CTNI-05. 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
Authors: Arrillaga-Romany Isabel , Trippa Lorenzo , Fell Geffrey , Lee Eudocia Quant , Rahman Rifaquat , Touat Mehdi , McCluskey Christine , Bruno Jennifer , Gaffey Sarah , Drappatz Jan , Lassman Andrew , Galanis Evanthia , Ahluwalia Manmeet , Colman Howard , Nabors L Burt , Hepel Jaroslaw , Elinzano Heinrich , Kaley Thomas , Mellinghoff Ingo K , Schiff David , Chukwueke Ugonma , Beroukhim Rameen , Nayak Lakshmi , McFaline-Figueroa J Ricardo , Batchelor Tracy , Lu-Emerson Christine , Bi Wenya Linda , Arnaout Omar , Peruzzi Pierpaolo , Haas-Kogan Daphne , Tanguturi Shyam , Cagney Daniel , Aizer Ayal , Welch Mary , Doherty Lisa , Lavallee Maria , Fisher-Longden Brittany , Dowling Shanna , Geduldig Jack , Watkinson Fiona , Santagata Sandro , Meredith David , Chiocca E Antonio , Reardon David , Ligon Keith , Alexander Brian , Wen Patrick 
Published: November 2021

Abstract

BACKGROUND
EGFR is amplified in over 50% of glioblastoma and 20-30% have EGFRvIII mutations. Neratinib is a potent inhibitor of EGFR/HER2 approved for metastatic HER2+ breast cancer. To efficiently evaluate the potential impact of neratinib on overall survival (OS) in newly-diagnosed glioblastoma and to simultaneously develop information regarding potential genomic biomarker associations, neratinib was included as an arm on the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. INSIGhT is a phase II platform trial using response adaptive randomization and deep genomic profiling to more efficiently test experimental agents in MGMT unmethylated glioblastoma and accelerate identification of novel therapies for phase III testing. Initial randomization was equal between neratinib, control, and two other experimental arms but subsequent randomization was adapted based on efficacy as determined by progression-free survival (PFS). We report preliminary results for the neratinib arm.

METHODS
Patients with newly diagnosed MGMT-unmethylated glioblastoma were randomized to receive either radiotherapy with concomitant and adjuvant temozolomide or standard radiochemotherapy followed by adjuvant neratinib (240 mg daily). Treatment continued until progression or development of unacceptable toxicities. The primary endpoint was OS. Association between neratinib efficacy and EGFR amplification was also investigated.

RESULTS
There were 144 patients (70 control; 74 neratinib). Neratinib was reasonably well-tolerated with no new toxicity signals identified. PFS was compared (HR 0.84; p=0.38, logrank test – not significant) between the neratinib (median 6.05 months) and control (median 5.82 months) arms. For patients EGFR pathway activation the PFS HR was 0.53 (p-value=0.03 – significant, median PFS: neratinib, 6.21 months, control, 5.26 months). However, there was no significant improvement in OS in EGFR amplified/mutated patients (HR 1.05; p-value 0.87) between neratinib (median 14.2) compared to the control arm (median 14.6).

CONCLUSION
Neratinib prolonged PFS in the EGFR positive subpopulation but there was no overall PFS benefit, or any OS improvement.