MEVITEM—a phase I/II trial of vismodegib + temozolomide vs temozolomide in patients with recurrent/refractory medulloblastoma with Sonic Hedgehog pathway activation

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2021-11, Vol.23 (11), p.1949-1960
• Main Authors: Frappaz, Didier, Barritault, Marc, Montané, Laure, Laigle-Donadey, Florence, Chinot, Olivier, Le Rhun, Emilie, Bonneville-Levard, Alice, Hottinger, Andreas F, Meyronnet, David, Bidaux, Anne-Sophie, Garin, Gwenaële, Pérol, David
• Format: Article
• Language: English
• Subjects: Anilides - therapeutic use; Cerebellar Neoplasms - drug therapy; Cerebellar Neoplasms - genetics; Clinical Investigations; Hedgehog Proteins - antagonists & inhibitors; Hedgehog Proteins - genetics; Humans; Medulloblastoma - drug therapy; Medulloblastoma - genetics; Pyridines - therapeutic use; Temozolomide - therapeutic use
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noab087

Abstract Background Vismodegib specifically inhibits Sonic Hedgehog (SHH). We report results of a phase I/II evaluating vismodegib + temozolomide (TMZ) in immunohistochemically defined SHH recurrent/refractory adult medulloblastoma. Methods TMZ-naïve patients were randomized 2:1 to receive vismodegib + TMZ (arm A) or TMZ (arm B). Patients previously treated with TMZ were enrolled in an exploratory cohort of vismodegib (arm C). If the safety run showed no excessive toxicity, a Simon’s 2-stage phase II design was planned to explore the 6-month progression-free survival (PFS-6). Stage II was to proceed if arm A PFS-6 was ≥3/9 at the end of stage I. Results A total of 24 patients were included: arm A (10), arm B (5), and arm C (9). Safety analysis showed no excessive toxicity. At the end of stage I, the PFS-6 of arm A was 20% (2/10 patients, 95% unilateral lower confidence limit: 3.7%) and the study was prematurely terminated. The overall response rates (ORR) were 40% (95% CI, 12.2-73.8) and 20% (95% CI, 0.5-71.6) in arm A and B, respectively. In arm C, PFS-6 was 37.5% (95% CI, 8.8-75.5) and ORR was 22.2% (95% CI, 2.8-60.0). Among 11 patients with an expected sensitivity according to new generation sequencing (NGS), 3 had partial response (PR), 4 remained stable disease (SD) while out of 7 potentially resistant patients, 1 had PR and 1 SD. Conclusion The addition of vismodegib to TMZ did not add toxicity but failed to improve PFS-6 in SHH recurrent/refractory medulloblastoma. Prediction of sensitivity to vismodegib needs further refinements.