Shifting EU Treatment Paradigms In CLL

The CLL market segment in the EU will now include a first-line combination therapy of AbbVie’s venetoclax and Roche’s obinutuzumab, which has recently been approved by the European Commission.

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Patients newly diagnosed with chronic lymphocytic leukemia (CLL) in Europe now have the option to take a combination of two targeted therapies for a year, after the European Commission approved a 12-month fixed-duration, chemotherapy-free combination of AbbVie Inc.’s Venclyxto (venetoclax) and Roche’s Gazyvaro (obinutuzumab) as a first-line therapy for the condition.

Fixed-duration combination therapy is likely to drive further growth in the worldwide market for CLL therapies, which analysts at Informa Pharma's R&D database, Biomedtracker, say could double to $8bn by 2026, compared with $4.2bn in 2017. CLL is often a disease of the elderly, who may welcome a limited duration therapy and one which is not a chemotherapy.

“Allowing patients to stop treatment will change the way we treat CLL and have a significant impact on patients,” said Michael Hallek, the lead investigator of the CLL14 study which provided evidence of the efficacy of the combination therapy, and director of the Center of Integrated Oncology at the University Hospital, Cologne, Germany. The EU approval of the combination was announced on 12 March by AbbVie and Roche.

According to Biomedtracker, marketed anticancers also driving the future growth of the CLL market segment include Johnson & Johnson/AbbVie’s Bruton’s tyrosine kinase inhibitor, Imbruvica (ibrutinib), which is already approved for continuous use either alone or in combination with obinutuzumab for untreated CLL in the EU, and is being evaluated in other combinations, with venetoclax, or nivolumab (Bristol-Myers Squibb Co.'s Opdivo).  (Also see "Janssen's Imbruvica Leads CLL Market Expansion In Europe" - Scrip, 15 Aug, 2019.)

And other products which may also enter the EU market in the not-to-distant future include AstraZeneca PLC/Acerta Pharma BV’s BTK inhibitor, Calquence (acalabrutinib) and BeiGene Ltd.’s zanubrutinib, and CAR-T therapies.  (Also see "AstraZeneca's Calquence Steps Up in First-Line CLL" - Scrip, 10 Dec, 2019.)

In the US, the venetoclax/obinutuzumab combination, ibrutinib/obinutuzumab, and acalabrutinib with and without obinutuzumab combinations have already gained CLL indications. Venetoclax is being jointly developed by AbbVie and Roche, who market it jointly in the US as Venclexta, while AbbVie markets it alone in Europe, as Venclyxto. Roche markets obinutuzumab both in the US (as Gazyva), and in Europe (as Gazyvaro).

Approval In 31 Countries

The EU approval of venetoclax plus obinutuzumab for first-line CLL use follows the positive opinion arrived at by the Committee for Medicinal Products for Human Use (CHMP) during its January 2020 meeting, and adds to the new treatment options now becoming available to CLL patients. The approval covers 31 European countries – the 27 member states of the EU plus Iceland, Liechtenstein, Norway and the UK.

Venetoclax is a selective inhibitor of B-cell lymphoma (BCL)-2, a protein over-expressed in CLL cells that has anti-apoptotic properties; it is already approved in the EU in combination with rituximab to treat CLL patients who have received at least one prior therapy, and as a monotherapy for CLL in the presence or absence of 17p deletion or TP53 mutation in patients unsuitable for, or failed on a B-cell receptor pathway inhibitor.

The EU approval was based on results from the Phase III CLL14 clinical trial primary analysis (median follow up of 28 months), which demonstrated superior progression-free survival (PFS) as assessed by investigators in patients treated with venetoclax/obinutuzumab compared with patients who received a standard of care chemotherapy regimen of chlorambucil/obinutuzumab (hazard ratio 0.35; 95% CI (0.23,0.53), p<0.0001, medians not yet reached).

And in an updated efficacy analysis of the CLL14 study (median follow-up of 40 months), the median PFS had not been reached in the venetoclax/obinutuzumab arm, and was 35.6 months (95% CI: 33.7,40.7] in the obinutuzumab/chlorambucil arm, giving a hazard ratio of 0.31 (95% CI: 0.22, 0.44). After completing one year of treatment, patients treated with the venetoclax/obinutuzumab had higher rates of undetectable minimal residual disease or complete responses compared with a standard of care regimen.

CLL is the most common form of leukemia, and is a slow-growing cancer diagnosed in around 95.000 patients every year in Europe, that has previously been addressed mainly with chemotherapeutic agents such as the oral DNA alkylating agent, chlorambucil.