FDA Approves First PI3K Inhibitor, PIQRAY®, for Breast Cancer

SUMMARY: The FDA on May 24, 2019 approved PIQRAY® (Alpelisib) in combination with FASLODEX® (Fulvestrant), to treat postmenopausal women and men, with Hormone Receptor (HR) positive, Human Epidermal growth factor Receptor 2 (HER2) negative, PIK3CA-mutated, advanced or metastatic breast cancer (as detected by an FDA-approved test), following progression on or after an endocrine-based regimen. The FDA also approved the companion diagnostic test, therascreen PIK3CA RGQ PCR Kit, to detect the PIK3CA mutation in a tissue and/or a liquid biopsy. Patients who are negative by the therascreen test using the liquid biopsy should undergo tumor biopsy for PIK3CA mutation testing. 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. Approximately 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients.Alpelisib - Mechanism-of-Action

The PhosphoInositide 3-Kinase (PI3K) pathway is an intracellular signaling pathway important in the regulation of cancer cell proliferation and metastasis. PI3K is a lipid kinase and has four distinct isoforms – alpha, beta, gamma and delta, which play a unique role in the survival of different tumor types and establishment of supportive tumor microenvironments. The alpha and beta isoforms are expressed in a wide variety of tissues whereas the gamma and delta isoforms are primarily expressed in hematopoietic cells such as B and T cells. The PI3K alpha isoform is particularly important in breast cancer and plays an important role in tumorigenesis, supporting tumor angiogenesis and stromal interactions, making this a viable target. PIK3CA is an oncogene that codes for the alpha isoform of PI3K, (PI3Kα), more specifically for the alpha isoform of p110. The PI3k pathway is the most frequently altered pathway in human cancers including breast cancer, and has been implicated in disease progression in a significant number of patients with breast cancer. Activation of the PI3K pathway in breast cancer has been associated with resistance to endocrine therapy and disease progression. Approximately 40% of patients with Hormone Receptor positive (HR+), HER2 negative breast cancers, harbor activating mutations in the PIK3CA isoform of PI3K, which is the most common mutation in HR+ breast cancer. Patients with advanced breast cancer harboring PIK3CA mutations typically have a poor prognosis. This provides a strong rationale for targeting the PI3K pathway in breast cancer.

PIQRAY® is an oral, alpha-specific PI3K inhibitor that specifically inhibits PIK3 in the PI3K/AKT kinase signaling pathway. Further, it was shown in preclinical studies that cancer cells with PIK3CA mutations are more sensitive to PIQRAY® than those without the mutation, across a broad range of tumor types. SOLAR-1 clinical trial, which was conducted to test this hypothesis, became the basis for this FDA approval.

SOLAR-1 is a global, double-blind, placebo-controlled, randomized phase III trial, which studied the benefit of PIQRAY® in combination with FASLODEX® (Fulvestrant) among postmenopausal women and men with PIK3CA-mutated HR+/HER2 negative advanced or metastatic breast cancer, who had progressed on or following prior Aromatase Inhibitor (AI) treatment with or without a Cyclin-Dependent Kinase (CDK) 4/6 inhibitor. In this study, 572 patients were randomized in a 1:1 ratio to receive PIQRAY® 300 mg orally daily or placebo once daily, in combination with FASLODEX® 500mg IM on days 1 and 15 of the first cycle and day 1 of each subsequent 28-day cycle. Patients were stratified based on visceral metastases and prior CDK4/6 inhibitor treatment. A total of 341 patients had PIK3CA mutations upon testing of the tumor tissue with 169 patients receiving the PIQRAY® combination and 172 patients receiving FASLODEX® alone. Enrolled patients had received one or more prior lines of hormonal therapy, but no chemotherapy for advanced breast cancer. They had not previously received FASLODEX® or any PI3K, Akt or mTOR inhibitor, and were not on concurrent anticancer therapy. Approximately half of the patients in each treatment group had lung or liver metastases and 6% had received prior CDK4/6 inhibitor therapy. The Primary endpoint was Progression Free Survival (PFS) for patients with the PIK3CA mutation. Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Clinical Benefit Rate, Health-Related Quality of Life, Efficacy in PIK3CA non-mutant cohort, Safety and Tolerability.

The Primary endpoint was met and at a median follow up of 20 months, the PFS was nearly twice as long in patients with PIK3CA mutations randomized to PIQRAY® plus FASLODEX® compared to the placebo plus FASLODEX® group. The median PFS was 11.0 months in the PIQRAY® group compared to 5.7 months in the placebo group (HR=0.65; P=0.00065). In patients with measurable, PIK3CA-mutated advanced breast cancer (N=262), the Overall Response Rate was 36% for the PIQRAY® plus FASLODEX® group versus 16% for placebo plus FASLODEX® group (P=0.0002). There was no significant PFS benefit noted in the PIK3CA-nonmutant patient group receiving PIQRAY® plus FASLODEX® The most frequent toxicities with PIQRAY® were hyperglycemia which could be managed with Metformin, nausea, decreased appetite and skin rash.

It was concluded that PIQRAY® given along with FASLODEX® significantly improved Progression Free Survival compared to Placebo plus FASLODEX® with manageable toxicities. The authors commented that this is the first study to show statistically significant, clinically meaningful PFS improvement with an alpha-specific PI3K inhibitor in PIK3CA-mutated HR+, HER2 negative advanced breast cancer, highlighting the importance of clinical genomics in advanced breast cancer. PIQRAY® is also the first novel drug approved under the Real-Time Oncology Review pilot program. It however remains unclear whether PIQRAY® should be incorporated into the current treatment paradigm upfront, along with endocrine therapy and a CDK 4/6 inhibitor, or sequentially following disease progression on a combination of endocrine therapy and a CDK 4/6 inhibitor. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the phase 3 SOLAR-1 trial. André F, Ciruelos EM, Rubovszky G, et al. Presented during the Presidential Symposium 1 at: 2018 ESMO Congress; October 19-23; Munich, Germany. Abstract LBA3_PR.

FDA Approves JAKAFI® for Acute GVHD

SUMMARY: The FDA on May 24, 2019 approved JAKAFI® (Ruxolitinib) for steroid-refractory acute Graft-Versus-Host Disease (GVHD) in adult and pediatric patients 12 years and older. Acute GVHD is a frequent and severe inflammatory complication of allogeneic Hematopoietic Cell Transplantation (HCT), and is a reaction of donor immune cells against host tissues. It is estimated that in the US over 8000 patients undergo allogeneic HCT each year and about 35-50% of recipients will develop acute GVHD, which remains a significant cause of morbidity and mortality in allogeneic HCT recipients. Following the preparative regimen, a series of inflammatory reactions lead to damage to the host epithelial cells by activated donor T cells. GVHD can be acute or chronic, with acute GVHD typically occurring within the first 100 days following an allogeneic transplant. Approximately 40% of patients with acute GVHD have severe disease, with a one year survival of 50% or less. Acute GVHD typically involves the skin, often starting in the palms and soles (rash/dermatitis), liver (hepatitis/jaundice), and gastrointestinal tract (abdominal pain/diarrhea). Acute GVHD is a clinical diagnosis, although histologic confirmation may be extremely helpful, if the symptoms and presentation are atypical. Risk factors for the development of acute GVHD include degree of HLA disparity, gender disparity, increased age of both the recipient and the donor, multiparous female donors, ineffective GVHD prophylaxis, intensity of the transplant conditioning regimen and the source of graft (peripheral blood or bone marrow greater than umbilical cord blood).

Patients with acute GVHD are often treated by optimizing their immunosuppression and adding methylprednisolone, with approximately 50% of patients responding to this intervention. If symptoms do not improve after a week or if progression is noted after 3 days of treatment, patients receive salvage immunosuppressive intervention, since no standard treatment with meaningful benefit has been identified.

JAKAFI® (Ruxolitinib) is a potent JAK1 and JAK2 inhibitor and exerts its mechanism of action by targeting and inhibiting the dysregulated JAK2-STAT signaling pathway. JAKAFI® in animal models was shown to reduce IL-1β, IL-6, or IFN-γ and TNF and other cytokines implicated in lymphocyte activation characteristic of GVHD. In previously published studies, JAKAFI® when used in patients with refractory GVHD demonstrated an Overall Response Rate of 85% in acute or chronic GVHD, with a 25% Complete Remission rate.

The present FDA approval was based on data from REACH1 study, which is an open-label, single-arm, multicenter, phase II trial of JAKAFI® in combination with corticosteroids, in patients with steroid-refractory grade II-IV acute GVHD. Of the 71 patients enrolled in this study, 49 patients were refractory to steroids alone, 12 patients had received two or more prior therapies for GVHD and 10 patients did not otherwise meet the FDA definition of steroid-refractory state. JAKAFI® was administered at 5 mg orally twice daily, and the dose could be increased to 10 mg twice daily after three days, in the absence of toxicity.

The Primary endpoint of this trial was the Day 28 Overall Response Rate (ORR), defined as a Complete Response (CR), Very Good Partial Response (VGPR) or Partial Response (PR), based on the Center for International Blood and Marrow Transplant Research (CIBMTR) criteria. The Day 28 ORR in the 49 patient’s refractory to steroids alone was 57% with a CR rate of 31%. The most frequently reported adverse reactions were infections (55%) and edema (51%), and the most common laboratory abnormalities were anemia, thrombocytopenia and neutropenia.

It was concluded that for patients with acute GVHD who do not adequately respond to steroids, therapies are limited and JAKAFI® is a new treatment option that fulfills this unmet need. Results from REACH1, a Single-Arm Phase 2 Study of Ruxolitinib in Combination with Corticosteroids for the Treatment of Steroid-Refractory Acute Graft-Vs-Host Disease. Jagasia M, Perales M-A, Schroeder MA, et al. Blood 2018 132:601; doi: https://doi.org/10.1182/blood-2018-99-116342

REVLIMID® (Lenalidomide)

The FDA on May 28, 2019 approved REVLIMID® in combination with a RITUXAN® (Rituximab) for previously treated Follicular Lymphoma (FL) and previously treated Marginal Zone Lymphoma (MZL). REVLIMID® is a product of Celgene Corp.

PIQRAY® (Alpelisib)

The FDA on May 24, 2019 approved PIQRAY® in combination with FASLODEX® (Fulvestrant) for postmenopausal women, and men, with Hormone Receptor (HR)-positive, Human Epidermal growth factor Receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer, as detected by an FDA-approved test following progression on or after an endocrine-based regimen. PIQRAY® is a product of Novartis Pharmaceuticals Corporation.

JAKAFI® (Ruxolitinib)

The FDA on May 24, 2019 approved JAKAFI® for steroid-refractory acute Graft-Versus-Host Disease (GVHD) in adult and pediatric patients 12 years and older. JAKAFI® is a product of Incyte Corporation.

FDA Approves Fixed Duration VENCLEXTA® for Frontline Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

SUMMARY: The FDA on May 15, 2019 approved VENCLEXTA® (Venetoclax) for adult patients with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). The FDA in 2018 had approved VENCLEXTA® for patients with CLL or SLL with or without 17p deletion, who have received at least one prior therapy. The American Cancer Society estimates that for 2019, about 20,720 new cases of CLL will be diagnosed in the US and 3,930 patients will die of the disease. B-cell CLL is the most common type of leukemia in adults, accounting for about 11% of all hematologic malignancies.

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by CLL cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death). VENCLEXTA® is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. BCR-Signal-Pathways-and-MOA-of-New-Agents

CLL14 Trial is a prospective, multicenter, open-label, randomized Phase III study, conducted in close collaboration with the German CLL Study Group (DCLLSG). This study was designed to evaluate the efficacy and safety of a fixed duration combination of VENCLEXTA® and GAZYVA® (Obinutuzumab) versus GAZYVA® and Chlorambucil in previously-untreated patients with CLL and coexisting medical conditions. In this trial, 432 treatment-naïve patients with CLL were randomized in a 1:1 ratio to receive fixed duration of 12 months of VENCLEXTA® in combination with six cycles of GAZYVA®, or 6 cycles of GAZYVA® in combination with Chlorambucil. Both treatment groups were well balanced and the median patient age was 72 years. The Primary endpoint was Progression Free Survival (PFS) assessed by an Independent Review Committee. Secondary endpoints included Minimal Residual Disease (MRD) status, Overall Response Rate, Complete Response, Complete Remission with Incomplete Hematologic Recovery (CRi), Overall Survival, duration of response, time to next CLL treatment, and safety.

The trial demonstrated a statistically significant improvement in PFS for patients who received VENCLEXTA® plus GAZYVA® compared with those who received GAZYVA® plus Chlorambucil (HR 0.33; P<0.0001), suggesting a 67% reduction in the risk of progression or death with the VENCLEXTA® plus GAZYVA® combination. The median PFS was not reached in either treatment groups after a median follow-up of 28 months. The Overall Response Rate was 85% in VENCLEXTA® plus GAZYVA® group compared to 71% in GAZYVA® plus Chlorambucil group (P=0.0007). The trial also demonstrated statistically significant improvements in rates of Minimal Residual Disease (MRD) negativity (less than one CLL cell per 104 leukocytes) in bone marrow and peripheral blood. The rate of MRD-negativity in the bone marrow was 57% in the VENCLEXTA® group compared with 17% in the GAZYVA® plus Chlorambucil group. The MRD-negativity rates in the peripheral blood were 76% versus 35%, respectively. Overall Survival data were not mature at this analysis. The most common adverse events in the VENCLEXTA® plus GAZYVA® group included neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema.

It was concluded that a combination of VENCLEXTA® and GAZYVA® among patients with previously untreated CLL significantly improved Progression Free Survival, compared to patients treated with standard of care GAZYVA® plus Chlorambucil. The authors added that VENCLEXTA® plus GAZYVA® is the only chemotherapy-free regimen of fixed duration, and is a major step forward in the management of previously untreated CLL patients. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-venetoclax-cll-and-sll

ELIQUIS® for Thromboprophylaxis in Ambulatory Patients with Cancer

SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke. Ambulatory cancer patients initiating chemotherapy are at varying risk for Venous Thromboembolism (VTE), which in turn can have a substantial effect on health care costs, with negative impact on quality of life. Approximately 20% of cancer patients develop VTE and there is a two-fold increase in the risk of recurrent thrombosis in patients with cancer, compared with those without cancer. The benefit of thromboprophylaxis in this patient population however is uncertain. This is because previously published randomized trials included cancer patients both at both low and high risk for VTE.Predicting-VTE-in-cancer-patients-using-a-Risk-Score

Khorana score is a validated risk tool which helps to identify patients at increased risk for VTE. Several studies have suggested benefit from thromboprophylaxis in patients with a score of 3 or higher, whereas the benefit of thromboprophylaxis in patients with a score of 2 is unclear, although there is a substantial risk of VTE in this group as well. The current recommendations are treatment with parenteral Low Molecular Weight Heparin (LMWH) preparations for at least 6 months or probably longer, as long as the cancer is active. This however can be inconvenient and expensive, leading to premature discontinuation of treatment. LMWH accelerates the inhibition by Antithrombin of activated Factor X, in the conversion of Prothrombin to Thrombin. Direct Oral AntiCoagulants (DOACs) have been proven to be noninferior to COUMADIN® (Warfarin), a Vitamin K antagonist, for the treatment of acute VTE, and are associated with less frequent and less severe bleeding and fewer drug interactions. The Direct Oral AntiCoagulants (DOACs) include PRADAXA® (Dabigatran), which is a direct Thrombin inhibitor and XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Edoxaban), BEVYXXA® (Betrixaban) which are Factor Xa inhibitors. Compared to COUMADIN® , the New Oral Anticoagulants have a rapid onset of action, wider therapeutic window, shorter half-lives (7-14 hours in healthy individuals), no laboratory monitoring and fixed dosing schedule.

The AVERT (Apixaban for the Prevention of Venous Thromboembolism in High-Risk Ambulatory Cancer Patients ) trial is a randomized, placebo-controlled, double-blind clinical trial which evaluated the efficacy and safety of apixaban (2.5 mg twice daily) for thromboprophylaxis in ambulatory patients with cancer who were at intermediate-to-high risk for venous thromboembolism (Khorana score 2 or more). Eligible patients (N=574) were randomized in a 1:1 ratio to receive apixaban or placebo and 563 patients were included in the modified intention-to-treat analysis. The first dose of apixaban or placebo was administered within 24 hours after the initiation of chemotherapy. The mean patient age was 61 years, and the common types of primary malignancies were gynecologic (25.8%), lymphoma (25.3%), and pancreatic (13.6%). Eligible patients included those who had a newly diagnosed cancer or progression of known cancer after complete or partial remission and who were initiating a new course of chemotherapy with a minimum treatment intent of 3 months. Inclusion required a Khorana score of 2 or higher. Exclusion criteria included hepatic disease associated with coagulopathy, platelet count of less than 50,000 per cubic millimeter, acute leukemia, myeloproliferative neoplasm, planned stem-cell transplantation and GFR of less than 30 ml/min. The Primary efficacy outcome was objectively documented venous thromboembolism over a follow-up period of 180 days. The main Safety outcome was a major bleeding episode.

Venous thromboembolism occurred in 4.2% in the apixaban group and 10.2% in the placebo group (HR=0.41; P<0.001). This benefit and was predominantly driven by a lower rate of pulmonary embolism in the apixaban group than in the placebo group. The rate of major bleeding was significantly higher with apixaban than with placebo in the modified intention-to-treat analysis (3.5% versus 1.8%, respectively; HR=2.00), but the rate however was not significantly higher with apixaban than with placebo in the analysis of outcomes during the treatment period (2.1% versus 1.1%, respectively; HR=1.89). There was no significant difference in the Overall Survival between the treatment groups and the authors attributed this to trial design and the fact that most of the patients had advanced cancer, which was the most common cause of death.

It was concluded that thromboprophylaxis with apixaban at a dose of 2.5 mg twice daily resulted in a significantly lower risk of venous thromboembolism when compared to placebo, among ambulatory cancer patients who were initiating chemotherapy, and had an intermediate to high risk of venous thromboembolism. Apixaban to Prevent Venous Thromboembolism in Patients with Cancer. Carrier M, Abou-Nassar K, Mallick R, et al. for the AVERT Investigators. N Engl J Med 2019;380:711-719


The FDA on May 14, 2019 approved BAVENCIO® (Avelumab) in combination with INLYTA® (Axitinib) for first-line treatment of patients with advanced Renal Cell Carcinoma (RCC). BAVENCIO® is a product of EMD Serono, Inc. and INLYTA® is a product of Pfizer, Inc.