Author: RR

FDA Approves VERZENIO® for Hormone Receptor Positive, HER2-Negative Breast Cancer

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SUMMARY: The FDA on September 28, 2017, approved VERZENIO® (Abemaciclib) in combination with FASLODEX® (Fulvestrant) for women with Hormone Receptor positive (HR-positive), HER2-negative, advanced or metastatic breast cancer, with disease progression following endocrine therapy. In addition, VERZENIO® was approved as monotherapy for women and men with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that 252,710 new cases of invasive breast cancer and 63,410 new cases of non-invasive breast cancer will be diagnosed in women in 2017 and 40,610 women are expected to die from the disease.

Cyclin Dependent Kinases (CDK) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. Cyclin Dependent Kinases 4 and 6 (CDK4 and CDK6), phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity and phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in hormone receptor positive breast cancer, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. The understanding of the role of Cyclin Dependent Kinases in the cell cycle, has paved the way for the development of CDK inhibitors.

VERZENIO® is an oral, selective inhibitor of CDK4 and CDK6 kinase activity, and prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation. VERZENIO® is structurally distinct from other CDK 4 and 6 inhibitors (such as Ribociclib and Palbociclib) and is 14 times more potent against cyclin D1/CDK 4 and cyclin D3/CDK 6, in enzymatic assays. VERZENIO® in the phase I trials was noted to be active in HR-positive, metastatic breast cancer, as monotherapy as well as in combination with FASLODEX®. Based on this preliminary data, two clinical trials, MONARCH 1 and MONARCH 2, were conducted.

The approval of VERZENIO® as monotherapy in HR-positive, metastatic breast cancer was based on MONARCH 1, which is a a single-arm, open-label, phase II, multicenter study, which enrolled women with measurable HR-positive, HER2-negative metastatic breast cancer, whose disease progressed during or after endocrine therapy, had received a taxane in any setting, and who received one or two prior chemotherapy regimens in the metastatic setting. This trial included 132 patients who received VERZENIO® 200 mg orally twice daily on a continuous schedule, until disease progression. The Objective Response Rate was 19.7%, with a median response duration of 8.6 months.

The approval of VERZENIO® in combination with FASLODEX® was based on MONARCH 2, which is an international, double-blind, phase III study in which 669 patients were randomized in a 2:1 ratio to receive either VERZENIO® plus FASLODEX® (N=446) or placebo plus FASLODEX® (N=223). Enrolled patients had HR-positive, HER2-negative metastatic breast cancer, with disease progression while receiving neoadjuvant or adjuvant endocrine therapy, within 12 months of adjuvant endocrine therapy, or while receiving endocrine therapy for metastatic breast cancer. Patients must not have received more than one endocrine therapy or any prior chemotherapy for metastatic breast cancer. Randomized patients received either VERZENIO® 150 mg or placebo orally twice daily plus FASLODEX® 500 mg IM on Day 1 and Day 15 of cycle 1 and then on Day 1 of cycle 2 and beyond (28-day cycles). Treatment was continued until disease progression or unmanageable toxicities. The mean patient age was 60 years, 82% of patients were postmenopausal, 72% had measurable disease, 56% had visceral disease, and 25% had primary endocrine therapy resistance. About 60% of patients had received chemotherapy in the adjuvant or neoadjuvant setting and 69% of the patients had prior therapy with Aromatase Inhibitors (AI). The Primary end point was Progression Free Survival (PFS), and Secondary end points included Overall Survival (OS), Objective Response Rate (ORR), Duration of Response, Clinical Benefit Rate, Quality of Life, and safety.

The median PFS for the group receiving VERZENIO® plus FASLODEX® was 16.4 months compared with 9.3 months for those taking placebo with FASLODEX® (HR= 0.55; P<0.0001). In patients with measurable disease, the Objective Response Rate for the group receiving VERZENIO® plus FASLODEX® was 48.1% compared to 21.3% in the placebo with FASLODEX® treated patients. The most common adverse events in the VERZENIO® versus placebo groups were diarrhea neutropenia, nausea and fatigue.

It was concluded that a combination of VERZENIO® plus FASLODEX® significantly improved Progression Free Survival and Objective Response Rates, with a tolerable safety profile, in patients with Hormone Receptor-positive and HER 2-negative metastatic breast cancer who progressed while receiving endocrine therapy. MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2− Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. Sledge GW, Toi M, Neven P, et al. DOI: 10.1200/JCO.2017.73.7585 Journal of Clinical Oncology 35, no. 25 (September 2017) 2875-2884.

MONARCH 1: Results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease. Dickler MN, Tolaney SM, Rugo HS, et al. J Clin Oncol 34, 2016 (suppl; abstr 510).

VERZENIO® (Abemaciclib)

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The FDA on September 28, 2017 approved VERZENIO® in combination with Fulvestrant for women with HR-positive, HER2-negative advanced or metastatic breast cancer, with disease progression following endocrine therapy. In addition, VERZENIO® was approved as monotherapy, for women and men with HR-positive, HER2-negative advanced or metastatic breast cancer, with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. VERZENIO® is a product of Eli Lilly and Company.

OPDIVO® (Nivolumab)

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The FDA on September 22, 2017 granted accelerated approval to OPDIVO®, for the treatment of HepatoCellular Carcinoma (HCC), in patients who have been previously treated with Sorafenib. OPDIVO® is a product of Bristol-Myers Squibb Co.

KEYTRUDA® (Pembrolizumab)

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The FDA on September 22, 2017 granted accelerated approval to KEYTRUDA® for patients with recurrent locally advanced or metastatic, Gastric or GastroEsophageal Junction adenocarcinoma, whose tumors express PD-L1, as determined by an FDA-approved test. KEYTRUDA® is a product of Merck & Co., Inc.

ALIQOPA® (Copanlisib)

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The FDA on September 14, 2017 granted accelerated approval to ALIQOPA®, for the treatment of adult patients with relapsed Follicular Lymphoma, who have received at least two prior systemic therapies. ALIQOPA® is a product of Bayer HealthCare Pharmaceuticals Inc.

JEVTANA® (Cabazitaxel)

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The FDA on September 14, 2017 approved a lower dose of JEVTANA® (20 mg/m2 every 3 weeks) in combination with Prednisone for the treatment of patients with metastatic Castration-Resistant Prostate Cancer, previously treated with a Docetaxel-containing treatment regimen. JEVTANA® (25 mg/m2 every 3 weeks) was approved for this indication in 2010. JEVTANA® is a product of Sanofi-Aventis.

LYNPARZA® (Olaparib)

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The FDA on August 17, 2017 granted regular approval to LYNPARZA® tablets for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy. LYNPARZA® is a product of AstraZeneca.

MYLOTARG® (Gemtuzumab ozogamicin)

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The FDA on September 1, 2017 approved MYLOTARG® for the treatment of newly-diagnosed CD33-positive Acute Myeloid Leukemia (AML) in adults and for treatment of relapsed or refractory CD33-positive AML in adults and in pediatric patients 2 years and older. MYLOTARG® may be used in combination with Daunorubicin and Cytarabine for adults with newly diagnosed AML, or as a stand-alone treatment for certain adult and pediatric patients. MYLOTARG® is a product of Pfizer Inc.

FDA Approves ALIQOPA®, a PI3K Inhibitor, for Follicular Lymphoma

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SUMMARY: The FDA on September 14, 2017, granted accelerated approval to ALIQOPA® (Copanlisib) for the treatment of adult patients with relapsed Follicular Lymphoma, who have received at least two prior systemic therapies. The American Cancer Society estimates that in 2017, about 72,240 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,140 individuals will die of this disease. Indolent NHLs are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL). Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas. Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach whereas those with B symptoms (fever, night sweats, and weight loss), painful lymphadenopathy/splenomegaly, organ compromise and cytopenias are generally considered candidates for therapy.. Follicular Lymphoma International Prognostic Index (FLIPI) is of prognostic value and is used to help with treatment choices. The Ann Arbor classification divides FL into four stages. Patients with stages I and II have localized disease and those with stages III and IV have advanced disease. The World Health Organization (WHO) further classified FL based on histology into low grade (grades 1 and 2) and high grade (grade 3a) FLs. Grade 3b FL which demonstrates diffuse areas of involvement is designated as Diffuse Large B-cell Lymphoma (DLBCL) and is treated as such. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance RITUXAN® (Rituximab). This can result in a median PFS of 6-8 yrs and a median Overall Survival of 12-15 yrs. However, approximately 30% of the patients will relapse in 3 years and treatment options are limited for patients with relapses, after multiple treatments.

ALIQOPA® is a pan-class 1, PI3K inhibitor with inhibitory activity predominantly against PI3K-α and PI3K-δ Isoforms expressed in malignant B cells. The alpha isoform is broadly expressed and involved in insulin signaling and angiogenesis, as well as resistance mechanisms to lymphoma whereas the delta isoform is expressed by leukocytes and is involved in B-cell signaling, development, and survival. ALIQOPA® has been shown to induce tumor cell death by apoptosis and inhibition of proliferation of primary malignant B cell lines. ALIQOPA® also inhibits several key cell-signaling pathways, including B-cell receptor (BCR) signaling, CXCR12 (C-X-C chemokine receptor 12) mediated chemotaxis of malignant B cells, and NFÏ°B (Nuclear Factor Kappa B) signaling in lymphoma cell lines.

The approval of ALIQOPA® was based on data from the CHRONOS-1 trial, which is an open-label, single arm, multicenter, phase II study of patients with relapsed, Indolent or aggressive Non Hodgkin Lymphomas. This trial included patients with Follicular lymphoma (Grades 1-3a), Marginal Zone Lymphoma, Small Lymphocytic Lymphoma, and LymphoPlasmacytic Lymphoma /Waldenstrom Macroglobulinemia . Eligible patients had relapsed or refractory disease and had received at least two prior systemic therapies. The efficacy data leading to the FDA approval included 104 patients with Follicular B-cell Non Hodgkin Lymphoma. In this trial, patients received 0.8 mg/kg or 60 mg of ALIQOPA® by IV infusion on days 1, 8, and 15 of a 28-day treatment cycle, until disease progression or development of unacceptable toxicity. The median patient age was 63 yrs and all study patients had prior exposure to RITUXAN® and one or more alkylating agents, and 60% of the patients had disease that was refractory to the last regimen received. The Primary endpoint was Objective Response Rate after a minimum of 16 weeks of treatment. Secondary endpoints included Progression Free Survival, Duration of Response, Overall Survival, safety, and Quality of Life.

The Objective Response Rate was 58.7%, with an estimated median response duration of 12.2 months. The Complete Response rate was 14.4% and partial response rate was 44.3% and 33.7% has stable disease. The most common adverse reactions included nausea, hyperglycemia, diarrhea, fatigue, hypertension, cytopenias and lower respiratory tract infections. According to the authors, safety was manageable compared with the other PI3K inhibitor approved by the FDA, ZYDELIG® (Idelalisib), which targets only the δ-isoform and has warnings against fatal or severe colitis, intestinal perforation, hepatotoxicity, and pneumonitis The safety advantage with ALIQOPA® may be due to the dose scheduling or the IV mode of delivery.

It was concluded that ALIQOPA® has significant activity in patients with relapsed/refractory indolent B-cell lymphoma, and the safety was manageable, compared with other PI3K inhibitors. Two phase III trials are underway, using ALIQOPA® in combination with RITUXAN®. Dreyling M, Santoro A, Mollica L, et al. Copanlisib in patients with relapsed or refractory indolent B-cell lymphoma: Primary results of the pivotal CHRONOS-1 study. Presented at: 2017 AACR Annual Meeting; April 1-5, 2017; Washington, DC. Abstract CT149.