The FDA on August 18, 2021 granted accelerated approval to JEMPERLI® for adult patients with MisMatch Repair deficient (dMMR) recurrent or advanced solid tumors, as determined by an FDA-approved test, that have progressed on or following prior treatment and who have no satisfactory alternative treatment options. JEMPERLI® is a product of GlaxoSmithKline LLC.
The FDA on August 13, 2021 approved WELIREG®, a Hypoxia-Inducible Factor inhibitor for adult patients with Von Hippel-Lindau (VHL) disease who require therapy for associated Renal Cell Carcinoma (RCC), Central Nervous System (CNS) Hemangioblastomas, or Pancreatic NeuroEndocrine Tumors (pNET), not requiring immediate surgery. WELIREG® is a product of Merck & Co.
The FDA on July 16, 2021 approved REZUROCK®, a kinase inhibitor, for adult and pediatric patients 12 years and older with chronic Graft-Versus-Host Disease (chronic GVHD), after failure of at least two prior lines of systemic therapy. REZUROCK® is a product of Kadmon Pharmaceuticals, LLC.
The FDA on June 16, 2021, approved AYVAKIT® for adult patients with advanced Systemic Mastocytosis, including patients with aggressive Systemic Mastocytosis, Systemic Mastocytosis with an associated hematological neoplasm, and Mast Cell Leukemia. AYVAKIT® is a product of Blueprint Medicines Corp.
SUMMARY: OsteoNecrosis of the Jaw (ONJ) is defined as progressive bone destruction in the maxillofacial region resulting in exposed bone, or bone that can be probed through an intraoral or extraoral fistula (or fistulae) in the maxillofacial region and that does not heal within 8 weeks, occurring in a patient who has received a Bone-Modifying Agent (BMA) or an angiogenic inhibitor agent and with no history of head and neck radiation. The condition may involve the mandible or the maxilla and can be challenging to treat and can cause significant pain, impacting patients quality of life. The true incidence ONJ is unknown.
Bone Modifying Agents that have been linked with ONJ principally include bisphosphonates such as Zoledronic acid and Pamidronate and Rank Ligand inhibitor, Denosumab. BMAs are an integral part of cancer management and have essential roles in supportive oncology for the treatment of hypercalcemia of malignancy and bone metastases, and prevention of Skeletal-Related Events (SREs) such as pathologic fractures and reduce the need for radiation or surgical intervention. BMAs disrupt the bone remodeling cycle by reducing osteoclast survival and function.
The SWOG Cancer Research Network designed this trial to prospectively assess the incidence of and predictive factors associated with OsteoNecrosis of the Jaw (ONJ), in patients with cancer receiving Zoledronic acid. The Primary objective was to prospectively assess the cumulative incidence of ONJ at 3 years. SWOG S0702 is a multicenter, prospective observational cohort study which enrolled 3491 patients with Metastatic Bone Disease (MBD) with either limited or no prior exposure to Bone Modifying Agents, who had received Zoledronic acid (ZOMETA®) within 30 days of registration. The median patient age was 63 years of whom 32% had breast cancer, 17% had myeloma, 20% had prostate cancer, 19% had lung cancer, and 12% had other malignancies. A baseline dental examination was performed in 65% of the patients. Over 65% of patients reported no alcohol use, 12% were current smokers and complete or partial dentures were observed in 22% of patients. The Primary end point was the diagnosis of confirmed ONJ, defined as an area of exposed bone in the maxillofacial region that had been present for at least 8 weeks in a patient receiving or previously exposed to a bisphosphonate, and who had not had radiotherapy to the craniofacial region. A suspected case of ONJ was defined by the same ONJ criteria but present for less than 8 weeks. All suspected and confirmed cases of ONJ were adjudicated by the study team. The median follow up was 3 years.
The cumulative incidence of confirmed ONJ at year 1 was 0.8%, at year 2 was 2% and at year 3 was 2.8%. The cumulative incidence at 3 years was highest in patients with myeloma (4.3%) and lowest in those with breast cancer (2.4%). ONJ risk was higher among patients with planned Zoledronic acid dosing intervals of less than 5 weeks versus those with planned intervals of 5 weeks or longer (cumulative incidence 3.2% versus 0.7%; P=0.009). ONJ risk was higher among patients with any dentures (cumulative incidence, 5% versus 2.9%; P=0.02) and removable dentures (cumulative incidence 6.5% versus 3%; P=0.03), and were about twice as likely to experience ONJ compared with patients without any dentures or without removable dentures, respectively. A higher rate of ONJ was associated with fewer total number of teeth (less than 25 versus more than 25), with a 3 year ONJ incidence of 4.4% versus 2.4% respectively (HR=0.51; P=0.006). Current smokers were more likely to experience ONJ than patients who were not current smokers (3.7% versus 2.4%; P=0.02)
The authors concluded that this prospective study of patients treated with Zoledronic acid provides clinicians with critical information about the overall risk and risk factors for developing ONJ. The authors added that when clinically appropriate, consideration should be given to use of Zoledronic acid dosing intervals of greater than 5 weeks to reduce the risk of ONJ.
Association of Osteonecrosis of the Jaw With Zoledronic Acid Treatment for Bone Metastases in Patients With Cancer. Van Poznak CH, Unger JM, Darke AK, JAMA Oncol. Published online December 17, 2020. doi:10.1001/jamaoncol.2020.6353.
SUMMARY: Sickle Cell Disease or Sickle Cell anemia is an Autosomal Recessive disorder and affects approximately 100,000 Americans. It is estimated that it affects 1 out of every 365 African-American births and 1 out of every 16,300 Hispanic-American births. The average life expectancy for patients with Sickle Cell Disease in the United States is approximately 40-60 years. Beta thalassemia affects at least 1000 Americans and according to the WHO, more than 300,000 babies are born worldwide each year with hemoglobin disorders such as Transfusion-Dependent beta-Thalassemia (TDT) and Sickle Cell Disease (SCD). Both diseases are caused by mutations in the hemoglobin beta-globin gene.
HbSS disease or Sickle Cell anemia is the most common Sickle Cell Disease genotype and is associated with the most severe manifestations. HbSS disease is caused by a mutation substituting thymine for adenine in the sixth codon of the beta-globin chain gene. This in turn affects the hemoglobin’s ability to carry oxygen and causes it to polymerize. This results in decreased solubility thereby distorting the shape of the red blood cells, increasing their rigidity and resulting in red blood cells that are sickle shaped rather than biconcave. These sickle shaped red blood cells limit oxygen delivery to the tissues by restricting the flow in blood vessels, leading to severe pain and organ damage (Vaso-Occlusive Crises). Oxidative stress is an important contributing factor to hemoglobin polymerization with polymer formation occurring only in the deoxy state. HbS/b-0 Thalassemia (double heterozygote for HbS and b-0 Thalassemia) is clinically indistinguishable from HbSS disease. Thalassemia is an inherited hemoglobinopathy associated with an erythroid maturation defect and is characterized by ineffective erythropoiesis and impaired RBC maturation. Mutations in the hemoglobin beta-globin gene result in reduced (B+) or absent (B0) beta-globin synthesis creating an imbalance between the alpha and beta globin chains of hemoglobin, resulting in ineffective erythropoiesis. Management of Sickle Cell Disease includes pain control, transfusion support and Hydroxyurea, whereas management of beta Thalassemia include transfusion support and iron chelation therapy. None of the presently available therapies addresses the underlying cause of these diseases nor do they fully ameliorate disease manifestations. Allogeneic bone marrow transplantation can cure both these genetic disorders, but less than 20% of eligible patients have a related HLA-matched donor. There is therefore a great unmet need to find new therapies for beta-Thalassemia and Sickle Cell Disease.
Fetal hemoglobin which consists of two alpha and two gamma chains is produced in utero, but the level of gamma-globulin decreases postnatally as the production of beta-globin and adult hemoglobin which consists of two alpha and two beta chains increases. It has been noted that elevated levels of fetal hemoglobin are associated with decreased morbidity and mortality in patients with Sickle Cell Disease and Thalassemia. BCL11A gene is a repressor of gamma-globin expression and fetal hemoglobin production in adult red blood cells. Downregulating BCL11A can therefore reactivate gamma-globin expression and increase fetal hemoglobin in RBC.
The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 nuclease gene editing technique cuts the DNA at the targeted location. The authors in this study used this gene-editing technique in Hematopoietic Stem and Progenitor Cells at the erythroid-specific enhancer region of BCL11A to down-regulate BCL11A expression in erythroid-lineage cells, restore gamma-globin synthesis, and reactivate production of fetal hemoglobin.
The authors reported the interim safety and efficacy data from 10 patients who received the investigational CRISPR-Cas9 nuclease gene-editing based therapy, following enrollment in CLIMB THAL-111 and CLIMB SCD-121 studies. These patients were infused with CTX001 (autologous CRISPR-Cas9-edited CD34+ Hematopoietic Stem and Progenitor Cells (HSPCs) that were genetically edited to reactivate the production of fetal hemoglobin. In the CLIMB THAL-111 and CLIMB SCD-121 open-label, PhaseI/II trials, patients with Transfusion-Dependent beta-Thalassemia and sickle cell disease , respectively, received a single intravenous infusion of CTX001. The production of CTX001 involved collection of CD34+ Hematopoietic Stem and Progenitor Cells (HSPCs) from patients by apheresis, following stem cell mobilization with either NEUPOGEN filgrastim and/or MOZOBIL® (plerixafor), after a minimum of 8 weeks of transfusions of packed red cells, to achieve a level of sickle hemoglobin of less than 30% in the patient with SCD. CTX001 was then manufactured from these CD34+ cells by editing with CRISPR-Cas9 with the use of a single-guide RNA molecule, following preclinical studies of BCL11A editing. Patients received myeloablation with pharmacokinetically adjusted, single-agent Busulfan, before the infusion of CTX001.
Eligible patients were between ages 18 and 35 years. In the CLIMB THAL-111 trial, eligible patients had a diagnosis of beta-Thalassemia (including the hemoglobin E genotype) with either homozygous or compound heterozygous mutations and had received transfusions of PRBC consisting of at least 100 ml/kg of body weight (or 10 units) per year during the previous 2 years. In the open-label CLIMB SCD-121 trial, eligible patients had a documented BS/BS or BS/B0 genotype and had a history of two or more severe vaso-occlusive episodes per year during the previous 2 years. Patients were monitored for engraftment, adverse events, total hemoglobin, hemoglobin fractions on high-performance liquid chromatography, F-cell expression (defined as the percentage of circulating erythrocytes with detectable levels of fetal hemoglobin), laboratory signs of hemolysis, requirements for transfusion support with PRBC, and occurrence of vaso-occlusive episodes in the patient with SCD. Bone marrow aspirates were obtained at 6 and 12 months after infusion, and DNA sequencing was used to measure the fraction of total DNA that was edited at the on-target site in CD34+ bone marrow cells and in nucleated peripheral-blood cells.
The Primary endpoint of the CLIMB THAL-111 trial was the proportion of patients with a transfusion reduction of 50% for at least six months, starting three months after CTX001 infusion. The Primary endpoint of CLIMB SCD-121 Sickle Cell Disease trial was the proportion of patients with fetal hemoglobin of 20% or more, sustained for at least three months, starting six months after CTX001 infusion.
CLIMB THAL-111 trial: Data was reported on 7 patients enrolled in the CLIMB THAL-111 trial, as they had reached at least three months of follow up after CTX001 infusion and therefore could be assessed for initial safety and efficacy. All seven showed a similar pattern of response, with rapid and sustained increases in total hemoglobin, fetal hemoglobin, and transfusion independence at last analysis. All 7 patients were transfusion independent with follow up ranging from 3-18 months after CTX001 infusion, with normal to near normal total hemoglobin levels at last visit. Their total hemoglobin levels ranged from 9.7 to 14.1 g/dL, and fetal hemoglobin ranged from 40.9% to 97.7%. Bone marrow allelic editing data collected from 4 patients with 6 months of follow up, and from one patient with 12 months of follow-up after CTX001 infusion showed the treatment resulted in a durable response. The safety data from all seven patients were generally consistent with an Autologous Stem Cell Transplant (ASCT) and myeloablative conditioning. There were four Serious Adverse Events (SAEs) considered related or possibly related to CTX001 reported in one patient and included headache, Hemophagocytic LymphoHistiocytosis (HLH), Acute Respiratory Distress Syndrome, and Idiopathic Pneumonia Syndrome. All four SAEs occurred in the context of HLH and resolved. Most of the non-SAEs were considered mild to moderate. CLIMB-111 is an ongoing trial and will enroll up to 45 patients and follow patients for approximately two years after infusion.
CLIMB SCD-121: Data was reported on 3 patients enrolled in the CLIMB SCD-121 sickle cell disease trial as they had reached at least three months of follow up after CTX001 infusion, and therefore could be assessed for initial safety and efficacy. Again, all 3 patients showed a similar pattern of response, with rapid and sustained increases in total hemoglobin and fetal hemoglobin, as well as elimination of Vaso-Occlusive Crises through last analysis. All 3 patients remained Vaso Occlusive Crises-free with follow up ranging from 3-15 months after CTX001 infusion and had hemoglobin levels in the normal to near normal range, including total hemoglobin from 11.5 to 13.2 g/dL and Fetal hemoglobin levels from 31.3% to 48.0%. Bone marrow allelic editing data collected from one patient with six months of follow-up and from one patient with 12 months of follow-up after CTX001 infusion demonstrated a durable response. Again the safety data were consistent with an ASCT and myeloablative conditioning. There were no Serious Adverse Events noted, thought to be related to CTX001, and the majority of non-SAEs were considered mild to moderate. CLIMB-121 is an ongoing open-label trial and will enroll up to 45 patients and follow patients for approximately two years after infusion.
It was concluded from this initial follow up that, CTX001 manufactured from Hematopoietic Stem Cells, edited of BCL11A with CRISPR-Cas9, has shown durable engraftment, with high levels of fetal hemoglobin expression, and the elimination of vaso-occlusive episodes or need for transfusion. The authors added that these preliminary results support further testing of CRISPR-Cas9 gene-editing approaches to treat other genetic diseases.
Safety and Efficacy of CTX001 in Patients with Transfusion-Dependent β- Thalassemia and Sickle Cell Disease: Early Results from the Climb THAL-111 and Climb SCD-121 Studies of Autologous CRISPR-CAS9–Modified CD34+ Hematopoietic Stem and Progenitor Cells. Frangoul H, Bobruff Y, Cappellini MD, et al. Presented at the 62nd ASH Annual Meeting and Exposition, 2020. Abstract#4
The FDA on November 25, 2020 granted accelerated approval to DANYELZA® in combination with Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) for pediatric patients one year of age and older, and adult patients with relapsed or refractory high-risk Neuroblastoma in the bone or bone marrow, demonstrating a partial response, minor response, or stable disease to prior therapy. DANYELZA® is a product of Y-mAbs Therapeutics, Inc.
SUMMARY: Tumor Mutational Burden (TMB) is a measure of the somatic mutation rate within a tumor genome and is emerging as a quantitative indicator for predicting response to Immune Checkpoint Inhibitors such as KEYTRUDA®, across a wide range of malignancies. These non-synonymous somatic mutations in the tumor genome generate larger number of neo-antigens which are more immunogenic. Immune Checkpoint Inhibitors are able to unleash the immune system to detect these neoantigens and destroy the tumor. TMB can be measured using Next-Generation Sequencing (NGS) and is defined as the number of somatic, coding base substitutions and short insertions and deletions (indels), per megabase of genome examined. Several studies have incorporated Tumor Mutational Burden (TMB) as a biomarker, using the validated cutoff of TMB of 10 or more mutations/Megabase as High and less than 10 mutations/Megabase as Low. (A megabase is 1,000,000 DNA basepairs). 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, thereby undoing PD-1 pathway-mediated inhibition of the immune response, and unleashing the tumor-specific effector T cells.
The authors in this publication prospectively explored the association of high tissue TMB with outcomes, following treatment with KEYTRUDA®, in patients with selected, previously treated, advanced solid tumors. KEYNOTE-158 is a multicenter, multicohort, non-randomized, open-label, Phase II basket trial investigating the antitumor activity and safety of KEYTRUDA® in multiple advanced solid tumors. Eligible patients had advanced unresectable or metastatic solid tumors (Anal, Biliary, Cervical, Endometrial, Mesothelioma, Neuroendocrine, Salivary, Small-cell lung, Thyroid, and Vulvar), who had progressed on, or were intolerant to one or more lines of standard therapy, had measurable disease, as well as tumor sample available for biomarker analysis.
This study enrolled 1073 patients of whom 1,050 patients were included in the efficacy analysis and TMB was analyzed in the subset of 790 patients, with sufficient tissue for testing. Of these 790 patients, 102 patients (13%) had tumors identified as TMB-High, defined 10 or more mutations /Megabase. TMB status was assessed in Formalin-Fixed Paraffin-Embedded tumor samples using the FoundationOne® CDx assay. Patients received KEYTRUDA® 200 mg IV every 3 weeks for up to 35 cycles. The median age in this study population of 102 patients was 61 years, ECOG PS was 0-1, and 56% of patients had at least 2 prior lines of therapy. Tumor response was assessed every 9 weeks for the first 12 months and every 12 weeks thereafter. The major efficacy outcome measures were Objective Response Rate (ORR) and Duration of Response (DOR) in the patients who received at least one dose of KEYTRUDA®. The key Secondary outcome measures included Progression Free Survival (PFS), Overall Survival (OS), and safety. The median study follow up was 37.1 months.
In the 102 patients whose tumors were TMB-H, KEYTRUDA® demonstrated an ORR of 29%, with a Complete Response rate of 4% and a Partial Response rate of 25%. The ORR in the non-TMB-High group was 6%. The median duration of response was not reached in the TMB-H group and was 33.1 months in those without high TMB, at the time of data cutoff. There was low correlation between TMB and PD-L1 expression. The most common adverse reactions for KEYTRUDA® were fatigue, decreased appetite, rash, pruritus, fever, nausea, diarrhea, cough, dyspnea, constipation, abdominal pain and musculoskeletal pain.
The authors concluded that high Tumor Mutational Burden status identifies a subgroup of patients who could have a robust tumor response to KEYTRUDA® monotherapy . They added that tissue TMB therefore could be a novel and useful predictive biomarker for response to KEYTRUDA® monotherapy in patients with previously treated recurrent or metastatic advanced solid tumors.
Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Marabelle A, Fakih MG, Lopez J, et al. Lancet Oncol. 2020;21:1353-1365.
SUMMARY: Hereditary factors play an important role in the risk of developing several cancers. Therefore, identification of a germline predisposition can have important implications for treatment decision making, risk-reducing interventions, cancer screening for early diagnosis, and germline testing of unaffected relatives. Previously published studies have been biased by estimating the prevalence of germline cancer susceptibility in patients with breast, prostate, and colorectal cancer from registry populations, genetic testing companies, and high-risk cancer clinics. Very few studies have compared the prevalence of germline findings in patients with cancer, not selected by practice guidelines, and the impact of universal testing strategy for inherited germline variants in patients with cancer has remained unclear. The purpose of this present study was to determine if universal genetic testing in patients with cancer identifies more inherited cancer predisposition variants than a guideline-based approach, and also find out if there is an association between universal genetic testing and clinical management.
The authors in this prospective, multicenter cohort study, assessed germline genetic alterations among patients with solid tumors, receiving care at Mayo Clinic Cancer Centers and Mayo Clinic Health System community oncology practice in the US, between April 2018, and March 2020, as a part of 2 year Interrogating Cancer Etiology Using Proactive Genetic Testing (INTERCEPT) program. Patients were NOT selected based on cancer type, stage of disease, family history of cancer, race/ethnicity, age at diagnosis, multifocal tumors, or personal history of multiple malignant neoplasms. Clinical, demographic, and family history data and pathologic information were collected on all patients from medical records or self-administered questionnaires.
Germline sequencing using a Next-Generation Sequencing panel of 84 genes was offered at no cost, utilizing the Invitae Multi-Cancer Panel. Whole Genome Sequencing, deletion and duplication analysis, and variant interpretation were performed and Pathogenic Germline Variants (PGV) were classified as High (relative risk more than 4), Intermediate (relative risk, 2-4), or Low (relative risk less than 2) penetrance, or recessive medically actionable variants. Test results were disclosed to the patient, and those with Pathogenic Germline Variants (PGVs) were invited for genetic counseling.
The authors compared multi-gene panel testing with guideline-based testing, using guidelines from the National Comprehensive Cancer Network (NCCN) and the National Society of Genetic Counselors (NSGC) and the American College of Medical Genetics (ACMG), to determine whether genetic testing was indicated for a particular patient. For patients who met the guidelines, the only genes tested were those recommended by the tumor-specific guideline. This study included patients with a broad mix of cancer types at various stages. The final analytic cohort consisted of 2984 patients, out of the 3095 patients enrolled in the study. The mean patient age was 61 years, 53% were male and 44% of patients had Stage IV disease at the time of genomic analysis. A family history of cancer in a first-degree relative was reported in 34% of the participants. The goals of this study were to examine the proportion of Pathogenic Germline Variants (PGVs) detected with a universal testing strategy compared with a targeted testing strategy based on clinical guidelines, as well as uptake of cascade genetic testing in families, when offered at no cost.
It was noted that Pathogenic Germline Variants (inherited mutation in a gene) associated with the development of their cancer was found in 13.3% of patients, including moderate and high-penetrance cancer susceptibility genes. In this study, 1 in 8 patients had a PGV, half of which would not have been detected using a guideline-based testing approach. Of those with a high-penetrance PGVs, 28.2% had modifications in their treatment, based on the finding. About 6.4% had incremental clinically actionable findings that would not have been detected by phenotype or family history-based testing criteria. However, only 17.6% of participants with PGVs had family members undergoing no-cost cascade genetic testing when offered.
It was concluded that in this large, prospective, multicenter cohort study with a broad mixture of cancer types and stages, universal multigene panel testing was associated with increased detection of clinically actionable heritable variants, compared with a targeted testing strategy based on clinical guidelines. Approximately 30% of patients with high-penetrance variants had modifications in their treatment, suggesting that wider clinical implementation of universal genetic testing and acceptance in oncology practice, may be beneficial.
Comparison of Universal Genetic Testing vs Guideline-Directed Targeted Testing for Patients With Hereditary Cancer Syndrome. Samadder NJ, Riegert-Johnson D, Boardman L, et al. JAMA Oncol. Published online October 30, 2020. doi:10.1001/jamaoncol.2020.6252
SUMMARY: Chemotherapy remains one of the mainstays of cancer treatment. However, chemotherapy-induced damage of Hematopoietic Stem and Progenitor Cells (HSPC) causes multi-lineage myelosuppression. Currently, available therapies such as Granulocyte-Colony Stimulating Factors (G-CSF) and Erythropoiesis-Stimulating Agents (ESAs) prevent the myelosuppressive effects of chemotherapy in only one lineage. Therapeutic agents that lead to protection of multiple lineages simultaneously would be clinically meaningful.
Trilaciclib is a highly potent, selective, and reversible, intravenous, Cyclin-Dependent Kinase 4 and 6 (CDK 4/6) inhibitor, that transiently maintains G1 cell cycle arrest of Hematopoietic Stem and Progenitor Cells (HSPC), and protects them from damage by cytotoxic chemotherapy. Chemotherapy-induced damage of Hematopoietic Stem and Progenitor Cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib proactively preserves HSPC and immune system function during chemotherapy (myelopreservation). Preclinical studies have demonstrated that Trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery. Additionally, Trilaciclib enhances immune response, and preserves immune system function.
Small Cell Lung Cancer (SCLC) was chosen as the testing platform, to explore the potential myelopreservation benefit of Trilaciclib for the following reasons: 1) Cytotoxic chemotherapy for SCLC is notable for its myelotoxicity. 2) SCLC tumor cells replicate independent of CDK4/6, through the obligate loss of Retinoblastoma (RB1), allowing assessment of Trilaciclib’s effects on the host, without any potential direct effects on the tumor. 3) SCLC is a chemosensitive tumor, and provides an optimal setting to demonstrate that Trilaciclib does not antagonize chemotherapy efficacy.
The authors in this publication, pooled data from three randomized, double-blind, placebo-controlled Phase II trials, in patients with Extensive-Stage Small Cell Lung Cancer (ES-SCLC), to understand the effects of Trilaciclib on specific myelosuppression endpoints, with greater statistical precision. Individual results from these three randomized trials have previously been reported. In this pooled analysis, 123 patients received Trilaciclib along with chemotherapy (N=123), and 119 patients received Placebo along with chemotherapy (N=119). The median age in both treatment groups was 64 years. The objectives of this pooled data analysis was to summarize the utilization of G-CSFs, ESAs and RBC transfusions, and hospitalizations due to Chemotherapy Induced Myelosuppression or sepsis, as well as explore the relationship between supportive care interventions and the myelopreservation benefits of Trilaciclib.
In the first study (NCT02499770), patients with newly diagnosed ES-SCLC received Trilaciclib 240 mg/m2 or Placebo IV, given daily on days 1 to 3, prior to chemotherapy, of each 21-day chemotherapy cycle with Etoposide and Carboplatin. In the second trial (NCT03041311), patients with newly diagnosed ES-SCLC received Trilaciclib 240 mg/m2 or Placebo IV, given daily on days 1 to 3, prior to chemotherapy, of each 21-day chemotherapy cycle with Etoposide, Carboplatin and Atezolizumab (TECENTRIQ®), followed by single-agent Atezolizumab alone, every 21 days. In the third study (NCT02514447), patients with previously treated ES-SCLC in the second or third line setting, received Trilaciclib 240 mg/m2 or Placebo IV daily, prior to Topotecan 1.5 mg/m2 IV given daily on days 1 to 5 of each 21-day cycle. The Primary outcome measures included percentage of patients with Severe (Grade 4) Neutropenia as well as duration of Severe Neutropenia. Supportive intervention endpoints included percentage of patients with RBC transfusions on or after week 5, and number of RBC transfusion events on or after week 5, as well as percentage of patients receiving ESAs. This study also explored the percentage of patients with hospitalizations due to Chemotherapy Induced Myelosuppression (neutropenia, anemia, thrombocytopenia) or sepsis, as well as incidence of hospitalizations due to Chemotherapy Induced Myelosuppression or sepsis, per 100 cycles.
It was noted that fewer patients receiving Trilaciclib had Severe Neutropenia (11.4% versus 52.9%) or Grade 3/4 anemia (20.3% versus 31.9%), compared to Placebo, respectively, and the use of supportive care interventions such as G-CSF and ESAs was significantly reduced. Hospitalizations due to Chemotherapy Induced Myelosuppression or sepsis occurred in significantly fewer patients and significantly less often among patients receiving Trilaciclib prior to chemotherapy, compared to those who received Placebo. Trilaciclib reduced the percentage of patients with Severe Neutropenia and duration of Severe Neutropenia, regardless of G-CSF administration. The proportion of patients receiving RBC transfusions was consistently lower with each cycle, among patients receiving Trilaciclib, whereas RBC transfusions in the Placebo group almost doubled over time.
It was concluded that Trilaciclib prior to chemotherapy significantly and meaningfully reduced Chemotherapy Induced Myelosuppression and the need for supportive care interventions, for the management of Severe Neutropenia and Grade 3/4 anemia, in patients with ES-SCLC. Chemotherapy-induced Severe Neutropenia was reduced with Trilaciclib, irrespective of G-CSF administration.
Trilaciclib Reduces the Need for Growth Factors and Red Blood Cell Transfusions to Manage Chemotherapy-Induced Myelosuppression. Ferrarotto R, Anderson I, Medgyasszay B, et al. Presented at: IASLC 2020 North America Conference on Lung Cancer; October 16-17, 2020.