Neratinib Shows Early Activity in EGFR Exon 18–Mutated, Metastatic NSCLC

Neratinib showcased early activity when used in patients with metastatic non–small cell lung cancer who harbor EGFR exon 18 mutations.

Neratinib (Nerlynx) showcased early activity when used in patients with metastatic non–small cell lung cancer (NSCLC) who harbor EGFR exon 18 mutations, according to interim data from the phase 2 SUMMIT trial.1

Results demonstrated that among 10 evaluable patients who received the EGFR inhibitor, 60% (n = 6) had a partial response (PR), with 40% (n = 4) of patients experiencing a confirmed PR. Moreover, 80% (n = 8) of patients derived clinical benefit with neratinib; this was defined as a confirmed complete response, PR, or stable disease for at least 16 weeks. The median duration of response (DOR) with the agent was 7.5 months, while the median progression-free survival (PFS) was 9.1 months.

Because the success criteria for the first and second stages of the Simon’s 2-stage design were met, enrollment to the second stage of this cohort continues, according to Puma Biotechnology, Inc.

“These early study results are very exciting and may prove to be an effective option for [patients with] NSCLC with EGFR exon 18 mutations for whom very few effective treatments exist once they fail first-line FDA approved TKI therapy,” Jonathan Goldman, MD, an associate professor of Hematology & Oncology and associate director of Drug Development and director of Clinical Trials in Thoracic Oncology at UCLA, stated in a press release.

In this cohort of the open-label, multicenter, multinational phase 2 basket trial, investigators set out to examine the safety and efficacy of neratinib in patients with EGFR exon 18–positive NSCLC.

To participate, patients had to have histologically confirmed lung cancers for which no curative therapy is available, documented EGFR exon 18 mutations identified via a local method, an ECOG performance status of 0 to 2, and measurable disease per RECIST v1.1 criteria.2 Patients who received previous treatment with an EGFR or pan-HER TKI were permitted. If patients had received any other anticancer drugs, had symptomatic or unstable brain metastases, or had a known KRAS mutation, they were excluded.

In the open-label, single-arm cohort, patients were administered oral neratinib monotherapy at a daily dose of 240 mg.

The primary end point of the trial was objective response rate (ORR) at first post-baseline tumor assessment, which was at week 8. Key secondary end points comprise ORR per RECIST criteria, DOR, clinical benefit rate, PFS, safety, and biomarkers.

The median age of patients included in the analysis was 67 years; 36% of patients were less than 65 years of age, while 64% were 65 years or older. Additionally, 45% of participants were female, while 55% were male. Fifty-five percent of patients had an ECOG performance status of 1 and 45% had a status of 0. The majority, or 91%, of participants were white. Patients had received a median of 2 prior therapies for metastatic or locally advanced disease. Fifty-five percent had received previous chemotherapy, and 27% had prior checkpoint inhibition.

Notably, 91% of patients had received previous treatment with a TKI. Fifty-eight percent of patients received a reversible first-generation EGFR TKI, either gefitinib (Iressa) or erlotinib (Tarceva); 25% received an irreversible EGFR T790M TKI in the form of osimertinib (Tagrisso); and 17% had been given the irreversible pan-HER TKI afatinib (Gilotrif).

With regard to safety, none of the 11 patients who received neratinib on the trial experienced grade 3 or higher diarrhea. However, 36% (n = 4) of patients had grade 1 diarrhea on the treatment, while 9% (n = 1) had grade 2 diarrhea. The time to first diarrhea was a median of 15 days, while the time to first grade 2 diarrhea was a median of 8 days. The duration of the grade 2 diarrhea was a median of 2 days per episode. No patients needed a dose hold or reduction while receiving treatment. Moreover, no patients experienced diarrhea that resulted in hospitalization.

“We are very pleased with the preliminary activity seen with neratinib in this cohort of patients with EGFRexon 18–mutated NSCLC who have previously been treated with EGFR-targeted TKIs,” Alan H. Auerbach, CEO and president of Puma Biotechnology, added in the release. “We believe that there is a need for new treatments for these patients and we look forward to the further development of neratinib in this patient population.”


  1. Puma Biotechnology announces interim results from the phase II SUMMIT trial of neratinib for EGFR exon 18 mutated, metastatic non-small cell lung cancer. News release. Puma Biotechnology, Inc. November 5, 2020. Accessed November 6, 2020.
  2. SUMMIT (PUMA-NER-5201) basket trial: EGFR exon 19 lung cancer cohort update. Puma Biotechnology, Inc. Accessed November 6, 2020.
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