Neratinib Joins NCCN Guidelines for HER2-Mutated Cervical Cancer

The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Cervical Cancer were updated to include neratinib (Nerlynx) as a second- or later-line treatment option for patients with recurrent or metastatic cervical cancer harboring a HER2 mutation.1,2

The agent carries a Category 2A recommendation, and the NCCN deemed neratinib “useful in certain circumstances” for this patient population.

The update to the NCCN Guidelines was supported by data from the phase 2 SUMMIT trial (NCT01953926), which showed that evaluable patients with HER2-mutated cervical cancer (n = 22) achieved a confirmed objective response rate (ORR) of 18.2% (95% CI, 5.2%-40.3%), which included a complete response rate of 4.5% and a partial response rate of 13.6%.3 Stable disease lasting at least 16 weeks was reported in 27.3% of patients, and the clinical benefit rate (CBR) was 45.5% (95% CI, 24.4%-67.8%). The median progression-free survival (PFS) and duration of response (DOR) were 5.1 months (95% CI, 1.7-7.2) and 7.6 months (5.6-12.3), respectively.

Notably, the confirmed ORR was 22.2% (95% CI, 6.4%-47.6%) in patients with adenocarcinoma (n = 18); patients with squamous cell carcinoma (n = 4) experienced a confirmed ORR of 0% (95% CI, 0%-60.2%). The respective CBRs for these populations were 55.6% (95% CI, 30.8%-78.5%) and 0% (95% CI, 0%-60.2%).

“We are pleased with the additional inclusion of neratinib in the NCCN Guidelines for Cervical Cancer for patients with HER2 activating mutations. Physicians use the NCCN Guidelines as the standard resource for determining the best course of treatment for patients,” Alan H. Auerbach, chief executive officer and president of Puma Biotechnology, stated in a news release.1 “We believe the updated NCCN Guidelines will increase awareness, which will help assist patients, their caregivers, and their health care providers in making informed decisions while treating this significant unmet need in advanced cervical cancer.”

Somatic HER2 mutations occur in approximately 3% to 6% of patients with cervical cancer and have been associated with a poor prognosis.3

SUMMIT was an open-label, multi-cohort, multi-tumor basket trial. The cervical cancer cohort included patients at least 18 years of age with histologically confirmed recurrent or metastatic cervical cancer who had no curative treatment available and harbored a somatic activating HER2 mutation. Other key inclusion criteria consisted of an ECOG performance status of 0 to 2 and adequate hematopoietic, hepatic, kidney, and cardiac function.

Prior treatment with another HER2-directed TKI was not permitted, and patients needed to complete radiotherapy more than 14 days prior to the start of study treatment.

Enrolled patients received neratinib at 240 mg once per day until disease progression, unacceptable toxicity, or withdrawal of consent. Loperamide prophylaxis was mandatory during cycle 1; the agent was given at 12 mg per day on days 1 to 14, then 8 mg per day on days 15 to 28, and the dose could not exceed 16 mg per day.

Confirmed ORR served as the trial’s primary end point. Secondary end points included CBR, DOR, PFS, and safety.

Regarding safety (n = 22), the rates of any-grade and grade 3 or higher treatment-related adverse effects (TRAEs) were 86.4% and 22.7%, respectively. The most common any-grade TRAEs were diarrhea (81.8%), nausea (40.9%), vomiting (22.7%), dysgeusia (18.2%), decreased appetite (18.2%), abdominal pain (18.2%), constipation (9.1%), dry skin (9.1%). headache (4.5%), asthenia (4.5%), fatigue (4.5%), and malaise (4.5%). Grade 3 or higher TRAEs included diarrhea (22.7%) and abdominal pain (4.5%).

No grade 4 diarrhea was reported. Two diarrhea events led to dose interruptions or holds; however, no patients experienced dose reductions or treatment discontinuation due to diarrhea.

References

1. Puma Biotechnology’s Nerlynx included in NCCN Clinical Practice Guidelines for the treatment of cervical cancer with a HER2 mutation. News release. December 23, 2024. Accessed December 23, 2024. https://investor.pumabiotechnology.com/news-releases/news-details/2024/Puma-Biotechnologys-NERLYNX-Included-in-NCCN-Clinical-Practice-Guidelines-for-the-Treatment-of-Cervical-Cancer-with-a-HER2-Mutation/default.aspx
2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Cervical Cancer Version 1.2025. December 19, 2024. Accessed December 23, 2024. https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf
3. Friedman CF, D'Souza A, Bello Roufai D, et al. Targeting HER2-mutant metastatic cervical cancer with neratinib: final results from the phase 2 SUMMIT basket trial. Gynecol Oncol. 2024;181:162-169. doi:10.1016/j.ygyno.2023.12.004