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ASCO 2019: Pick #2 Fixed duration Venetoclax + Obinutuzumab in untreated CLL (chronic lymphocytic leukemia)

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Dr. Brian Koffman, the Executive Vice President (EVP) and Chief Medical Officer (CMO) of the CLL Society, counts down his top ten CLL related abstract from ASCO or the American Society of Clinical Oncology Annual Meeting held May 31 – June 4, 2019, Chicago, IL.

#2

Effect of fixed-duration venetoclax plus obinutuzumab (VenG) on progression-free survival (PFS), and rates and duration of minimal residual disease negativity (MRD–) in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities.

Professor Michael Hallek, from Cologne (Koeln) and the German team that does so much important chronic lymphocytic leukemia research, led this large trial, CLL14 that led to the approval of venetoclax plus obinutuzumab (VenG) as a new fixed duration non-chemo for frontline CLL treatment.

This trial studied patients with significant medical problems or co-morbidities (CIRS or Cumulative Illness Rating Scale >6 or decreased renal function) who would not tolerate harsh therapies and compared the old oral chemotherapy drug, chlorambucil with the new targeted therapy venetoclax, both combined with the potent monoclonal antibody, obinutuzumab.

Chlorambucil plus venetoclax (ClbG) is an already approved therapy for CLL so if this new combination (VenG) proved to be superior in this phase 3 study of 432 patients with 216 in each treatment group, then VenG would likely be approved. And to no-one’s surprise, that is exactly what happened as chlorambucil is an ineffective therapy on its own and venetoclax is extremely potent in treating chronic lymphocytic leukemia.  Both are improved by adding obinutuzumab.

Takeaways:

  • VenG provided superior Progression Free Survival (PFS). Patients lived longer without disease progression.
  • VenG allowed more patients to reach undetectable minimal residual disease (U-MRD or MRD-) with 76% and 56% have no detectable CLL in the peripheral blood and in the harder to clear bone marrow respectively.
  • 3 out of 10 VenG patients had no cancers cells found down to the level of 1 in a million (U-MRD-6). That is impressive.
  • Four out of five VenG patients were U-MRD 1 year after stopping treatment compared to only 27% on ClbG.

Conclusions:

Or maybe I should say “forgone conclusions” as no-one really expected ClbG to come close to VenG in terms of efficacy and it didn’t. Now that the trial is in the books, we have the convincing data, and the combo is approved in the USA and other countries it is would hard to imagine when patient should be treated with ClbG if VenG is available.

One could even argue that this trial never should have been done and a tougher comparator should have been chosen. But while I think we all predicted these results, now we have the proof.

From my perspective, the more interesting studies are asking what is the best non-chemo combo? VenG? Venetoclax plus ibrutinib? Combos with acalabrutinib or duvelisib or the many newer drugs in development?

What is the best to combine or sequence all these great new drugs that we have?

Those trials are coming, but never fast enough for patients in need now.

Here is my brief overview video of the trial, one of the most important abstracts presented at ASCO 2019.

Here is the actual ASCO abstract.

Thanks for reading

Stay strong, we are all in this together

Brian