NCCN Guidelines Add Neratinib for Patients With Breast Cancer

Positive data from 2 phase 2 studies, SUMMIT and MutHER, have led to the addition of neratinib as a monotherapy or in combination to the National Comprehensive Cancer Network Guidelines for patients with breast cancer.

Neratinib (Nerlynx) has been added to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for patients with breast cancer.1

These updated NCCN guidelines recommend neratinib with or without fulvestrant (Faslodex) or trastuzumab (Herceptin) and fulvestrant for patients with estrogen receptor (ER)-positive/HER2-negative or ER-negative/HER2-negative metastatic stage IV breast cancer and activating mutations in the HER2 gene as detected by next generation sequencing of tumor tissue or ctDNA.

The basis of the NCCN’s decision comes from findings of the phase 2 SUMMIT (NCT01953926) trial and the phase 2 MutHER (NCT01670877) trial.

In the update, the NCCN also included dose-escalation in the neratinib dosing schedule for patients with recurrent unresectable or metastatic breast cancer. Previously, the neratinib dose-escalation schedule was included in the 2022 NCCN Guidelinesfor breast cancer under preoperative/adjuvant therapy regimens as an approach to improve the tolerability of neratinib in the treatment of adjuvant HER2-positive breast cancer.

The SUMMIT trial included 45 patients who had received prior CDK4/6 inhibitor therapy and had locally assessed hormone receptor (HR)-positive/ HER2-negative metastatic breast cancer. Data from the trial demonstrated a clinical benefit and showed that treatment with neratinib combined with fulvestrant and trastuzumab led to an objective response rate of 38%. This included 1 complete response (CR; 2%) and 16 partial responses (PR; 36%).2

Moreover, the median progression-free survival (PFS) of 8.2 months (95% CI, 4.2-15.1), the clinical benefit rate was 47% (95% CI, 32%-62%), and the median duration of response was 14.4 months (95% CI, 6.4-not evaluable [NE]).

Regarding safety, the most common any-grade adverse events (AEs) seen in patients with HR-positive disease who were administered treatment with the triplet included diarrhea (90.2%), nausea (72.5%), vomiting (52.9%), and fatigue (43.1%). Grade 3 AEs that were the most frequent in this group were diarrhea (51.0%), vomiting (7.8%), decreased appetite (7.8%), and fatigue (5.9%). Additionally, there were 2 grade 4 AEs reported, including 1 patient who had a coma and 1 patient who had muscle weakness.

Results from the phase 2 MutHER trial (NCT01670877) which evaluated neratinib in combination with fulvestrant in 40 patients with HER2-mutated, non-amplified metastatic breast cancer also influenced this addition to the NCCN guidelines.3 Patients enrolled in the trial had a median age of 63 years (range, 35-82) and a median of 3 prior lines of therapy in the metastatic setting.

In the study, oral neratinib was given at the standard dose of 240 mg once a day along with fulvestrant administered as an intramuscular injection at 500 mg on day 1 and day 15 of the first 28-day cycle, then on the first day of each subsequent cycle.

Findings showed that the median PFS was 24.0 weeks (95% CI, 15.7-31.0) with the combination. Three PRs were observed, and 1 case of stable disease at progression was seen with the addition of trastuzumab for 24 weeks or more.

For the safety profile, the combination was consistent with prior studies and the most common AEs included diarrhea (85%), nausea (53%), and fatigue (50%). Diarrhea was the most common grade 3 AE (25%) and no grade 4 AEs were observed. Notably, no patients discontinued treatment due to an AE.

Neratinib was first granted FDA approval in 2017 as extended adjuvant treatment for patients with early-stage, HER2-positive breast cancer following a 12-4 recommendation from the FDA’s Oncologic Drugs Advisory Committee.

Approval was based on data from the phase 3 ExteNET trial (NCT00878709) and the phase 2 CONTROL trial. In the primary analysis of the ExteNET trial, the invasive disease-free survival (iDFS) rate at 5 years was 90.2% (95% CI, 88.3%-91.8%) vs 87.7% (95% CI, 85.7%-89.4%) for patients administered placebo. Additionally, after a median follow-up of 5.2 years (interquartile range, 2.1-5.3), patients given neratinib had 116 iDFS events vs 163 for those given placebo (HR, 0.73; 95% CI, 0.57-0.92; P =.0083).

Puma biotechnology’s NERLYNX® included in NCCN clinical practice guidelines for the treatment of breast cancer with a HER2 mutation. News release. Puma Biotechnology. February 1, 2023. Accessed February 2, 2023.
Oaknin A, Friedman CF, Roman LD, et al. Neratinib in patients with HER2-mutant, metastatic cervical cancer: findings from the phase 2 SUMMIT basket trial. Gynecol Oncol. 2020;159(1):150-156. doi:10.1016/j.ygyno.2020.07.025
Ma CX, Luo J, Freedman RA, et al. The Phase II MutHER Study of Neratinib Alone and in Combination with Fulvestrant in HER2-Mutated, Non-amplified Metastatic Breast Cancer. Clin Cancer Res. 2022;28(7):1258-1267. doi:10.1158/1078-0432.CCR-21-3418

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