The role of ABT-199 in the development of combination therapies in lymphoma.
Following yesterday’s blockbuster win for PCYC and JNJ – the Phase 3 trial versus Arezza was stopped early on clear PFS and OS benefit – it seems a little deflating to return to AbbVie, whose Bcl2 inhibitor ABT-199 has been dogged by Tumor Lysis Syndrome (TLS) problems, some fatal, and recent rumors of oversight problems at one clinical site. I stated the other day that ibrutinib would win the medical marketplace for B cell lymphoma treatment, based on its impressive suite of clinical trials, and the results announced yesterday support that opinion. I still believe that combo therapy is the critical path forward in this field, and ibrutinib and idelalisib are the clear leading candidates for combo treatment protocols.
However, ABT-199 remains a wildcard and could be transformative if developed carefully. The drug demonstrates ORR and CR responses in B cell lymphoma that are very dramatic, as detailed earlier. In the spirit of our earlier January posts, lets look at the clinical trial spectrum for ABT-199. There are five trials listed for ABT-199 monotherapy in oncology, including the phase 1 extension. These include trials in relapsed/resistant NHL, CLL, high-risk CLL (del17p), MM, and AML. The inclusion of acute myeloid leukemia (AML) distinguishes ABT-199 from the other lymphoma drugs, and is based on the mechanism of action and profiling of different tumor types for sensitivity to Bcl2 inhibition.
The combination trials are very narrow in scope and reflect the fact that the ABT-199 is partnered with Roche/Genentech, and therefore the anti-CD20 mAbs used are those developed by Roche, that is, rituximab and obinutuzumab (Gazyva). Obinutuzumab is already approved for the treatment of previously untreated CLL, i.e., as first line therapy. The obinutuzumab trial with ABT-199 is sponsored by Roche/Genentech, illustrating the depth of this collaborative effort. Roche has an ongoing preclinical BTK program, and it will be interesting to see if a combination trial with ABT-199 is eventually filed.
Here are the combination trials listed:
|Trial Number||Phase||date filed||Combination||Indication|
|NCT01594229||1||4/20/2012||bendamustine/rituximab||rrNHL and DLBCL|
|NCT01671904||1||8/10/2012||bendamustine/rituximab||CLL (rr & untreated)|
|NCT01682616||1b||6/26/2012||rituximab||rrCLL and SLL|
|NCT01685892||1||9/12/2012||Obinutuzumab||CLL (rr & untreated)|
The ultimate success of the program will depend in large measure on controlling the TLS issue. Its worth reminding ourselves that TLS did not suddenly become a toxicity concern in the treatment of B cell lymphoma. It occurs with anti-CD20 treatment and with chemotherapy treatment, as a result of triggering the death of a large number of tumor cells. The problem for ABBV and ABT-199 is that TLS does not seem to be related to dose given, remaining somewhat unpredictable (aside from worrying when patients present with bulky disease, which indicates huge number of tumor cells in the lymph nodes, bone marrow, etc). The recent outcry over moving one patient from one dose to another (150mg to 1200mg if I remember right) seems a little silly when a dose of 50mg can trigger TLS in a lymphoma patient. That said, the burden is on AbbVie to demonstrate that they can provide better efficacy than the competing drugs (ibrutinib and idelalisib), safely. If they can do this, I predict that ABT-199 will have a big role to play in the treatment of B cell lymphoma. If they continue to struggle then this drug will will still have a role, but may be relegated to second line or even salvage therapy status. Given the resources behind it, from both AbbVie and Roche, I imagine that a huge effort will be brought to bear on understanding and controlling the TLS toxicity.