the opportunity to get the drug; there's also training for patients and their caregivers on how to manage this, because as you mentioned, there's no point in getting a new drug out if the patient cannot benefit and receive the full effect of the drug. That includes making sure that you can stay on treatment as long as it's effective for you.
Dr. Mouabbi: That's perfect. Is there anything to help the health care provider in their clinic during their day to day?
Dr. Doti: We also have the same materials that we're developing for patients and caregivers. There are versions for physicians and for nurses. We have a very comprehensive training approach on our Social Omnichannel. There are different things that you can consult. We are also going into a lot of congresses with unbranded medical education opportunities to talk about how to manage this new mechanism of action in this new setting. We don't want people to get confused about PI3K vs the PI3K pathway, because that could derail someone from making the choice. There are other options for patients with PIK3CA alterations, but this is a broader innovation that can help more patients. We generally don't compare trials that are not actually meant to be compared, but what we've seen, at least in this cross-trial comparison, is that safety in this pathway—because of this four days on, three days off schedule—is looking more promising than continuous inhibition of one part of the pathway.
Dr. Mouabbi: Perfect, because you mentioned that, I'm going to stay on that topic. Yes, the recommended dose of capivasertib is something we are seeing for the first time. The recommendation is 400 mg twice a day, four days on, followed by three days off. Now, you did explain a little bit about the rationale. You're giving a break, so you don't have a complete inhibition in order to minimize side effects yet get therapeutic efficacy. But this is going to be challenging for providers and for patients on this alternative scheduling to remember to take the doses. What is your company trying to implement to assist patients in adhering to this treatment regimen?
Dr. Doti: For every patient, we provide a starter kit that includes everything that I just mentioned in terms of awareness and how to identify adverse events and manage them—how to manage them at home, but also how to reach out to the health care provider as soon as possible. We also have a starter kit that includes a pill reminder and how to use it, similar to what we have with other chronic diseases. You have the Monday, Tuesday, and Wednesday slots, etc. Then of course you have the information on why this is important and why should you use it in this way. There is going to be some learning for all of us, but I think that the tradeoff between what you get in terms of the safety profile is definitely worth it. As I mentioned before, we're doubling the results that we have with endocrine therapy alone, with a safety profile that's not perfect, but completely manageable for the type of disease that we are dealing with.
Dr. Mouabbi: Perfect. How about a blister pack?
Dr. Doti: Yes, that's also in the plans. We are also working on how to change the way that the drug is presented to patients to make sure that this is as simple as possible. Again, you know this because you've been working in oncology for a long time. There are going to be improvements in not only in the way that we communicate and educate, but also how we deliver the drug to patients. There's only one objective here, which is in order for patients to get the maximum effect of a compound, you need to stay on it as long as you can and that you can tolerate in order to derive benefit from it. And that's what we want to do.
Dr. Mouabbi: Excellent. All right, my last question to you is, although the study that led to the FDA approval, the CAPItello-291 trial, showed the progression-free survival improvement in the overall population—which was very exciting to everybody—the FDA approval is specifically for patients harboring PIK3CA/AKT1/PTEN alterations. What are your thoughts on the reasons behind this narrower approval? And is there a future where you can see expansion of the label that could maybe include all-comers, not only the patients with a specific mutation in that pathway?
Dr. Doti: I cannot speak about the agency's point of view, but when you see our trial specifically, there's benefit for all-comers. There's more benefit in the AKT1-altered patients than in the all-comers. There's a proportion of patients for whom we were not able to get data on the status of AKT1 pathway. Our overall survival data in the New England Journal of Medicine paper shows that the trends towards overall survival benefit are still immature. We will continue to look at the data, and depending on those results, we can definitely have more conversations with the agencies.
Dr. Mouabbi: That's perfect. Well, I want to thank you so much, Dr. Carlos Doti, for giving us insights on this exciting FDA approval of capivasertib. I'm sure it's going to help a lot of patients, and it's going to make our lives as clinicians much easier, given that we have another excellent tool in our treatment landscape. Thank you very much.
Dr. Doti: Thank you for having me.
About Dr. Mouabbi and Dr. Doti
Jason Mouabbi, MD, is an Assistant Professor in the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, where he specializes in the treatment of lobular breast cancers. His research focuses on the management of breast cancer subtypes and their impact on treatment. He also serves as Chair of the Scientific Advisory Board of the Lobular Breast Cancer Alliance. Dr. Mouabbi has been the recipient of multiple honors and awards, including the Guiding Researchers and Advocates to Scientific Partnerships (GRASP) Advocate Choice Award in 2022 and the Lester & Sue Smith Breast Cancer Award of Excellence in 2021.
Carlos Doti, MD, is the Vice President, Head of Medical Affairs, US Oncology at AstraZeneca. As the Vice President and Head of Medical Affairs for US Oncology Business Unit, he leads the teams responsible for the development and delivery of medical strategy across AstraZeneca's US oncology portfolio. Since joining AstraZeneca in 2016, he has held various Medical Affairs leadership roles in the Oncology Business Unit within the international markets and on a global level. Most recently, he served as the Global Medical Franchise Head of Hematology, where he led the delivery of integrated confidence and evidence generation plans, while implementing new development initiatives. Prior to joining AstraZeneca, he was with Pfizer and Novo Nordisk, where he served in various leadership roles in Latin America Medical Affairs. He received his MD from the University of Buenos Aires, where he specialized in hematology. As a practicing physician, he specialized in hematology and bone marrow transplant.
For More Information
Turner NC, Oliveira M, Howell SJ, et al (2023). Capivasertib in hormone receptor-positive advanced breast cancer. N Engl J Med, 388(22):2058-2070. DOI:10.1056/NEJMoa2214131
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.