Approval of Obinutuzumab (O) or Gazyva in Combination with Chlorambucil (C) for Untreated CLL Patients with Other Co-morbidities in Quebec, England and Wales

Take Away Points:

• Obinutuzumab (O) has been approved for use in combination with chlorambucil (C) for untreated CLL patients with other medical problems.
• The C-O combination resulted in improved outcomes when compared to chlorambucil alone or C in combination with rituximab (R).

Approvals:

We are sharing the good news that on June 2, 2015, Quebec, often the leader in getting new therapies to patients in Canada, is the first province to approve the use of obinutuzumab (O) in combination with chlorambucil (C), old school chemotherapy. The press release is here. Obinutuzumab or Gazyva (also known as Gazyvaro in Europe) is a third generation monoclonal antibody (mAb).

Also on June 2, 2015, there was a similar approval for patients in England and Wales. These two approvals, occurring on both sides of the Atlantic, were based on the trial reported in NEJM that demonstrated the superiority of the C-O over C-R (rituximab) or C alone in untreated frailer CLL patients with co-morbidities. Details of the NICE approval are here.

This provides for a gentle but effective option for patients who have other medical problems besides CLL, and that is the majority of elderly CLL patients, a group that has been excluded from many other clinical trials.

The approval is for the combination, and is not approved for treatment with the non-chemo antibody alone. In the USA, where Gazyva has been approved since Nov. 1, 2013, some doctors are using it off label as a single agent in the hope for similar efficacy and the avoidance of the risks associated with chemo, even gentle chemo. Once a drug is approved in the USA, a physician can use it pretty much however she or he wants. Getting insurance to pay for an off-label use is a whole other issue.

Clinical Trial:

This trial showed that when O was added to C that the combo resulted in meaningfully increased response rates, overall survival (OS) and progression free survival (PFS) compared to C alone. This is not surprising as comparing a new therapy to C alone is often chosen, as C is an easier comparator to defeat in the type of head to head trial the FDA favors to gain drug approval.

What was more impressive was that the C-O combination prolonged PFS and improved complete response rates (CR) from 20.7% compared to the complete response rates of 7.0% achieved by the combination of C-R.

The rate of neutropenia (low neutrophil count) was highest in the C-O cohort, but there were no more serious infections. Other side effects were similar in all the groups, except of course for the high rate of infusion reactions commonly seen with the first dose of O.

So at least in combination with chlorambucil, O seems to be a better choice than R.

Does this mean that O is always as better choice, say in combination with bendamustine (B) or fludarabine and cyclophosphamide (FC)?  It is tempting to think so, but without the data, we don’t know.

Background on obinutuzumab and chlorambucil:

For more on how the chlorambucil, an alkylating agent works, please see our discussion of chemotherapy.

For a discussion of obinutuzumab and how it differs from other monoclonal antibodies, please jump to this page and if you want to go deeper, follow the links found there.

Brian Koffman 6/10/15