691P - Everolimus (EVE) exposure in patients (pts) with previously treated advanced gastric cancer (aGC)

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Anti-Cancer Agents & Biologic Therapy
Gastric Cancer
Presenter Salah-Eddin Al-Batran
Authors S. Al-Batran1, N. Tebbutt2, J. Xu3, G. Luppi4, H. Smith5, C. Costantini6, W. Cheung5, S. Rizvi7, T. Sahmoud8, L. Shen9
  • 1Medizinische Klinik Ii Für Hämatologie Und Onkologie, Institut für klinische Forschung (IKF) am Krankenhaus Nordwest - UCT, Universitäres Centrum für Tumorerkrankungen Frankfurt, 60488 - Frankfurt/DE
  • 2Medical Oncology, Austin Hospital, AU-3084 - Heidelberg/AU
  • 3Digistive Oncology, 307 Hospital of PLA, Beijing/CN
  • 4Oncology, Azienda-Ospedaliero Universitaria di Modena, Modena/IT
  • 5Oncology, Novartis Pharmaceuticals Corporation, Florham Park/US
  • 6Oncology, Novartis Pharma AG, Basel/CH
  • 7Oncology Clinical Research And Development, Novartis Pharmaceuticals, US-07932 - Florham Park/US
  • 8Global Oncology Clinical Development, Novartis Pharmaceuticals, US-07932 - Florham Park/US
  • 9Department Of Gi Oncology, Peking University Cancer Hospital, 100142 - Beijing/CN

Abstract

Background

In GRANITE 1, EVE did not significantly improve overall survival (OS) over best supportive care (BSC) in previously treated AGC (median OS 5.4 mo with EVE vs 4.3 mo with BSC; HR, 0.90; P = .1244). Median progression-free survival (PFS) was 1.7 mo with EVE vs 1.4 mo with BSC (HR, 0.66; P < .0001). This analysis examined EVE exposure and its relationship with efficacy and safety.

Methods

Pts with confirmed AGC who progressed after 1 or 2 chemotherapy lines were randomized 2:1 to EVE 10 mg/d + BSC or placebo + BSC. Primary endpoint was OS. EVE Cmin and Cmax were determined in whole blood from samples collected predose and 1 and 2 h postdose on day 1 of wk 5 using liquid chromatography/mass spectrometry (lower limit of quantification 0.3 ng/mL). Cox models adjusted for region (Asia/rest of world [ROW]) and gastrectomy (yes/no) were used to explore relationships between PFS and time-normalized (TN) EVE Cmin. A linear mixed-effects model was used to explore the relationship between change from baseline in target lesion size and TN Cmin. Kaplan-Meier curves for select adverse events (AEs) by TN Cmin categories were prepared.

Results

656 pts were enrolled from Jul 2009 to Dec 2010 and received EVE (n = 439) or placebo (n = 217). Median age was 62 y, 74% were men, 55% were from Asia, and 50% had previous gastrectomy. Mean ± SD Cmin and Cmax were 16.1 ± 10.8 ng/mL and 72.8 ± 36.5 ng/mL in pts receiving EVE 10 mg/d at sampling. EVE Cmin and Cmax were similar in pts from Asia and ROW and in pts with and without gastrectomy. No significant relationship between TN Cmin and PFS was observed (HR, 0.83; 95% CI, 0.65-1.06). A 2.72-fold increase in TN Cmin corresponded to a significant 7.6% reduction from baseline in target lesion volume. No differences in noninfectious pneumonitis, stomatitis/oral mucositis, or infection/infestation risk in pts with TN Cmin <10 ng/mL vs 10-25 ng/mL were observed. More renal events occurred in the TN Cmin 10-25 ng/mL group (4 vs 1 in TN Cmin <10 ng/mL group).

Conclusion

EVE exposure was consistent with that previously observed for EVE 10 mg/d. Region and prior gastrectomy did not impact exposure. Increased EVE Cmin corresponded to a greater reduction in tumor volume. EVE exposure did not affect the risk of selected clinically notable AEs except for renal events (more common with higher Cmin).

Disclosure

S. Al-Batran: Research grants and honoraria for serving on advisory boards for Novartis, Sanofi-Aventis, and Roche.

N. Tebbutt: Undertaken research sponsored by Novartis.

G. Luppi: Member of Novartis advisory board.

H. Smith: Novartis employee; owns stock in Novartis.

C. Costantini: Novartis employee.

W. Cheung: Novartis employee; owns stock in Novartis.

S. Rizvi: Novartis employee; owns stock in Novartis.

T. Sahmoud: Novartis employee; owns stock in Novartis.

L. Shen: Research funding from Novartis.

All other authors have declared no conflicts of interest.