Category: Hem/Onc Updates

FDA Approves ZEJULA® for Newly Diagnosed Patients with Advanced Ovarian Cancer

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SUMMARY: The FDA on April 29, 2020 approved ZEJULA® (Niraparib) for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to first-line platinum-based chemotherapy. It is estimated that in the United States, approximately 21,750 women will be diagnosed with ovarian cancer in 2020 and 13,940 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, and accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5 year Overall Survival rate of about 20-30%.MOA-of-PARP-Inhibitors

DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. The PARP (Poly ADP Ribose Polymerase) family of enzymes, include PARP1 and PARP2. In the context of DNA repair, BRCA1 and BRCA2 genes recognize and repair double strand DNA breaks via Homologous Recombination (HR) pathway. Homologous Recombination is a type of genetic recombination, and is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway. At least 15 genes are involved in the Homologous Recombination Repair (HRR) pathway including BRCA1 and BRCA2 genes. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. BRCA1 and BRCA2 are tumor suppressor genes and functional BRCA proteins repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. Mutations in BRCA1 and BRCA2 account for about 20-25% of hereditary breast cancers and about 5-10% of all breast cancers. They also account for 15% of ovarian cancers, in addition to other cancers such as Colon and Prostate. BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic). Somatic mutations account for a significant portion of overall BRCA1 and BRCA2 aberrations. Loss of BRCA function due to frequent somatic aberrations likely deregulates HR pathway, and other pathways then come in to play, which are less precise and error prone, resulting in the accumulation of additional mutations and chromosomal instability in the cell, with subsequent malignant transformation. HRD therefore indicates an important loss of DNA repair function. Hereditary Epithelial Ovarian Cancer was thought to be caused almost exclusively by mutations in BRCA1 and BRCA2. It however is now well known that about 50% of the high grade serous ovarian cancers have aberrations in HR repair pathway. Deregulated HR pathway increases sensitivity to platinum drugs. Majority of the women with germline BRCA mutations (gBRCA) are positive for HR deficiency.

PARP is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair. In the presence of a PARP inhibitor, there is synthetic lethality because loss of both genes, leading to cell death. Thus PARP inhibitors are only harmful to cancer cells. ZEJULA® is a highly selective PARP 1/2 inhibitor, that causes cumulative DNA damage and cell death by inhibiting PARP. Previously published phase III study among patients with platinum-sensitive, recurrent ovarian cancer (NEJM 2016;375:2154-2164) concluded that Niraparib significantly prolonged Progression Free Survival (PFS) compared to placebo, and this benefit was achieved regardless of the presence or absence of germline BRCA mutations or HRD status.

PRIMA trial is a randomized, double-blind, placebo-controlled, international Phase III trial conducted to test the efficacy and safety of ZEJULA® maintenance therapy after a response to platinum-based chemotherapy, in patients with newly diagnosed advanced ovarian cancer at high risk for relapse. It should be noted that at the time PRIMA trial was designed, AVASTIN® (Bevacizumab) was not approved for first-line treatment in all participating countries. A total of 733 patients with newly diagnosed, high risk, advanced ovarian cancer were randomly assigned in a 2:1 ratio to receive ZEJULA® (N=487) or placebo (N=246) once daily in 28-day cycles for 36 months or until disease progression, after a response to platinum-based chemotherapy regimen. Patients received a dose of 200-300mg once daily, based on body weight and platelet count. Enrolled patients were at high risk for progressive disease with 23.1% having Stage III ovarian cancer with residual disease after primary debulking surgery, 66.7% had received neoadjuvant chemotherapy, 35% had Stage IV ovarian cancer, and 30.5% had a Partial Response to first-line platinum-based chemotherapy. Tumor samples were tested for HRD status and HRD was defined by either presence of tumor BRCA mutation or Genomic Instability Score (GIS) of 42 or more. Of the randomized patients, 50.9% had tumors with HRD, 30.4% had BRCA mutations and 20.5% were BRCA wild type. The treatment groups were well balanced. The Primary endpoint was Progression Free Survival (PFS) in patients who had tumors with HRD, and then in the overall population, as determined on hierarchical testing. Secondary end points included Overall Survival, time until the first subsequent therapy, PFS 2, defined as time from randomization to progression while the patient was receiving a subsequent anticancer therapy and Patient-Reported Outcomes. The median duration of follow-up at the time of the data cutoff was 13.8 months.

There was a statistically significant improvement in PFS for patients randomized to ZEJULA® compared with placebo in the HRD group, as well as the overall population. The median PFS in the HRD group was 21.9 months for patients receiving ZEJULA® compared with 10.4 months for those receiving placebo (HR=0.43; P<0.001). The median PFS in the overall population was 13.8 months for patients receiving ZEJULA® compared with 8.2 months for those receiving placebo (HR=0.62; P<0.001). At the 24-month interim analysis, the rate of Overall Survival was 84% in the ZEJULA® group and 77% in the placebo group (HR=0.70). The most common adverse reactions in patients receiving ZEJULA® were cytopenias, fatigue, AST/ALT elevation, hypertension, low grade nausea and decreased appetite.

It was concluded that among patients with newly diagnosed advanced ovarian cancer who had responded to platinum-based chemotherapy, ZEJULA® significantly prolonged Progression Free Survival, compared to those who received placebo, regardless of the presence or absence of Homologous Recombination Deficiency.
Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. González-Martín A, Pothuri B, Vergote I, et al. for the PRIMA/ENGOT-OV26/GOG-3012 Investigators. N Engl J Med 2019; 381:2391-2402

FDA Approves Subcutaneous DARZALEX® in Multiple Myeloma

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SUMMARY: The FDA on May 1, 2020 approved DARZALEX® (Daratumumab) and Hyaluronidase-fihj (DARZALEX FASPRO®), for adult patients with newly diagnosed or Relapsed/Refractory multiple myeloma. This new product allows for subcutaneous dosing of DARZALEX®.

DARZALEX FASPRO® is now approved for these previously approved indications for IV DARZALEX®
1) In combination with VELCADE® (Bortezomib), Melphalan and Prednisone in newly diagnosed patients who are ineligible for Autologous Stem Cell Transplant (ASCT)
2) In combination with REVLIMID® (Lenalidomide) and Dexamethasone in newly diagnosed patients, who are ineligible for ASCT and in patients with Relapsed or Refractory multiple myeloma who have received at least one prior therapy
3) In combination with VELCADE® and Dexamethasone in patients who have received at least one prior therapy
4) As monotherapy, in patients who have received at least three prior lines of therapy including a Proteasome Inhibitor (PI) and an Immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent.

DARZALEX® is a human IgG1 antibody that targets CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Dependent Cytotoxicity (CDC) and direct Apoptosis. Additionally, DARZALEX® may play a role in immunomodulation, by depleting CD38-positive regulator immune suppressor cells, and thereby expanding T cells, in patients responding to therapy.Mechanism-of-Action-of-Daratumumab

This FDA approval is based on COLUMBA Trial, which is a randomized, open-label, multicenter Phase III study, which included 522 patients with multiple myeloma, who had received at least three prior lines of therapy including a Proteasome Inhibitor (PI) and an immunomodulatory drug (IMiD), or whose disease was refractory to both a PI and an IMiD. Patients were randomly assigned to receive a fixed dose of subcutaneously (SC) administered formulation of DARZALEX® 1800 mg weekly for cycles 1-2, every two weeks for cycles 3-6 and every four weeks for cycle 7 and thereafter (N=263), with the subcutaneous preparation given over 3-5 minutes at alternating left and right abdominal sites. In the intravenous group, patients received DARZALEX® 16 mg/kg IV weekly for cycles 1-2, every two weeks for cycles 3-6 and every four weeks for cycle 7 and thereafter (N=259). Each cycle was 28 days. Treatment in both patient groups was continued until disease progression or unacceptable toxicity. The median age was 67 years and the median number of prior therapies was four in each treatment group. Patient characteristics were similar between the two arms except that more patients in the subcutaneous arm had high-risk cytogenetics (26%) compared with the intravenous group (17%). The median duration of treatment was approximately 5 months, with a median of 6 completed cycles of treatment. The median duration of infusion was consistently 5 minutes at each visit in the subcutaneous group. However, in the IV arm, the first infusion lasted 7 hours, the second infusion was 4.3 hours, and subsequent infusions lasted a median of 3.4 hours. The study co-Primary endpoints were Overall Response Rate (ORR) and pharmacokinetic endpoint of the maximum C-trough on cycle 3, day 1 pre-dose.

At a median follow up of 7.5 months, the ORR was 41% for the subcutaneous administered formulation of DARZALEX® compared to 37% for IV DARZALEX® (P<0.0001). The ORR was similar across all clinically relevant subgroups, including body weight. The ratio of geometric means of C-trough for the SC administered formulation of DARZALEX® over IV DARZALEX® was 108%. The Progression Free Survival was comparable between the SC administered formulation of DARZALEX and the current IV formulation of DARZALEX (HR=0.99; P<0.9258). A lower rate of infusion-related reactions was observed in the group that received the SC DARZALEX® compared to IV DARZALEX® (13% vs. 35%, respectively).

It was concluded that the subcutaneous formulation of DARZALEX® resulted in non-inferior pharmacokinetics and efficacy compared to the current IV formulation, and also importantly offers the potential for a fixed-dose administration, shorter administration times and a lower rate of infusion-related reactions with improved safety profile, in patients with Relapsed or Refractory multiple myeloma.

Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial. Mateos M-V, Nahi H, Legiec W, et al. The Lancet Haematology. Published: March 23, 2020. DOI: https://doi.org/10.1016/S2352-3026(20)30070-3.

FDA Approves TRODELVY® for Advanced Triple Negative Breast Cancer

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SUMMARY: The FDA on April 22, 2020, granted accelerated approval to TRODELVY® (Sacituzumab govitecan-hziy), for adult patients with metastatic Triple-Negative Breast Cancer (TNBC), who received at least two prior therapies for metastatic disease. Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer will be diagnosed in 2020 and about 42,170 women will die of the disease.

Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients and African American females. It is usually aggressive, and tumors tend to be high grade, and patients with TNBC are at a higher risk of both local and distant recurrence and often develop visceral metastases. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers. The lack of known recurrent oncogenic drivers in patients with metastatic TNBC, presents a major therapeutic challenge. Overall survival among patients with pretreated metastatic TNBC has not changed over the past 2 decades and standard chemotherapy is associated with low response rates of 10-15% and a Progression Free Survival of only 2-3 months.

TRODELVY® is an Antibody-Drug Conjugate (ADC) in which SN-38, an active metabolite of Irinotecan, a Topoisomerase I inhibitor, is coupled to the humanized Anti-Trophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody (hRS7 IgG1κ), through the cleavable CL2A linker. SN-38 cannot be given directly to patients because of its toxicity and poor solubility. Trop-2, a transmembrane calcium signal transducer, stimulates cancer-cell growth, and this cell surface receptor is overexpressed in several epithelial cancers including cancers of the breast, colon and lung, and has limited expression in normal human tissues. Trop-2 is expressed in more than 85% of breast tumors including Triple Negative Breast Cancer. Upon binding to Trop-2, the anti-TROP-2 monoclonal antibody is internalized and delivers SN-38 directly into the tumor cell, making it a suitable transporter for the delivery of cytotoxic drugs. Further, the cleavable linker enables SN-38 to be released both intracellularly into the tumor cells as well as the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the active drug in bystander cells to which the conjugate has not bound. Thus, TRODELVY®-bound tumor cells are killed by intracellular uptake of SN-38, whereas the adjacent tumor cells are killed by the extracellular release of SN-38.

IMMU-132-01 is a Phase I/II, basket design, open-label, single-group, multicenter trial involving patients with various types of advanced epithelial cancers, who have received at least one previous therapy for metastatic disease. (One example of a basket design is a single drug evaluated in multiple baskets, with each basket representing a different malignancy or tumor site with the same target). A total of 108 patients with metastatic Triple-Negative Breast Cancer (TNBC) were enrolled between June 2013 and February 2017. Patients received TRODELVY® 10 mg/kg IV on days 1 and 8 every 21 days. Tumor imaging was obtained every 8 weeks, and patients were treated until disease progression or intolerance to therapy. The median patient age was 55 years. Enrolled patients had a median of 3 prior anticancer regimens and 98% had received taxanes and 86% had received anthracyclines. The Primary efficacy end point was the Objective Response Rate (ORR). Other efficacy end points included Time to Response and Duration of Response in patients who had a response, the Clinical Benefit Rate (defined as a Complete or Partial Response or stable disease for at least 6 months), Progression Free and Overall Survival. The median duration of follow up for this basket of 108 patients with metastatic TNBC was 9.7 months.

The Objective Response Rate was 33.3% including a Complete Response Rate of 2.8%. The median Time to Response was 2.0 months and the median Duration of Response was 7.7 months. The Clinical Benefit Rate was 45.4%. There was no meaningful difference in response rates in the various patient subgroups including patient age, onset of metastatic disease, number of previous therapies and the presence or absence of visceral metastases. The median PFS was 5.5 months and median OS was 13.0 months. The most common adverse reactions were, possibly severe neutropenia and diarrhea, fatigue, nausea, vomiting, alopecia and abdominal discomfort.

It was concluded that TRODELVY® was associated with durable Objective Responses in patients with heavily pretreated metastatic Triple Negative Breast Cancer. This unique Antibody Drug Conjugate may be of potential benefit for other Trop-2 expressing advanced epithelial solid tumors.
Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer. Bardia A, Mayer IA, Vahdat LT, et al. N Engl J Med. 2019;380:741-751.

ELIQUIS® May Be Safer for the Treatment of Venous Thromboembolism Associated with Cancer

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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 high risk of recurrent VTE, as well as bleeding in this patient group, makes anticoagulant treatment challenging. Treatment with parenteral Low Molecular Weight Heparin (LMWH) preparations is often recommended for this patient group, based on efficacy data. LMWH accelerates the inhibition by Antithrombin of activated Factor X, in the conversion of Prothrombin to Thrombin. Parenteral LMWH however can be inconvenient and expensive, leading to premature discontinuation of treatment.Anticoagulants

Direct Oral Anticoagulant agents have been proven to be as effective as COUMADIN® (Warfarin), a Vitamin K antagonist, for the treatment of 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), require no laboratory monitoring and have a fixed dosing schedule.

Three open-label, randomized, controlled trials have compared direct Factor Xa inhibitors with subcutaneous LMWH FRAGMIN® (Dalteparin). In the Hokusai VTE Cancer noninferiority trial, SAVAYSA® (Edoxaban)‎ when compared with FRAGMIN® was associated with a lower rate of recurrent VTE, but this was offset by a similar increase in the risk of major bleeding. In the SELECT-D trial, XARELTO® was associated with relatively low VTE recurrence in patients with cancer, but with higher clinically relevant non-major bleeding, compared with FRAGMIN®. In the ADAM VTE Trial, oral ELIQUIS® therapy was associated with very low rates of bleeding and significantly lower VTE recurrence compared to parenteral FRAGMIN®. The inconsistent results from these studies have been attributed to patient selection (cancer type, types of cancer therapies and prognosis), duration of treatment, and primary efficacy outcomes of these studies. SAVAYSA® and XARELTO® are often recommended as alternatives to LMWH in patients with cancer, although higher risk of clinically important bleeding has been reported with both these agents, particularly in patients with GI malignancies, including pancreatic cancer.

The Caravaggio trial is a multinational, randomized, open-label, noninferiority trial which was conducted to assess whether oral ELIQUIS® would be noninferior to subcutaneous FRAGMIN® (Dalteparin), a LMWH, for the prevention of recurrent VTE in patients with cancer, without increasing the risk of major bleeding. In this study, 1155 patients with cancer who had symptomatic or incidental acute proximal DVT or PE were randomly assigned to receive ELIQUIS® 10 mg orally twice daily for the first 7 days, followed by 5 mg orally twice daily (N=576) or FRAGMIN® 200 IU/kg administered subcutaneously once daily for the first month, followed by 150 IU/kg subcutaneous once daily (N=579). The demographic and clinical characteristics of the patients in both treatment groups were well balanced and advanced active cancers associated with high thromboembolic risk such as lung and colorectal cancers were well represented. This study included patients receiving a variety of cytotoxic and biologic therapies. Anticoagulant treatments were administered for 6 months. The Primary endpoint was objectively confirmed recurrent VTE during the trial period. The principal safety outcome was major bleeding.

The Primary endpoint of recurrent VTE occurred in 5.6% of patients in the ELIQUIS® group and in 7.9% of patients in the FRAGMIN® group (HR=0.63; P<0.001 for noninferiority). Major bleeding occurred in 3.8% of patients in the ELIQUIS® group and 4.0% of patients in the FRAGMIN® group (HR=0.82; P=0.60). Major GI bleeding occurred in 1.9% of patients in the ELIQUIS® group and in 1.7% of patients in the FRAGMIN® group and major non-gastrointestinal bleeding occurred in 1.9% and 2.2% of patients respectively. There were no fatal bleeding episodes noted in the ELIQUIS® group, whereas 2 patients had a fatal bleed in the FRAGMIN® group. These findings with regards to bleeding are in contrast to the results of previously published studies, which showed a higher incidence of bleeding with other Direct Oral AntiCoagulants, compared with FRAGMIN®, in a similar patient population.

It was concluded that in this study which included patients with predominantly advanced active cancer and acute symptomatic VTE, oral ELIQUIS® was noninferior to subcutaneous FRAGMIN® for the treatment of cancer-associated VTE, without an increased risk of major bleeding. The authors added that these findings may expand the proportion of patients with both cancer and VTE who would be eligible for treatment with ELIQUIS®, including patients with active gastrointestinal malignancies. It should be noted however that LMWH should still be preferred for patients who have undergone surgery involving the upper GI tract, as Direct Oral AntiCoagulants are absorbed in the stomach or proximal small bowel, as well as for those patients with bleeding or thrombocytopenia, recurrent VTE, CNS cancers, or those with severe renal impairment, and in the perioperative setting.
Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer. Agnelli G, Becattini C, Meyer G, et al. for the Caravaggio Investigators. N Engl J Med 2020; 382:1599-1607

FDA Approves TUKYSA® for HER2+ Breast Cancer

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SUMMARY: The FDA on April 17, 2020, approved TUKYSA® (Tucatinib) in combination with Trastuzumab and XELODA® (Capecitabine), for adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer will be diagnosed in 2020 and about 42,170 women will die of the disease.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. HER2-targeted therapies include HERCEPTIN® (Trastuzumab), TYKERB® (Lapatinib), PERJETA® (Pertuzumab) and KADCYLA® (ado-Trastuzumab emtansine). Dual HER2 blockade with HERCEPTIN® and PERJETA®, given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2 positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival (OS). The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies. Patients progressing on Dual HER2 blockade often receive KADCYLA® which results in an Objective Response Rate (ORR) of 44% and a median PFS of 9.6 months, when administered after HERCEPTIN® and a taxane. There is however no standard treatment option for this patient population following progression on KADCYLA®.

It is estimated that close to 50% of patients with HER2-positive metastatic breast cancer develop brain metastases. Systemic HER2-targeted agents, including Tyrosine Kinase Inhibitors, as well as chemotherapy have limited antitumor activity in the brain. Local therapeutic interventions for brain metastases include neurosurgical resection and Stereotactic or Whole-Brain Radiation Therapy.

TUKYSA® (Tucatinib) is an oral Tyrosine Kinase Inhibitor that is highly selective for the kinase domain of HER2 with minimal inhibition of Epidermal Growth Factor Receptor. In a Phase 1b dose-escalation trial, TUKYSA® in combination with HERCEPTIN® and XELODA® (Capecitabine) showed encouraging antitumor activity in patients with HER2-positive metastatic breast cancer, including those with brain metastases.

HER2CLIMB is an international, randomized, double-blind trial in which the combination of TUKYSA® plus HERCEPTIN® and XELODA® was compared with placebo plus HERCEPTIN® and XELODA®. A total of 612 patients with unresectable locally advanced or metastatic HER2-positive breast cancer, who were previously treated with HERCEPTIN®, PERJETA® (Pertuzumab) and KADCYLA® (ado-Trastuzumab emtansine) were enrolled. Patients were randomly assigned in a 2:1 ratio to receive either TUKYSA® 300 mg orally twice daily throughout the treatment period (N=410) or placebo orally twice daily (N=201), in combination with HERCEPTIN® 6 mg/kg IV once every 21 days, following an initial loading dose of 8 mg/kg, and XELODA® 1000 mg/m2 orally twice daily on days 1 to 14 of each 21-day cycle. Stratification factors included presence or absence of brain metastases, ECOG Performance Status and geographic region. The median patient age was 54 years and patient demographic as well as disease characteristics at baseline were well balanced between the two treatment groups. In the total treatment population, 47.5% had brain metastases at baseline, 48.3% in the TUKYSA® combination group and 46% in the placebo combination group. The median duration of follow up in the total treatment population was 14 months. The Primary endpoint was Progression Free Survival (PFS) among the first 480 patients who underwent randomization. Secondary end points assessed in the total treatment population (612 patients) included, Overall Survival (OS), PFS among patients with brain metastases, confirmed Objective Response Rate (ORR), and safety.

The Primary endpoint of PFS at 1 year was 33.1% in the TUKYSA®-combination group and 12.3% in the placebo-combination group (HR for disease progression or death=0.54; P<0.001), and the median duration of PFS was 7.8 months and 5.6 months, respectively. This represented a 46% reduction in the risk of cancer progression or death in the TUKYSA®-combination group compared to patients who received HERCEPTIN® and XELODA® alone. The Overall Survival at 2 years was 44.9% in the TUKYSA®-combination group and 26.6% in the placebo-combination group (HR for death=0.66; P=0.005), and the median Overall Survival was 21.9 months and 17.4 months, respectively. This represented a 44% reduction in the risk of death in the TUKYSA®-combination group compared to the placebo-combination group. Among the patients with brain metastases, PFS at 1 year was 24.9% in the TUKYSA®-combination group and 0% in the placebo-combination group (HR=0.48; P<0.001), and the median PFS was 7.6 months and 5.4 months, respectively. This represented a 52% reduction in the risk of cancer progression or death in the TUKYSA®-combination group compared to the placebo-combination group. Among the patients with measurable disease at baseline, the confirmed Objective Response Rate was 40.6% in the TUKYSA®-combination group and 22.8% in the placebo-combination group (P<0.001). Common adverse events in the TUKYSA® group included diarrhea, Palmar-Plantar Erythrodysesthesia syndrome, nausea, vomiting and fatigue. Diarrhea and abnormal liver function tests were more common in the TUKYSA®-combination group than in the placebo-combination group.

It was concluded that in heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, the addition of TUKYSA® to HERCEPTIN® and XELODA® resulted in clinically significant improvement in PFS and OS, compared to the placebo-combination group. This trial is unique in that it included patients with active brain metastases, either untreated or progressing.

Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. Murthy RK, Loi S, Okines A, et al. N Engl J Med 2020;382:597-609.

FDA Approves PEMAZYRE®, First Targeted Therapy for Cholangiocarcinoma

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SUMMARY: The FDA on April 17, 2020 granted accelerated approval to PEMAZYRE® (Pemigatinib), for the treatment of adults with previously treated, unresectable locally advanced or metastatic Cholangiocarcinoma with a Fibroblast Growth Factor Receptor 2 (FGFR2) fusion or other rearrangement, as detected by an FDA-approved test. The FDA also approved the FoundationOne® CDX (Foundation Medicine, Inc.), as a companion diagnostic for patient selection.

Bile Duct cancer (Cholangiocarcinoma), comprise about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. Klatskin tumor is a type of Cholangiocarcinoma that begins in the hilum, at the junction of the left and right bile ducts. It is the most common type of Cholangiocarcinoma, accounting for more than half of all cases. About 8,000 people in the US are diagnosed with Cholangiocarcinoma each year and approximately 20% of the cases are suitable for surgical resection, whereas a majority of patients at diagnosis have advanced disease. The 5-year survival is less than 10%, with limited progress made over the past two decades. There is therefore an unmet need for new effective therapies.

FGFRs (Fibroblast Growth Factor Receptors) play an important role in tumor cell proliferation and survival, migration and angiogenesis. Activating fusions, rearrangements, translocations and gene amplifications in FGFRs result in dysregulation of FGFR signaling, and may contribute to the pathogenesis of various cancers, including Cholangiocarcinoma. FGFR2 fusions or rearrangements occur almost exclusively in intrahepatic Cholangiocarcinoma, where they are observed in 10-16% of patients. PEMAZYRE® is a potent, selective, oral kinase inhibitor of FGFR isoforms 1, 2 and 3, which in preclinical studies has demonstrated selective pharmacologic activity against cancer cells with FGFR alterations.FGFR-Signaling-Pathway

The FIGHT-202 ((FIbroblast Growth factor receptor in oncology and Hematology Trials) is a Phase II, multi-center, open-label, single-arm study which evaluated the safety and efficacy of PEMAZYRE® (Pemigatinib) in adult patients with previously treated, locally advanced or metastatic Cholangiocarcinoma with documented FGFR2 fusion or rearrangement. Patients were enrolled into one of three cohorts: Cohort A with FGFR2 fusions or rearrangements (N=107), Cohort B with other FGF/FGFR genetic alterations (N=20) or Cohort C with no FGF/FGFR genetic alterations (N=18). All patients received PEMAZYRE® 13.5 mg orally once daily, two weeks on and one week off, on a 21-day cycle, until radiological disease progression or unacceptable toxicity. The median patient age of the entire enrolled patient group was 59 years and patients were scanned every eight weeks to assess response to PEMAZYRE®. The Primary endpoint of FIGHT-202 was Objective Response Rate (ORR) in Cohort A, assessed by Independent Review per RECIST criteria. Secondary endpoints included ORR in Cohorts B, A plus B, and C, Duration of Response (DOR), Disease Control Rate (DCR), Progression Free Survival (PFS), Overall Survival (OS), and safety.

It was noted that PEMAZYRE® monotherapy resulted in an Objective Response Rate of 36%, with Complete Response Rate of 2.8% and a Partial Response Rate of 33%. Among those who had a response, 63% had a response lasting 6 months or longer and 18% had a response lasting 12 months or longer. The median Duration of Response was 7.5 months and the Disease Control Rate (DCR) was 82%. The median PFS and median OS were 6.9 months and 21.1 months, and the OS data was not mature at the time of data cutoff. In Cohorts B and C, none of the patients achieved a response. The most common Adverse Events were hyperphosphatemia, alopecia, diarrhea, fatigue, nail toxicities and dysgeusia. Hyperphosphatemia was managed with diet modifications, phosphate binders, diuretics or dose modifications. Fewer patients discontinued therapy in Cohort A compared to Cohort B and C.

It was concluded that based on Overall Response Rate and Duration of Response, PEMAZYRE® is the first and only FDA-approved treatment for previously treated patients with Cholangiocarcinoma, harboring FGFR2 gene rearrangements or fusions.

Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Abou-Alfa GK, Sahai V, Hollebecque A, et al. Lancet Oncol. 2020 Mar 20. pii: S1470-2045(20)30109-1. doi: 10.1016/S1470-2045(20)30109-1. [Epub ahead of print]

FDA Approves BRAFTOVI® in Combination with ERBITUX® for Metastatic Colorectal Cancer

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SUMMARY: The FDA on April 8, 2020, approved BRAFTOVI® (Encorafenib) in combination with ERBITUX® (Cetuximab) for the treatment of adult patients with metastatic ColoRectal Cancer (CRC) with a BRAF V600E mutation, detected by an FDA-approved test, after prior therapy. Colorectal Cancer is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 147,950 new cases of CRC will be diagnosed in the United States in 2020 and about 53,200 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Advanced colon cancer is often incurable and standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab) as well as anti VEGF agent AVASTIN® (Bevacizumab), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC (mCRC), whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now also clear that even among the KRAS Wild Type patient group about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Patients with stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy. Approximately 8-15% of all metastatic CRC tumors present with BRAF V600E mutations and BRAF V600E is recognized as a marker of poor prognosis in this patient group. These patients tend to have aggressive disease with a higher rate of peritoneal metastasis and do not respond well to standard treatment intervention. Approximately 20% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group.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. The BRAF V600E mutations results in constitutive activation of the MAP kinase pathway. Inhibiting BRAF can transiently reduce MAP kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR. It should be noted that BRAF V600E-mutated CRC is inherently less sensitive to BRAF inhibition than Malignant Melanoma.

BRAFTOVI® (Encorafenib) is a BRAF inhibitor and has target binding characteristics that differ from other BRAF inhibitors such as ZELBORAF® (Vemurafenib) and TAFINLAR® (Dabrafenib), with a prolonged target dissociation half-life and higher potency. The combination of BRAFTOVI® along with anti-EGFR monoclonal antibody ERBITUX® (Cetuximab) showed promising activity in early-phase clinical trials.

The present FDA approval was based on BEACON CRC (Binimetinib, Encorafenib, and Cetuximab Combined to Treat BRAF-Mutant Colorectal Cancer) trial, which is an international, multicenter, randomized, open-label, Phase III study in which the efficacy and safety of BRAFTOVI® plus ERBITUX® with or without a MEK inhibitor MEKTOVI® (Binimetinib), was compared with the investigators’ choice of ERBITUX® combined with either Irinotecan or Fluorouracil, Folinic acid, and Irinotecan, in patients with BRAF V600E-mutant mCRC, whose disease has progressed after one or two prior regimens. Eligible patients were required to have BRAF V600E mutation-positive metastatic CRC (detected by the Qiagen therascreen® BRAF V600E RGQ PCR kit), with disease progression after one or two prior regimens. In this trial, 665 patients were randomly assigned in a 1:1:1 ratio to receive either triplet therapy of BRAFTOVI® 300 mg orally daily, MEKTOVI® 45 mg orally twice daily, and ERBITUX® 400 mg/m2 IV as an initial dose, then 250 mg/m2 IV weekly (N=224), doublet-therapy of BRAFTOVI® and ERBITUX® administered in the same doses and on the same schedule as the triplet regimen (N=220) or investigators’ choice of ERBITUX® combined with either Irinotecan or Fluorouracil, Folinic acid, and Irinotecan (N=221). Patients were stratified according to previous Irinotecan use and treatment was administered in 28-day cycles until disease progression. The co-Primary end points were Overall Survival (OS) in the triplet-therapy group as compared with the control group and Secondary end points included OS in the doublet-therapy group as compared with the control group, as well as Progression Free Survival, Duration of Response, and Safety in all groups. This study was not powered to compare the triplet-therapy group against the doublet-therapy group. The Overall Response Rate (ORR) and Duration of Response were assessed by blinded Independent Central Review in the subset of the first 220 patients assigned to receive either BRAFTOVI® and ERBITUX® or the control group.

The median OS was 8.4 months in the BRAFTOVI® plus ERBITUX® group, compared to 5.4 months in the control group (HR=0.60; P=0.0003), and this represented 40% reduction in the risk of death among the BRAFTOVI® plus ERBITUX® group. Median PFS was 4.2 months in the BRAFTOVI® plus ERBITUX® group compared to 1.5 months in the control group (HR=0.40; P< 0.0001). The ORR was 20% and 2% respectively. The median Duration of Response was 6.1 months for the BRAFTOVI® plus ERBITUX® group and Not Reached in the control arm. The median OS was 9.0 months in the triplet-therapy group and 5.4 months in the control group (HR for death=0.52; P<0.001). This represented 48% reduction in the risk of death in the triplet-therapy group. Both the triplet and doublet regimens reduced the risk of Quality of Life (QoL) deterioration by about 45% by different QoL assessment instruments, compared with the control regimen. The most common adverse reactions in the BRAFTOVI® plus ERBITUX® group were fatigue, nausea, diarrhea, dermatitis acneiform, abdominal pain, decreased appetite, arthralgia, and rash.

It was concluded from the BEACON CRC trial that a combination of BRAFTOVI®, MEKTOVI® and ERBITUX® as well as a combination of BRAFTOVI® plus ERBITUX® resulted in significantly longer Overall Survival and a higher Response Rate than standard therapy, in patients with metastatic Colorectal Cancer, with the BRAF V600E mutation.
Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. Kopetz S, Grothey A, Yaeger R, et al. N Engl J Med 2019; 381:1632-1643

FDA Approves KEYTRUDA® for BCG-Unresponsive, High-Risk Non-Muscle Invasive Bladder Cancer

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SUMMARY: The FDA on January 8, 2020, approved KEYTRUDA® (Pembrolizumab) for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, Non-Muscle Invasive Bladder Cancer (NMIBC) with Carcinoma In Situ (CIS) with or without papillary tumors, who are ineligible for or have elected not to undergo cystectomy.

The American Cancer Society estimates that for 2020, about 81,400 new cases of bladder cancer will be diagnosed in the US and about 17,980 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but is less common in women and the average age at the time of diagnosis is 73. Approximately 50% of all bladder cancers are non-invasive or in situ cancers. Patients with high-risk, Non-Muscle Invasive Bladder Cancer that has become unresponsive to BCG treatment, are often given the treatment option of radical cystectomy, which includes removing the entire urinary bladder and a prostatectomy for men or total hysterectomy in women. While highly curative, this surgical procedure carries substantial risk for morbidity and mortality, and can negatively impact patient’s quality of life. Further, a significant proportion of patients are medically ineligible for a radical cystectomy, and even if eligible, refuse surgery and opt for other less effective treatments, which could compromise outcomes.

KEYTRUDA® 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. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response. KEYTRUDA® is presently approved by the FDA for the treatment of patients with locally advanced or metastatic Urothelial carcinoma who are not eligible for Cisplatin-containing chemotherapy or for those with disease progression during or following platinum-containing chemotherapy, based on its durable antitumor activity in this patient group. Upregulation of the PD-1 pathway has been observed in BCG-resistant NMIBC, suggesting that KEYTRUDA® may be of benefit in this group of patients.

This new FDA approval for KEYTRUDA® was based on the KEYNOTE-057 study, which is a multicenter, single-arm trial that enrolled 148 patients with high-risk NMIBC, of whom 96 patients had BCG-unresponsive CIS with or without papillary tumors. BCG-unresponsive high-risk Non-Muscle Invasive Bladder Cancer was defined as persistent disease despite adequate BCG therapy, disease recurrence after an initial tumor-free state following adequate BCG therapy, or T1 disease following a single induction course of BCG. Eligible patients had received adequate BCG therapy and were unable/unwilling to undergo radical cystectomy. All patients had undergone TransUrethral Resection of Bladder Tumor (TURBT) to remove resectable disease. Patients with residual Carcinoma In Situ, not amenable to complete resection were permitted. Patients received KEYTRUDA® 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC or progressive disease, or up to 24 months of therapy without disease progression. The median age was 73 years and the median number of prior BCG instillations was 12. More than half of patients (56.9%) had a PD-L1 Combined Positive Score (CPS) of less than 10, and most patients in this analysis had refused prior cystectomy. The Primary end point was Complete Response Rate (CRR) as defined by negative results for cystoscopy with TURBT/biopsies as applicable, urine cytology, and CT Urography imaging. Secondary end points included Duration of Response and Safety.

At a median follow up was 28 months the Complete Response Rate was 41% and the median Duration of Response was 16.2 months. Forty-six percent (46%) of responding patients experienced a Complete Response lasting at least 12 months. The most frequent adverse reactions were fatigue, diarrhea, rash, pruritis, musculoskeletal pain, peripheral edema and hypothyroidism.

It was concluded from this study that KEYTRUDA® had encouraging activity in bladder cancer patients, with high-risk, BCG-unresponsive Carcinoma in Situ, with or without papillary tumors. The authors added that this study demonstrates that immune activation with systemically administered treatment can result in local activity in the bladder, as well as long-term durable remissions of cancer.
Keynote 057: Phase II trial of Pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guérin (BCG). Balar AV, Kulkarni GS, Uchio EM, et al. J Clin Oncol 37, 2019 (suppl 7S; abstr 350)

FDA Approves IMFINZI® for Advanced Small Cell Lung Cancer

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SUMMARY: The FDA on March 27, 2020 approved IMFINZI® (Durvalumab) in combination with Etoposide and either Carboplatin or Cisplatin as first-line treatment for patients with Extensive-Stage Small Cell Lung Cancer (ES-SCLC). The American Cancer Society estimates that for 2020 about 228,820 new cases of lung cancer will be diagnosed and about 135,720 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Small cell lung cancer (SCLC) accounts for approximately 13-15% of all lung cancers and is aggressive. Patients with extensive stage SCLC are often treated with a combination of Carboplatin or Cisplatin with Etoposide as first line treatment and the tumor response rates are as high as 60-80%. However, majority of the patients relapse within months of completing initial therapy, with a median Overall Survival (OS) of approximately 10 months. Patients often receive HYCAMTIN® (Topotecan) for recurrent or progressive SCLC (second-line treatment) and after failure on second-line therapy, treatment options are limited. The 5 year survival rate for Extensive Stage SCLC (ES-SCLC) is less than 5%, with a median survival of 9-10 months from the time of diagnosis.Unleashing-T-Cell-Function-with-PD-1-and-PD-L1-Antibodies

Based on the premise that SCLC has a high mutation rate, it was hypothesized that these tumors may be immunogenic and more recently immunotherapy with checkpoint inhibitors has demonstrated clinical activity in Extensive Stage SCLC. IMFINZI® (Durvalumab) is a selective, high-affinity, human IgG1 monoclonal antibody, that blocks the binding of Programmed Death Ligand 1 (PD-L1) to Programmed Death 1 (PD-1) receptor and CD80, thereby unleashing the T cells to recognize and kill tumor cells.

IMFINZI® is approved by the FDA for the treatment of patients with locally advanced, unresectable Stage III Non-Small Cell Lung Cancer, who have not progressed following chemoradiotherapy. Additionally, IMFINZI® is also approved for the treatment of patients with locally advanced or metastatic Urothelial carcinoma who have disease progression during or following Platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with Platinum-containing chemotherapy.

This present FDA approval was based on CASPIAN trial, which is a multicenter, randomized, controlled, open-label, Phase III study, in which the efficacy of IMFINZI® with or without CTLA-4 inhibitor Tremelimumab, in combination with Etoposide plus either Cisplatin or Carboplatin (Platinum-Etoposide), was compared to chemotherapy alone, in treatment-naive patients with ES-SCLC. Patients were randomly assigned in a 1:1:1 ratio to IMFINZI® plus Platinum-Etoposide, IMFINZI® plus Tremelimumab plus Platinum-Etoposide, or Platinum-Etoposide alone. This study allocated 268 patients to the IMFINZI® plus Platinum-Etoposide group and 269 patients to the Platinum-Etoposide group. Treatment with Platinum-Etoposide consisted of Etoposide 80-100 mg/m2 IV on days 1-3 of each cycle with investigator’s choice of either Carboplatin AUC 5-6 mg/mL per min or Cisplatin 75-80 mg/m2 IV administered on day 1 of each cycle. Patients received up to four cycles of Platinum-Etoposide along with IMFINZI® 1500 mg IV with or without Tremelimumab 75 mg IV every 3 weeks, followed by maintenance IMFINZI® 1500 mg IV every 4 weeks in the immunotherapy treatment groups, or up to six cycles of Platinum-Etoposide IV every 3 weeks plus Prophylactic Cranial Irradiation (at the treating physicians discretion), in the Platinum-Etoposide control group. The median patient age was 62 years and 10% of the patients had CNS metastases. PCI was administered to 8% of patients in the Platinum-Etoposide group. The Primary endpoint was Overall Survival (OS). Additional efficacy outcome measures included Progression Free Survival (PFS) and Objective Response Rate (ORR). The authors reported the results for the IMFINZI® plus Platinum-Etoposide group, compared to the Platinum-Etoposide group, from a planned interim analysis.

The median OS was 13.0 months in the IMFINZI® plus chemotherapy group, compared with 10.3 months in the chemotherapy alone group (HR=0.73; P=0.0047), with a 27% reduction in the risk of death. Approximately 34% of patients who received IMFINZI® were alive at 18 months as compared to 25% in the control arm of the trial. Additionally, IMFINZI® plus chemotherapy demonstrated a higher PFS rate at 12 months (17.5% versus 4.7%), a 10.3% increase in confirmed ORR (67.9% versus 57.6%), and improved Duration of Response at 12 months (22.7% versus 6.3%). The most common adverse reactions noted were nausea, fatigue, asthenia, and alopecia.

It was concluded that the addition of IMFINZI® to first line Platinum-Etoposide chemotherapy combination significantly improved Overall Survival in patients with Extensive Stage-Small Cell Lung Cancer, when compared to chemotherapy alone.
Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Paz-Ares L, Dvorkin M, Chen Y, CASPIAN investigators, et al. Lancet. 2019;394:1929-1939

FDA Approves REBLOZYL® for Patients with Lower-Risk Myelodysplastic Syndromes

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SUMMARY: The FDA on April 3, 2020 approved REBLOZYL® (Luspatercept-aamt) for the treatment of anemia, failing an Erythropoiesis Stimulating Agent, and requiring two or more RBC units over 8 weeks, in adult patients with very low- to intermediate-risk MyeloDysplastic Syndromes with Ring Sideroblasts (MDS-RS) or with Myelodysplastic/Myeloproliferative neoplasm with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T).

It is estimated that in the US approximately 13,000 people are diagnosed with MyeloDysplastic Syndromes (MDS) each year. MyeloDysplastic Syndromes are a heterogenous group of stem cell disorders characterized by marrow failure resulting in cytopenias with associated cytogenetic abnormalities, and abnormal cellular maturation with morphologic changes in clonal cells. Majority of the individuals diagnosed with MDS are aged 65 years and older and die as a result of infection and/or bleeding consequent to bone marrow failure. About a third of patients with MDS develop Acute Myeloid Leukemia (AML).

Patients with Lower-risk MDS (Revised IPSS-Very Low, Low, or Intermediate risk ) often present with symptomatic anemia and these patients are in chronic need for RBC transfusions which in turn can result in iron overload and can have a negative impact on quality of life and Overall Survival. These patients are treated with Erythropoiesis Stimulating Agents (ESAs) as first line therapy. ESAs such as Darbepoetin alfa and Epoetin alfa are re-engineered and recombinant DNA technology products of Erythropoietin (EPO), and they stimulate erythropoiesis by binding and activating the EPO receptor. However, transfusion-dependent patients with serum EPO levels above 200 U per liter are less likely to respond to ESAs. Additionally, patients with MDS with ring sideroblasts have a shorter median duration of response to ESAs, than those who do not have ring sideroblasts. Patients with Lower-risk MDS with chromosome 5q deletion (del 5q) who are transfusion dependent are treated with Lenalidomide, regardless of previous treatment with ESAs. In contrast, only 39% of patients with non-del(5q) Lower-risk MDS receive second line therapy besides RBC transfusions, and there are few treatment options for patients who are refractory to, unresponsive to, or ineligible for ESAs. There is therefore an unmet clinical need for safe and effective treatment options, to reduce the RBC transfusion burden in these patients.Luspartercept-Restores-Red-Blood-Cell's-Ability-to-Mature

Signaling by the SMAD2 and SMAD3 pathway exerts an inhibitory effect on red cell maturation. This pathway is constitutively activated in the bone marrow cells of patients with MDS and diseases associated with ineffective erythropoiesis such as β-thalassemia. REBLOZYL® (Luspatercept) is a recombinant soluble fusion protein and is first-in-class erythroid maturation agent that enhances erythropoiesis by promoting late-stage Red Blood Cell precursor differentiation and maturation. It targets select Transforming Growth Factor (TGF)-β superfamily ligands such as GDF11, that regulate late-stage erythropoiesis. This results in a reduction in aberrant SMAD2 and SMAD3 signaling, thereby promoting late-stage RBC precursor differentiation and maturation. In a Phase II study, treatment of Lower-risk MDS patients with REBLOZYL® resulted in 38% of patients being transfusion independent for 8 weeks or longer and this benefit was even more so among patients with 15% or more ring sideroblasts.

The MEDALIST trial is a randomized, double-blind, placebo-controlled Phase III study which evaluated the efficacy and safety of REBLOZYL® in patients with anemia secondary to MDS, defined as Very Low-Risk, Low-Risk, or Intermediate-Risk with Ring Sideroblasts, according to the Revised International Prognostic Scoring System (R-IPSS). Eligible patients were refractory, intolerant, or ineligible to receive ESAs and required RBC transfusions. A total of 229 patients (N=229) were randomized 2:1 to receive either REBLOZYL® at a starting dose level of 1mg/kg SC with titration up to 1.75 mg/kg if needed (N=153), or placebo SC (N=76), every 3 weeks for 24 weeks or more. The median age was 71 years and median time from diagnosis was 41.8 months. Approximately 95% of patients had previously received ESAs and 90% had an SF3B1 mutation. SF3B1 mutation defines a homogeneous subgroup of MDS patients with Ring Sideroblasts, who have isolated erythroid dysplasia and favorable prognosis. The Primary endpoint was RBC transfusion independence for 8 weeks or more between week 1 and 24. A key Secondary endpoint was RBC transfusion independence for 12 weeks or more between week 1 and 24.

Among those receiving REBLOZYL®, 38% achieved the Primary endpoint of RBC transfusion independence for 8 weeks or more, compared with 13% receiving placebo (P<0.0001). Further among those receiving REBLOZYL®, 28% achieved the key Secondary endpoint of RBC transfusion independence for 12 weeks or more compared with 8% receiving placebo (P<0.001). The median duration of the longest, single continuous period of response to REBLOZYL® was 30.6 weeks, and 13.6 weeks in the placebo group. Among patients who had a baseline transfusion burden of 4 to less than 6 units per 8 weeks, 37% of those in the REBLOZYL® group and 4% of those in the placebo group had a response. Additionally, patients receiving REBLOZYL® were more likely to achieve an mHI-E (modified Hematologic Improvement-Erythroid) response, (defined as a reduction in transfusion of 4 or more RBC units per 8 weeks or a mean hemoglobin increase of 1.5 g/dL or more per 8 weeks, in the absence of transfusions), compared with patients receiving placebo (53% versus 12% during weeks 1-24; P<0.0001). A mean increase in hemoglobin level of at least 1 g/dL during weeks 1 to 24 was noted in 35% of patients who received REBLOZYL® and in 8% of patients who received placebo. The most common adverse events of any grade associated with REBLOZYL® included fatigue, diarrhea, asthenia, nausea and dizziness, and the incidence of adverse events decreased over time.

It was concluded that treatment with REBLOZYL® significantly reduced the severity of anemia in patients with Lower-risk MDS with ring sideroblasts, who had been RBC transfusion-dependent, and who had disease that was refractory to, or unlikely to respond to ESAs. Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes. Fenaux P, Platzbecker U, Mufti GJ, et al. N Engl J Med 2020; 382:140-151