New Data Support Venetoclax for a Variety of Indications

An an email interview with Pharmacy Times, Ginna Laport, MD, vice president and global head of lymphoma/chronic lymphocytic leukemia (CLL) development franchise at Genentech, discussed the growing body of research surrounding the use of venetoclax (Venclexta; Genentech). In addition to current indications for CLL and acute myeloid leukemia (AML), venetoclax is continuing to be investigated for AML, CLL, myelodysplastic syndromes (MDS), and multiple myeloma (MM).

Can you give an overview of Venclexta's mechanism of action?

Ginna Laport, MD: Venclexta is a first-in-class targeted medicine designed to selectively bind and inhibit the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers and other tumors, BCL-2 builds up and prevents cancer cells from dying or self-destructing, a process called apoptosis. Venclexta blocks the BCL-2 protein and works to help restore the process of apoptosis.

What are its current indications and how is it changing treatment landscapes for these disease states?

Ginna Laport, MD: Venclexta has proven to be an important fixed-duration treatment option and will continue to play a key role in its approved indications. In the United States, Venclexta is approved in combination with Rituxan (rituximab) for the treatment of adult patients with CLL who have received at least one prior therapy; in combination with Gazyva (obinutuzumab) for the treatment of adult patients with previously untreated CLL; and as a monotherapy for the treatment of CLL in the presence of 17p deletion or TP53 mutation in people who are unsuitable for or have failed a B-cell receptor pathway inhibitor.

Venclexta is also approved in combination with azacitidine, decitabine, or low-dose cytarabine for the treatment of newly-diagnosed AML in adults 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy.

What is it currently being investigated for?

Ginna Laport, MD: Genentech is continuing to investigate Venclexta in combination with approved and investigational molecules in a robust clinical development program across several disease areas including AML, CLL, MM, MDS.

An ongoing phase 3 [NCT02993523] study of Venclexta plus azacitidine and a Phase 1b [NCT02203773] study of Venclexta plus a hypomethylating agent for first-line AML treatment in patients with poor-risk cytogenetics, with or without a TP53 mutations. [There is also] a phase 1b [NCT03625505] trial of the investigational combination of Venclexta plus gilteritinib in patients with relapsed or refractory FLT3-mutated AML with or without prior tyrosine kinase inhibitor exposure.

Data on Venclexta in CLL will be presented at [the European Hematology Association; EHA], including results of a 5-year post-hoc analysis of data from the pivotal Phase 3 CLL14 study [NCT02242942] evaluating Venclexta plus Gazyva in first-line CLL. The 5-year results to be presented at EHA 2022 are the longest follow-up to date from CLL14 of this fixed-duration, chemotherapy-free regimen. Venclexta is being evaluated in the phase 3 CRISTALLO trial in patients with previously untreated CLL, with minimal residual disease (MRD) as a primary endpoint.

In July 2021, Venclexta in combination with azacitidine was granted Breakthrough Therapy Designation (BTD) by the FDA for the treatment of adult patients with previously untreated intermediate, high- and very high-risk MDS. The designation was granted based on interim results from the Phase 1b M15-531 [NCT02942290] study investigating Venclexta plus azacitidine in people with previously untreated higher-risk MDS.

Venclexta is being evaluated in the ongoing phase 3 CANOVA trial in patients with relapsed/refractory MM with a t(11;14) mutation. The CANOVA study results will be presented in the second half of 2022.

Where do you see treatment gaps or opportunities that Venclexta could fill?

With our approved indications for Venclexta and our ongoing clinical trials of Venclexta in combination with approved and investigational medicines, we are working toward benefiting as many patients as possible.

We recognize the need for additional treatment options for patients with incurable diseases such as CLL. Our aim is to explore novel treatment combinations with Venclexta for patients with CLL so physicians are able to tailor treatments to the specific needs of each patient at every stage of their treatment journey.

We continue to explore new and potential development options with Venclexta to further improve outcomes in AML. In our ongoing development program in AML, we have demonstrated the following:

• Efficacy and safety data from the phase 3 VIALE-A study in AML published in the New England Journal of Medicine in August 2020 and presented as a late-breaking abstract at EHA 2020 showed the Venclexta-based combination reduced the risk of death (OS) by 34% compared to azacitidine alone (median OS = 14.7 months vs. 9.6 months; HR: 0.66, 95% CI: 0.52–0.85, p<0.001) in people with previously untreated AML.
• Results from a post-hoc analysis of the VIALE-A study presented at EHA 2021 suggest the value of continued research to understand the role of MRD monitoring in AML. Data indicated patients who achieved a composite complete remission and [undetectable minimal residual disease; uMRD] following treatment with Venclexta and azacitidine had increased duration of response, event-free survival and overall survival (OS) compared with those who were MRD-positive following treatment.

What adverse events should pharmacists be aware of?

In CLL/small lymphocytic leukemia, the most common adverse reactions (≥20%) for VENCLEXTA when given in combination with obinutuzumab or rituximab or as monotherapy were neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema.

In AML, the most common adverse reactions (≥30%) in combination with azacitidine or decitabine or low-dose cytarabine were nausea, diarrhea, thrombocytopenia, constipation, neutropenia, febrile neutropenia, fatigue, vomiting, edema, pyrexia, pneumonia, dyspnea, hemorrhage, anemia, rash, abdominal pain, sepsis, musculoskeletal pain, dizziness, cough, oropharyngeal pain, and hypotension.

What is pharmacists' role in treating patients with Venclexta?

Pharmacists play an important role in reviewing a patient’s medicines to identify any potential drug interactions that could lead to adverse events. They also counsel on dose modifications due to toxicity.

Is there anything you would like to add?

At Genentech, we are focused on driving scientific innovation to deliver better outcomes at every step of a patient’s cancer journey. Blood cancers are challenging to treat at all stages, and we are committed to elevating treatment standards by delivering options that provide the best outcomes for patients at all stages of their blood cancer.