Neratinib Displays Encouraging Efficacy in HER2-Mutant Metastatic Breast Cancers

Based on updated findings from the phase 2 SUMMIT trial, a neratinib triplet and neratinib doublet can induce responses in patients with HER2-positive breast cancer.

The combination of neratinib (Nerlynx), fulvestrant (Faslodex), and trastuzumab (Herceptin) achieved positive overall response rates (ORRs) in patients with heavily pretreated hormone receptor (HR)–positive/HER2-negative, HER2-mutant metastatic breast cancer, and neratinib/trastuzumab showed promise in those with metastatic HER2-mutant triple-negative breast cancer (TNBC), updated findings from the phase 2 SUMMIT trial (NCT01953926) show.1

Komal Jhaveri, MD, a medical oncologist with Memorial Sloan Kettering Memorial Cancer Canter, presented the data from the ongoing trial during the 2021 San Antonio Breast Cancer Symposium. Neratinib appeared to have efficacy in patients irrespective of histology or distribution of mutation.

“Tumor shrinkages were noted in patients whose tumors harbored oncogenic mutations across all domains. It was interesting to see that responses were seen for both ductal and lobular histologies,” she said. “These responses were also seen despite co-mutations in PIK3CA and ERBB3. These lollipop plots suggest that HER2 mutations were distributed throughout the kinase, transmembrane, and the extracellular domains, and responses were reported in patients with HER2 mutations in any of these domains in all neratinib-containing cohorts.”

For patients with HR-positive, HER2-mutated metastatic breast cancer who had previously received CDK4/6 inhibitors (n = 33), the triplet regimen induced an ORR of 42.4%, including 1 complete response (CR; 3.0%) and 13 partial responses (PR; 39.4%). The clinical benefit rate was 51.5%. The median duration of response (DOR) was 14.4 months (95% CI, 6.4–not evaluable [NE]) with a median progression-free survival (PFS) of 7.0 months (95% CI, 4.2-12.7). The median duration of treatment was 6.5 months (95% CI, 0.7-22.1).

In the TNBC cohort (n = 18), neratinib plus trastuzumab induced an ORR of 33.3% including 1 CR (5.6%) and 5 PRs (27.8%); the best ORR was 38.9%. The median DOR was NE and the median PFS was 6.2 months (95% CI, 2.1-8.2). The median duration of treatment was 4.4 months (95% CI, 0.3-15.4).

HER2 mutations are relatively rare and occur in approximately 2% to 12% of solid tumors, depending on the histology type. Neratinib is an oral, irreversible, pan-HER tyrosine kinase inhibitor that is currently indicated for use in patients with HER2-positive— amplified/overexpressed—breast cancer in the adjuvant and metastatic setting. C

SUMMIT is an open-label, multicenter, multinational, basket study evaluating the safety and efficacy of daily neratinib for the treatment of patients who have solid tumors with activating HER2 (ERBB2) mutations or lung cancers with EGFR exon 18 mutations.

Patients in the TNBC cohort received 240 mg of daily neratinib and 8 mg/kg trastuzumab initially followed by 6 mg/kg of trastuzumab every 3 weeks. In the metastatic breast cancer cohort, which comprised patients with hormone receptor (HR)–positive, HER2-negartive disease, patients who previously received CDK4/6 inhibitors were previously enrolled in a non-randomized cohort and received 240 mg of daily neratinib plus 500 mg of fulvestrant on day 1 and 15 of cycle 1 and 8 mg/kg of trastuzumab every 4 weeks, followed by 6 mg/kg of trastuzumab every 3 weeks thereafter.

The trial was later amended to randomly assign patients with metastatic breast cancer to neratinib/trastuzumab/fulvestrant, fulvestrant/trastuzumab, or fulvestrant alone. Seven patients were included in each of these randomized cohorts. Patients in the non–neratinib-containing arms could crossover at disease progression.

All patients in SUMMIT received anti-diarrheal prophylaxis with loperamide monotherapy for the first 2 treatment cycles.

In the non-randomized metastatic breast cancer cohort (n = 26), the efficacy results showed that the ORR for patients who received was 46.2%, which consisted of all PRs; the best ORR was 57.7%, which was also the clinical benefit rate. The median DOR was 14.4 months (95% CI, 6.4-NE) and the median PFS was 8.2 months (95% CI, 4.0-15.1). The median duration of treatment was 8.7 months (range, 1.0-22.1).

In the randomized cohorts, there was 1 PR and 1 CR in the triplet arm and no responses in the non–neratinib-containing arms. The median PFS was 6.2 months (95% CI, 2.1-NE) with the triplet compared with 3.9 months (95% CI, 1.9-4.1) with fulvestrant/trastuzumab and 4.1 months (95% CI, 1.6-4.1) for fulvestrant alone.

“This proves the hypothesis that neratinib appears to be critical for the inhibition of HER2 mutations,” Jhaveri said. “Based on these results, the independent data monitoring committee recommended to close the non–neratinib-containing cohorts and to further expand the triplet arm.”

In the combined metastatic breast cancer cohort, 48.5% of patients had an ECOG score of 0 or 1. Most patients had lobular (66.7%) or ductal (27.3%) disease. Patients received a median of 5 (range, 1-11) prior regimens for locally advanced or metastatic disease and all received prior endocrine therapy. Twenty-seven (81.8%) patients received prior chemotherapy.

In the TNBC cohort, 50% of patients had an ECOG score of 0 and 50% had a score of 1. Patients had other (44.4%), ductal (38.9%), or lobular (16.7%) histologies. No patient had mixed ductal and lobular disease. Patients received a median of 3.5 (range, 1-7) prior therapies.

Diarrhea was the most common all-grade treatment-emergent adverse event, appearing in 90.9% of patients in the metastatic breast cancer group and 88.9% of the TNBC group. There was no incidence of grade 4 diarrhea in either group but 45.5% of patients with MBC and 16.7% in the TNBC cohort experienced grade 3 diarrhea.

“Grade 3 diarrhea was higher than is anticipated with the triplet combination and compliance with loperamide prophylaxis is imperative,” Jhaveri said.

The neratinib/fulvestrant combination showed modest efficacy in patients with heavily pretreated estrogen receptor-positive, HER2-mutant MBC but failed to meet prespecified criteria for clinical benefit rate in data from part 2 of the phase 2 MutHER study (NCT03289039) during the 2021 AACR Annual Meeting.2 That study enrolled a total of 40 patients, half of whom had ductal histology and 42.5% with lobular.


1. Jhaveri K, Haeseong P, Waisman J, et al. Neratinib + fulvestrant + trastuzumab for hormone-receptor positive, HER2-mutant metastatic breast cancer, and neratinib + trastuzumab for HER2-mutant metastatic triple-negative disease: latest updates from the SUMMIT trial. Presented at 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS4-10.

2. Ma CX, Luo J, Freedman R, et al. A phase II trial of neratinib (NER) or NER plus fulvestrant (FUL) (N+F) in HER2 mutant, non-amplified (HER2mut) metastatic breast cancer (MBC): Part II of MutHER. Presented at: 2021 AACR Annual Meeting; April 10-15, 2021; virtual. Abstract CT026.