FDA APPROVES VENETOCLAX/OBINUTUZUMAB

[Motoli]

For treatment-naive CLL patients. This is a fixed duration treatment!!!

Great news!!

[Sushibruno]

What exactly does this mean?

[Motoli]

FDA Approves Chemotherapy-Free Regimen, Venetoclax Plus Obinutuzumab, as First-Line Treatment for CLL/SLL

By The ASCO Post

Posted: 5/15/2019 4:10:27 PM

Last Updated: 5/15/2019 4:10:27 PM

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The U.S. Food and Drug Administration (FDA) has approved venetoclax (Venclexta) in combination with obinutuzumab (Gazyva) for the treatment of people with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

The approval is based on the results of the randomized phase III CLL14 study, which evaluated 12-month, fixed-duration treatment with venetoclax plus obinutuzumab compared to obinutuzumab plus chlorambucil. Results showed the combination of venetoclax plus obinutuzumab produced a durable and significant reduction in the risk of progression-free survival, as assessed by independent review committee, by 67% compared to obinutuzumab plus chlorambucil, a current standard of care (hazard ratio [HR] = 0.33; 95% confidence interval [CI] = 0.22-0.51; P < .0001).

In addition, venetoclax plus obinutuzumab showed deep and clinically meaningful responses characterized by a higher rate of minimal residual disease (MRD)-negativity in the bone marrow compared to obinutuzumab plus chlorambucil (MRD-negativity of 57% vs 17%) and peripheral blood (MRD-negativity of 76% vs 35%).

Results of the study will be presented at the ASCO Annual Meeting in June 2019. The CLL14 study is being conducted in cooperation with the German CLL Study Group (GCLLSG), headed by Michael Hallek, MD, of the University of Cologne.

The most common adverse reactions with venetoclax plus obinutuzumab were low white blood cell count, diarrhea, fatigue, nausea, low red blood cell count, and upper respiratory tract infection.

The FDA rapidly reviewed and approved the supplemental new drug application under the FDA’s Real-Time Oncology Review and Assessment Aid pilot programs.

[MsLockYourPosts Passed Volunteer in reply to Motoli]

It’s so frustrating when phase lll studies include chlorambucil in the comparator arm! With newer, non chemo drugs now approved, it’s time to do some serious, head to head comparisons of combos using them, or including them with FCR or BR. The results of this study are not a surprise, and great that V+O showed good results, but there is no way that I would volunteer for a randomized study like this one, which is clearly designed to get approval for O+V. I would not want to end up in the arm that is set up to fail in comparison.

Researchers are finding it hard to find enough study participants for the many trials in process and coming up. Studies like this one are one reason many are hesitant about volunteering for trials.

[Motoli in reply to MsLockYourPosts]

There is some logic and discipline in the design of clinical trials and, what we see today, is the result of trials that begun time ago.

It is not feasible nor ethical to do factorial experiments considering all possible drugs available at any given time. Hence, trials are sequential, and some treatments are used as "comparators", e.g., FCR is a "comparator" for treatments in a specific subset of patients (mutated, young and fit, intact TP53).

There are new, recently started, trials that combine venetoclax with ibrutinib, with and without obinutuzumab. The latter is more powerful than rituximab, and it does not follow that, because ibrutinib may inhibit rituximab (if applied concomitantly, but not necessarily sequentially), then venetoclax will inhibit obinutuzumab.

Knowledge is imperfect but progress is sustained. In one year, immunochemotherapy is essentially dead, and now we have an approved fixed duration treatment that is non-chemo!!

The last 4 years have encompassed enormous breakthroughs in CLL treatments.

We have fabulous docs such as Hallek, Rai, Mayo, Furman, Byrd, Brown, Shanafelt and many others!! And some are great scientists as well.

Cheers.

[Corkyrissa in reply to Motoli]

I did the obinutuzumab plus chlorambucil in 2015. Had neutropenia 3 months later. Was ok till 2917 then started ibrutinib in August 2917. God Bless we are all in this together 🙏🏻❤️

[AdrianUK in reply to MsLockYourPosts]

This particular study was only for patients who were considered specifically unfit for FCR and at the time the study was designed and went through ethics committees (which would have been several years ago probably before ibrutinib was licensed at all and certainly before it was licensed for first line treatment) the other arm was the at the time recognised licensed treatment for that specific group of patients. In fact for patients who don’t want ibrutinib or who aren’t fit for it the C+O would still be an option that would be considered I am sure by at least some doctors. Especially if ibrutinib was also unsuitable for some reason. And O is believed to be a lot better than R.

You can argue about whether or not the design is correct NOW for that group of patients but back THEN it definitely was. I would be surprised if some people didn’t still get O+C today with the idea that the relative weakness of the C is compensated for by the strength of the O.

I do think we should be careful about casting aspersions and doubt on the suitability of licensed treatments for CLL to be used according to their licensed indication which has never been rescinded.

You can see that when they designed this study they didn’t dare hope that V alone would be suitable for being a monotherapy treatment for anyone with CLL and due to that uncertainty they restricted it to a group with limited options.

I don’t think we will be seeing many newer trials with c as a comparator and certainly not in monotherapy.

The great thing about this study is that hopefully it will lead to another alternative to C+O which is a combination that until recently for a certain group of people was the only real option they had if Full chemo and more recently ibrutinib was not suitable.

See the BNF entry for O which lists the NICE decision of when it should be used with C (a decision only made in 2015!)

And see the inclusion criteria of the study which showed you had to have significant medical co morbidity to be allowed in clinicaltrials.gov/ct2/show...

[maggiesgrandmom]

Does anyone know if this combination is approved for second treatment in the US?

[AdrianUK in reply to maggiesgrandmom]

As I mentioned earlier the Product information now simply says the drug is licensed for CLL/SLL without further specifying. Having said the companies commercial web page for the drug is just promoting it with rituximab and emphasising the time limited nature.

In terms of advertising they will be in a bind as you can only make a claim based on the data you have in front of you. Bizarrely that means that if you stuck to the clinical trials the later and hence more severe the illness is the less what you combine. Ie for first line take with what we know is a more effective CD20 antibody then second like take with the older less effective CD20 and third line or for 17p take alone!

The idea of the CD20 antibodies is to try and enable a joint effect allowing all drugs to finish after two years for most people. Perhaps with the more severe and established illness there is less benefit anyway since CD20 May be less effective in that group and it may not be realistic to expect to be able to stop all drugs anyway.

Of course in a USA context some doctors are likely to be able to mix and match tho of course that is dependent on what the insurance companies are willing to pay for.

In the Uk we will almost certainly be stuck following the studies rigidly since that is the only combination/ population parings that have been actually studied. That is once the new data is even reviewed and approved and IF and a bit IF NICE decides first line use is economically viable.

[HopeME]

Hi Adrian: At what point does the the UK's National Health Organization (I'm not certain of its official name) start utilizing clinical trial data and subsequent approvals from the US and other countries to treat folks in the UK? I realize cost is a major consideration but this aside isn't the UK's health organization watching trials around the world? It's too bad clinical trials couldn't extend across country boundaries. I realize it is complex but in a perfect world...........