Final ASH13 SnapShot: AbbVie’s ABT-199

Update on ABT-199. 12-3-2013, by @PDRennert 

I reviewed the status of ABT-199 back in August, following ASCO (see link). At the time I felt the drug was being overlooked in the hype around ibrutinib and idelalisib. This was based on impressive response rates and the sense that AbbVie had gotten a handle on how to dose safely. After all, tumor lysis syndrome (TLS) is not uncommon in the treatment of lymphomas, and can be dealt with by dose modification or intervention.

At ASH we get a further look at this drug. Abstract #872, to be presented by J. Seymour, introduces a modified dosing regimen. Patients (rrCLL/SLL, n = 56) were given single doses of ABT-199 at day -3 or day -7, then started on daily dosing after that. This is a Phase 1 monotherapy trial designed to determine MTD. The efficacy readouts were pretty dramatic. ORR = 84% with CR = 21% and PR = 63%. Within the CR group (n = 12), 8 patients had no or very low minimal residual disease. There were 12 discontinuations due to progressive disease (21%). The response rate was not related to del(17p) status but the PR rate was lower in fludarabine-refractory patients (these patients are all at high risk).

Notably, among the usual AEs (diarrhea, neutropenia, URIs, etc) there was an 11% grade 3/4 TLS rate. This is 6 patients. Problematically, TLS was not clearly dose associated: 2 @ 50mg, 1 @ 100mg, 2 @ 200mg and 1 @ 1200mg, this last one resulting in sudden death. So dose optimization remains in progress.

The observation that response was not related to del(17q) status or other aberrations in the TP53 locus in rrCLL patients will be discussed in more detail by M.A. Anderson (Abstract #1304).

M. Davids (Abstract #1789) will present a similar study in a variety of rrNHL patients, including MZL, MCL, DLBCL, FL and WG. Of the 32 patients enrolled and followed for a median time of 6 months, 18 discontinued due to progressive disease (that’s 56%). AEs were typical (nausea, diarrhea, cytopenias, URIs). There were 2 mild episodes of TLS. For FL and DLBCL, doses of 600mg or higher were required for efficacy. The responses were good given this difficult mix of patients. Note that the text and table in this abstract don’t entirely line up, so best to hear the current results at the meeting. The implication here however is that ABT-199 is safer in these patient populations than in rrCLL, a theme we also heard at ASCO.

Aside from the clinical data there is an awful lot of preclinical modeling using cell lines or patient derived cells in vitro or in vivo (mouse). The point of all this nice work is to show the potential of combination therapy using ABT-199 along with other drugs. A few examples:

-  2-DG + ABT-199 kills all Myeloma subtypes (#1921)

-  ibrutinib + ABT-199 is effective against MCL cells and CLL cells (#645 and # 3080)

-  imatinib + ABT-199 kills chronic phase CML cells

-  BTK inhibitor R406 + ABT-199 kills DLBCL cells

   etc, etc

The CML observation points to another trend, which is efficacy of ABT-199 in settings beyond NHL, including ALL (#3919), AML (#885) and MM (#4453). There are others…

On balance this remains an exciting and potentially important drug. The issue of TLS in certain subtypes of NHL remains to be solved, while in other, difficult NHLs there appears to be clear and compelling efficacy with less toxicity.