History
In 2015, the United States Food and Drug Administration (FDA) granted the breakthrough therapy designation to venetoclax for people with CLL or SLL who have relapsed, become intolerant to, or refractory to previous treatment.
In April 2016, the FDA approved venetoclax for use in those with CLL who have 17p deletion (deletion located on the chromosome 17 short arm) and who have been treated with at least one prior therapy.[13][14][15][16] Based on overall response rate, the indication was approved under accelerated FDA approval.[8]
The efficacy of venetoclax was tested in a single-arm clinical trial of 106 participants with CLL who have a 17p deletion and who had received at least one prior therapy.[14] Trial participants took venetoclax orally every day, beginning with 20 mg and increasing over a five-week period to 400 mg.[14] Results showed that 80 percent of trial participants experienced a complete or partial remission of their cancer.[14] The trial was conducted in the US, Canada, France, Germany, Poland, the United Kingdom, and Australia.[16]
The application for venetoclax was granted priority review and accelerated approval along with breakthrough therapy designation and orphan drug designation.[14]
Venetoclax was approved for use in the European Union in December 2016.[17]
In June 2018, the FDA granted regular approval to venetoclax for people with CLL or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy.[18]
Approval was based on MURANO (NCT02005471), a randomized (1:1), multicenter, open-label trial of venetoclax with rituximab (VEN+R) versus bendamustine with rituximab (B+R) in 389 participants with CLL who had received at least one prior line of therapy.[18] Participants in the VEN+R arm completed a 5-week ramp-up venetoclax schedule and then received venetoclax 400 mg once daily for 24 months measured from the rituximab start date.[18] Rituximab was initiated after venetoclax ramp-up and given for 6 cycles (375 mg/m2 intravenously on cycle 1 day 1 and 500 mg/m2 intravenously on day 1 of cycles 2–6, with a 28-day cycle length).[18] The comparator arm received 6 cycles of B+R (bendamustine 70 mg/m2 on days 1 and 2 of each 28-day cycle and rituximab at the above described dose and schedule).[18]
The application for venetoclax in combination with rituximab was granted priority review along with a breakthrough therapy designation.[18]
In November 2018, in the United States, venetoclax was approved in combination with azacitidine or decitabine or low-dose cytarabine for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.[19]
Accelerated approval was based on two open-label non-randomized trials in participants with newly diagnosed AML who were >= 75 years of age or had comorbidities that precluded the use of intensive induction chemotherapy.[19] Efficacy was established based on the rate of complete remission (CR) and CR duration.[19]
Study M14-358 (NCT02203773) was a non-randomized, open-label clinical trial of venetoclax in combination with azacitidine (n=67) or decitabine (n=13) in newly diagnosed participants with AML.[19] In combination with azacitidine, 25 participants achieved a CR (37%, 95% CI: 26, 50) with a median observed time in remission of 5.5 months (range: 0.4–30 months).[19] In combination with decitabine, 7 participants achieved a CR (54%, 95% CI: 25, 81) with a median observed time in remission of 4.7 months (range: 1.0–18 months).[19] The observed time in remission is the time from start of CR to data cut-off date or relapse from CR.[19] In a phase 3 study of azacitidine and venetoclax in untreated acute myeloid leukemia not eligible for standard induction chemotherapy, the addition of venetoclax to azacitidine resulted in an improvement in median overall survival (14.7 months versus 9.6 months) and improved complete remission rates.[20]
Study M14-387 (NCT02287233) was a non-randomized, open-label trial of venetoclax in combination with low-dose cytarabine (n=61) in newly diagnosed participants with AML, including participants with previous exposure to a hypomethylating agent for an antecedent hematologic disorder.[19] In combination with low-dose cytarabine, 13 participants achieved a CR (21%, 95% CI: 12, 34) with a median observed time in remission of 6 months (range: 0.03–25 months).[19]
In May 2019, the label was extended by accelerated approval to include all adults with CLL/SLL disregarding prior treatment or mutation status.[21]
Approval was based on CLL14 (NCT02242942), a randomized (1:1), multicenter, open label, actively controlled trial of venetoclax in combination with obinutuzumab (VEN+G) versus obinutuzumab in combination with chlorambucil (GClb) in 432 participants with previously untreated CLL with coexisting medical conditions.[21]
The major efficacy outcome was progression-free survival (PFS) assessed by an independent review committee.[21] The trial demonstrated a statistically significant improvement in PFS for participants who received VEN+G compared with those who received GClb (HR 0.33; 95% CI: 0.22, 0.51; p<0.0001).[21] Median PFS was not reached in either arm after a median follow-up duration of 28 months.[21] The overall response rate was 85% in VEN+G arm compared to 71% in GClb arm, p=0.0007.[21] The trial also demonstrated statistically significant improvements in rates of minimal residual disease negativity (less than one CLL cell per 104 leukocytes) in bone marrow and peripheral blood.[21] Overall survival data were not mature at this analysis.[21]
The FDA used the Real-Time Oncology Review and Assessment Aid Pilot Program for this application and granted priority review as well as orphan drug and breakthrough therapy designations.[21] Approval was granted 3.7 months ahead of the Prescription Drug User Fee Act (PDUFA) date.[21]
