Author: RR

Five-Year Outcomes with TAFINLAR® plus MEKINIST® in Metastatic Melanoma

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SUMMARY: It is estimated that in the US, approximately 96,480 new cases of Melanoma will be diagnosed in 2019 and about 7,230 patients are expected to die of the disease. The incidence of Melanoma has been on the rise for the past three decades. Surgical resection with a curative intent is the standard of care for patients with early stage Melanoma, with a 5-year survival rate of 98% for stage I disease and 90% for stage II disease. Patients with locally advanced or metastatic Melanoma historically have had poor outcomes. With the development and availability of immune checkpoint inhibitors and BRAF and MEK inhibitors, this patient group now has significantly improved outcomes. In treatment naïve patients receiving anti-PD-1 therapies such as KEYTRUDA® (Pembrolizumab) or OPDIVO® (Nivolumab) in phase 3 trials, the Progression Free Survival (PFS) rates have ranged from 27-31%, with an Overall Survival (OS) rate of 46% at 4 years. The 5-year OS among patients receiving KEYTRUDA® was 43%, and in those treated with a combination of OPDIVO® plus YERVOY® (Ipilimumab), 4-year PFS and OS rates were 37% and 53%, respectively.BRAF-and-MEK-Inhibition-in-MAPK-Pathway

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been detected in 6-8% of all malignancies. The most common BRAF mutation in Melanoma is at the V600E/K site and is detected in approximately 50% of Melanomas, and result in constitutive activation of the MAPK pathway.

TAFINLAR® (Dabrafenib), is a selective oral BRAF inhibitor and MEKINIST® (Trametinib) is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway. It has been well established that patients who have unresectable or metastatic Melanoma with a BRAFV600E or V600K mutation have prolonged PFS and OS when treated with a combination of BRAF and MEK inhibitors. However, long-term 4 and 5-year clinical outcomes in these patient’s have not been reported.

Two randomized Phase III trials helped address this issue. COMBI-d involved 423 patients randomized to TAFINLAR® plus MEKINIST® (N=211) or to TAFINLAR® plus placebo (N=212). In COMBO-v, 704 patients were randomized to TAFINLAR® plus MEKINIST® (N=352) or to single-agent ZELBORAF® (Vemurafenib; N=352). In a previously published pooled analysis of patients treated in the COMBI-d and COMBI-v trials, 3-year PFS and OS were 23% and 44% respectively. Further, there was a significant association between several baseline factors such as performance status, age, sex, number of organ sites with metastasis, serum LDH level and both PFS as well as OS.

In this review, the researchers analyzed pooled long term survival data from two randomized Phase III COMBI-d and COMBI-v trials, which involved previously untreated, unresectable or metastatic Melanoma patients, with BRAFV600E or V600K mutation, who had received BRAF inhibitor TAFINLAR® 150 mg orally twice daily along with a MEK inhibitor MEKINIST® 2 mg orally once daily. These two trials evaluated the efficacy and safety of TAFINLAR® plus MEKINIST®, as compared with BRAF inhibitor monotherapy. The long term, 5-year survival data from these two trials was reported, along with clinical characteristics of the patients who derived long-term benefit from this treatment. The Primary end points in the COMBI-d and COMBI-v trials were PFS and OS, respectively. The median patient age in these trials was 55 years, 3% of patients had nonmetastatic disease and two-thirds had M1c metastatic disease.

A total of 563 patients (211 in the COMBI-d trial and 352 in the COMBI-v trial) were randomly assigned to receive TAFINLAR® plus MEKINIST®. The PFS rates were 21% at 4 years and 19% at 5 years. The OS rates were 37% at 4 years and 34% at 5 years. The 5-year OS rate was 71% among patients who had a Complete Response and 55% among those who had a normal Lactate Dehydrogenase level plus fewer than three metastatic organ sites at baseline.

It was concluded that first-line treatment with TAFINLAR® plus MEKINIST® led to long-term benefit in approximately one third of the patients who had unresectable or metastatic Melanoma with a BRAF V600E or V600K mutation. The authors added that this is the largest data set and longest follow-up in this patient population treated with BRAF and MEK inhibitors. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. Robert C, Grob JJ, Stroyakovskiy D, et al. June 4, 2019. DOI: 10.1056/NEJMoa1904059

KEYTRUDA® (Pembrolizumab)

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The FDA on June 10, 2019 approved KEYTRUDA® for the first-line treatment of patients with metastatic or unresectable recurrent Head and Neck Squamous Cell Carcinoma (HNSCC). KEYTRUDA® is a product of Merck.

POLIVY® (Polatuzumab vedotin-piiq)

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The FDA on June 10, 2019 granted accelerated approval to POLIVY®, a CD79b-directed Antibody-Drug Conjugate indicated in combination with Bendamustine and a Rituximab product for adult patients with relapsed or refractory Diffuse Large B-Cell Lymphoma (DLBCL), Not Otherwise Specified, after at least two prior therapies. POLIVY® is a product of Genentech, Inc.

XOSPATA® (Gilteritinib)

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The FDA on May 29, 2019 approved the addition of overall survival data in labeling for XOSPATA®, indicated for adult patients who have relapsed or refractory Acute Myeloid Leukemia (AML) with a FLT3 mutation, as detected by an FDA-approved test. XOSPATA® is a product of Astellas Pharma US, Inc.

REVLIMID® plus RITUXAN® (R2) Significantly Improves Progression Free Survival in Relapsed or Refractory Indolent Lymphoma

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SUMMARY: The American Cancer Society estimates that in 2019, about 74,200 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,970 individuals will die of this disease. Indolent Non Hodgkin Lymphomas 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 (FL).GELF-Criteria-for-Initiating-Treatment-of-Follicular-Lymphoma

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. 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. 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 OS 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.

REVLIMID® (Lenalidomide) is an oral immunomodulatory agent (IMiD) with activity in lymphoid malignancies, primarily through immune modulation, by reactivating and heightening immune system responses to malignant cells. REVLIMID® synergizes with anti-CD20 antibodies such as RITUXAN® and GAZYVA® (Obinutuzumab) and enhances the function of T and NK cells, increases Antibody-Dependent Cellular Cytotoxicity (ADCC), and repair defective synapse formation in B-cell lymphoma cells, thereby restoring the immune system’s ability to kill tumor cells, without permanently damaging the healthy microenvironment, or causing long-term immune suppression. Chemo-free combination immunotherapy with REVLIMID® and RITUXAN® or the R2 regimen, has shown promising activity in phase II studies. RELEVANCE phase III trial compared REVLIMID® plus RITUXAN®, followed by RITUXAN® maintenance, with the standard of care treatment of RITUXAN® plus chemotherapy, followed by RITUXAN® maintenance, in patients with previously untreated Follicular Lymphoma and concluded that R2 regimen showed similar efficacy, with a more favorable safety profile, making it a potential chemo-free first line option, for patients with Follicular Lymphoma. Single agent RITUXAN® is commonly used in the second-line treatment of Follicular Lymphoma (25-47% of patients), according to studies in the United States and Europe.

AUGMENT trial is a prospective, Phase III, multicenter, randomized study in which 358 patients with relapsed or refractory grades 1-3a Follicular Lymphoma (82%) or Marginal Zone Lymphoma (18%) were randomly assigned to receive either REVLIMID® plus RITUXAN® (N=178) or placebo plus RITUXAN® (N=180). Eligible patients had at least one prior chemotherapy, immunotherapy, or chemoimmunotherapy and two or more previous doses of RITUXAN®, and had relapsed, refractory, or progressive disease, but not RITUXAN®-refractory. Patients with greater than grade 1 neuropathy were excluded. The median age was 63 years, over 50% of the patients had high tumor burden based on GELF criteria, and over 40% of patients had at least 2 prior systemic regimens. REVLIMID® plus RITUXAN® regimen consisted of REVLIMID® 20 mg orally daily (10 mg for Creatinine Clearance 30-59 mL/min) on days 1 to 21 plus RITUXAN® 375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 to 5 every 28 days for 12 cycles. Placebo plus RITUXAN® was administered similarly. The Primary end point was PFS assessed by the Independent Review Committee (IRC) and Secondary end points included Overall Response Rate (ORR), Complete Response (CR), Duration of Response, Overall Survival (OS), and time to next anti-lymphoma treatment. The median follow-up was 28.3 months.

The median PFS was 39.4 months in the REVLIMID®/ RITUXAN® group versus 14.1 months in the placebo plus RITUXAN® group (HR=0.46, P<0.001). This meant a reduced risk of disease progression by 54% and increased median PFS by more than 2 years compared with RITUXAN® monotherapy. This benefit was consistent across all prespecified subgroups, except for the Marginal Zone Lymphoma subgroup and it may be difficult to draw strong conclusions in this small subgroup because these patients made up only 18% of the overall patient population. Response rates as assessed by IRC were 78% in the REVLIMID®/ RITUXAN® group versus 53% in the placebo plus RITUXAN® group (P<0.001), with Complete Response occurring in 34% versus 18% respectively (P=0.001). The median Duration of Response was 36.6 versus 21.7 months (P =0.0015), median Event-Free Survival was 27.6 versus 13.9 months (HR = 0.51, P<0.001) and the median time to next anti-lymphoma treatment was Not Reached versus 32.2 months (P=0.007).

It was concluded that the R2 regimen (REVLIMID® plus RITUXAN®) significantly prolonged Progression Free Survival in patients with relapsed or refractory indolent lymphoma and represents an important new treatment option for this patient group. AUGMENT: A Phase III Study of Lenalidomide Plus Rituximab Versus Placebo Plus Rituximab in Relapsed or Refractory Indolent Lymphoma. Leonard JP, Trneny M, Izutsu K, et al. J Clin Oncol 2019;37:1188-1199.

Late Breaking Abstract – ASCO 2019 Five-Year Survival Data for KEYTRUDA® in Advanced NSCLC

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2019 about 228,150 new cases of lung cancer will be diagnosed and 142,670 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. High level of Programmed Death-Ligand 1 (PD-L1) expression is defined as membranous PD-L1 expression on at least 50% of the tumor cells, regardless of the staining intensity. It is estimated that based on observations from previous studies, approximately 25% of the patients with advanced NSCLC have a high level of PD-L1 expression, and high level of PD-L1 expression has been associated with significantly increased response rates to KEYTRUDA®.Unleashing-T-Cell-Function-with-PD-1-and-PDL1-Antibodies

The FDA approved KEYTRUDA® for the first-line treatment of patients with Stage III Non-Small Cell Lung Cancer (NSCLC) who are not candidates for surgical resection or definitive chemoradiation, as well as those with metastatic NSCLC whose tumors express PD-L1 (Tumor Proportion Score-TPS of 1% or more), as determined by an FDA-approved test. KEYTRUDA® is also approved for the first-line treatment of advanced NSCLC with high PD-L1 expression (Tumor Proportion Score of 50% or more), based on KEYNOTE-024 trial, as well as in combination with Pemetrexed and Carboplatin, as first-line treatment of patients with metastatic non-squamous NSCLC, based on KEYNOTE-021 study. It is also indicated for previously treated advanced NSCLC with a much lower level of PD-L1 expression such as PD-L1 Tumor Proportion Score of 1% or higher, based on KEYNOTE-010 trial.

The authors in this publication presented the 5-year Overall Survival (OS) for patients enrolled in the Phase 1b KEYNOTE-001 study, which was the first trial evaluating KEYTRUDA® in advanced NSCLC. In this trial, 550 patients were enrolled of whom 101 patients were treatment-naïve (N=101) and 449 patients were previously treated (N=449). Patients received KEYTRUDA® 2 mg/kg IV every 3 weeks or KEYTRUDA® 10 mg/kg IV every 2 or 3 weeks. The protocol in the recent years was changed to a straight dose of KEYTRUDA® 200 mg IV every 3 weeks, which is the typical regimen used in clinical practice. The Primary endpoint was Objective Response Rate (ORR). Secondary endpoints included Progression Free Survival (PFS), Overall Survival (OS) and Duration of Response (DOR). The median follow up was 60.6 months and 18% of participants (N=100) were still alive at that point.

The 5-year OS in the treatment-naïve patients (N=101) was 23.2% and 15.5% in previously treated patients (N=449). In treatment-naive patients, the 5-year OS rate among patients whose tumors expressed PD-L1 expression of 50% or more was 29.6%, compared with 15.7% with PD-L1 expression levels below 50%. In patients who had received previous treatment, the 5-year OS rate among patients whose tumors expressed PD-L1 expression of 50% or more was 25% compared with 12.6% with PD-L1 expression levels between 1% and 49%. Only 3.5% of people with PD-L1 expression levels below 1% were alive after 5 years. The investigator-reported ORR was 41.6% in treatment-naïve patients and 22.9% in previously treated patients. Median Duration of Response was 16.8 months and 38.9 months respectively. Immune-mediated adverse events were reported in 17% of patients at 5 years. Hypothyroidism was the most commonly reported immune-mediated adverse event, followed by pneumonitis, hyperthyroidism and skin toxicities.

It was concluded that the 5-year data from the KEYNOTE-001 trial showed that treatment with KEYTRUDA® was safe and effective and substantially increased Overall Survival in patients with advanced NSCLC. These data provide the longest efficacy and safety follow-up for NSCLC patients treated with KEYTRUDA®. Five-year long-term overall survival for patients with advanced NSCLC treated with pembrolizumab: Results from KEYNOTE-001. Garon EB, Hellmann MD, Costa EC, et al. J Clin Oncol. 2019;37(suppl; abstract LBA9015).

FDA Approves JAKAFI® for Acute GVHD

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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

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

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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.

REVLIMID® (Lenalidomide)

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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)

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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.