Category: Hem/Onc Updates

OPDIVO® Combination Improves Overall Survival in Advanced Esophageal Carcinoma

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SUMMARY: The American Cancer Society estimates that in 2022, about 20,640 new cases of esophageal cancer will be diagnosed in the US and about 16,410 individuals will die of the disease. It is the sixth most common cause of global cancer death. Squamous Cell Carcinoma is the most common type of cancer of the esophagus among African Americans, while Adenocarcinoma is more common in Caucasians. Squamous Cell Carcinoma accounts for approximately 85% of cases.

Majority of esophageal cancers are unresectable at diagnosis, and most patients treated with curative intent eventually will relapse and only about 20% of patients will survive at least 5 years following diagnosis. Patients with advanced esophageal cancer have a median survival of less than a year when treated with the standard Fluoropyrimidine plus Platinum based chemotherapy. For those patients progressing on first line chemotherapy, treatment options are limited, with a 5-year relative survival rate of 8% or less.

OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. It has been noted that approximately 50% of patients with advanced esophageal Squamous Cell Carcinoma express tumor-cell Programmed Death Ligand 1 (PD-L1) greater than 1%. In the ATTRACTION-3 multicentre, Phase III trial, treatment with OPDIVO® was associated with a significant improvement in Overall Survival, compared with chemotherapy, in previously treated patients with advanced Esophageal Squamous Cell Carcinoma, regardless of PD-L1 expression. In the CheckMate 649 Phase III trial involving patients with gastric, gastroesophageal junction, or esophageal adenocarcinoma, first-line treatment with OPDIVO® plus chemotherapy resulted in a significant Overall Survival (OS) and Progression Free Survival (PFS) benefit, as compared with chemotherapy alone, as well as durable Objective Response Rate (ORR), with an acceptable safety profile.

CheckMate 648 is a global, open-label, Phase III trial in which the efficacy and safety of both an Immune Checkpoint Inhibitor in combination with chemotherapy and a dual Immune Checkpoint Inhibitor combination was evaluated in previously untreated patients with advanced esophageal Squamous Cell Carcinoma. The researchers herein reported the results for OPDIVO® plus chemotherapy and for OPDIVO® plus YERVOY® (Ipilimumab) as compared with chemotherapy alone.

In this study, 970 patients with previously untreated, unresectable, advanced, recurrent or metastatic esophageal Squamous Cell Carcinoma were randomly assigned 1:1:1 to receive OPDIVO® plus chemotherapy (N=321), OPDIVO® plus YERVOY® (N=325), or chemotherapy alone. Patients in the OPDIVO® plus chemotherapy group received OPDIVO® 240 mg IV every 2 weeks and chemotherapy consisted of Fluorouracil 800 mg/m2 IV Days 1-5 and Cisplatin 80 mg/m2 IV on Day 1, given every 4 weeks. The OPDIVO® plus YERVOY® group received OPDIVO® 3 mg/kg IV every 2 weeks plus YERVOY® 1 mg/kg IV every 6 weeks. Treatment was continued until disease progression or unacceptable toxicity. Patients could receive OPDIVO® or OPDIVO® plus YERVOY® for a maximum of 2 years. Demographic and baseline clinical characteristics were balanced across the treatment groups and in patients with tumor-cell PD-L1 expression of 1% or greater (49% of patients in each treatment group had tumor-cell PD-L1 expression of 1% or greater). The Primary end points were Overall Survival (OS) and Progression Free Survival (PFS), as determined by Blinded Independent Central Review (BICR), with hierarchical testing performed first in patients with tumor-cell PD-L1 expression of 1% or greater and then in the overall population. The Secondary end points included Objective Response Rate (ORR), which was also assessed by BICR.

After a minimum follow up period of 13 months, Overall Survival was significantly longer with OPDIVO® plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (15.4 months versus 9.1 months; HR=0.54; P<0.001) and in the overall population (13.2 months versus 10.7 months; HR=0.74; P=0.002). These findings suggested a 46% and 26% lower risk of death respectively with OPDIVO® plus chemotherapy, than with chemotherapy alone. Overall Survival was also significantly longer with OPDIVO® plus YERVOY® than with chemotherapy among patients with tumor-cell PD-L1 expression of 1% or greater (13.7 months versus 9.1 months; HR=0.64; P=0.001) and in the overall population (12.7 months versus 10.7 months; HR=0.78; P=0.01).

There was a significant improvement in Progression Free Survival seen with OPDIVO® plus chemotherapy over chemotherapy alone among patients with tumor-cell PD-L1 expression of 1% or greater (HR=0.65; P=0.002). This PFS benefit was not seen with OPDIVO® plus YERVOY®, as compared with chemotherapy. The incidence of Grade 3 or 4 treatment-related Adverse Events was 47% with OPDIVO® plus chemotherapy, 32% with OPDIVO® plus YERVOY® and 36% with chemotherapy alone.

Treatment with either OPDIVO®-based regimens resulted in a higher Complete Response rate, as well as in more durable responses, than chemotherapy alone. Of the three treatment regimens, OPDIVO® plus chemotherapy led to the highest Objective Response Rate and OPDIVO® plus YERVOY® resulted in the longest median Duration of Response.

It was concluded that first-line treatment of advanced esophageal squamous-cell carcinoma with either OPDIVO® plus chemotherapy or OPDIVO® plus YERVOY® resulted in a significantly longer Overall Survival benefit and durable responses, than chemotherapy alone.

Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. Doki Y, Ajani JA, Kato K, et al. N Engl J Med 2022;386:449-462

General Review: An Approved Treatment Option for Acute Myeloid Leukemia

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Written by: Thomas E Boyd, MD, Texas Oncology
Content Sponsored by: Bristol-Myers Squibb
Dr. Boyd is a paid consultant for BMS and was compensated for his contribution in drafting this article.

Acute myeloid leukemia (AML) is a deadly disease that is more common in older adults.1 In 2021, it is estimated that there will be 20,240 new cases of AML in the United States, representing 1.1% of all new cancer cases.1 Additionally, there will be an estimated 11,400 deaths due to AML, representing 1.9% of all cancer deaths in the US in 2021.1 Once a patient is diagnosed with AML, beginning treatment as soon as possible is essential for disease management and survival.2

Currently, patients usually follow one of two paths for initial treatment of AML: conventional intensive induction chemotherapy or a less intensive option, with some patients going onto hematopoietic stem cell transplant after either initial treatment.3 The choice of treatment path is based on both patient- and disease-related characteristics such as medical fitness, age, cytogenetic and molecular testing, and risk of adverse events.2 With the progress seen in our understanding of the biology of AML, our knowledge of the molecular underpinnings of AML pathology has greatly improved over the years.4 This deeper understanding of disease at the molecular level has helped pave the way for a wave of approved therapies, with several new drug approvals beginning in 2017.5

A major goal of AML treatment is achieving remission.6 However, proliferative AML cells may still persist in remission, leading to a risk of relapse.4 Continued treatment of AML in first remission may improve overall survival.8

The large, multicenter QUAZAR®AML-001 trial established the efficacy and safety of ONUREG®(azacitidine) tablets, the first and only FDA-approved continued AML treatment for patients in first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy.8 Eligible patients were ages 55 years or older, diagnosed with AML, were within 4 months of achieving first CR or CRi with intensive induction chemotherapy, and may have received consolidation therapy.8 Patients could not enroll in the study if they were candidates for hematopoietic stem cell transplantation at the time of screening.8 Additional criteria included an ECOG performance status (PS) 0-3 and intermediate- or poor-risk cytogenetics, defined as normal cytogenetics +8, t(9;11), or other undefined, and complex (≥3 abnormalities): -5; 5q-; -7; 7q-; 11q23 – non t(9;11); inv(3); t(3;3); t(6;9); or t(9;22), respectively.8

Quazar-AML-Trial-DesignA total of 472 patients were randomized 1:1 to receive either ONUREG® 300 mg or placebo orally on Days 1 through 14 of each 28-day cycle.8 Baseline demographics and disease-related characteristics were well balanced between the ONUREG and placebo arms.8 Across both arms, 72% of patients were 65 years or older, and most patients (92%) had an ECOG PS of 0 or 1. Additionally, approximately three-quarters of patients received 1 or 2 cycles of consolidation therapy.8

With a >2-year median overall survival and a statistically significant survival benefit of ~10 months for patients with AML in first remission compared to placebo, ONUREG met its primary endpoint (24.7 months in the treated arm vs 14.8 months in the placebo arm, hazard ratio (HR) 0.69, 95% confidence interval (CI): 0.55-0.86; P=0.0009).8

The most common adverse reactions (ARs, ≥ 10%) associated with ONUREG® treatment included nausea, vomiting, diarrhea, fatigue/asthenia, constipation, pneumonia, abdominal pain, arthralgia, decreased appetite, febrile neutropenia, dizziness, and pain in extremity.8 Serious ARs occurred in 15% of patients who received ONUREG®, with select Grade 3/4 ARs shown in the table below.8 Eight percent of patients permanently discontinued ONUREG®, 35% of patients required a treatment interruption due to an AR, and 14% of patients required a dose reduction.8

Quazar-Toxicities
ONUREG® is approved for continued treatment of adult patients with acute myeloid leukemia who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy.8 ONUREG® is an oral hypomethylating agent, offering a convenient, once-daily dosing that patients can take at home.8 However, it is important to emphasize that ONUREG® should not be substituted for intravenous or subcutaneous azacitidine, because the indications and dosing regimen differ between these formulations.8 As the first and only FDA-approved continued AML treatment for patients in first remission, ONUREG® remains an option for appropriate patients.

IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
ONUREG® is contraindicated in patients with known severe hypersensitivity to azacitidine or its components.
WARNINGS AND PRECAUTIONS
Risks of Substitution with Other Azacitidine Products
Due to substantial differences in the pharmacokinetic parameters, the recommended dose and schedule for ONUREG® are different from those for the intravenous or subcutaneous azacitidine products. Treatment of patients using intravenous or subcutaneous azacitidine at the recommended dosage of ONUREG® may result in a fatal adverse reaction. Treatment with ONUREG® at the doses recommended for intravenous or subcutaneous azacitidine may not be effective. Do not substitute ONUREG® for intravenous or subcutaneous azacitidine.
Myelosuppression
New or worsening Grade 3 or 4 neutropenia and thrombocytopenia occurred in 49% and 22% of patients who received ONUREG®. Febrile neutropenia occurred in 12%. A dose reduction was required for 7% and 2% of patients due to neutropenia and thrombocytopenia. Less than 1% of patients discontinued ONUREG® due to either neutropenia or thrombocytopenia. Monitor complete blood counts and modify the dosage as recommended. Provide standard supportive care, including hematopoietic growth factors, if myelosuppression occurs.
Increased Early Mortality in Patients with Myelodysplastic Syndromes (MDS)
In AZA-MDS-003, 216 patients with red blood cell transfusion-dependent anemia and thrombocytopenia due to MDS were randomized to ONUREG® or placebo. 107 received a median of 5 cycles of ONUREG® 300 mg daily for 21 days of a 28-day cycle. Enrollment was discontinued early due to a higher incidence of early fatal and/or serious adverse reactions in the ONUREG® arm compared with placebo. The most frequent fatal adverse reaction was sepsis. Safety and effectiveness of ONUREG® for MDS have not been established. Treatment of MDS with ONUREG® is not recommended outside of controlled trials.
Embryo-Fetal Toxicity
ONUREG® can cause fetal harm when administered to a pregnant woman. Azacitidine caused fetal death and anomalies in pregnant rats via a single intraperitoneal dose less than the recommended human daily dose of oral azacitidine on a mg/m2 basis. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ONUREG® and for at least 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ONUREG® and for at least 3 months after the last dose.
ADVERSE REACTIONS
Serious adverse reactions occurred in 15% of patients who received ONUREG®. Serious adverse reactions in ≥2% included pneumonia (8%) and febrile neutropenia (7%). One fatal adverse reaction (sepsis) occurred in a patient who received ONUREG®.
Most common (≥10%) adverse reactions with ONUREG® vs placebo were nausea (65%, 24%), vomiting (60%, 10%), diarrhea (50%, 21%), fatigue/asthenia (44%, 25%), constipation (39%, 24%), pneumonia (27%, 17%), abdominal pain (22%, 13%), arthralgia (14%, 10%), decreased appetite (13%, 6%), febrile neutropenia (12%, 8%), dizziness (11%, 9%), pain in extremity (11%, 5%).
LACTATION
There are no data regarding the presence of azacitidine in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with ONUREG® and for 1 week after the last dose.

Please see full Prescribing Information for ONUREG®.

References
1. National Cancer Institute. SEER Cancer Statistics Factsheets: Acute Myeloid Leukemia. http://seer.cancer.gov/statfacts/html/amyl.html. Accessed April 21, 2021.
2. Medeiros BC, Satram S. Real world treatment patterns and comparative effectiveness among elderly patients with acute myeloid leukemia in the United States. Ann Hematol Oncol. 2020;7(1):1283.
3. Burnett A, Wetzler M, Löwenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011;29(5):487-494.
4. Brinda B, Khan I, Parkin B, Konig H. The rocky road to personalized medicine in acute myeloid leukaemia. J Cell Mol Med. 2018;22(3):1411-1427.
5. Lai C, Doucette K, Norsworthy K. Recent drug approvals for acute myeloid leukemia. J Hematol Oncol. 2019;12(100):1-20.
6. Medeiros BC. Interpretation of clinical endpoints in trials of acute myeloid leukemia. Leuk Res. 2018;68:32-29.
7. Medeiros BC, Chan SM, Daver NG, Jonas BA, Pollyea DA. Optimizing survival outcomes with post-remission therapy in acute myeloid leukemia. Am J Hematol. 2019;94:803-811.
8. ONUREG® [Prescribing Information]. Summit, NJ: Celgene Corporation; 2021.

© 2021 Celgene Corporation.
ONUREG is a trademark of Celgene Corporation, a Bristol-Myers Squibb company.
QUAZAR is a registered trademark of Celgene Corporation, a Bristol-Myers Squibb company.
1/22 2011-US-2100199

Overall Survival Benefit with the Addition of Capecitabine to Adjuvant Chemotherapy

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SUMMARY: 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 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence.

Patients with early stage breast cancer often receive adjuvant chemotherapy to improve Overall Survival (OS), and this is even more so true for HER positive and triple negative (ER, PR and HER negative) breast cancer patients, who are at an increased risk to develop recurrent disease. Meta-analyses conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) has shown a 20-25% relative risk reduction in breast cancer mortality with first-generation adjuvant chemotherapy regimens such as CMF (Cyclophosphamide/Methotrexate/Fluorouracil) and additional survival benefit with the Anthracyclines and Taxane based regimens. This benefit is dependent on the type of chemotherapy administered and chemotherapy dose intensity.

XELODA® (Capecitabine) is an oral prodrug of fluorouracil which is presently approved for the treatment of advanced breast cancer, but NOT for neoadjuvant or adjuvant treatment of early breast cancer. Meta-analysis of randomized trials has found that addition of Capecitabine to standard adjuvant chemotherapy regimens prolongs Disease Free Survival (DFS), whereas replacing a standard agent with Capecitabine did not improve DFS. Preclinical models have suggested that chemotherapy agents such as taxanes, and Cyclophosphamide increase thymidine phosphorylase concentration in the cancer cell, potentially leading to improved conversion of Capecitabine to fluorouracil within the tumor, suggesting that concomitant administration of Capecitabine with these agents improves efficacy, compared with single-agent Capecitabine. The researchers in this publication addressed the question whether addition of Capecitabine to these regimens could lead to improved survival outcomes.

The Finland Capecitabine Trial (FinXX) is a randomized, open-label, multicenter, Phase III trial that evaluated the addition of Capecitabine to an adjuvant chemotherapy regimen containing a taxane and an anthracycline for the treatment of early breast cancer. In this study, 1,500 patients with axillary node-positive or high-risk node-negative early breast cancer were randomly assigned to 6 cycles of either the Capecitabine arm- TX-CEX (N=753) or to the control group-T-CEF (N=747). TX-CEF consisted of Docetaxel 60 mg/m2 IV day 1 and Capecitabine 900 mg/m2 PO BID on days 1-15 of a 21-day cycle for 3 cycles followed by CEX consisting of Cyclophosphamide 600 mg/m2 IV Day 1, Epirubicin 75 mg/m2 IV on Day 1 and Capecitabine 900 mg/m2 PO BID on days 1-15 of a 21 day cycle for 3 cycles. T-CEF consisted of Docetaxel 80 mg/m2 IV Day 1, every 3 weeks for 3 cycles followed by CEF consisting of Cyclophosphamide 600 mg/m2 IV, Epirubicin 75 mg/m2 IV and Fluorouracil 600 mg/m2 IV, all administered on Day 1, every 3 weeks for 3 cycles. Adjuvant endocrine therapy was initiated within 2 months after completion of chemotherapy if the tumor was ER or PR-positive. Radiotherapy was given after completion of chemotherapy according to each institution’s practice. Adjuvant Trastuzumab was approved while the trial accrual was ongoing and was allowed for women with HER2-positive cancer after May 2005, and adjuvant Trastuzumab was administered to 13% patients assigned to TX-CEF and 11% patients assigned to T-CEF. The median patient age was 52.5 yrs, 76% of patients had ER-positive tumors, 19% had HER2-positive cancer, 13% had Triple Negative Breast Cancer, more than 90% had T1 or T2 tumors, and 89% were node positive. The researchers then performed a protocol-scheduled analysis of Overall Survival on the basis of approximately 15-year follow up of the patients.

At a median follow up of 15.3 years, the Overall Survival was 77.6% in the TX-CEX group and 73.3% in the T-CEF group (HR=0.81; P=0.037). Exploratory subgroup analysis suggested that patients with ER-negative disease and those with Triple Negative Breast Cancer lived longer with the addition of Capecitabine (TX-CEX regimen), than those treated with T-CEF.

It was concluded that the addition of Capecitabine to a chemotherapy regimen significantly improved Overall Survival at median follow up of 15 years in a patient population with early breast cancer, suggesting that Capecitabine may be an important addition to adjuvant chemotherapy in patients with high risk disease.

Adjuvant Capecitabine for Early Breast Cancer: 15-Year Overall Survival Results from a Randomized Trial. Joensuu H, Kellokumpu-Lehtinen P-L , Huovinen R, et al. DOI: 10.1200/JCO.21.02054 Journal of Clinical Oncology. Published online January 12, 2022.

FDA Approves ENJAYMO® for Cold Agglutinin Disease

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SUMMARY: The FDA on February 4, 2022 approved ENJAYMO® (Sutimlimab-jome) to decrease the need for Red Blood Cell transfusion due to hemolysis in adults with Cold Agglutinin Disease (CAD). CAD is a chronic and rare autoimmune hemolytic anemia estimated to impact the lives of 5,000 individuals in the U.S. and accounts for 15% of patients with Auto Immune Hemolytic Anemia. It is twice as common in women compared to men and is characterized by hemolysis triggered by exposure to cold temperatures usually 3-4 degrees C (37-39 degrees F). The median age at symptom onset is about 65 years, whereas the median age at diagnosis is about 72 years. The median survival is approximately 11 years.

Cold Agglutinin Disease is a complement-mediated disease and majority of the cases of CAD are mediated by IgM antibodies, unlike warm Auto Immune Hemolytic Anemia, which is predominantly IgG-driven. The circulating IgM antibodies in the body core are not bound to the RBC surface. However, as blood shifts toward the peripheral circulation and cools, IgM antibodies transiently bind to the RBC membrane resulting in agglutination. This in turn activates the complement cascade, binding C3b to the cell surface. As C3b-coated cells return toward the body core, IgM antibody dissociates, and the C3b-coated RBC are destroyed by receptor-specific macrophages present predominantly in the liver and to a lesser degree in the spleen, resulting in extravascular hemolysis and some element of intravascular hemolysis. The severity of hemolysis depends on the thermal amplitude, rather than the serum concentration of IgM antibodies. CAD can be Primary/Idiopathic or Secondary to different underlying disorders such as infections, lymphoproliferative disorders, immunoproliferative disorders, as well as connective tissue diseases.

Patients with CAD usually present with chronic anemia with hemoglobin levels ranging from 4.5 g/dL to 8 g/dL, and over 50% of patients require transfusion support, and therapy is often considered in 75% of the patients. In addition to hemolysis, clinical manifestations include cold-induced circulatory symptoms such as livedo reticularis, Raynaud disease, acrocyanosis and, rarely, cutaneous necrosis. Hemoglobinuria and Splenomegaly tends to be less severe. There has been no approved treatment for CAD. Therapies have included corticosteroids, alkylating agents, purine nucleoside analogs and Rituximab, with little benefit.

ENJAYMO® is a first-in-class humanized monoclonal antibody that is designed to selectively target and inhibit C1 complex in the classical complement pathway, which is part of the innate immune system. By blocking C1 complex, ENJAYMO® inhibits C1-activated hemolysis in CAD and prevents the premature destruction of normal RBC. ENJAYMO® does not inhibit the Lectin and alternative complement pathways.

CARDINAL study is an open-label, single-arm, multicenter trial conducted to assess the efficacy and safety of ENJAYMO® in patients with confirmed CAD and a recent history of RBC transfusion. In this study, eligible patients with CAD (N=24) entered Part A of the study. This consisted of a 26-week treatment period during which patients received ENJAYMO® at a dose of 6.5 g IV for patients weighing less than 75 kg, and 7.5 g IV for those weighing 75 kg or more, on days 0 and 7, after which they received an infusion every 2 weeks. After the 26-week treatment period, patients were eligible to continue to the open-label extension study (Part B). The mean patient age was 71.3 yrs and two thirds of patients had failed prior therapies. CAD diagnosis was defined as the presence of chronic hemolysis, a positive polyspecific Direct Antiglobulin Test result, a monospecific Direct Antiglobulin Test result strongly positive for C3d, a cold agglutinin titer of 1:64 or higher measured at 4°C, a Direct Antiglobulin Test result for IgG of 1+ or less, and no overt malignant disease. Patients with a diagnosis of Systemic Lupus Erythematosus (SLE) or other autoimmune disorder with antinuclear antibodies at screening, overt malignant disease, treatment with Rituximab monotherapy within 3 months before enrollment or treatment with Rituximab combined with chemotherapy within 6 months before enrollment were excluded.

The Primary end point was a composite of a normalization of the hemoglobin level to 12 g or more per deciliter or an increase in the hemoglobin level of 2 g or more per deciliter from baseline, without RBC transfusion from week 5 through week 26. Secondary end points included improvements in hemoglobin level, normalization of bilirubin and LDH level, and Quality of Life, as assessed with the use of the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale (scores range from 0 to 52, with a higher score indicating less fatigue. The authors herein reported the results of Part A of the study.

The majority of patients (54%) met the prespecified Primary endpoint criteria with 63% of patients achieving a hemoglobin12 g/dL or more or an increase of at least 2 g/dL and 71% of patients remained transfusion-free after week five. Approximately 92% of patients did not use other therapies for CAD.

With regard to Secondary endpoints, there was a mean increase in the hemoglobin level of 2.29 g/dL at week 3, and 3.18 g/dL at the 26-week treatment assessment time point, from the mean baseline level of 8.6 g/dL. The mean bilirubin levels normalized by week 3, from a mean baseline level of 3.23 mg/dL and clinically meaningful reductions in fatigue were observed by week 1 and were maintained throughout the study. The activity in the classic complement pathway was rapidly inhibited, as assessed by a functional assay. Increased hemoglobin levels, reduced bilirubin levels, and reduced fatigue coincided with inhibition of the classic complement pathway. There were no cases of meningococcal infections and none of the patients experienced thromboembolism.

It was concluded that in this pivotal study, ENJAYMO® had a rapid and sustained treatment benefit in most patients with Cold Agglutinin Disease by preventing chronic hemolysis, markedly increasing hemoglobin levels, and improving quality of life.

Sutimlimab in Cold Agglutinin Disease. Röth A, Barcellini W, D’Sa S, et al. N Engl J Med 2021;384:1323-1334

Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,470 new cases will be diagnosed in 2022 and 12,640 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, immunomodulatory agents and CD 38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, Multiple Myeloma (MM) in 2022 remains an incurable disease.

High Dose Melphalan followed by Autologous Stem Cell Transplantation (HDM/ASCT) remains an important treatment option for transplant eligible patients. REVLIMID® (Lenalidomide) was approved by the FDA in 2017 as maintenance therapy for patients with multiple myeloma following Autologous Stem Cell Transplant (ASCT) and to date is the only drug approved for this indication. Maintenance or Continuous Treatment in patients with newly diagnosed multiple myeloma following induction treatment can result in significantly longer PFS and OS, compared to those patients who receive therapy for a fixed duration of time.

The role of consolidation treatment for newly diagnosed, transplant-eligible patients with multiple myeloma has not been conclusively established and needed prospective evaluation. The present prospective clinical trial was conducted to study the relevance of consolidation therapy using Bortezomib, Lenalidomide, and Dexamethasone (VRD) followed by Lenalidomide maintenance, compared with Lenalidomide maintenance alone, in transplant-eligible newly diagnosed multiple myeloma patients.

The EMN02/HOVON95 trial is an open-label, Phase III study, performed by the European Myeloma Network (EMN) in which 1197 previously untreated transplant-eligible patients with symptomatic Stages I-III Multiple Myeloma were randomly assigned initially to four cycles of Bortezomib, Melphalan, and Prednisone (VMP) or High-Dose Melphalan followed by Autologous Stem Cell Transplantation (HDM/ASCT). Within 2 months after ASCT or last VMP treatment, 878 eligible patients underwent a second randomization to either two 28-day cycles of VRD consolidation treatment, which consisted of Bortezomib 1.3 mg/m2 either IV or SC once daily on days 1, 4, 8, and 11, combined with Lenalidomide 25 mg orally once daily, days 1-21 and Dexamethasone 20 mg orally once daily, on days 1, 2, 4, 5, 8, 9, 11, and 12 (N=451 – Arm B) or no consolidation (N=427 – Arm A). Patients then received Lenalidomide maintenance 10 mg orally once daily on days 1-21 of a 28-day cycle, starting 1-2 months after ASCT or consolidation, and treatment was continued until disease progression or toxicity. The Primary end point was Progression Free Survival (PFS) defined as time from second randomization to disease progression or death. Secondary end points included Partial Response or higher, Overall Survival (OS) from second randomization until death from any cause, and toxicity. Predefined high-risk prognostic subgroups for PFS were cytogenetic abnormalities defined by FISH and included deletion (17p) in 20% or more of enriched plasma cells, t(4;14) in 10% or more of enriched plasma cells, t(14;16) in 10% or more of enriched plasma cells; and amplification 1q. This was in addition to the standard clinical variables such as Hemoglobin level, Serum Creatinine and LDH. Disease assessment was performed before and after consolidation and every 2 months until progression. Bone marrow Minimal Residual Disease (MRD) assessment was performed by multicolor flow cytometry in bone marrow with a detection of 10−4 to 10−5.

At a median follow-up of 74.8 months after the second randomization, the median PFS was significantly prolonged in the VRD consolidation group, compared those who did not receive consolidation treatment (59.3 versus 42.9 months, HR=0.81; P=0.016). This PFS benefit was observed across most predefined subgroups, including Stage, standard-risk cytogenetics, and prior treatment groups. VRD consolidation was however not beneficial in patients with del(17p). Stage III disease and addition of chromosome 1q by FISH at diagnosis were significant adverse prognostic factors for PFS from second randomization. The median duration of maintenance treatment with Lenalidomide was 33 months. Complete Response (CR) or more after consolidation versus no consolidation, and before start of maintenance treatment was 34% versus 18%, respectively (P<0.001). Complete Response or more on protocol including maintenance treatment was 59% with consolidation and 46% without consolidation (P<0.001). Minimal Residual Disease analysis in a subgroup of 226 VRD-consolidated patients with CR or stringent CR or Very Good Partial Response before start of maintenance treatment demonstrated a 74% MRD-negativity rate. Toxicities related to VRD consolidation were acceptable and manageable.

It was concluded from this study that consolidation followed by maintenance treatment after either Bortezomib, Melphalan and Prednisone or High-Dose Melphalan and Autologous Stem Cell Transplantation, significantly improves Progression Free Survival and Overall Response Rate in transplant-eligible and Lenalidomide-naïve newly diagnosed patients with Multiple Myeloma, compared to maintenance treatment alone.

Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma. Sonneveld P, Dimopoulos MA, Beksac M, et al. J Clin Oncol. 2021;39:3613-3622.

LAG-3 Inhibitor Relatlimab and OPVIDO® in Advanced Untreated Melanoma

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SUMMARY: The American Cancer Society’s estimates that for 2022, about 99,780 new cases of melanoma of the skin will be diagnosed in the United States and 7,650 people are expected to die of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age.

A better understanding of Immune checkpoints has opened the doors for the discovery of novel immune targets. Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies have been developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By blocking the Immune checkpoint proteins, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response.

YERVOY® (Ipilimumab), a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 was compared with PD-1 inhibitors, OPDIVO® (Nivolumab) and KEYTRUDA® (Pembrolizumab) in patients with advanced melanoma, and both OPDIVO® and KEYTRUDA® have demonstrated superior Overall Survival (OS), Progression Free Survival (PFS), and Objective Response Rate (ORR), and with a better safety profile. In the CheckMate 067, which is a double-blind Phase III study, results from the 6.5 year analysis showed that a combination of OPDIVO® plus YERVOY® demonstrated significant improvement in OS and PFS, when compared to single agent OPDIVO® or single agent YERVOY®.

In an attempt to improve outcomes and enhance the risk-benefit profiles of immunotherapy combinations, alternate Immune checkpoints are being explored. LAG-3 (Lymphocyte-Activation Gene 3 (LAG-3), is a cell-surface receptor expressed on immune cells including activated CD4+ T cells, and negatively regulates T-cell proliferation, inhibits T-cell activation and effector T-cell function. LAG-3 is upregulated in several tumor types, including malignant melanoma.

Relatlimab is a first-in-class human IgG4 LAG-3–blocking antibody that binds to LAG-3 and restores the effector function of exhausted T cells, resulting in T cell proliferation, activation and a therapeutic response. In preclinical studies, dual inhibition of LAG-3 and PD-1 showed synergistic antitumor activity, and in a Phase I/II trial, the combination of Relatlimab and Nivolumab, demonstrated durable Objective Responses in patients with Relapsed/Refractory melanoma following treatment with PD-1 inhibitors.

RELATIVITY-047 is a Phase II/III, global, multicenter, double-blind, randomized trial in which a fixed-dose combination of Relatlimab and Nivolumab was compared with Nivolumab alone, in patients with previously untreated metastatic or unresectable melanoma. In this study, 714 patients were randomly assigned 1:1 to receive Relatlimab 160 mg and Nivolumab 480 mg in a fixed-dose combination (N=355) or single agent Nivolumab 480 mg (N=359). Both regimens were administered as an IV infusion over 60 minutes every 4 weeks, and treatment was continued until disease progression, unacceptable toxicities, or withdrawal of consent. Both treatment groups were well balanced and patients were stratified according to LAG-3 expression (1% or more versus less than 1%), PD-L1 expression (1% or more versus less than 1%), BRAF V600 mutation status, and metastasis stage (M0 or M1 with normal LDH levels versus M1 with elevated LDH levels). More patients in the Relatlimab-Nivolumab group had Stage M1c disease, and a larger proportion had three or more sites with at least one metastatic lesion. The Primary end point was Progression Free Survival (PFS) as assessed by blinded Independent Central Review. Secondary end points included Overall Survival and Objective Response Rate (ORR). The median follow up was 13.2 months and the use of subsequent therapies upon progression was similar in the two treatment groups.

The median PFS was 10.1 months with Relatlimab-Nivolumab as compared with 4.6 months with Nivolumab (HR=0.75; P=0.006). The PFS benefit at 12 months with Relatlimab-Nivolumab was 47.7% compared to 36.0% with Nivolumab. The PFS benefit was more so with Relatlimab- Nivolumab across key prespecified subgroups, compared to single agent Nivolumab. Patients with poor prognosis characteristics, such as visceral metastases, high tumor burden, elevated levels of serum LDH, or mucosal or acral melanoma, had better outcomes with Relatlimab-Nivolumab combination, than with single agent Nivolumab. Further, a benefit with Relatlimab-Nivolumab was also noted across BRAF mutant and wild-type subgroups, compared to Nivolumab. Expression of LAG-3 or PD-L1 was not useful in predicting a benefit of Relatlimab-Nivolumab over single agent Nivolumab and appears to NOT have a clear role in treatment selection.

Grade 3 or 4 toxicities occurred in 18.9% of patients in the Relatlimab-Nivolumab group and in 9.7% of patients in the single agent Nivolumab group. The Safety profile of Relatlimab-Nivolumab appeared favorable, when compared with dual checkpoint inhibition with a CTLA-4 inhibitor and PD-1 inhibitor combination (Ipilimumab-Nivolumab) in the CheckMate 067 trial, in which Adverse Events were noted in 59% of patients.

It was concluded that inhibition of two immune checkpoints, LAG-3 and PD-1, provided greater benefit with regards to Progression Free Survival, than inhibition of PD-1 alone, in patients with previously untreated metastatic or unresectable melanoma. The authors added that these results validate blocking LAG-3 in combination with PD-1 as a therapeutic strategy for patients with melanoma, and establishes LAG-3 as the third immune checkpoint pathway, thus providing more treatment options for patients with advanced melanoma.

Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. Tawbi HA, Schadendorf D, Lipson EJ, et al. for the RELATIVITY-047 Investigators. N Engl J Med 2022;386:24-34.

Adjuvant VERZENIO® in High Risk Early Stage Breast Cancer: Updated Efficacy and Ki-67 Analysis

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SUMMARY: 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 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor (HR)-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. Majority of these patients are diagnosed with early stage disease and are often cured with a combination of surgery, radiotherapy, chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment. This may be more relevant for those with high risk disease, among whom the risk of recurrence is even greater during the first 2 years while on adjuvant endocrine therapy, due to primary endocrine resistance. More than 75% of the early recurrences are seen at distant sites.

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

Cell-Cycle-Inhibition-by-ABEMACICLIBVERZENIO® (Abemaciclib) is an oral, selective inhibitor of CDK4 and CDK6 kinase activity, and prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation. VERZENIO® is structurally distinct from other CDK 4 and 6 inhibitors (such as Ribociclib and Palbociclib) and is 14 times more potent against Cyclin D1/CDK 4 and Cyclin D3/CDK 6, in enzymatic assays, but potentially less toxic than earlier pan-CDK inhibitors. At higher doses, only VERZENIO® causes significant cancer cell death, compared with other CDK4/6 inhibitors, suggesting that this drug may be affecting proteins, other than CDK4/6. Additionally, preclinical studies have demonstrated that VERZENIO® may have additional therapeutic benefits for a subset of tumors that are unresponsive to treatment or have grown resistant to other CDK4/6 inhibitors. It has also been shown to cross the blood-brain barrier.

VERZENIO® is presently approved by the FDA as monotherapy as well as in combination with endocrine therapy for patients with HR-positive, HER2- negative advanced breast cancer. The addition of VERZENIO® to FASLODEX® (Fulvestrant) resulted in a statistically significant improvement in Overall Survival (OS) among patients with HR-positive, HER2-negative advanced breast cancer, who had progressed on prior endocrine therapy. The goal of monarchE was to evaluate the additional benefit of adding a CDK4/6 inhibitor to endocrine therapy in the adjuvant setting, for patients with HR-positive, HER2-negative, high risk, early breast cancer.

The International monarchE trial, is an open-label, randomized, Phase III study, which included 5637 patients, who were pre- and postmenopausal, with HR-positive, HER2-negative early breast cancer, and with clinical and/or pathologic risk factors that rendered them at high risk for relapse. The researchers defined high risk as the presence of four or more positive axillary lymph nodes, or 1-3 three positive axillary lymph nodes, with either a tumor size of 5 cm or more, histologic Grade 3, or centrally tested high proliferation rate (Ki-67 of 20% or more). Following completion of primary therapy which included both adjuvant and neoadjuvant chemotherapy and radiotherapy, patients were randomly assigned (1:1) to VERZENIO® 150 mg orally twice daily for 2 years plus 5-10 years of physicians choice of endocrine therapy as clinically indicated (N=2808), or endocrine therapy alone (N=2829). The median patient age was 51 years, about 43% of the patients were premenopausal, and 95% of patients had prior chemotherapy. Approximately 60% of patients had 4 or more positive lymph nodes. The Primary endpoint was Invasive Disease Free Survival (IDFS), and Secondary end points included Distant Relapse Free Survival (DRFS), Overall Survival (OS), and Safety. The researchers provided updated results from the prespecified Primary outcome analysis, additional follow-up analysis conducted at regulatory request, as well as outcomes from prespecified subpopulations, based on Ki-67 levels.

At the time of Primary outcome analysis, with a median follow up of 19 months, 1,437 patients (25.5%) had completed the 2 year treatment period and 3,281 patients (58.2%) were in the 2 year treatment period. The combination of VERZENIO® plus endocrine therapy demonstrated superior Invasive Disease Free Survival (IDFS) compared to endocrine therapy alone, with a 29% reduction in the risk of developing invasive disease (P=0.0009; HR=0.71). The 2-year IDFS in the combination group was 92.3% and 89.3% in the endocrine therapy alone treatment group, with an absolute improvement of 3.0%. Further, there was an improvement in the 2-year distant Relapse Free Survival (DRFS) rate among patients who received the combination treatment compared with those who received endocrine therapy alone, corresponding to an absolute difference of 3.0% at 2 years (93.8% versus 90.8%, respectively; HR=0.69; P<0.001).

With 8 months of additional follow up, at a median of 27 months and with 90% of patients off treatment, the benefit with the combination of VERZENIO® plus endocrine therapy was maintained for IDFS (HR=0.70; P<0.0001) and DRFS (HR=0.69; P<0.0001), demonstrating a 30% risk reduction for IDFS and 31% risk reduction for DRFS. There was continued treatment benefit over time that extended beyond the 2-year treatment period of VERZENIO®. With more patients at risk for recurrence at 3 years, the data demonstrated absolute improvements in 3-year IDFS and DRFS rates of 5.4% and 4.2%, respectively. This treatment benefit in IDFS and DRFS was noted across prespecified subgroups. Further, the benefit with VERZENIO® was consistent, regardless of Ki-67 index. Overall Survival data was immature at the time of this analysis.

It was concluded that adjuvant VERZENIO® combined with endocrine therapy continued to demonstrate statistically significant and clinically meaningful improvement in Invasive Disease Free Survival and Distant Relapse Free Survival, among patients with HR-positive, HER2-negative, node-positive, high risk, early breast cancer, regardless of Ki-67 status.

Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Harbeck N, Rastogi P, Martin M, et al. Annals of Oncology 2021;32: 1457-1459.

ENHERTU® in HER2-Mutant Non Small Cell Lung Cancer

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SUMMARY: The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 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. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. HER2 is a Tyrosine Kinase Receptor expressed on the surface of several tumor types including Breast, Gastric, Lung and Colorectal cancers. It is a growth-promoting protein and HER2 overexpression/HER2 gene amplification is often associated with aggressive disease and poor prognosis in certain tumor types. However, HER2 overexpression and gene amplification are associated with distinct molecular entities and have limited therapeutic value in lung cancer.

HER2 mutations unlike HER2 overexpression and gene amplification are oncogenic drivers, and have been detected in 2 to 3% of NSCLCs. They are more often detected in female patients and never-smokers, and almost exclusively in Adenocarcinomas. Majority of of HER2 mutations (80-90%) occur in exon 20, as either a duplication or an insertion of 12 nucleotides, resulting in the addition of four amino acids (YVMA) at codon 775 in the kinase domain. This distinct molecular entity is characterized by specific pathological and clinical behavior. These acquired HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis. There are currently no therapies approved specifically for the treatment HER2 mutant NSCLC, and is therefore an unmet need.

ENHERTU® (Trastuzumab Deruxtecan) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to HERCEPTIN® (Trastuzumab), attached to a potent cytotoxic Topoisomerase I inhibitor payload by a cleavable tetrapeptide-based linker. ENHERTU® has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike KADCYLA® (ado-Trastuzumab emtansine), which is also an Antibody-Drug Conjugate, ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), the released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, minimizing systemic exposure. ENHERTU® is approved in the US for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who received two or more prior anti-HER2 based regimens, and locally advanced or metastatic HER2-positive Gastric or GastroEsophageal Junction adenocarcinoma who have received a prior Trastuzumab based regimen. Translational research demonstrated that HER2-mutant NSCLC may preferentially internalize the HER2 receptor Antibody-Drug Conjugate complex regardless of HER2 protein expression, and overcome resistance to other HER2-targeted agents.
Mechanism-of-Action-ENHERTU
DESTINY-Lung01 is a global, multicenter, open-label, two-cohort, Phase II study, conducted to evaluate the efficacy and safety of ENHERTU® in patients with HER2 mutant or HER2 overexpressing (defined as ImmunoHistoChemistry-IHC 3+ or IHC 2+), unresectable and metastatic non-squamous NSCLC. A total of 91 patients with HER2-mutant NSCLC were enrolled between May 30, 2018, and July 21, 2020 and treated with ENHERTU®. Patients who had previously been treated with a HER2 antibody or an Antibody-Drug Conjugate were ineligible for participation, but those who had previously received a HER2 Tyrosine Kinase Inhibitor such as Afatinib, Pyrotinib, or Poziotinib were eligible. The median patient age was 60 yrs and enrolled patients had a median of two prior lines of therapy, with majority of patients having received platinum-based chemotherapy (95%) and anti-PD-1 or PD-L1 treatment (66%). About 20% of patients received Docetaxel and 14% received HER TKIs. For the majority of patients (93%), HER2 mutations were located in the kinase domain. Patients received ENHERTU® 6.4 mg/kg every 3 weeks by intravenous infusion. The Primary endpoint was Objective Response Rate (ORR) as assessed by Independent Central Review. Secondary endpoints included Disease Control Rate (DCR), Duration of Response (DoR), Progression Free Survival (PFS), Overall Survival (OS) and Safety. At the time of data cutoff, the median duration of treatment was 6.9 months and treatment was ongoing for 16% of patients.

At a median follow up 13.1 months, the ORR was 55% and the median Duration of Response was 9.3 months. Responses were observed across different HER2 mutation subtypes. The median PFS was 8.2 months and the median OS was 17.8 months. The most common Grade 3 or higher drug-related Adverse Event was neutropenia noted in 19% of patients and adjudicated drug-related Interstitial Lung Disease occurred in 26% of patients and resulted in 2 deaths.

It was concluded that ENHERTU® demonstrated promising clinical activity, with a high Objective Response Rate and durable responses, in a heavily pretreated population of patients with HER2-mutated NSCLC.

Trastuzumab Deruxtecan in HER2-Mutant Non–Small-Cell Lung Cancer. Li BT, Smit EF, Goto Y, et al., for the DESTINY-Lung01 Trial Investigators. N Engl J Med 2022; 386:241-251

Elacestrant in Metastatic Breast Cancer Progressing on CDK4/6 Therapy and ESR1-Mutant Subtype

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SUMMARY: 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 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence. Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors), 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, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay for the management of ER+/HER2- metastatic breast cancer as first-line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression, including development of ESR1 (Estrogen Receptor gene alpha) mutations.

ESR1 is the most common acquired mutation noted in breast tumors as they progress from primary to metastatic setting. These mutations promote ligand independent Estrogen Receptor activation and have been shown to promote resistance to estrogen deprivation therapy. It appears that ESR1 mutations are harbored in metastatic ER+ breast cancers with prior Aromatase Inhibitor (AI) therapy, but not in primary breast cancers, suggesting that ESR1 mutations may be selected by prior therapy with an AI, in advanced breast cancer. In a recently published study (JAMA Oncol.2016;2:1310-1315), ESR1 mutations Y537S and D538G mutations detected in baseline plasma samples from ER+/HER- advanced breast cancer patients, was associated with shorter Overall Survival. In this study it was noted that there was a three-fold increase in the prevalence of these mutations in patients who had failed first line hormonal therapy for metastatic disease, compared with those who were initiating first line therapy for advanced breast cancer (33% versus 11%).

Fulvestrant is a parenteral, Selective Estrogen Receptor Degrader (SERD) and is the only SERD approved for the treatment of postmenopausal women with HR-positive metastatic breast cancer. However, acquired ESR1 mutations can also occur following Fulvestrant treatment, possibly because of poor bioavailability and incomplete ER blockade when administered intramuscularly. There is therefore an urgent unmet need for an alternate SERD that has activity in tumors harboring ESR1 mutations, and has improved bioavailability allowing oral administration.

Elacestrant is an oral, nonsteroidal, Selective Estrogen Receptor Degrader (SERD) that degrades the Estrogen Receptor (ER) in a dose-dependent manner and inhibits estradiol-dependent functions of ER target gene transcription induction and breast cancer cell proliferation. Estradiol-stimulated tumor growth was diminished by Elacestrant in the ER+ xenograft models derived from heavily pretreated patients, including models resistant to CDK 4/6 inhibitors, Fulvestrant and those harboring ESR1 mutations Y537S and D538G. In an early Phase I trial, Elacestrant was noted to have an acceptable safety profile, and demonstrated single-agent activity with confirmed Partial Responses in heavily pretreated patients with ER+ metastatic breast cancer.

EMERALD trial is a multicenter, International, randomized, open-label, Phase III study designed to evaluate the benefit of Elacestrant in patients with ER+ HER2- advanced or metastatic breast cancer. In this study, 477 postmenopausal women with ER+/HER2- metastatic breast cancer were randomly assigned 1:1 to receive either Elacestrant 400 mg orally daily (N=239) or the Standard of Care which included investigator’s choice of Fulvestrant or an Aromatase Inhibitor including Anastrozole, Letrozole, or Exemestane (N=238). Treatment was given until disease progression. Both treatment groups were well balanced. The median patient age was 63 years, and patients must have progressed or relapsed on or after 1 or 2 lines of endocrine therapy for advanced disease, one of which was given in combination with a CDK4/6 inhibitor, had 1 or fewer lines of chemotherapy for advanced disease, and had an ECOG performance status of 0 or 1. In the study, 48% had tumors with mutated ESR1 and these patients were evenly distributed in both treatment groups. Patients were stratified by ESR1-mutation status, prior treatment with Fulvestrant, and visceral metastases. The co-Primary end points were Progression Free Survival (PFS) in the overall population, and in those with ESR1 mutations. Overall Survival (OS) was a Secondary end point.

Treatment with Elacestrant resulted in a statistically significant and clinically meaningful improvement in PFS, compared with Standard of Care. There was a 31% reduction in the risk of progression or death in the Elacestrant group for all patients (HR=0.69; P=0.0018) and a 45% reduction in the risk of progression or death among those with ESR1 mutations (HR=0.55; P=0.0005).

The PFS at 12 months with Elacestrant was 22.3% in all patients compared with 9.4% for those receiving the Standard of Care treatment. Among the ESR1 mutation group, the 12 month PFS rate was more pronounced and was 26.8% with Elacestrant, compared to 8.2% with Standard of Care. The benefits with Elacestrant compared with Standard of Care, was consistent across multiple prespecified subgroups including patients who had received prior Fulvestrant. There also was a trend toward improved Overall Survival in patients who received Elacestrant, compared with Standard of Care. The final OS results however are not expected until late 2022. Elacestrant was well tolerated and treatment discontinuation rate was not significantly different between the two treatment groups.

It was concluded that Elacestrant is the first oral Selective Estrogen Receptor Degrader that demonstrated significant and clinically meaningful improvement in PFS compared with Standard of Care endocrine therapy in patients with ER+/ HER2- metastatic breast cancer in the second/third line after treatment with a CDK4/6 inhibitor, and has the potential to become the new standard of care in the study population.

Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of the EMERALD phase 3 trial. Bardia A, Neven P, Streich G, et al. Presented at 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS2-02.

Blood Test Plus Risk Model May Predict Who May Benefit From Lung Cancer Screening

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SUMMARY: The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 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 and Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

In the National Lung Screening Trial (NLST) with Low Dose CT (LDCT) screening for lung cancer, there was a 20% reduction in mortality. Following the publication of the results of NLST, and NCCN issued guideline in 2011, the United States Preventive Services Task Force (USPSTF) recommended Lung Cancer screening with Low Dose CT scan in high risk patients. CMS in 2015 determined that there was sufficient evidence to reimburse for this preventive service. The USPSTF expanded the criteria for Lung Cancer screening in 2021 and recommended annual screening with Low-Dose CT for adults aged 50 to 80 years who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years. The new USPSTF 2021 criteria were given a B recommendation, as there was additional research needed, to improve uptake of LDCT screening and to develop biomarkers to more accurately identify individuals, who would benefit from screening.

The authors in a previously published study identified the precursor form of Surfactant Protein B (Pro-SFTPB) as predictive of Lung Cancer risk. They were also able to, in a proof-of-principle study, demonstrate that a four Marker Protein panel (4MP) consisting of Pro-SFTPB, Cancer Antigen 125, CarcinoEmbryonic Antigen, and Cytokeratin-19 fragment, has the potential to identify individuals at risk for developing Lung Cancer, better than Pro-SFTPB alone.

The purpose of this study was to determine whether a blood-based four Marker Protein biomarker panel together with the PLCOm2012 Lung Cancer prediction model would better identify individuals for Lung Cancer screening, compared with current US Preventive Services Task Force (USPSTF) criteria.

The PLCO Cancer Screening Trial was a randomized multicenter trial which evaluated the impact of screening for Prostate, Lung, Colorectal, and Ovarian cancer, on disease-specific mortality. In this study, a biorepository was created for blood specimens that were annually collected, after obtaining consent from the intervention group participants. In this study there were 42,450 individuals in the intervention group who have ever smoked, and 85% of the participants in this intervention arm had at least one blood specimen collection. Individuals with histologically-confirmed lung cancers from the ever-smoked participants in the intervention group, who were diagnosed within 6 years of study entry, and with pre-diagnostic blood specimen available (N= 552), were included in the current study.

Non cancer participants who have ever smoked (N=2193) were randomized 4:1 with lung cancer diagnosed cases and were followed for an additional 13 years during which time they remained cancer-free. For each selected participant, all blood samples collected within 6 years of study entry, or up to the time of diagnosis for lung cancer cases, were included in the study specimen set (N=10,008 blood specimens). The mean age of the study population was 65 years, and 64% were male, 60% were former smokers and 40% were current smokers. The baseline information for the PLCOm2012 model included age, race or ethnic group, education, Body Mass Index, Chronic Obstructive Pulmonary Disease, personal history of cancer, family history of lung cancer and smoking status (current versus former), intensity, duration, and quit time. Levels of the 4 marker proteins in the serum were determined using bead-based immunoassays and biomarker scores were calculated for the combined 4 marker proteins. The researchers assessed the performance of the 4 marker protein panel in combination with the PLCOm2012 lung cancer prediction model, and compared the combination with current USPSTF lung cancer screening criteria, among pre-diagnosis lung cancer, and non-lung cancer serum samples, from the PLCO Cancer Screening Trial.

Using prediagnostic case, and non-case serum samples from the PLCO Cancer Screening Trial data, a combined four-marker protein panel along with PLCO m2012 model showed statistically significant improvement in sensitivity by 11.9% and 9.9% and specificity by 12.9% and 6.9% ,compared with USPSTF 2013 and the recent USPSTF 2021 criteria, respectively. If the 4MP along with PLCOm2012 model was applied to individuals with 10 or more pack-year smoking history, the improved performance of this combination would have resulted in referral to screening of 12.6% more lung cancer cases among the 119 cases who would otherwise receive a lung cancer diagnosis within a year, as well as nonreferral of 29.6% of the 14,061 non-cases. When compared with the USPSTF 2021 criteria, the 4MP plus PLCOm2012 model would have identified for annual screening 9.2% more lung cancer cases and would have reduced referral by 13.7% among non-cases, compared with USPSTF 2021 criteria.

It was concluded that the 4MP plus PLCOm2012 model yielded superior predictive performance and sensitivity and specificity for ruling individuals into LDCT screening, compared with USPSTF 2013 or USPSTF 2021 eligibility criteria, and with the PLCOm2012 model alone. The authors added that the public health benefit is significant, as it better identifies individuals at high risk of lung cancer and expands upon the number of individuals who would be considered eligible for lung cancer screening, thereby addressing some of the limitations of current screening eligibility criteria. These findings have important implications for improving lung cancer screening programs and reducing the burden of lung cancer through personalized risk assessment.

Blood-Based Biomarker Panel for Personalized Lung Cancer Risk Assessment. Fahrmann JF, Marsh T, Irajizad E, et al. J Clin Oncol. Published online January 7, 2022. doi:10.1200/JCO.21.01460.