Biotech Values

[jq1234]

MetMab/cMET/Tivantinib

1) Are these treatments really spectacular - or is their benefit *only* that they allow identification of targeted populations?

I'd say both. Another example of OS HR better than PFS HR.

2) How does the FDA treat these drugs - e.g. MetMab is having to run a ph iii despite spectacular results in a ph ii pre-defined subgroup, yet Criz and PLX4032 got lickety split approval.

They all have to run a confirmatory trial with target population only. Crizotinib ran a single arm confirmatory trial was mainly due to small overall population IMO. Vemurafenib had to run a large randomized trial even after spectacular ph2 result - ph3 was stopped early. This type of trial has much higher probability of being stopped early.

3) Why do they actually reduce PFS in the non-targetted population? I can understand it reducing the OS in the non-targeted pop by general toxicity to the patient - but how does it speed up the tumor growth?

This is a complicated question without firm answer. There are many examples of non-target population with worse result, for example, Iressa (EGFR inhibitor) for those without EGFR mutation.

First, this shows the complicated nature of tumor growth, for those without certain mutation, most likely what promote tumor growth might be different from those with certain mutation. For MET receptor:

Among the many important signaling cascades induced by MET receptor activation are the phosphatidylinositol-3-kinase (PI3K)/Akt and the RAS/mitogen-activated protein kinase (MAPK) pathways. Furthermore, there is a substantial amount of cross-talk and interaction between the MET receptor pathway and those of the EGFR, vascular endothelial growth factor receptor (VEGFR), and beta-catenin/Wnt pathways.

Second, the answer could also be complicated in NSCLC where different mutations (squamous, non-squamous, EGFR, KRAS, wild type etc) often react to different treatments differently. For cMET inhibitor Tivantinib, they picked non-squamous as their ph3 population in combination with erlotinib - later post-hoc analysis showed non-squmous typically with high MET.

An exploratory immunohistochemistry (IHC) analysis was conducted of archival tissue from a concluded Phase 2 clinical trial with tivantinib and erlotinib in NSCLC. Findings confirmed that in this trial non-squamous NSCLC tumors were more often positive for c-MET expression than squamous NSCLC tumors. In this study, 76 percent of evaluable patients with non-squamous tumors were c-MET positive, and 12 percent of evaluable patients with squamous tumors were c-MET-positive, a percentage that is consistent with existing literature.

Data analysis showed that treatment with the combination of tivantinib and erlotinib improved progression-free survival (HR = 0.58, p = 0.28) and overall survival (HR = 0.46, p = 0.21) in patients with non-squamous histology and c-MET-positive tumors, as measured by IHC, compared with patients who received with erlotinib plus placebo.

What this shows is there are other inter-play factors beyond MET high vs MET low these trials typically can't take into consideration.