Neratinib Combo Shows Substantial Benefit in HER2-Mutant mBC

News
Article

According to Manali Bhave, MD, neratinib plus fulvestrant plus trastuzumab and should be considered as a therapeutic option with clinically meaningful benefit in patients with HER2-mutant metastatic breast cancer.

Manali Bhave, MD

Manali Bhave, MD

Treatment with neratinib (Nerlynx) in combination with fulvestrant and trastuzumab (Herceptin) demonstrated a clinically meaningful benefit in patients with hormone receptor-positive, HER2-negative, HER2-mutant metastatic breast cancer (mBC), according to an outcomes and biomarker analysis of the SUMMIT trial (NCT01953926).1

“The SUMMIT study allowed us to understand the clinical utility and implications of targeting HER2 with neratinib in patients with HER2-mutated, HR-positive mBC. While the presence of HER2 mutations in all breast cancers is relatively low, there is a higher incidence of HER2 mutations in HR-positive and particularly lobular breast cancers,” Manali Bhave, MD, told Targeted Oncology™.

“To date, we have utilized IHC or FISH testing to identify HER2 as a target in metastatic breast cancer. However, as we increase genomic sequencing in patients with metastatic breast cancer, we are able to identify targetable mutations such as PIK3CA, ESR1 and now HER2. The objective response rate for patients who received a combination of neratinib + fulvestrant + trastuzumab [Herceptin] was 39% and presents a clinically meaningful treatment option after progression on CDK4/6 inhibitors for patients with HR-positive mBC who harbor a HER2 mutation,” said Bhave, assistant professor, Department of Hematology and Medical Oncology, Emory University School of Medicine and interim medical director, Early Phase I Developmental Therapeutics Winship Cancer Institute of Emory University.

Overall, the study explored multiple cohorts of patients with HER-mutant or EGFR exon 18-mutant solid tumors, and a total of 582 patients were enrolled on the study. Patients were randomized 1:1:1 to receive either neratinib plus fulvestrant and trastuzumab, fulvestrant and trastuzumab alone, or fulvestrant monotherapy. Results from these cohorts were previously reported.

In this analysis, investigators reported results from a cohort of the phase 2 SUMMIT trial which evaluated the triplet compared with fulvestrant alone in patients with HER2-mutated disease, who were previously treated with a CDK4/6 inhibitor.

DNA damage and cancer. DNA, background Generative AI | Image Credit: © Катерина Євтехова - www.stock.adobe.com

DNA | Image Credit: © Катерина Євтехова - www.stock.adobe.com

Confirmed ORR is the primary end point for the breast and cervical cancer cohorts of the SUMMIT trial. The secondary end points being investigated in the study include progression-free survival (PFS), confirmed objective response rate (ORR), ORR, clinical benefit rate (CBR), duration of response (DOR), overall survival, and the incidence of treatment-emergent adverse events.

In 57 patients, the combination of neratinib, fulvestrant and trastuzumab achieved an ORR of 39% (95% CI, 26%-52%). The CBR was 54%. Patients also had a median DOR of 14.4 months (95% CI, 6.4-21.7). The median PFS in the overall population was 8.3 months (95% CI, 6.0-15.1).

When responses were accessed by HER2 mutation type, the best changes in tumor size from baseline were shown in the V777L, S310F, and L755S populations. Specifically, amongst the V777L, L755S, and S310F groups, the ORRs were 63%, 24%, and 33%, respectively. Further, despite the L755S subgroup having a lower response rate compared with the other mutational subgroups, patients with this mutation had a median PFS of 15.1 months.

Efficacy was assessed by histology and responses were seen in the ductal and lobular subgroups, who demonstrated ORRs of 39% and 41%, respectively. Median DOR in the ductal subgroup was 14.3 months (95% CI, 4.1 to not estimable [NE]), the CBR was 61% (95% CI, 39%-80%), and the median PFS was 8.3 months (95% CI, 4.3-18.6).

In the lobular subgroup, the median DOR was 14.4 months (95% CI, 5.0-21.7). The CBR observed in this group was 52% (95% CI, 32%-71%), and the median PFS was 8.3 months (95% CI, 4.2-18.0).

Importantly, HER2 subgroup efficacy was also evaluated. According to central HER2 mutation confirmation, a HER2 mutation was detected in 48 of the 57 patients in the triplet vs fulvestrant cohort. Of those with a HER2 mutation, the ORR was 42%, the CBR was 58%, and the median PFS was 10.2 months (95% CI, 6.1-18.6). In patients for whom no HER2 mutation was detected, there were no response to therapy, and the median PFS was 4.2 months (95% CI, 1.8-6.2).

A number of patients in the study had multiple mutations, including HER2 and ERBB3, HER2 and ESR1, HER2 and CDH1, HER2 and TP53, and HER2 and PIK3CA. Patients who derived the most benefit were those who harbored both HER2 and ERBB3 mutations as well as those with HER2 and ESR1 mutation. This HER2/ERBB3 group had an ORR of 40%, a CBR of 67%, and a median PFS of 25.7 months (95% CI, 1.0-NE). In the HER2/ESR1 group, the ORR was 50%, CBR was 67%, and median PFS was 8.3 months (95% CI, 1.9-18.6).

The HER2/TP53 group appeared to derive the least benefit from the triplet. The ORR in this group was only 23%, with a CBR of 38%. The median PFS for this group was 6.0 months (95% CI, 1.9-8.3).

For safety, the most common treatment-emergent adverse event was diarrhea, which occurred in 93% of patients, and of those, 29% of the patients were in the neratinib plus fulvestrant and trastuzumab arm. Cases of grade 3 diarrhea were seen in 53% of patients. The diarrhea was manageable with dose interruptions in 27 patients and dose reductions in 13. There were 2 withdrawals from study treatment.

These findings underscore the need for an increase in early initiation of next-generation sequencing to detect HER2 mutations at the time of breast cancer diagnosis or endocrine resistance. Further, these findings warrant continued investigation into the efficacy and safety of neratinib-containing regimens in patients with HR-positive, HER2-mutant early breast cancer.

“Genomic sequencing allows us to potentially identify targetable mutations with therapeutic implications. While the incidence of a HER2 mutation/alternation is relatively low, approximately 3%-8% of patients with HR-positive mBC may harbor a HER2 mutation. The SUMMIT study showed an ORR of 39% with neratinib plus fulvestrant plus trastuzumab in patients with HR-positive mBC with HER2 mutations with progression on prior CDK 4/6 inhibitors and should be considered as a therapeutic option with clinically meaningful benefit in this patient population,” Bhave stated.

REFERENCES:

Jhaveri K, Eli LD, Wilders H, et al. Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial. Ann Oncol. Published August 18, 2023. doi:10.1016/j.annonc.2023.08.003

Recent Videos
Related Content