NCCN Guidelines Recommend Capivasertib, Fulvestrant for Certain Patients With Breast Cancer

Patient with breast cancer approved for capivasertib combined with fulvestrant - Image Credit: Seventyfour - stock.adobe.com

The National Comprehensive Cancer Network (NCCN) Guidelines for breast cancer recently added capivasertib (Truqap) combined with fulvestrant (Faslodex) for patients with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer. The combination was first added as a category 1 recommendation—a preferred second or subsequent-line therapy in patients with PIK3CA or AKT1–activating mutations or PTEN alterations—in December 2023.¹

The FDA approved capivasertib combined with fulvestrant for the treatment of adult patients with hormone receptor (HR)–positive, HER2-negative, locally advanced or metastatic breast cancer harboring 1 or more PIK3CA, AKT1, or PTEN alterations after progression on at least 1 endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy in November 2023.² The agency's green light was based on results from the phase 3 CAPItello-291 trial (NCT04305496), in which capivasertib plus fulvestrant showed a median progression-free survival (PFS) of 7.3 months (95% CI, 5.5-9.0) vs 3.1 months (95% CI, 2.0-3.7) among patients treated with placebo plus fulvestrant.

This guideline update is significant because HR-positive breast cancer is the most common type of breast cancer, impacting more than half of the population diagnosed with breast cancer tumors.³ PIK3CA, AKT1, and PTEN alterations frequently occur in HR-positive breast tumors, affecting up to half of patients with advanced HR-positive breast cancer.

CAPItello-291 was a double-blind, randomized trial that focused on the efficacy of capivasertib combined with fulvestrant (n = 355) compared with a placebo group (n = 353).⁴ Patients included in the experimental group were given 400 mg of capivasertib twice daily for 4 days on and 3 days off combined with 500 mg of fulvestrant for days 1 and 15, then 4 weeks following. Both the experimental (n = 155) and placebo (n = 134) cohorts had patients with AKT pathway-altered tumors.

The overall response rate was 22.9% among patients in the experimental cohort vs 12.2% for patients in the placebo group. Patients with an AKT pathway alteration had an overall response rate of 28.8% in the experimental group and 9.7% in the placebo cohort. Adverse events identified throughout the study were rash (12.1%), diarrhea (9.3%), and hyperglycemia (2.3%). These observations were consistent with data from earlier studies that tested capivasertib.

More recent updates to the NCCN breast cancer guidelines have included changing olaparib from a category 2A to a category 1 recommendation for those with HR-negative/HER2-negative and HR-positive/HER2-negative disease harboring BRCA1/2 mutation and residual disease after preoperative therapy in version 1.2024 of the guidelines.⁵ Another addition was the regimen of paclitaxel/carboplatin plus trastuzumab plus pertuzumab for patients with HER2-positive disease, which is a category 2A, or other recommended regimen.

In version 2.2024 of the guidelines, a footnote was added to relevant pages in the guidelines to note that a denosumab biosimilar is an appropriate substitute for denosumab.⁶ This change was in response to the FDA approval of biosimilars for denosumab in March 2024.^6,7

The FDA also granted accelerated approval to fam-trastuzumab deruxtecan-nxki (Enhertu) for patients with unresectable or metastatic HER2-positive solid tumors based on results from the DESTINY-PanTumor02 trial (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 trial (NCT04744831).⁸ Fam-trastuzumab deruxtecan-nxki is currently a preferred category 1 second-line therapy for HR-positive/HER2-negative breast cancer with visceral crisis or endocrine refractory, triple-negative breast cancer with no germline BRCA1/2 mutation, and in second-line HR-positive or HR-negative and HER2-positive breast cancer.⁶

References

1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 5.2023. Accessed June 12, 2024. https://www.nccn.org/guidelines/guidelines-process/transparency-process-and-recommendations

2. Ryan C. FDA approves capivasertib plus fulvestrant in advanced HR+/HER2– breast cancer with PIK3CA, AKT1, or PTEN alterations. AJMC^®. November 20, 2023. Accessed June 12, 2024. https://www.ajmc.com/view/fda-approves-capivasertib-plus-fulvestrant-in-advanced-hr-her2-breast-cancer-with-pik3ca-akt1-or-pten-alterations

3. ‌Truqap (capivasertib) plus Faslodex approved in the US for patients with advanced HR-positive breast cancer. Press release. AstraZeneca; November 17, 2023. Accessed June 5, 2024. https://www.astrazeneca.com/media-centre/press-releases/2023/truqap-approved-in-us-for-hr-plus-breast-cancer.html#!

4. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor-positive advanced breastcancer. N Engl J Med. 2023;388(22):2058-2070. doi:10.1056/NEJMoa2214131

5. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 1.2024. Accessed June 12, 2024. https://www.nccn.org/guidelines/guidelines-process/transparency-process-and-recommendations

6. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 2.2024. Accessed June 12, 2024. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf

7. Joszt L. FDA approves first 2 denosumab biosimilars. AJMC^®. March 5, 2024. Accessed June 12, 2024. https://www.ajmc.com/view/fda-approves-first-2-denosumab-biosimilars

8. Joszt L. Trastuzumab deruxtecan receives FDA approval for HER2-rositive solid tumors. AJMC^®. April 5, 2024. Accessed June 12, 2024. https://www.ajmc.com/view/trastuzumab-deruxtecan-receives-fda-approval-for-her2-positive-solid-tumors