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Approval of Azacitidine Tablets For Acute Myeloid Leukemia

The FDA approved azacitidine tablets for continued treatment of patients with acute myeloid leukemia who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and those who are not able to complete intensive curative therapy.

FDA; oncology resear... - Click to enlarge in new windowFDA; oncology research. FDA; oncology research

Efficacy was investigated in QUAZAR (NCT01757535), a multi-center, randomized, double-blind, placebo-controlled trial. Patients (n=472) who achieved CR or CRi with intensive induction chemotherapy with or without receiving subsequent consolidation therapy were randomized 1:1 to receive azacitidine tablets 300 mg (n=238) or placebo (n=234) orally on days 1-14 of each 28-day cycle.


The main efficacy outcome measure was overall survival (OS). Median OS was 24.7 months (95% CI: 18.7, 30.5) in the azacitidine tablets arm and 14.8 months (95% CI: 11.7, 17.6) in the placebo arm (HR 0.69; 95% CI: 0.55, 0.86; p=0.0009). A subgroup analysis showed consistency in the OS benefit for patients in either CR or CRi.


Adverse reactions in >=10 percent patients receiving azacitidine tablets were nausea, vomiting, diarrhea, fatigue/asthenia, constipation, pneumonia, abdominal pain, arthralgia, decreased appetite, febrile neutropenia, dizziness, and pain in extremity.


The recommended azacitidine tablets dose is 300 mg orally once daily with or without food on days 1-14 of each 28-day cycle. Continue azacitidine tablets until disease progression or unacceptable toxicity.


Breakthrough Therapy Designations for Plinabulin in Chemo-Induced Neutropenia

Plinabulin has received the Breakthrough Therapy Designation (BTD) for the chemotherapy-induced neutropenia (CIN) indication from both the FDA and China's Center for Drug Evaluation (CDE) of the National Medical Products Administration.


The FDA's BTD is intended to expedite the development and review of a drug candidate that is planned to treat a serious or life-threatening disease or condition in which clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. The CDE in China established its BTD program in July 2020 to facilitate the research and development of innovative drugs that treat severe life-threatening or quality-of-life impairing diseases with no existing therapy or with proven evidence to demonstrate clear clinical benefits compared to existing therapies. Products with BTD from the CDE may be considered for conditional approval and priority review when submitting New Drug Applications.


"Receipt of Breakthrough Therapy Designation from the FDA acknowledges both the significant unmet need among patients with CIN and the highly encouraging clinical results generated by plinabulin," said Douglas Blayney, MD, global principal investigator for plinabulin's CIN studies and Professor of Medicine at the Stanford University School of Medicine.


"This should expedite plinabulin's move into the clinic, which is beneficial for patients. The currently approved CIN prevention agents are all G-CSF-based and not available to all patients. Even with the use of G-CSFs, over 80 percent of cancer patients undergoing chemotherapy may still experience grade 4 neutropenia, which could lead to severe infection, hospitalization, and even death. Thus, CIN still represents an unmet medical need."


The Breakthrough Therapy application is based on the strength of the totality of the clinical data generated so far.


Shown in positive interim analysis results from the PROTECTIVE-2 phase III study, the clinically meaningful primary endpoint was the prevention of severe neutropenia, an "industry first," building on the previous standard for approval, the duration of severe neutropenia. In the protocol-specified interim analysis, plinabulin, in combination with pegfilgrastim, was significantly better than pegfilgrastim alone in achieving the primary endpoint with p<0.01, along with a well-tolerated safety profile and fewer grade 4 adverse events, compared to pegfilgrastim alone.


These results were further strengthened by other CIN studies that have confirmed plinabulin's early onset action in week 1 with protecting neutrophils in various cancer types and various chemotherapies, which is complementary to week 2 neutrophil protection with G-CSFs.


Plinabulin is a differentiated immune and stem cell modulator. It is currently in late-stage clinical development to increase overall survival in cancer patients, as well as to alleviate CIN. The durable anticancer benefits of plinabulin have been associated with its effect as a potent antigen-presenting cell inducer (through dendritic cell maturation) and T-cell activation (Chem and Cell Reports 2019).


Plinabulin's CIN data highlights the ability to boost the number of hematopoietic stem/progenitor cells (HSPCs), or lineage-/cKit+/Sca1+ (LSK) cells in mice. Effects on HSPCs could explain the ability of plinabulin to not only treat CIN, but also reduce chemotherapy-induced thrombocytopenia and increase circulating CD34+ cells in patients.


The PROTECTIVE-1 (Study 105) and PROTECTIVE-2 (Study 106) trials are both multicenter, double-blind, active-controlled phase III trials to support plinabulin's broad application in preventing CIN-plinabulin for concurrent administration with myelosuppressive chemotherapy regimens in patients with non-myeloid malignancies for the presentation of CIN.


PROTECTIVE-1 (Study 105) was designed to evaluate the safety and efficacy in non-small cell lung cancer, breast cancer, and prostate cancer patients with risk factors, treated with docetaxel (day 1 dose) in a 21-day cycle with a single dose of plinabulin (40 mg, day 1 dose) versus a single dose of pegfilgrastim (6 mg, day 2). Docetaxel is one example of an intermediate-risk chemotherapy. This is a non-inferiority study in CIN efficacy comparing plinabulin and pegfilgrastim in high-risk patients (intermediate chemotherapy, plus one or more additional risk factor). Study 105 phase III interim data had achieved statistical significance based on the primary endpoint of the duration of severe neutropenia in the first cycle.


PROTECTIVE-2 (Study 106) study was designed to evaluate the safety and efficacy in breast cancer, treated with docetaxel, doxorubicin, and cyclophosphamide (TAC, day 1 dose) in a 21-day cycle with plinabulin (40 mg, day 1 dose) in combination with pegfilgrastim (6 mg, day 2 dose) versus a single dose of pegfilgrastim (6 mg, day 2 dose) alone. TAC is an example of high-risk chemotherapy. Plinabulin and G-CSFs have complementary mechanisms in preventing CIN. This is a superiority study in CIN efficacy in the rate of grade 4 neutropenia prevention (primary endpoint), comparing the combination head-to-head against pegfilgrastim, and is currently enrolling. Literature shows that the grade 4 neutropenia rate for TAC and pegfilgrastim at 6 mg is 83-93 percent, which presents severe unmet medical needs.


Orphan Drug Designation for KP1237 in Multiple Myeloma

KP1237 has received Orphan Drug Designation from the FDA for multiple myeloma. It is an antibody-redirecting molecule (ARMa) that targets CD38, a clinically validated target for multiple myeloma.


KP1237 is being evaluated both as a systemic therapy for daratumumab-relapsed/refractory multiple myeloma patients, and in combination with autologous natural killer (NK) cells in newly diagnosed multiple myeloma patients who are minimum residual disease-positive (MRD+) post-autologous stem cell transplant. Clinical trials to support both these programs are planned to begin in the fourth quarter of 2020. A third clinical program in multiple myeloma using KP1237 in combination with allogeneic NK cells is also under development.


Pralsetinib for Adults With Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer

The FDA approved pralsetinib for the treatment of adults with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA-approved test. This indication was approved under the FDA's accelerated approval program based on data from the phase I/II ARROW study. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.


Pralsetinib is a once-daily, oral precision therapy designed to selectively target RET alterations, including fusions and mutations. RET-activating fusions and mutations are key disease drivers in many cancer types, including NSCLC and medullary thyroid cancer (MTC), and treatment options that selectively target these genetic alterations are limited. In NSCLC, RET fusions represent approximately 1-2 percent of patients. Biomarker testing for these fusions is the most effective way to identify people who are eligible for treatment with pralsetinib.


In the study, pralsetinib produced durable clinical responses in people with RET fusion-positive NSCLC with or without prior therapy, and regardless of RET fusion partner or central nervous system involvement. Pralsetinib demonstrated an overall response rate of 57 percent (95% CI: 46%, 68%) and complete response rate of 5.7 percent in the 87 people with NSCLC previously treated with platinum-based chemotherapy. Median duration of response was not reached (95% CI: 15.2 months, not reached). In the 27 people with treatment-naive NSCLC, the ORR was 70 percent (95% CI: 50%, 86%) with an 11 percent CR rate. The most common adverse reactions (>=25%) were fatigue, constipation, musculoskeletal pain, and hypertension.


The FDA has also granted Priority Review to pralsetinib for the treatment of people with advanced or metastatic RET-mutant MTC and RET fusion-positive thyroid cancer, and is expected to make a decision on approval by February 28, 2021. This New Drug Application was accepted for review under the FDA's Real-Time Oncology Review pilot program, which aims to explore a more efficient review process to ensure safe and effective treatments are available to patients as early as possible.


Efficacy & Potential Safety Concerns With Combining Atezolizumab + Paclitaxel for Breast Cancer

On September 8, 2020, the FDA alerted health care professionals, oncology clinical investigators, and patients that a clinical trial studying the use of atezolizumab and paclitaxel in patients with previously untreated, inoperable, locally advanced, or metastatic triple-negative breast cancer (mTNBC) showed the drug combination did not work to treat the disease.


Atezolizumab in combination with paclitaxel is not approved for use in breast cancer. However, atezolizumab in combination with paclitaxel protein-bound-a different combination therapy-is currently approved for the treatment of adult patients with mTNBC whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells of any intensity covering >= 1% of the tumor area), as determined by an FDA-approved test. Continued approval of atezolizumab in combination with paclitaxel protein-bound may be contingent on proven benefit of the treatment in additional trials.


Health care professionals should not replace paclitaxel protein-bound with paclitaxel in clinical practice. The trial, IMpassion131, was a phase III, multicenter, randomized, double-blind, placebo-controlled trial of atezolizumab in combination with paclitaxel compared with placebo and paclitaxel for patients with mTNBC.


In this clinical trial, treatment with atezolizumab and paclitaxel did not significantly reduce the risk of cancer progression and death compared with placebo and paclitaxel in the PD-L1-positive population. Additionally, interim overall survival results favored paclitaxel + placebo over paclitaxel + atezolizumab in both the PD-L1-positive population and total population.


FDA will review the findings of IMpassion131 and will communicate new information regarding the IMpassion131 results and any potential changes to prescribing information. FDA is also evaluating the use of atezolizumab and paclitaxel in ongoing clinical trials for breast cancer and will recommend additional changes as appropriate.


Patients taking atezolizumab and paclitaxel for other approved uses should continue to take their medication as directed by their health care professional.