On November 20, 2021 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported that investigators presented results from the neratinib arm of the Phase II Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT Trial) at the 2021 Society for Neuro-Oncology Annual Meeting (Press release, Puma Biotechnology, NOV 20, 2021, View Source [SID1234595867]). The presentation, entitled "Preliminary results of the neratinib arm in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT): a phase II platform trial using Bayesian adaptive randomization," was presented as an oral presentation in the Abstract Session: Clinical Trials II Session. A copy of the presentation is available on the Puma Biotechnology website.

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The INSIGhT trial is a multisite investigator-initiated Phase II screening adaptive platform trial where patients with newly diagnosed unmethylated glioblastoma who are IDH R132H mutation negative and with genomic data available for biomarker grouping are eligible. All patients receive radiation therapy and temozolomide and then patients are randomized to receive either adjuvant temozolomide or adjuvant treatment with an experimental agent (neratinib). At the initiation of INSIGhT, three experimental arms, each with a proposed genomic biomarker, are tested simultaneously. Initial randomization is equal across arms. As the trial progresses, randomization probabilities adapt on the basis of accumulating results using Bayesian estimation of the biomarker-specific probability of treatment impact on progression-free survival. Treatment arms were allowed to drop because of low probability of treatment impact on overall survival. The primary endpoint of INSIGhT is overall survival (OS). Progression-free survival (PFS) analysis is used to influence randomization. For the neratinib arm of the trial, patients received 240 mg of neratinib daily as a single agent with mandatory loperamide prophylaxis.

For the neratinib arm of the trial, there were 149 patients in the intent-to-treat population, including 81 patients treated with neratinib and 68 patients in the control arm. For the intent-to-treat population, PFS was not significantly longer (HR 0.75; p=0.12, log rank test) with neratinib (median 6.0 months) versus the control arm (median 4.7 months) and there was no significant improvement in OS (HR 1.01; p=0.75) between neratinib (median 13.8 months) vs. the control arm (median 14.7 months). For patients with activation of the EGFR pathway, defined as patients with either EGFR amplification or mutation, PFS was significantly longer (HR 0.58; p=0.04, log rank test) with neratinib (median 6.3 months) vs. the control arm (median 4.6 months); however, there was no significant improvement in overall survival (HR 0.97; p= 0.94) between neratinib (median 14.4 months) vs. the control arm (median 15.3 months).

Neratinib was generally well tolerated in the trial and toxicities for neratinib were similar to that previously described. For the 81 patients treated with neratinib, there were 6 cases (7.4%) of grade 3 diarrhea and no cases of grade 4 diarrhea. No new toxicity signals were identified in the trial.

Isabel Arrillaga-Romany, MD, PhD, Director of Neuro-Oncology Clinical Trials at Mass General Cancer Center, an investigator on the trial who presented the data at SNO, said, "Although preliminary results did not achieve the primary endpoint, subgroup analyses demonstrated improved PFS in patients with EGFR activation and a non-significant trend toward improved overall survival in patients with EGFRVIII mutations, which could warrant further investigation. Additionally, we are very pleased that this trial reinforced feasibility of randomized Bayesian adaptive platform trials for newly diagnosed glioblastoma."

Alan H. Auerbach, Chief Executive Officer and President of Puma, added, "We would like to thank the INSIGHT trial investigators and the patients for their participation in the trial. This is the first data demonstrating an effect of neratinib in EGFR amplified or mutated glioblastoma. While we are not looking to pursue further clinical investigations of neratinib in this indication, we are evaluating the potential to develop a backup compound HKI-357, which has preclinically demonstrated better EGFR activity, in this indication."