Bad news for anti-stem cell approaches

OncoMed announced setbacks in the development of drugs aimed at cancer stem cells:

  1. Tarextumab, which targets Notch 2/3 receptors, plus chemotherapy failed to slow progression-free survival in patients with small cell lung cancer compared to chemotherapy, alone. Biomarkers indicative of Notch pathway activation did not reveal activity of the treatment;
  2. Brontictuzumab, which targets Notch 1, was not tolerable in combination with Taiho Oncology’s Lonsurf (trifluridine/tipiracil) for the third-line treatment of patients with colorectal cancer;
  3. Demcizumab, which targets DLL4 (an activator of Notch), failed a midstage trial in patients with treatment-naive pancreatic cancer;
  4. Bayer decided not to license vantictumab (wich targets Frizzled membrane proteins that activate the Wnt pathway) and ipafricept (which binds Wnt ligands).

These compounds figured prominently in the OncoMed pipeline. we have discussed them on this blog, previously, in the context of bone toxicity induced by vantictutmab. So, the drug was exhibiting in vivo activity, albeit, off-target.

Regarding tarextumab:

The PINNACLE trial randomised 145 previously untreated patients with extensive-stage SCLC to receive tarextumab in combination with etoposide plus carboplatin or cisplatin, or to receive chemotherapy plus placebo. 

According to OncoMed, results showed that median PFS in the tarextumab arm was 5.6 months, versus 5.5 months in the placebo group. Meanwhile, median OS was 9.3 months among tarextumab-treated patients, compared with 10.3 months for those who only received chemotherapy. Additionally, overall response rates in the tarextumab and placebo groups were 68.5 percent and 70.8 percent, respectively. OncoMed also noted that five individual Notch biomarkers had failed to identify a definitive subset of patients with a treatment effect on either PFS or OS. 

We wait to see whether targeting Notch and Wnt via other compounds and approaches can provide clinical benefit.