Biotech Values

[iwfal]

ARQL -

[This significantly increases the chance of success for the ongoing phase 3 trial ARQ 197 Plus Erlotinib Versus Placebo Plus Erlotinib for the Treatment of Non-squamous, Non-small-cell Lung Cancer]

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.

FYI - After checking the 'existing literature', of which there is remarkably little, I would disagree with their statement. See

http://www.ncbi.nlm.nih.gov/pubmed/22052229 - which says:

The proportion of high MET gene dosage was 10.58% (22/208) with higher incidence in squamous cell carcinoma (11.86%) and smokers (16.18%), although the differences with adenocarcinoma and nonsmokers were nonsignificant.

I believe this is a test based upon gene copies, so not exactly the same thing as Roche found most predictive (protein levels) and ARQL tested for (they used IHC in your above cite). But still not comforting.
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http://cancerres.aacrjournals.org/content/65/4/1479.long

Among NSCLC, strong c-Met expression (2+) was evident in 6 of 9 (67%) adenocarcinoma, 4 of 7 (57%) large cell, and 4 of 7 (57%) squamous cell carcinoma. We did not see any significant total c-Met staining in normal lung tissues ( Fig. 2A). - and note that they used IHC.

Very small samples - but not aligned with the, as you note elsewhere, post hoc results seen by ARQL.

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And a final note - there are a variety of hints that Met expression in nsclc is highly dependent on number of previous chemo regimens (see, for example, the first cite above which notes: High MET gene dosage was significantly associated with higher tumor stage (stage I + II versus stage III + IV; p = 0.0254) and prior chemotherapy for stage III + IV adenocarcinoma patients (35.71% versus 7.41%; p = 0.0145) ). It is not the only cite that indicates this - but I'd agree the data is still sparse.

So, why does this matter? In the ARQL ph ii they allowed all categories of second line with no limits to number of previous chemos. They got an ITT OS HR of 0.88. In their ph iii they are using a protocol more similar to Roche's for their ph ii - <=2 previous chemo regimens. And Roche got a ITT OS HR=1.09.

All told the ARQL ph iii feels a little too based upon post hoc mining. And even for a viable drug that adds huge risk IMO.

Comments welcome.

PS There is one piece of supporting data which cannot be entirely discounted - and that is that Roche too noted that the squamous patients did less well than the non-squamous. As usual, interpreting ph ii data is generally an inherently uncertain operation - but in general I would suggest uncertainty normally doesn't bode particularly well for the ph iii. (FWIW My working assumption regarding the squamous met data is that the data all aligns if you believe that squamous patients generally have fewer chemo options and no TKIs and thus fewer previous regimens to build up met levels.)