Capivasertib: CAPItello-291 Results with Slides Nicholas Turner SABCS 2022

Capivasertib: CAPItello-291 Results with Slides Nicholas Turner SABCS 2022

Presentation from the SABCS 2022 (San Antonia Breast Cancer Symposium)

Thank you very much. Carlos. So it’s a pleasure to present the prime results of CAPItello-291 phase III study on behalf of my co-authors. Akt activation is very frequent in hormone receptor positive HER2-negative advanced breast cancer through genetic alterations in the pathway, but also make a current cancers without genetic alterations. AKT signaling is also implicated in the clinical development of endocrine (therapy) resistance. So Capivasertib was developed as a potent and selective inhibitor of all 3 Akt isoforms. In a previous phase II trial, the faction trial kava cert added to full vest significantly increased PFS and OS both overall with more pronounced benefit in those (solid) tumors that had pathway alterations. The CAPItello-291 study recruited patients with hormone receptor positive, HER2-negative advanced breast cancer, all of whom had progressed on a prior aromatase inhibitor. Up to two prior lines of endocrine therapy and one prior line of chemotherapy were allowed for advanced breast cancer.

Prior CDK4/6 inhibitors were allowed, and at least 51% were required. And I highlight that also. Diabetics not requiring insulin were allowed. 708 enrolled patient treatment groups were randomized, one-to-one to Fulvestrant and Capivasertib or Fulvestrant and placebo with the randomization stratified by the presence of liver metastasis prior CDK4/6 inhibitor use and region and Capivasertib was given 4 days on, 3 days off a regimen selected early in clinical development to maximize the therapeutic. There were two Co-primary endpoints PFS by investigate assessment overall and in Akt (inhibitors) pathway, altered (solid) tumors, which we meant the presence of at least one qualifying mutation in PIK3CA AKT1, or PTEN key secondary endpoint for overall survival and objective response rate.

In terms of baseline and tumor characteristics and prior treatments, these were well-balanced overall. And in the Akt pathway, altered (solid) tumors, 69% of patients had a CDK4/6 inhibitor before for advanced breast cancer, and 18% had a prior chemotherapy. So to show you the two co-primary endpoints, first of all, investigator assessed PFS (progression free survival) overall. So overall median progression free survival (PFS) on placebo and Fulvestrant was a life expectancy of 3.6 months, and this increased to 7.2 months on Capivasertib and Fulvestrant. And the adjusted hazard ratio here was six. As you can see, the curves separate early and then stay separated for the duration of follow. And here the second co-primary endpoint investigates or assessed PFS (progression free survival) in the Akt (inhibition) pathway altered population here.

Medium PFS (progression free survival) was 3.1 months on placebo, and this improved to 7.3 months on Capivasertib with an adjusted hazard of 0.5, again, highly statistically significant. I show you here a exploratory analysis of investigator assessed PFS in the non-altered population that per protocol included unknowns. Here the hazard ratio was 0.7 and then excluding unknowns the hazard ratio was 0.79 with very similar looking curve. I show you here the pre-specified subgroup analyses showing that Capivasertib had consistent benefit across all pre-specified subgroups. I highlight two patients with and without liver metastases had similar benefit from Capivasertib and also patients who had prior CDK4/6 inhibitors or had not had prior CDK4/6 inhibitors had consistent benefit.

This is a planned (statistical) analysis of overall survival that was requested by the regulators at this time. Point to assess for no detriment. I highlight there was no planned analysis of superiority at this time point, and overall the hazard ratio was 0.74 and Akt (inhibitor) pathway altered cancers .69. In terms of adverse events, the most common adverse event was diarrhea that occurred in 72.4% of patients. The majority of this was grade one, although 9.3% of patients did have grade 3 diarrhea, there were two rash terms in over 10%, and in terms of a group term of rash, rash occurred in 38% of patients, 12.1%, grade 3, but I highlight both.

Hypoglycemia and stomatitis were relatively uncommon, both having grade 3 events only in 2% of patients. And so to conclude, Capivasertib and Fulvestrant provided a statistically significant and clinically meaningful improvement in PFS overall and in Akt pathway tumors. The clinical benefit of Capivasertib was consistent across all clinically relevant subgroups, including those patients who’ve been previously treated with a CDK4/6 inhibitor and with liver metastasis. Overall survival follow up is ongoing for future planned analyses of overall survival. And the safety profile of Capivasertib was consistent with that previously reported with a relatively low discontinuation rate. And this combination of Capivasertib and Fulvestrant has the potential to be a future treatment options for this population of patients. Thank you. 

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5 Key Takeaways from the Double Blind, Randomised CAPItello-291 Clinical Trial

1. Capivasertib plus Fulvestrant – Fulvestrant: 2 intramuscular injections of 500 mg administered on Day 1 of Weeks 1 and 3 of the first cycle, and then on Day 1 of Week 1 of each subsequent cycle. Capivasertib: 400 mg (2 oral tablets) BD administered on an irregular weekly basis. Days 1 through 4 of each week of a 28-day study treatment cycle are dosed.

2. Placebo + Fulvestrant (vs placebo)

   Two 500 mg intramuscular injections of fulvestrant are administered on Day 1 of Weeks 1 and 3 of cycle 1, and then on Day 1 of Week 1 of each subsequent cycle. Placebo: 400 mg (2 oral tablets) BD administered intermittently each week. Days 1 through 4 of each week of a 28-day treatment cycle are dosed.

3. Capivasertib is a new pyrrolopyrimidine derivative and an orally bioavailable inhibitor of the serine/threonine protein kinase AKT (protein kinase B) with possible antitumor action.

4. In the general study population, the objective response rate (ORR) was 22.9% for the capivasertib plus FASLODEX arm compared to 12.2% for the placebo plus FASLODEX arm, and 28.8% versus 9.2%, respectively, in the biomarker-altered population. Despite the immaturity of the overall survival (OS) data at the time of study, preliminary statistics are positive. The clinical trial will continue to evaluate OS as a secondary endpoint of importance.

5. The safety profile of the combination of capivasertib and (the new dosing FDA approval of) FASLODEX was comparable to that reported in prior clinical studies examining this combination. Diarrhea (72.4%), nausea (34.6%), rash (group term including rash, rash macular, maculo-papular rash, rash papular, and rash pruritic; 38%), exhaustion (20.8%), and vomiting (20%) were the most common adverse events (AEs) with capivasertib plus FASLODEX in the whole study population. Diarrhea (9.3%) and rash (12%) were the most common AEs of grade 3 or higher occurring in at least 5% of patients.

Q&A With Professor Nicholas Turner On the CAPItello-291 on Capivasertib in Patients with Hormone Receptor Positive, HER2-negative Advanced Breast Cancer

Thank you, Nick. Can you tell us whether the majority of the IKT ultra tumors have PIK3CA mutations? And also do you have a sense that this drug is, might be better tolerated that PI3Ks kinase (inhibitor) alpha inhibitors? The data is not in this slide deck, but it is in the deck we’re presenting in the conference. So the majority of the pathway alt tumors were PI3Ks, although 5.2% had Akt one mutations and 7.2%. PTEN alterations. Your second question, Carlos. It’s difficult of course, to do cross trial comparisons, and there are different CTCA  versions in the different slides, but one prominent difference is there’s substantially less hypoglycemia. With Capivasertib as well as less stomatitis and diarrhea. And certainly my personal experience is I’ve found it easier to give CAP AIB to, to patients than PIK3CA kinase inhibitors. 

Thank you. Questions from the audience or in the webcast? What is the median time on treatment? For our fellowship is about 6 months. Yes. I don’t have, we don’t actually have that information yet, Carlos. It’ll be very important for us to present that in the future. No questions? Yes, please. Hi Neil Osterweil from MDedge. Is testing for Akt currently in the panel? Is Akt currently tested for in panels genetic panels. In genetic panels? Thank you. Yes. Sorry. So sorry, I just couldn’t hear, I’m sorry. Couldn’t hear a key word. Excuse me.. Yeah. The vast majority of patients when they’re tested for mutations and their tumor tissue or liquid biopsies have panel testing. And Akt one and PTEN are in, I think, all standard panels as well as PIK3CA. Yeah. Good. Thank you. But in this study you selected PTEN loss by Immunohistochemistry, correct?  No, this study was all genetic testing in the pathway. So testing was done on tissue with the FoundationOneCDx Assay. Oh, good. Okay. So that would capture all the relevant alterations. Thank you very much.

Nicholas Turner, MD, PhD – About The Author, Credentials, and Affiliations

Professor Nicholas Turner specializes in breast cancer (cell lines) treatment as an Academic Consultant Medical Oncologist. He is the Team Leader of the Breast Cancer Now Toby Robins Research Centre and the Principal Investigator of numerous national and international clinical trials of individualized breast cancer therapy. Professor Nicholas Turner specializes in breast cancer treatment as an Academic Consultant Medical Oncologist. He is a Team Leader at The Institute of Cancer Research, London’s Breast Cancer Now Toby Robins Research Centre.

Before graduating in 1997 from the University of Oxford Medical School, Professor Turner studied Natural Sciences at Cambridge University. After finishing standard medical training in London, he specialized in medical oncology at The Royal Free and University College Hospital and earned a PhD from the Institute of Cancer Research in 2006. In 2008, he joined the Breast Unit of The Royal Marsden and the Institute of Cancer Research as a Senior Lecturer and Honorary Consultant in Medical Oncology. As a Cancer Research UK Clinician Scientist Fellow, he devotes the majority of his time to academic clinical research, both in the laboratory and in clinical trials, studying potential medicines for the treatment of breast cancer.

Professor Turner is the Principal Investigator for a number of national and international Breast Cancer individualized therapy clinical trials. He is the Deputy Editor of Breast Cancer Research, the Breast Theme head for The Royal Marsden National Institute of Health Research Biomedical Research Centre, and a member of the organizing committees for numerous international breast cancer conferences.