MLN8237 (ALISERTIB), AN INVESTIGATIONAL AURORA A KINASE INHIBITOR, IN PATIENTS (PTS) WITH NON-SMALL CELL LUNG CANCER (NSCLC), SMALL CELL LUNG CANCER (SCLC), BREAST CANCER (BRC), HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC), AND GASTROESOPHAGEAL CANC

Background

Aurora A Kinase plays a key role in centrosome maturation and spindle formation in mitosis, and is frequently amplified or overexpressed in various human cancers. MLN8237 is an investigational, oral, selective AAK inhibitor being evaluated in pts with hematologic and non-hematologic malignancies. Here we report ph 2 results from an ongoing multicenter ph 1/2 trial of MLN8237 in pts with advanced solid tumors (NCT01045421).

Methods

Pts aged ≥18 y with relapsed/refractory NSCLC, SCLC, BrC, HNSCC, or GE adenocarcinoma, ECOG PS 0–1, measurable disease by RECIST, and ≤2 prior cytotoxic chemotherapy regimens (≤4 in BrC) were eligible. Ph 2 enrollment followed a two-stage Simon's design; to proceed to the second stage, at least two responses were required in the first 20 response-evaluable pts enrolled in that tumor cohort. The primary and secondary ph 2 objectives were overall response rate and safety profile, respectively. Response was assessed by RECIST v1.1. MLN8237 was administered orally as an enteric-coated tablet at the MTD of 50 mg BID for 7 d followed by 14-d rest in 21-d cycles (determined in ph 1).

Results

As of March 29 2012, 226 pts have been treated in ph 2: HNSCC (n = 54), BrC (n = 53), GE adenocarcinoma (n = 53); SCLC (n = 40), and NSCLC (n = 26); median age was 61 y (range 30–88). Best responses achieved are: partial response in 17 pts (BrC, n = 6; SCLC, n = 4; H&N, n = 3; GE adenocarcinoma, n = 3; NSCLC, n = 1), and stable disease in 92 pts. Median cycles of treatment is 2 (range: 1–15). 89% of pts reported drug-related adverse events (AEs); the most common included neutropenia (44%), fatigue (38%), alopecia (38%), diarrhea (30%), and anemia (27%). Grade ≥3 drug-related AEs were seen in 53% of pts and included neutropenia (36%), leukopenia (10%), and anemia (10%). 21 pts (9%) discontinued due to AEs; there were 19 on-study deaths (none drug-related).

Conclusions

These emerging ph 2 data suggest antitumor activity for MLN8237, and further support a developing safety profile that is generally well tolerated across a range of solid tumors.

Disclosure

B. Melichar: Honoraria Roche, Novartis, advisory board Roche.

R.H. Alvarez: Consultancy (BMS, Roche), Honoraria (BMS), Research funding (GSK, Cylene Pharmaceuticals, Millennium Pharmaceuticals Inc., Novartis, Prometheus Therapeutics and Diagnostics, Eisai).

J. Bennouna: Honoraria (AMGEN), Membership on Board of Directors, Speakers Bureau, Advisory Committee (Roche, AMGEN, Sanofi-Aventis).

C. Schusterbauer: Employment (Millennium Pharmaceuticals, Inc.).

B. Zhang: Employment (Millennium Pharmaceuticals, Inc.) and stock ownership (Takeda).

E. Benaim: Employment (Millennium Pharmaceuticals, Inc.) and stock ownership (Takeda).

P. Rosen: Research funding (Millennium Pharmaceuticals Inc.).

All other authors have declared no conflicts of interest.

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