On June 23, 2017 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported the presentation of results from the pivotal Phase 2 study of VENCLYXTO (venetoclax), a first-in-class oral B-cell lymphoma-2 (BCL-2) inhibitor (Press release, AbbVie, JUN 23, 2017, View Source [SID1234519652]). VENCLYXTO monotherapy responses in 158 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and 17p deletion showed that 77 percent (95% confidence interval [CI]: 69.9, 83.5) achieved an overall response rate (ORR = complete remission [CR] + complete remission with incomplete marrow recovery [Cri] + partial remission [PR] + nodular partial remission [nPR]) (primary endpoint),1 18 percent achieved a complete remission (CR +CRi) (secondary endpoint), 53 percent achieved a partial remission (PR), 6 percent achieved an nPR,3 and 27 percent achieved blood minimal residual disease (MRD) negativity, as measured by flow cytometry (exploratory endpoint).1 These results, which were based on an investigator assessment, will be presented in an oral session on Sunday, June 25, at the 22nd European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress in Madrid.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

VENCLYXTO monotherapy was granted conditional marketing authorization in the EU for the treatment of CLL in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor; and for the treatment of CLL in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.3 VENCLYXTO is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S.

"These response rates associated with venetoclax treatment in patients with CLL and 17p deletion who relapsed or were refractory to prior treatments were evaluated in one of the two pivotal studies that were included in the EU summary of product characteristics for VENCLYXTO for use in this patient population," said Prof. Dr. Stephan Stilgenbauer of the Department of Internal Medicine at Ulm University in Germany, who will present the study results at the EHA (Free EHA Whitepaper) Annual Congress. "In addition, we are encouraged by the results of the secondary and exploratory endpoints included in this Phase 2 trial."

Design and Results of Pivotal Phase 2 Study Presented at EHA (Free EHA Whitepaper) Congress
In the pivotal Phase 2 study, patients with relapsed/refractory CLL harboring 17p deletion received VENCLYXTO 400 mg daily following a four to five-week dose titration phase until they experienced progressive disease or discontinued due to other reasons.1 Assessment of minimal residual disease (MRD) in peripheral blood was performed with the first clinical assessment of complete remission (CR) or partial remission (PR) with nodes less than 2 cm and then every 12 weeks until MRD negativity.1 This means fewer than one CLL cell in 10,000 leukocytes (white blood cells) could be detected.4 A total of 158 study participants had received a median of two prior therapies, and 11 percent had previously received a B-cell receptor signaling inhibitor.1 The median age of study participants was 67 years, and the median duration of VENCLYXTO therapy was 16.7 months (range: 0-34.4).1

An initial analysis of results from 107 patients by an independent review committee showed that VENCLYXTO resulted in an overall response rate (ORR = CR + CRi + PR +nPR) of 79 percent (95% confidence interval [CI]: 70.5, 86.6), a CR +CRi rate of 7 percent, a PR rate of 69 percent, and an nPR rate of 3 percent.3 Subsequently, 51 additional patients were enrolled in a safety expansion cohort.1 Results of the full study cohort of 158 patients showed the investigator-assessed ORR was 77 percent (95% CI: 69.9, 83.5),1 the CR +CRi rate was 18 percent, the PR rate was 53 percent, and the nPR rate was 6 percent.3 Among 18 patients who had received prior BCR inhibitor treatment, the ORR was 61 percent and the CR rate was 11 percent.1 Among the full trial cohort of 158 patients, 27 percent demonstrated MRD negativity (exploratory endpoint) in peripheral blood by flow cytometry.1 A total of 101 patients were evaluable for blood MRD by flow cytometry.1 Progression-free survival (PFS) and overall survival (OS) (secondary endpoints) over 24 months were estimated to be 52 percent and 72 percent, respectively.1

In the study, the most commonly reported adverse events were neutropenia (42 percent), nausea (37 percent), diarrhea (37 percent), anemia (24 percent) and fatigue (22 percent).1 The most common grade 3-4 adverse events were neutropenia (39 percent), thrombocytopenia (15 percent) and anemia (14 percent). Infection rate (77 percent all grades, 22 percent grade 3-4) and spectrum were consistent with the underlying disease.1 The rate of laboratory tumor lysis syndrome (TLS) was 5 percent, with no cases of clinical TLS.1

Phase 1b Venetoclax Data Presented at EHA (Free EHA Whitepaper) Congress
Results from an ongoing Phase 1b investigational study of venetoclax were also presented at the EHA (Free EHA Whitepaper) Congress. This open-label, multicenter study is evaluating the safety and tolerability of venetoclax in combination with rituximab in patients with relapsed CLL/small lymphocytic leukemia (SLL).5 The primary objectives of this study are to assess the safety profile, determine the maximum tolerated dose, and establish the recommended Phase 2 dose of venetoclax when administered in combination with rituximab.5

This analysis evaluated responses in 49 patients with previously-treated CLL/SLL who were treated with venetoclax and rituximab therapy.2 Patients who achieved CR or MRD negativity could stop therapy and remain on the study. Patients who manifested progressive disease (per iWCLL criteria) while off therapy could re-initiate venetoclax and subsequent rituximab therapy. A total of 21 patients discontinued the study.2 A total of 12 had progressive disease while on therapy (five with Richter’s transformation and seven with CLL progression).2 The other nine patients either withdrew consent (five), failed to report for follow-up evaluations (one), discontinued due to adverse events related to venetoclax (one with tumor lysis syndrome and one with worsening peripheral neuropathy) or discontinued due to adverse events considered not related to therapy (one).2 A total of 16 patients stopped venetoclax per protocol.2

In the Phase 1b study, the most commonly reported adverse events were upper respiratory tract infection, neutropenia and mild GI issues. Grade 3-4 adverse events were reported for 37 patients (76 percent); the most common were neutropenia (53 percent), thrombocytopenia (16 percent) and anemia (14 percent).2

As of April 5, 2017, the ORR was 86 percent. 51 percent of patients had achieved an investigator-assessed CR/CRi, 35 percent had achieved PR/nPR, and 59 percent had achieved MRD negativity.2

"We are encouraged by the early results from this Phase 1b study of continuous venetoclax in patients with relapsed/refractory CLL/SLL and in those who received venetoclax in combination with rituximab," said Gary Gordon, M.D., Ph.D., vice president, oncology clinical development, AbbVie. "We remain committed to developing and delivering therapies that address unmet needs in certain patients with CLL."

About VENCLYXTO (venetoclax)
VENCLYXTO (venetoclax), an oral B-cell lymphoma-2 (BCL-2) inhibitor, is indicated for the treatment of chronic lymphocytic leukaemia (CLL) in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor; and for the treatment of CLL in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.3 It is also being evaluated for the treatment of patients with various blood cancer types.3,6,7,8,9 The BCL-2 protein prevents apoptosis (programmed cell death) of some cells, including lymphocytes, and can be overexpressed in CLL cells.3 VENCLYXTO, which is given once-daily, is designed to selectively inhibit the function of the BCL-2 protein.3

VENCLYXTO is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research with venetoclax, which is currently being evaluated in Phase 3 clinical trials for the treatment of relapsed/refractory CLL and frontline CLL, along with studies in several other cancers.

Venetoclax is currently approved in several countries in Europe, as well as in Argentina, Australia, Mexico, Puerto Rico, Israel, USA, and Canada. AbbVie, in collaboration with Roche and Genentech, is currently working with regulatory agencies around the world to bring this medicine to eligible patients in need.

Important VENCLYXTO (venetoclax) EU Safety Information
Contraindications

Hypersensitivity to the active substance or to any of the excipients. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase. Concomitant use of preparations containing St. John’s wort.

Special Warnings & Precautions for Use
Tumour lysis syndrome (TLS), including fatal events, has occurred in patients with previously treated CLL with high tumour burden when treated with VENCLYXTO. VENCLYXTO poses a risk for TLS in the initial 5-week dose-titration phase. Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLYXTO and at each dose increase. Patients should be assessed for risk and should receive appropriate prophylaxis for TLS. Blood chemistries should be monitored and abnormalities managed promptly. More intensive measures (including IV hydration, frequent monitoring and hospitalization) should be employed as overall risk increases.

Neutropenia (grade 3 or 4) has been reported and complete blood counts should be monitored throughout the treatment period.

Live vaccines should not be administered during treatment or thereafter until B-cell recovery.

Drug Interactions
CYP3A inhibitors may increase VENCLYXTO plasma concentrations. At initiation and dose-titration phase: Strong CYP3A inhibitors are contraindicated due to increased risk for TLS and moderate CYP3A inhibitors should be avoided. If moderate CYP3A inhibitors must be used, physicians should refer to the SmPC for dose adjustment recommendations. At steady daily dose: If moderate or strong CYP3A inhibitors must be used, physicians should refer to the SmPC for dose adjustment recommendations.

Avoid concomitant use of P-gp and BCRP inhibitors at initiation and during the dose titration phase. CYP3A4 inducers may decrease VENCLYXTO plasma concentrations.

Avoid coadministration with strong or moderate CYP3A inducers. These agents may decrease venetoclax plasma concentrations.

Co-administration of bile acid sequestrants with VENCLYXTO is not recommended as this may reduce the absorption of VENCLYXTO.

Adverse Reactions
The most commonly occurring adverse reactions (>=20%) of any grade were neutropenia/neutrophil count decreased, diarrhoea, nausea, anemia, upper respiratory tract infection, fatigue, hyperphosphatemia, vomiting and constipation.

The most frequently occurring adverse reactions (>=2%) were pneumonia, febrile neutropenia and TLS.

Discontinuations due to adverse reactions occurred in 9.1% of patients and dosage adjustments due to adverse reactions occurred in 11.8% of patients.

Specific Populations
VENCLYXTO may cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid pregnancy during treatment. Advise nursing women to discontinue breastfeeding during treatment.

This is not a complete summary of all safety information. See VENCLYXTO full summary of product characteristics (SmPC) at www.ema.europa.eu. Globally, prescribing information varies; refer to the individual country product label for complete information.