Olaparib as Adjuvant Treatment for Germline BRCA-Mutated HER2-Negative High-Risk Early Breast Cancer
Olaparib has been approved for the adjuvant treatment of patients with germline BRCA-mutated (gBRCAm) HER2-negative high-risk early breast cancer who have already been treated with chemotherapy either before or after surgery. The FDA approval was based on results from the OlympiA Phase III trial published in The New England Journal of Medicine (2021; doi: 10.1056/NEJMoa2105215).
In the trial, olaparib demonstrated a statistically significant and clinically meaningful improvement in invasive disease-free survival, reducing the risk of invasive breast cancer recurrences, second cancers, or death by 42 percent versus placebo HR=0.58; 95% CI: 0.46-0.74; p<0.0001).
New updated results from the OlympiA trial also showed olaparib demonstrated a statistically significant and clinically meaningful improvement in the key secondary endpoint of overall survival, reducing the risk of death by 32 percent versus placebo (HR=0.68; 95% CI: 0.50-0.91; p=0.0091). The safety and tolerability profile of olaparib in this trial was in line with that observed in prior clinical trials.
"Today's approval of olaparib is great news for patients with a specific inherited form of breast cancer," noted Andrew Tutt, PhD, FRCR, MRCP, MB, ChB, Global Chair of the OlympiA Phase III trial and Professor of Oncology at The Institute of Cancer Research, London and King's College London. "Most breast cancers are identified in the early stages and many patients will do very well, but for those with higher risk disease at diagnosis, the risk of cancer returning can be unacceptably high and new treatment options are needed. OlympiA has shown that identifying a BRCA1/2 mutation in women with high-risk disease opens the additional option of eligibility for olaparib treatment, which reduces the risk of recurrence and improves survival for these breast cancer patients."
Olaparib is now indicated for the adjuvant treatment of adult patients with deleterious or suspected deleterious gBRCAm HER2-negative high-risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy. Patients are to be selected for treatment based on an FDA-approved companion diagnostic test for olaparib.
Olaparib is approved in the U.S., EU, Japan, and several other countries for the treatment of patients with gBRCAm, HER2-negative, metastatic breast cancer previously treated with chemotherapy based on results from the OlympiAD Phase III trial.
Approval of Pacritinib for Treatment of Myelofibrosis & Thrombocytopenia
The FDA approved pacritinib for the treatment of adults with intermediate or high-risk primary or secondary myelofibrosis (post-polycythemia vera or post-essential thrombocythemia) with a platelet count below 50 x 109/L. Pacritinib is a novel oral kinase inhibitor with specificity for JAK2 and IRAK1, without inhibiting JAK1. The recommended dosage of pacritinib is 200 mg orally twice daily. It is the first approved therapy that specifically addresses the needs of patients with cytopenic myelofibrosis.
"Today's approval of pacritinib establishes a new standard of care for myelofibrosis patients suffering from cytopenic myelofibrosis," said John Mascarenhas, MD, Associate Professor, Medicine, Hematology, and Medical Oncology at the Tisch Cancer Institute Icahn School of Medicine at Mount Sinai. "Myelofibrosis with severe thrombocytopenia, defined as blood platelet counts below 50 x 109/L, has been shown to result in poor survival outcomes coupled with debilitating symptoms. Limited treatment options have rendered this disease as an area of urgent unmet medical need. I am pleased to see that a new, efficacious, and safe treatment option is now available for these patients."
The accelerated approval is based on efficacy results from the pivotal Phase III PERSIST-2 study of pacritinib in patients with myelofibrosis (platelet counts less than or equal to 100 x 109/L). Patients were randomized 1:1:1 to receive pacritinib 200 mg twice daily (BID), pacritinib 400 mg once daily (QD), or best available therapy (BAT). Prior JAK2 inhibitor therapy was permitted.
In this study, in the cohort of patients with baseline platelet counts below 50 x 109/L who were treated with pacritinib 200 mg BID, 29 percent of patients had a reduction in spleen volume of at least 35 percent compared to 3 percent of patients receiving best available therapy, which included ruxolitinib.
The most common adverse reactions (>=20%) following pacritinib 200 mg twice daily were diarrhea, thrombocytopenia, nausea, anemia, and peripheral edema. The most frequent serious adverse reactions (>=3%) following pacritinib 200 mg twice daily were anemia, thrombocytopenia, pneumonia, cardiac failure, disease progression, pyrexia, and squamous cell carcinoma of the skin.
HPN328 for Treatment of Small Cell Lung Cancer
The FDA granted orphan drug designation for HPN328, a delta-like ligand 3 (DLL3)-targeting drug discovery platform for the treatment of small cell lung cancer (SCLC). A Phase I/II clinical trial is currently ongoing for HPN328 in the SCLC patient population.
HPN328 binds to human and non-human primate DLL3, CD3 [epsilon], and albumin with similar affinities. The Phase I/II trial is an open-label study of HPN328 as monotherapy to assess the safety, tolerability, and pharmacokinetics in patients with advanced cancers associated with expression of DLL3. The first part of the trial is designed to determine a dose for additional clinical investigations.
As of the December 13, 2021, clinical update, 15 patients had been enrolled in dose cohorts ranging from 15 [mu]g to 7,200 [mu]g per week using both fixed and step dose administration once weekly by intravenous infusion. Enrolled patients had a median of two lines (range 1-5) of prior therapy and included SCLC patients who had relapsed after platinum chemotherapy, as well as patients with other malignancies with high-grade neuroendocrine tumors associated with DLL3 expression.
HPN328 has been well-tolerated with Grade 1-2 cytokine release syndrome reported in 33 percent of patients, no dose-limiting toxicity observed, and maximum tolerated dose had not been reached. Among four patients with SCLC receiving the two highest doses tested to date-1,215 [mu]g fixed dose and 3,600-7,200 [mu]g step dose-three had target lesion reduction, including one confirmed RECIST partial response. The patient with a cPR experienced a target lesion reduction of 53 percent at Week 10.
Following dose escalation, researchers may further evaluate the safety and efficacy of HPN328 in additional parallel cohorts. The primary outcome measure will be to determine efficacy for the Phase II dose based on the overall response rate as determined by RECIST.
Ivosidenib Tablets + Azacitidine for Previously Untreated IDH1-Mutated AML
The FDA accepted a supplemental New Drug Application (sNDA) for ivosidenib tablets as a potential treatment for patients with previously untreated IDH1-mutated acute myeloid leukemia (AML). The sNDA was granted Priority Review, which accelerates the review and shortens the review time goal from 10 months to 6 months. This is typically given to drugs that may offer major advances in treatment or may provide a treatment where no adequate therapy exists.
The sNDA acceptance is supported by results from the AGILE study, a global Phase III trial in patients with previously untreated IDH1-mutated AML, which were presented at the 2021 American Society of Hematology Annual Meeting and Exposition. The data demonstrated that treatment with ivosidenib tablets in combination with azacitidine significantly improved event-free survival (EFS) (HR=0.33, 95% CI: 0.16, 0.69, 1-sided P=0.0011). In addition, the combination of ivosidenib tablets with azacitidine showed a statistically significant improvement in overall survival (OS) (HR=0.44 [95% CI: 0.27, 0.73]; 1-sided P=0.0005), with a median OS of 24.0 months.
Ivosidenib tablets are currently approved in the U.S. as monotherapy for the treatment of adults with IDH1-mutant relapsed or refractory AML, and for adults with newly diagnosed IDH1-mutant AML who are >=75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy. Recently, ivosidenib tablets were approved as a first and only targeted therapy for patients with previously treated IDH1-mutated cholangiocarcinoma.
The AGILE trial is a global, Phase III, multicenter, double-blind, randomized, placebo-controlled clinical trial designed to evaluate the efficacy and safety of ivosidenib tablets in combination with azacitidine, compared with placebo in combination with azacitidine, in adults with previously untreated IDH1-mutated AML who are not candidates for intensive chemotherapy (>=75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy). The study's primary endpoint is EFS, defined as the time from randomization until treatment failure, relapse from remission, or death from any cause, whichever occurs first. Treatment failure is defined as failure to achieve complete remission by Week 24.
Novel Immunostimulant 7HP349 for Anti-PD-1-Resistant Metastatic Melanoma
The FDA granted Fast Track designation to 7HP349, a clinical-stage immunostimulant, in combination with a CTLA-4 inhibitor for the treatment of patients with unresectable or metastatic malignant melanoma following treatment failure with a PD-1 inhibitor.
7HP349 is designed as an oral therapy to be used in combination with an immunotherapy to improve the effectiveness of potentially any immunotherapeutic, including but not limited to immune checkpoint inhibitors and infectious disease vaccines, through a unique mechanism of action. 7HP349 is an allosteric activator of the integrins VLA-4 and LFA-1, which are essential elements in the generation of an effective antigen-specific immune response. These integrins underlie rate-limiting steps in lymphocyte recruitment, extravascular trafficking, T-cell activation, and effector functions. Following a successful first-in-human Phase I clinical trial completed in 2021, 7HP349 will be entering Phase Ib/IIa trials in PD-1 refractory solid tumors and influenza vaccination of the elderly.