Notch signaling is implicated in cancer stem cell biology and is an appealing target in the treatment of SCLC. TRXT, a fully human anti-Notch2/3 antibody, has shown preclinical efficacy in SCLC. A randomized phase 1b/2 study was conducted.
This was a randomized, placebo-controlled, multi-center study. Pts were randomized 1:1 to platinum (cisplatin 75 mg/m2 or carboplatin AUC of 5 mg/ml*min on day 1, investigator’s choice) + etoposide (EP) 100 mg/m2 on days 1-3 + TRXT 15 mg/kg on day 1 or EP + placebo (pbo) every 21 days. Chemotherapy was used for 6 cycles, and TRXT/pbo was continued until disease progression. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), safety, and PFS/OS in 5 biomarker groups.
145 pts were enrolled (137 treated). Demographics and baseline pt characteristics were balanced between arms. PFS was similar between the treatment arms (median 5.5 mo in EP+pbo vs 5.5 mo in EP+TRXT, HR = 0.97, p = 0.94). OS was also similar between the treatment arms (median 10.3 mo in EP+pbo vs 9.3 mo in EP+TRXT, HR = 1.01, p = 0.95). ORR was 70.8% in EP+pbo vs 68.6% in EP+TRXT (p = 0.83). There were no statistically significant differences in OS or PFS according to Notch3, Hes1, Hey2, Hey1, or Hes6 gene expression levels. Adverse events (AE) were more common in EP+TRXT; most commonly increased drug-related AEs included diarrhea (33.8/76.8%), thrombocytopenia (17.6/58.0%), decreased appetite (23.5/37.7%), hypokalemia (7.4/33.3%), and vomiting (13.2/31.9%). Most commonly increased grade 3 or higher AEs in the EP+TRXT arm included thrombocytopenia (10.3/40.6%), anemia (20.6/27.5%), pneumonia (4.4/15.9%), diarrhea (0/18.9%), and hypokalemia (4.4/13%). AEs with fatal outcome were more common in EP+TRXT (4.4/8.7%).
Tarextumab in combination with platinum-based therapy did not improve PFS, OS, ORR in previously untreated SCLC. Biomarker analysis failed to establish a predictive marker for TRXT efficacy. Pts treated with TRXT experienced more toxicity. Clinical development of TRXT has been discontinued.
Clinical trial identification
Legal entity responsible for the study
S.V. Liu: Consultant: Ariad, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Genentech, Lilly, Pfizer. A. Kapoun, L. Faoro: Employee and stock holder at OncoMed Pharmaceuticals. All other authors have declared no conflicts of interest.