Neratinib Is Effective Against EGFR Exon 18 Mutations in NSCLC

Amy Cummings, MD

Neratinib (Nerlynx) demonstrated single-agent efficacy with significant response and survival rates in tyrosine kinase inhibitor (TKI)-refractory patients with non– small cell lung cancer (NSCLC) whose tumors harbor EGFR exon 18 mutations. Investigators reported that the agent was well tolerated with no major grade 3 or higher toxicities, according to data from an interim analysis of the SUMMIT (NCT01953926) trial presented at the International Association for the Study of Lung Cancer 2021 Targeted Therapies of Lung Cancer Meeting.¹

The phase 2 multicenter, multinational, open-label basket trial looked at the use of the TKI neratinib in different tumor types with 1 or 2 mutations. In an interim analysis of the data, treatment with neratinib yielded significant response results for patients with EGFR exon 18 NSCLC. Eleven patients were included in the analysis from the basket trial: 10 had been pretreated with a TKI, 6 had prior chemotherapy, and 3 had received prior checkpoint inhibitors. Nine patients were pretreated with multiple therapies previously listed. Of the 10 patients who were previously treated with a TKI, the objective response rate was 40% (95% CI, 12%- 74%), which was the primary end point of the analysis.¹

The overall response rate was 60% (95% CI, 26%-88%) in patients previously treated with a TKI and 54% (95% CI, 23%-83%) in all 11 efficacy evaluable patients. Secondary end points of the analysis included duration of response (DOR), progression free survival (PFS), the clinical benefit rate, and safety. The median DOR was 7.5 months (95% CI, 1.9-9.2) in both groups, with a clinical benefit rate of 80%, defined as confirmed complete response, partial response, and stable disease lasting over 16 weeks, for patients previously treated with TKIs. Median PFS was 6.9 months in all patients, but in TKI-pretreated patients PFS lasted 9.1 months.

“Preclinical studies have demonstrated an augmented sensitivity of exon 18 mutations to second-generation irreversible EGFR TKIs, such as neratinib, compared with first- or third- generation inhibitors,” explained Amy L. Cummings, MD, the lead author on the preliminary analysis of the SUMMIT data presented at the conference. “A [previous] proof-of-concept phase 2 trial of neratinib in 167 patients with TKI-refractory EGFR-mutated NSCLC showed 3 partial responses, and 1 stable disease with a median PFS of 52.7 weeks. [This] suggested potential efficacy of [neratinib] in this subset of patients.”

Historically, NSCLC tumors that harbor EGFR mutations respond to TKIs, but responses for the point mutation EGFR exon 18 are less clear, according to findings from previous studies.2 Cummings, a medical oncologist at the David Geffen School of Medicine at UCLA, described a 2015 study evaluating 1402 patients with tumors that harbored EGFR exon 18 mutations, including G719X, E709X, and Del(18). According to the results, these mutations are highly sensitive to neratinib and were present in 3.2% of patients in the analysis.

Investigators retrovirally transfected Ba/F3 cells in the absence of IL3, and NIH/3T3 cells forming foci and indicating their oncogenic abilities for treatment. They then determined the 90% inhibitory concentrations of different TKI inhibitors, finding that cells transfected with G719A and E709K had a higher sensitivity to neratinib through the course of treatment. In comparison with first-generation TKIs to neratinib and afatinib (Gilotrif), patients with lung cancers harboring G719X mutations had a response rate of 80% compared with 35% to 56% in patients taking first-generation TKIs.2 In the analysis of patients in the SUMMIT trial, those whose NSCLC harbored a G719X compound mutation had the shortest duration of treatment at 16 weeks, exhibiting stable disease in that time period (FIGURE1).

Safety was a secondary end point for the study; neratinib was well tolerated by all 11 patients, with just 1 experiencing a treatment-related adverse effect (TRAE) of decreased appetite that was greater than grade 3. Diarrhea was the most common TRAE, with 4 patients reporting grade 1 diarrhea and 1 patient reporting grade 2, but there was no evidence of grade 3 diarrhea. Other grade 1 or 2 TRAEs included vomiting (4 patients), constipation (3 patients), and nausea (3 patients). No patients required modification of treatment due to diarrhea or other TRAEs.

The current analysis evaluated 11 patients from the larger SUMMIT basket study. It involved not only patients harboring an EGFR mutation in their tumors but also those with HER and HER2 mutations in their solid tumors. Other cohorts include neratinib monotherapy in HER2-mutated cancers such as cervical, and salivary gland disease containing EGFR exon 18 mutations, as well as combination treatments with neratinib in breast cancer.³

The cohort data presented at the conference was specifically for patients with NSCLC exhibiting the EGFR exon 18 mutation that was histologically confirmed to not have a curative therapy. Moreover, patients had to have an ECOG performance score of 0 to 2, with 5 patients having a score of 0 and 6 patients having a score of 1. The 11 patients in the cohort received 240 mg of neratinib daily. The median age of patients in the analysis was 67 years, including 5 female patients and 6 male patients. Ten patients were White and there was only 1 Black patient in the cohort. The data cutoff was August 21, 2020.¹

“EGFR mutation represents an important unmet medical need [in patients with NSCLC], and these encouraging luminary results with single-agent neratinib warrant future investigation. Enrollment in the SUMMIT study is currently ongoing,” Cummings concluded.

_References:

_{1. Cummings A, Valentina B, Dooms C, et al. Neratinib efficacy in patients with EGFR exon 18-mutant non-small cell lung cancer (NSCLC): findings from the SUMMIT basket trial. Talk presented at: International Association for the Study of Lung Cancer 2021 Targeted Therapies of Lung Cancer Meeting; February 17-20, 2021; Virtual. Accessed March 11, 2021. https://bit.ly/3rSdPCv}

_{2. Kobayashi Y, Togashi Y, Yatabe Y, et al. EGFR exon 18 mutations in lung cancer: molecular predictors of augmented sensitivity to afatinib or neratinib as compared with first- or third-generation TKIs. Clin Cancer Res. 2015;21(23):5305-5313. doi:10.1158/1078-0432.CCR-15-1046}

_{3. Puma Biotechnology presents interim results from the phase II SUMMIT trial of neratinib for EGFR exon 18-mutated, metastatic non-small cell lung cancer at WCLC 2020. News release. Puma Biotechnology. January 29, 2021. Accessed March 11, 2021. https://bit.ly/3qCw519}