Neratinib Shows Promise in HER2-Mutant Cervical Cancer

Anishka D'Souza, MD

Treatment with neratinib (Nerlynx) led to a clinical benefit rate (CBR) of 54.5% in patients with HER2-mutant cervical cancer, according to results from the ongoing phase II SUMMIT basket trial.

In addition, of the 11 patients treated in the updated interim efficacy results, 3 experienced a partial response (PR) to treatment, for an objective response rate (ORR) of 27.3% (95% CI, 6.0-61.0). Duration of response for each patient was 5.6 months, 5.9 months, and 7.4 months, with the longest responder still on treatment at this time.

“Neratinib led to durable responses and disease control in metastatic patients with HER2-mutant cervical cancer,” Anishka D'Souza, MD, assistant professor of clinical medicine, Keck School of Medicine, USC, said during her presentation at the 2019 SGO Annual Meeting. “And this was a relatively well-tolerated treatment.”

Somatic HER2 mutations are observed in approximately 5% of metastatic cervical cancers, are oncogenic, and are associated with poor prognoses, D'Souza said. “Recurrent cervical cancer is a relatively treatment-resistant disease if not resectable, with limited treatment options and few long-term, durable responses,” she added. “Most of these women will die of their disease in a few years, so there is a need for additional treatment options.”

However, neratinib—an oral, irreversible tyrosine kinase inhibitor of EGFR (ERBB1), HER2 (ER882), and HER4 (ER884)—has demonstrated single-agent clinical activity in multiple HER2-mutant cancers.

In the trial—which is evaluating the agent as either a monotherapy or in combination with paclitaxel or trastuzumab (Herceptin) for the treatment of biliary tract, cervical, ovarian, salivary gland, bladder, HR-positive and -negative breast, lung, KRAS/NRAS/BRAF wild-type colorectal cancers, and solid tumors—patients with HER2-mutant cervical cancer received 240 mg of oral neratinib once daily.

Key inclusion criteria were the presence of a documented HER2 mutation and ECOG status of 0 to 2. Patients were ineligible if they had prior treatment with any pan-HER TKI or had symptomatic or unstable brain metastases.

ORR at first post-baseline tumor assessment served as the primary endpoint. Secondary endpoints included confirmed ORR, CBR, progression-free survival (PFS), safety, and biomarkers.

Eleven patients with HER2-mutant cervical cancer were evaluable for efficacy. Median age was 50 years (range, 29-64), and the majority were white (54.5%), and had an ECOG score of 1 (72.7%) and M0 disease (63.6%). Overall, 72.7% of patients had adenocarcinoma, 18.2% had squamous cell carcinoma, and 9.1% had adenosquamous carcinoma.

The median number of total prior regimens was 2 (range, 1-4), including 9 patients (81.8%) with radiation, 7 (63.6%) with surgery, and 6 (54.5%) with bevacizumab.

Six patients derived clinical benefit from the agent, including the 3 PRs as well as 3 patients who experienced stable disease for 16 weeks or more, for a CBR of 54.5% (95% CI, 23.4-83.3). Median PFS was 7 months (95% CI, 0.7-20.1).

Common AEs of any grade included diarrhea (81.8%), nausea (54.5%), decreased appetite (45.5%), abdominal pain (36.4%), dyspnea (36.4%), epistaxis (27.3%), headache (27.3%), malaise (27.3%), peripheral edema (27.3%), pain (27.3%) and vomiting (27.3%). Because diarrhea was the most common AE, high-dose loperamide prophylaxis was mandatory during cycle 1.

No treatment discontinuations or reductions occurred within the cervical cancer cohort. One grade 3 diarrhea occurred in the group, but the duration of the AE was only 1 day.

D'Souza also noted that HER2 mutations can be detected by readily available next-generation assays. Therefore, future directions include the initiation of a liquid biopsy pilot screening program (HER-Seq) to identify patients with HER2 mutations. “This is an ongoing study and we are continuing to enroll patients to expand our data set,” she added.

D’Souza A, Roman LD, Saura C, et al. Neratinib in patients with HER2-mutant, metastatic cervical cancer: findings from the phase 2 SUMMIT ‘basket’ trial. Presented at: 2019 SGO Annual Meeting. March 16-19, 2019; Honolulu, HI. Abstract 18.

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