Neratinib Elicits Durable Responses in Metastatic or Recurrent HER2-Mutated Cervical Cancer

Single-agent neratinib (Nerlynx) produced robust responses in patients with metastatic or recurrent HER2-mutated cervical cancer, according to updated data from phase 2 SUMMIT basket trial (NCT01953926) presented at the 2022 ESMO Congress.

Among 22 treated patients, neratinib elicited an objective response rate (ORR) of 18.2% (95% CI, 5.2%-40.3%), which included a complete response (CR) rate of 4.5%, a partial response (PR) rate of 13.6%, and a stable disease (SD) rate of 27.3%. The clinical benefit rate (CBR) was 45.5% (95% CI, 24.4%-67.8%).

When broken down by histology, patients with adenocarcinoma (n = 18) experienced an ORR of 22.2% (95% CI, 6.4%-47.6%) with the agent, which comprised a CR rate of 5.6%, a PR rate of 16.7%, and a SD rate of 33.3%. In this group, the CBR with neratinib was 55.6% (95% CI, 30.8%-78.5%). No patients with squamous cell carcinoma (n = 4) responded to treatment with the agent.

“Neratinib led to durable responses and disease control in patients with metastatic or recurrent HER2-mutant cervical cancer,” lead study author Claire F. Friedman, MD, of Memorial Sloan Kettering Cancer Center, and colleagues, wrote in a poster featuring the data. “[The] safety profile [of the agent] was consistent with previous reports in metastatic HER2-positive or HER2-mutant tumors.”

Patients with recurrent or metastatic cervical cancer who progress on frontline platinum-based chemotherapy regimens have a wide range of active drugs available, but response rates have not exceeded 24%. As such, there is a need for novel therapeutic options for this population. Moreover, to date, no targeted therapies have been developed for those with metastatic disease.

In February 2020, the FDA approved neratinib for use in combination with capecitabine for patients with advanced or metastatic HER2-positive breast cancer who have received 2 or more prior anti-HER2–based regimens in the metastatic setting.2 In cervical cancer, and other HER2-mutant cancers, the agent has showcased encouraging single-agent activity, according to prior data from SUMMIT. At the 2022 ESMO Congress, investigators shared final data from the cervical cancer cohort.

The international, open-label, multicohort, multitumor, SUMMIT basket trial enrolled patients with persistent, recurrent, or metastatic cancers with a documented HER2 mutation and an ECOG performance status of 0 to 2.

Patients were excluded from the trial if they received prior treatment with a pan-HER TKI, such as lapatinib (Tykerb), afatinib (Gilotrif), dacomitinib (Vizimpro), or neratinib (Nerlynx). Moreover, patients could not have symptomatic or unstable brain metastases.

Study participants received neratinib monotherapy at 240 mg daily. The trial utilized a Simon 2-stage design. If at least 1 response was recorded in the first evaluable 7 patients, the cohort would expand to stage 2 with 18 patients. If there were at least 4 responses in stage 2, the cohort would expand further or break out.

The primary end point of the trial was ORR at the time of the first post-baseline tumor assessment, which was done at week 8. Secondary end points included confirmed ORR, duration of response (DOR), CBR, progression-free survival (PFS), safety, and biomarker analysis.

Among the 22 patients with cervical cancer, the median age was 55 years (range, 29-74). The majority of patients were White (68.2%) and had an ECOG performance status of 1 (68.2%). Moreover, 31.8% of patients had FIGO stage I disease at the time of diagnosis, 22.7% had stage II disease, 9.1% had stage III disease, and 27.3% had stage IV disease; this information was missing in 9.1% of patients. Most patients (81.8%) had adenocarcinoma.

Additionally, 59.1% of patients had a positive human papillomavirus status. Furthermore, 63.6% of patients underwent prior surgery, and 77.3% received prior radiotherapy. Prior systemic treatments included platinum-based chemotherapy (100.0%), bevacizumab (Avastin; 72.7%), and pembrolizumab (Keytruda; 18.2%).

The median duration of treatment with neratinib was 3.7 months (range, 0.5-67.5).

Additional data showed that among all patients with cervical cancer, the median DOR was 7.6 months (95% CI, 5.6-12.3) and the median PFS was 5.1 months (95% CI, 1.7-7.2). When broken down by histology, those with adenocarcinoma experienced a median DOR of 7.6 months (95% CI, 5.6-12.3) and a median PFS of 5.5 months (95% CI, 3.7-10.9). Patients with squamous cell carcinoma experienced a median PFS of 1.7 months (95% CI, 0.7-3.5).

Regarding specific HER2 mutations, patients with S310F or S310Y single mutations (n = 10) achieved an ORR of 30% (95% CI, 6.7%-65.2%) with neratinib; the CBR in this group was 40.0% (95% CI, 12.2%-73.8%). The median DOR in these patients was 9.3 months (95% CI, 5.6-12.3), and the median PFS was 3.7 months (95% CI, 0.5-14.1).

Those with S310F or S310Y double mutations (n = 3) experienced an ORR of 33.3% (95% CI, 0.8%-90.6%), with a CBR of 66.7% (95% CI, 9.4%-99.2%). In this group, the median DOR was 5.9 months (95% CI, not estimable [NE]–NE) and the median PFS was 6.5 months (95% CI, 1.7-7.7).Notably, no responses were observed in patients with D769H or D769N mutations (n = 2), other kinase domain mutations (n = 2), or transmembrane domain mutations (n = 5).

Additionally, study authors noted that prior use of bevacizumab did not appear to affect the efficacy of neratinib.

The safety profile of neratinib in patients with HER2-mutated cervical cancer was consistent with other reports of its single-agent use. All patients experienced at least 1 any-grade adverse effect (AE), and 45.5% of patients had at least 1 grade 3 or higher AE. Additionally, 84.6% of patients experienced at least 1 treatment-related AE (TRAE) of any grade; 22.7% had at least 1 TRAE that was grade 3 or higher.

The most common TRAEs of any grade included diarrhea (81.8%), nausea (40.9%), vomiting (22.7%), decreased appetite (18.2%), abdominal pain (18.2%), and dysgeusia (18.2%). Regarding grade 3 or higher TRAEs, 22.7% of patients experienced diarrhea and 4.5% of patients had abdominal pain. Study authors noted that instances of diarrhea were manageable with antidiarrheal prophylaxis.

“These encouraging results support further investigation of neratinib in patients with persistent, metastatic or recurrent HER2-mutant cervical cancer following platinum failure,” the study authors concluded.

Reference

Friedman CF, D’Souza AA, Tinker AV, et al. Neratinib in HER2-mutant, recurrent/metastatic cervical cancer (R/M CC): updated findings from the phase 2 SUMMIT basket trial. Ann Oncol. 2022;33(suppl 7):S803-S804. doi:10.1016/j.annonc.2022.07.687