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

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In a recent update, the National Comprehensive Cancer Network (NCCN) recommended capivasertib combined with fulvestrant for hormone receptor–positive and HER2-negative locally advanced or metastatic breast cancer, targeting patients with specific genetic mutations.

Patient with breast cancer taking oral medicine - Image Credit: Seventyfour - stock.adobe.com

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

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