Olutasidenib for R/R AML With a Susceptible IDH1 Mutation
The FDA approved olutasidenib capsules for adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test. The FDA also approved the Abbott RealTime IDH1 Assay to select patients for olutasidenib.
Approval was based on Study 2102-HEM-101 (NCT02719574), an open-label, single-arm, multicenter clinical trial that included 147 adult patients with relapsed or refractory AML with an IDH1 mutation confirmed using the above assay. Olutasidenib was given orally,150 mg twice daily, until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation. The median treatment duration was 4.7 months (range: 0.1-26 months). Sixteen (11%) patients underwent hematopoietic stem cell transplantation following olutasidenib.
Efficacy was established on the rate of complete remission (CR) plus complete remission with partial hematologic recovery (CRh), the duration of CR+CRh, and the rate of conversion from transfusion dependence to independence. The CR+CRh rate was 35 percent (95% CI: 27%, 43%), including 32 percent CR and 2.7 percent CRh. The median time to CR+CRh was 1.9 months (range: 0.9-5.6 months), and the median duration of CR+CRh was 25.9 months (95% CI: 13.5 months, not reached).
Among the 86 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 29 (34%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 61 patients who were independent of both RBC and platelet transfusions at baseline, 39 (64%) remained transfusion independent during any 56-day post-baseline period.
The most common adverse reactions (>=20%) were nausea, fatigue/malaise, arthralgia, constipation, leukocytosis, dyspnea, fever, rash, mucositis, diarrhea, and transaminitis. The prescribing information contains a Boxed Warning alerting health care professionals and patients about the risk of differentiation syndrome which can be fatal.
The recommended olutasidenib dose is 150 mg taken orally twice daily on an empty stomach (at least 1 hour before or 2 hours after a meal) until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treatment is recommended for a minimum of 6 months allowing for clinical response.
Update On Atezolizumab U.S. Indication for Metastatic Bladder Cancer
The U.S. indication of atezolizumab has been voluntarily withdrawn for the treatment of adults with locally advanced or metastatic urothelial carcinoma (mUC, bladder cancer) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (PD-L1-stained tumor-infiltrating immune cells covering >=5% of the tumor area) or are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.
Industry experts made this decision following consultation with the FDA, in accordance with the requirements of the FDA's Accelerated Approval Program. The Phase III IMvigor130 trial was designed to evaluate atezolizumab plus platinum-based chemotherapy for the first-line treatment of people with previously untreated advanced bladder cancer. IMvigor130 was the designated postmarketing requirement to convert the accelerated approval to regular approval, and it did not meet the co-primary endpoint of overall survival for atezolizumab plus chemotherapy compared with chemotherapy alone. These data will be presented at an upcoming medical meeting.
This decision does not affect other approved indications for atezolizumab in the U.S. Industry experts will work with the FDA over the coming weeks to complete the withdrawal process and notify health care professionals in the U.S. about this withdrawal. Patients in the U.S. being treated with atezolizumab for previously untreated mUC should discuss their care with their health care provider.
FDA Clearance of Two IND Applications to Treat Numerous Cancers
The FDA granted clearance for two Investigational New Drug (IND) applications to initiate Phase I clinical trials. PYX-201, a novel antibody-drug conjugate (ADC) product candidate, will be investigated for the potential treatment of several solid tumors, including breast, head and neck, lung, and thyroid cancer. PYX-106, an immunotherapy product candidate, will be investigated for the potential treatment of solid tumors, including bladder, cholangiocarcinoma, colorectal, and kidney cancer.
The first-in-human trial of PYX-201 will be a dose-escalation trial to determine the recommended Phase II dose. The study will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy in patients with solid tumors known to have significant expression of extradomain-B (EDB) of fibronectin.
The first-in-human trial of PYX-106 will be a dose-escalation trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy in patients with tumors known to have significant infiltration of M2 macrophages and expression of Siglec-15 in order to determine the recommended Phase II dose.
PYX-201 is a non-internalizing ADC product candidate that binds to EDB fibronectin, an integral component of the extracellular matrix in the tumor that is overexpressed in many malignancies and is minimally expressed in most normal adult tissues. As shown in patient-derived xenograft (PDX) model studies of NSCLC and pancreatic cancer, its highly cell-permeable auristatin payload is enzymatically released after binding, which directly attacks cancer cells and other components that form the supportive tumor infrastructure. Auristatin elicits an antitumor immune response by inducing immunogenic cell death and dendritic cell maturation. While its effects are primarily due to its non-internalizing activity, a fraction of PYX-201 may also be internalized, further enhancing its antitumor activity.
PYX-106 is an immunotherapy product candidate in development that blocks the activity of Siglec-15, an emerging immune suppressor expressed across a broad range of tumors. Siglec-15 expression does not overlap with one of the most common targets in immuno-oncology, PD-1, supporting its potential use alone and in combination with current immunotherapies. PYX-106 may benefit patients who do not respond to current standards of care. In preclinical studies, PYX-106 has demonstrated broad immune activation, strong binding affinity, and a 7-day half-life. Cumulatively, these advantages may translate to superior anticancer activity and more flexible dosing regimens.
RMAT & Fast Track Designations for CAR T-Cell Therapy
The FDA granted CB-010 Regenerative Medicine Advanced Therapy (RMAT) designation for relapsed or refractory large B-cell lymphoma (LBCL) and Fast Track designation for relapsed or refractory B-cell non-Hodgkin lymphoma (r/r B-NHL). CB-010, an allogeneic anti-CD19 CAR T-cell therapy with a PD-1 knockout, is being evaluated in the ongoing ANTLER Phase I clinical trial in patients with R/R B-NHL, which can enroll three LBCL subtypes: diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, and high-grade B-cell lymphoma. CB-010 is the first allogeneic anti-CD19 CAR T-cell therapy in the clinic with a PD-1 knockout, a genome-editing strategy designed to improve the persistence of antitumor activity by limiting premature CAR T-cell exhaustion.
Encouraging safety data and antitumor activity for CB-010 at dose level 1 (40x106 CAR-T cells) have been reported from the ANTLER trial. As presented at the European Hematology Association 2022 Congress, 6 of 6 patients (100%) achieved a complete response (CR) as best response after treatment with CB-010 at dose level 1 (40x106 CAR-T cells). Subsequently, at 6 months, three of six patients (50%) maintained a CR. Fifteen months is the longest CR maintained to date, observed in the first patient dosed in the ANTLER trial. CB-010 was generally well-tolerated at dose level 1.