Author: RR

ASH 2021 Guidelines for Management of VTE in Patients with Cancer

RR

SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke. Ambulatory cancer patients initiating chemotherapy are at varying risk for Venous Thromboembolism (VTE), which in turn can have a substantial effect on health care costs, with negative impact on quality of life.

Approximately 20% of cancer patients develop VTE and about 20% of all VTE cases occur in patients with cancer. There is a two-fold increase in the risk of recurrent thrombosis in patients with cancer, compared with those without cancer, and patients with cancer and VTE are at a markedly increased risk for morbidity and mortality. The high risk of recurrent VTE, as well as bleeding in this patient group, makes anticoagulant treatment challenging.

American Society of Hematology (ASH) formed a multidisciplinary guideline panel and the guidelines summarized below are based on updated and original systematic reviews of evidence, conducted under the direction of the McMaster University GRADE Center with international collaborators. The main objective is to support patients, clinicians, and other health care professionals in their decisions about the prevention and treatment of VTE in patients with cancer.

RECOMMENDATIONS
Primary prophylaxis for hospitalized medical patients with cancer.
♦ For patients without VTE, the panel suggests using thromboprophylaxis over no thromboprophylaxis and in whom pharmacologic thromboprophylaxis is used, the panel suggests using Low Molecular Weight Heparin (LMWH) over UnFractionated Heparin (UFH).
♦ For patients without VTE, the panel suggests using pharmacologic thromboprophylaxis over mechanical thromboprophylaxis or a combination of pharmacologic and mechanical thromboprophylaxis.
♦ For hospitalized medical patients with cancer, the ASH guideline panel suggests discontinuing thromboprophylaxis at the time of hospital discharge rather than continuing thromboprophylaxis beyond the discharge date.
Primary prophylaxis for patients with cancer undergoing surgery.
♦ For patients without VTE undergoing a surgical procedure at lower bleeding risk, the panel suggests using pharmacologic rather than mechanical thromboprophylaxis and for those undergoing a surgical procedure at high bleeding risk, the panel suggests using mechanical rather than pharmacologic thromboprophylaxis.
♦ For patients without VTE undergoing a surgical procedure at high risk for thrombosis, except in those at high risk of bleeding, the panel suggests using a combination of mechanical and pharmacologic thromboprophylaxis rather than mechanical prophylaxis alone or pharmacologic thromboprophylaxis alone.
♦ For all patients, the panel suggests using LMWH or Fondaparinux for thromboprophylaxis rather than UFH.
♦ The panel makes no recommendation on the use of Vitamin K Antagonists (VKAs) or Direct Oral AntiCoagulants (DOACs) for thromboprophylaxis, as there are no data.
♦ The panel suggests using postoperative thromboprophylaxis over preoperative thromboprophylaxis.
♦ For patients who have undergone a major abdominal/pelvic surgical procedure, the panel suggests continuing pharmacologic thromboprophylaxis, postdischarge rather than discontinuing at the time of hospital discharge.
Primary prophylaxis in ambulatory patients with cancer receiving systemic therapy.
♦ For patients at low and intermediate risk for thrombosis receiving systemic therapy, the panel recommends/suggests no thromboprophylaxis over parenteral thromboprophylaxis respectively. For patients at high risk, the panel suggests parenteral thromboprophylaxis (LMWH) over no thromboprophylaxis.
♦ The panel recommends no thromboprophylaxis over oral thromboprophylaxis with VKAs.
♦ For patients at low risk for thrombosis, the panel suggests no thromboprophylaxis over oral thromboprophylaxis with a DOAC (Apixaban or Rivaroxaban). For patients at intermediate risk, the panel suggests thromboprophylaxis with a DOAC (apixaban or rivaroxaban) or no thromboprophylaxis. For patients at high risk, the panel suggests thromboprophylaxis with a DOAC (Apixaban or Rivaroxaban) over no thromboprophylaxis.
♦ For patients with multiple myeloma receiving Lenalidomide, Thalidomide, or Pomalidomide-based regimens, the panel suggests using low-dose Aspirin or fixed low-dose VKAs or LMWH.
Primary prophylaxis for patients with cancer with Central Venous Catheter (CVC).
♦ The panel suggests not using parenteral or oral thromboprophylaxis.
Initial treatment (first week) for patients with active cancer and VTE.
♦ The panel suggests DOAC (Apixaban or Rivaroxaban) or LMWH be used for initial treatment of VTE.
♦ The panel recommends/suggests LMWH over UFH and Fondaparinux respectively, for initial treatment of VTE.
Short-term treatment for patients with active cancer (initial 3-6 months).
♦ The panel suggests DOACs (Apixaban, Edoxaban, or Rivaroxaban) over LMWH and VKAs, and LMWH over VKAs.
♦ For patients with incidental (unsuspected) Pulmonary Embolism (PE), or SubSegmental PE (SSPE), the panel suggests short-term anticoagulation treatment rather than observation.
♦ For patients with visceral/splanchnic vein thrombosis, the panel suggests treatment with short-term anticoagulation or observation.
♦ For patients with CVC-related VTE receiving anticoagulant treatment, the panel suggests keeping the CVC over removing the CVC.
♦ For patients with recurrent VTE despite receiving therapeutic LMWH, the panel suggests increasing the LMWH dose to a supratherapeutic level or continuing with a therapeutic dose.
♦ For patients with recurrent VTE despite anticoagulation treatment, the panel suggests not using an Inferior Vena Cava filter over using a filter.
Long-term treatment (>6 months) for patients with active cancer and VTE.
♦ The panel suggests long-term anticoagulation for secondary prophylaxis (> 6 months) rather than short-term treatment alone (3-6 months), and the panel suggests continuing indefinite anticoagulation over stopping after completion of a definitive period of anticoagulation.
♦ For patients requiring long-term anticoagulation (> 6 months), the panel suggests using DOACs or LMWH.

American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Lyman GH, Carrier M, Ay C, et al. Blood Adv 2021;5: 927–974.

FDA Approves LIBTAYO® for Advanced Basal Cell Carcinoma

RR

SUMMARY: The FDA on February 9, 2021, granted regular approval to LIBTAYO® (Cemiplimab-rwlc) for patients with locally advanced Basal Cell Carcinoma (laBCC) previously treated with a HedgeHog pathway Inhibitor (HHI) or for whom a HHI is not appropriate, and granted accelerated approval to LIBTAYO® for patients with metastatic BCC (mBCC) previously treated with a HHI or for whom a HHI is not appropriate.

BCC is the most common type of skin cancer in the U.S., with approximately two million new cases diagnosed every year. Exposure to UltraViolet rays is a significant risk factor. Majority of BCCs are diagnosed early and cured with surgery and radiation. However, a small proportion of tumors can become locally advanced or progress to metastatic disease and can be painful and disfiguring. The primary systemic treatment options for these patients with advanced BCC are oral HedgeHog pathway inhibitors such as ERIVEDGE® (Vismodegib) and ODOMZO® (Sonidegib). There are however no FDA-approved treatment options available, for patients who progress on, or are intolerant to HedgeHog Inhibitors (HHIs).

LIBTAYO® is a fully human IgG4, high affinity anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor on tumor-infiltrating T cells and blocks its interaction with tumor derived 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. LIBTAYO® was previously approved by the FDA in 2018 as the first systemic treatment for adults with metastatic Cutaneous Squamous Cell Carcinoma (CSCC) or locally advanced CSCC, who are not candidates for curative surgery or curative radiation.

The present FDA approval of LIBTAYO® was based on results from an interim analysis of an ongoing open-label, multi-center, non-randomized Phase II trial (Study 1620), involving patients with unresectable locally advanced BCC or metastatic BCC (nodal or distant). This was the first and largest prospective clinical trial (N=132) among this patient population, with 112 patients included in the efficacy analysis. Patients in both cohorts (locally advanced and metastatic) had either progressed on HHI therapy, had not had an objective response after 9 months on HHI therapy, or were intolerant of prior HHI therapy. Eligibility required that locally advanced BCC patients were not candidates for curative surgery or curative RT, per multidisciplinary assessment. All patients received LIBTAYO® 350 mg IV over 30 minutes every 3 weeks for up to 93 weeks, until disease progression, unacceptable toxicity, or completion of planned treatment. No PD-L1 or Tumor Mutational Burden (TMB) testing was required before starting treatment with LIBTAYO®. The Primary efficacy endpoint was confirmed Objective Response Rate (ORR) and a key Secondary endpoint was Duration of Response (DOR), as assessed by Independent Central Review.

Among the 84 patients with locally advanced BCC, the confirmed ORR was 29% with a median DOR not reached, and 79% of responders maintained their response for at least 6 months. Among 28 patients with metastatic BCC, the confirmed ORR was 21%, with a median DOR not reached, and all responders maintained their responses for at least 6 months. The most common adverse reactions (incidence 20% or more) were fatigue, musculoskeletal pain, diarrhea, rash, and pruritis.

It was concluded from this study that LIBTAYO® is the first agent to provide clinically meaningful anti-tumor activity including durable responses, in patients with advanced BCC, after progression or intolerance on HHI therapy.

Interim Analysis of Phase 2 Results for Cemiplimab in Patients with Metastatic Basal Cell Carcinoma (mBCC) who Progressed on or are Intolerant to Hedgehog Inhibitors (HHIs). Lewis KD, Peris K, Sekulic A, et al. Presented at the 2021 Winter Clinical Dermatology Conference, January 16–24, Virtual Conference (encore of SITC 2020 poster presentation).

LIBTAYO® (Cemiplimab-rwlc)

RR

The FDA on February 9, 2021 granted regular approval to LIBTAYO® for patients with Locally Advanced Basal Cell Carcinoma (laBCC) previously treated with a HedgeHog pathway Inhibitor (HHI) or for whom a HHI is not appropriate, and granted accelerated approval to LIBTAYO® for patients with metastatic BCC (mBCC) previously treated with a HHI or for whom a HHI is not appropriate. LIBTAYO® is a product of Regeneron Pharmaceuticals, Inc.

BREYANZI® (Lisocabtagene maraleucel)

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The FDA on February 5, 2021 approved BREYANZI® for the treatment of adult patients with Relapsed or Refractory (R/R) Large B-Cell Lymphoma after two or more lines of systemic therapy, including Diffuse Large B-Cell Lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), High-Grade B-Cell Lymphoma, Primary Mediastinal Large B-Cell Lymphoma, and Follicular Lymphoma Grade 3B. BREYANZI® is a product of Juno Therapeutics, Inc.

UKONIQ® (Umbralisib)

RR

The FDA on February 5, 2021 granted accelerated approval to UKONIQ®, a kinase inhibitor including PI3K-delta and casein kinase CK1-epsilon, for the following indications:
• Adult patients with Relapsed or Refractory Marginal Zone Lymphoma (MZL) who have received at least one prior anti-CD20-based regimen;
• Adult patients with Relapsed or Refractory Follicular Lymphoma (FL) who have received at least three prior lines of systemic therapy.

UKONIQ® is a product of TG Therapeutics Inc.

Key Breast Cancer Risk Genes Identified from Two Large Studies

RR

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 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease largely due to metastatic recurrence.

Genetic testing for cancer susceptibility with multigene testing panels is now becoming widely available and affordable. Identification of pathogenic variants in predisposition genes such as BRCA1 and BRCA2 among carriers has provided benefit through early intervention. However, the evidence of an association with cancer is often weak for many other genes on multigene testing panels, and estimates of the cancer risks associated with such variants are often not available. Further, estimates of the prevalence of pathogenic variants in predisposition genes in the general population are lacking.

Two large breast cancer case-control studies analyzed the associations between a number of commonly accepted cancer susceptibility genes and breast cancer risk.

The multinational study by Dorling et al. used a panel of 34 commonly accepted cancer susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls (unaffected woman) from 25 countries participating in the Breast Cancer Association Consortium. The authors estimated odds ratios for breast cancer overall and tumor subtypes and evaluated missense-variant associations and classification of pathogenicity. The researchers found strong evidence of an association with breast cancer risk for Protein-Truncating Variants (genetic variants) caused by frameshift mutations in 9 genes, with a significant risk for breast cancer and P value of less than 0.0001 for 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2 – Odds Ratios ranging from 2.1 for ATM to 10.6 for BRCA1), and a P value of less than 0.05 for the other 4 genes (BARD1, RAD51C, RAD51D, and TP53 – Odds Ratio ranging from 1.8 for RAD51D to 3.06 for TP53). Further, it was noted that for the genetic variants in most of these genes, the Odds Ratio differed according to breast cancer subtype. Protein-Truncating Variants in ATM and CHEK2 were more strongly associated with ER-positive disease than with ER-negative disease, whereas genetic variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D were more strongly associated with ER-negative disease than with ER-positive disease. It was also found that rare missense variants in CHEK2 overall, as well as variants in specific domains in ATM, were associated with moderate breast cancer risk. The researchers also noted that none of the other 25 genes in the panel were informative for the prediction of breast cancer risk. This study places Protein-Truncating Variants in BRCA1, BRCA2, and PALB2 in the high-risk category and Protein-Truncating Variants in ATM, BARD1, CHEK2, RAD51C, and RAD51D in the moderate-risk category.

The US study by Hu et al. used a panel of 28 cancer predisposition genes to perform sequencing on samples from 32,247 women with breast cancer and 32,544 controls (unaffected women) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. The researchers assessed the associations between pathogenic variants in each gene and the risk of breast cancer.
The researchers noted that pathogenic variants in 12 established breast cancer predisposition genes were detected in 5% of breast cancer patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with Odds Ratios of 7.62 and 5.23 respectively and pathogenic variants in PALB2 were associated with a moderate risk (Odds Ratio 3.83). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of ER-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of ER-positive breast cancer. Pathogenic variants in the other 16 candidate breast cancer predisposition genes were not associated with an increased risk of breast cancer.

Taken together, the results from these two large case-control studies suggested that variants in 8 genes – BRCA1, BRCA2, PALB2, BARD1, RAD51C, RAD51D, ATM, and CHEK2, had a significant association with breast cancer risk and majority of the other genes tested did not have a significant association with disease. Further, the distribution of mutations among women with breast cancer was different from the distribution among controls (unaffected women). Among breast cancer patients, the majority of mutations were in BRCA1, BRCA2, and PALB2, and among controls, the majority of mutations were in CHEK2 and ATM.

It can be concluded that, these two studies define the genes that are of utmost clinical value for inclusion on sequencing panels, for the prediction of breast cancer risk, and provides estimates of the prevalence of the pathogenic variants in the unaffected population. The authors added that these estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes.

Breast Cancer Risk Genes – Association Analysis in More than 113,000 Women. Breast Cancer Association Consortium; Dorling L, Carvalho S, Allen J, et al. N Engl J Med 2021;384:428-439.

A Population-Based Study of Genes Previously Implicated in Breast Cancer. Hu C, Hart SN, Gnanaolivu R, et al. N Engl J Med 2021;384:440-451.

FDA Approves UKONIQ® for Relapsed or Refractory Marginal Zone and Follicular Lymphomas

RR

SUMMARY: The FDA on February 5, 2021 granted accelerated approval to UKONIQ® (Umbralisib), a kinase inhibitor including PI3K-delta and Casein Kinase CK1-epsilon, for adult patients with Relapsed or Refractory Marginal Zone Lymphoma (MZL) who have received at least one prior anti-CD20-based regimen and adult patients with Relapsed or Refractory Follicular Lymphoma (FL) who have received at least three prior lines of systemic therapy. The American Cancer Society estimates that in 2021, about 81,560 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,720 individuals will die of this disease. Indolent Non Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL). Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas (FL).

Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance RITUXAN® (Rituximab). This can result in a median PFS of 6-8 yrs and a median OS of 12-15 yrs. However, approximately 30% of the patients will relapse in 3 years and treatment options are limited for patients with relapses, after multiple treatments.

UKONIQ® is an oral, once-daily, dual inhibitor of Phosphatidylinositol-3-Kinase-delta (PI3Kδ) and Casein Kinase 1-epsilon (CK1-epsilon) that exhibits improved selectivity for the delta isoform of PI3K. In contrast with other PI3K inhibitors, there was a low incidence of immune-mediated toxicities with UKONIQ® possibly attributable to enhanced selectivity for the PI3Kδ isoform as well as inhibition of CK1-epsilon.

The present FDA approval was based on the UNITY-NHL trial (NCT02793583), which is global, multicenter, open-label, multicohort, Phase IIb registration study, designed to evaluate the safety and efficacy of UKONIQ® in previously treated NHL patients. This study had a total 208 patients with indolent NHL and included 69 patients with MZL (splenic, nodal, extranodal), 117 patients with FL (grade 1, 2, 3a), and 22 patients with Small Lymphocytic Lymphoma (SLL). MZL patients were Relapsed/Refractory to 1 or more prior lines of treatment, which included an anti-CD20, while FL and SLL patients were Relapsed/Refractory to 2 or more prior lines of therapy, which included an anti-CD20 and an alkylating agent. UKONIQ® was administered at 800 mg orally once daily in 28-day treatment cycles until disease progression or unacceptable tolerability. The median age was 66 years and the median duration of treatment exposure was 8.4 months. Pneumocystis jiroveci Pneumonia (PCP) and anti-viral prophylaxis were mandated for all patients. The Primary endpoint of the study was Overall Response Rate (ORR) as assessed by an Independent Review Committee (IRC) and Secondary endpoints included Duration of Response (DoR), Progression Free Survival (PFS), Time To Response (TTR), and Safety.

With a median follow up of 27.8 months, the ORR for patients with MZL was 49%, with a 16% Complete Response (CR) rate and a Disease Control Rate (CR+PR+SD) of 82.6%. The ORR was consistent amongst MZL subtypes and no patients who achieved CR had experienced disease progression to date. Additionally, the median DoR and median PFS was not reached for this patient population.

Among patients with FL, with a median follow up of 27.5 months, the ORR was 45%, with 5% achieving a CR, and a DCR of 79.5%. The median TTR was 4.6 months and the median DoR was 11.1 months. The median PFS was 10.6 months.

Among SLL patients, with a median follow up of 29.3 months, the ORR was 50%, with 4.5% achieving a CR, and a DCR of 86.4%. The median TTR was 2.7 months and the median DoR was 18.3 months. The median PFS was 20.9 months.

The most common toxicities included increased creatinine, diarrhea/colitis, fatigue, transaminase elevation, musculoskeletal pain, neutropenia, anemia, thrombocytopenia, upper respiratory tract infection, nausea, vomiting, abdominal pain, reduced appetite, and cutaneous reactions.

It was concluded from this study that UKONIQ® has a favorable benefit-risk profile and achieved meaningful clinical activity in a heavily pretreated population of patients with indolent NHL. The authors added that the safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and treatment discontinuations.

Umbralisib, the Once Daily Dual Inhibitor of PI3Kδ and Casein Kinase-1ε Demonstrates Clinical Activity in Patients with Relapsed or Refractory Indolent Non-Hodgkin Lymphoma: Results from the Phase 2 Global Unity-NHL Trial. Zinzani PL, Samaniego F, Jurczak W, et al. Presented at the 62nd ASH Annual Meeting and Exposition, December 5-8, 2020. Abstract # 2934.

TIBSOVO® Improves Survival in IDH1 Mutated Advanced Cholangiocarcinoma

RR

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

Isocitrate DeHydrogenase (IDH) is a metabolic enzyme that helps generate energy from glucose and other metabolites, by catalyzing the conversion of Isocitrate to Alpha-Ketoglutarate. Alpha-ketoglutarate is required to properly regulate DNA and histone methylation, which in turn is important for gene expression and cellular differentiation. IDH mutations lead to aberrant DNA methylation and altered gene expression thereby preventing cellular differentiation, with resulting immature undifferentiated cells. IDH mutations can thus promote leukemogenesis in Acute Myeloid Leukemia (AML) and tumorigenesis in solid tumors and can result in inferior outcomes. There are three isoforms of IDH. IDH1 is mainly found in the cytoplasm, as well as in peroxisomes, whereas IDH2 and IDH3 are found in the mitochondria, and are a part of the Krebs cycle. Approximately 20% of patients with AML, 70% of patients with Low-grade Glioma and secondary Glioblastoma, 50% of patients with Chondrosarcoma, 20% of patients with Intrahepatic Cholangiocarcinoma, 30% of patients with Angioimmunoblastic T-cell lymphoma and 8% of patients with Myelodysplastic syndromes/Myeloproliferative neoplasms, are associated with IDH mutations.

TIBSOVO® (Ivosidenib) is an oral, targeted, small-molecule inhibitor of mutant IDH1. The FDA in July, 2018, approved TIBSOVO® for adult patients with relapsed or refractory AML with a susceptible IDH1 mutation. A previously published Phase I study demonstrated the safety and activity of TIBSOVO® in patients with IDH1 mutated advanced Cholangiocarcinoma.MOA-of-Ivosidenib

ClarIDHy is an international, randomized, double-blind, Phase III study, in which 187 previously treated patients with advanced Cholangiocarcinoma with an IDH1 mutation were randomly assigned 2:1 to receive TIBSOVO® 500 mg orally once daily (N=126) or matched placebo (N=61). All patients had advanced unresectable Cholangiocarcinoma. The median age was 62 years, 91% had intrahepatic Cholangiocarcinoma, 93% of patients had metastatic disease and 47% had received two prior therapies. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Safety, Objective Response Rate (ORR) and Overall Survival (OS). Crossover from placebo to TIBSOVO® was permitted upon radiographic disease progression.

This study met its Primary endpoint and the median PFS was 2.7 months for patients treated with TIBSOVO® compared to 1.4 months with placebo (HR=0.37; P<0.0001). More importantly, the median PFS at 6 and 12 months were 32% and 22% in the TIBSOVO® group, whereas no patients randomized to the placebo group were progression-free for 6 or more months, at the time of data cutoff.

The authors now reported the results of final analysis which showed an improvement in the secondary endpoint of OS, favoring patients randomized to TIBSOVO® compared to those randomized to placebo. However, statistical significance was not reached. The median OS for patients in the TIBSOVO® arm was 10.3 months compared to 7.5 months for patients in the placebo arm (HR=0.79; 1-sided P=0.093). A high proportion of patients in the placebo arm (70.5%) crossed over to TIBSOVO®. After adjusting for crossover from placebo to TIBSOVO®, the median OS for patients in the placebo arm was 5.1 months (HR=0.49; 1-sided P<0.0001).

The 6-month survival rate for patients in the TIBSOVO® arm was 69% compared to 57% of patients in the placebo arm, not adjusted for crossover. The 12-month survival rate for patients in the TIBSOVO® arm was 43% compared to 36% for patients in the placebo arm, not adjusted for crossover. Treatment with TIBSOVO® preserved patients’ physical functioning from baseline, as assessed by the EORTC QLQ-C30 questionnaire, whereas patients in the placebo arm experienced decline from baseline starting cycle 2. The most common Adverse Events of any grade for TIBSOVO® were nausea (38%), diarrhea (33.1%) and fatigue (28.9%). Adverse Events leading to discontinuation were more common with placebo compared with total TIBSOVO® (8.5% versus 6.6%).

It was concluded that treatment with TIBSOVO® in patients with advanced Cholangiocarcinoma with an IDH1 mutation, resulted in significant improvement in Progression Free Survival as well as favorable Overall Survival trend, when compared to Placebo, despite a high rate of crossover. This is the first pivotal study demonstrating the clinical benefit of targeting IDH1 mutation in this patient group. This new oral, non-cytotoxic, targeted treatment option, with a tolerable safety profile, will be a welcome addition to treat this aggressive disease, for which there is an unmet need for new therapies.

Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation. Zhu A, Macarulla T, Javle MM, et al. J Clin Oncol 39, 2021 (suppl 3; abstr 266)

Real-World Data: Surgery Improves Survival in Treatment Responsive Metastatic Breast Cancer

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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 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease largely due to metastatic recurrence. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene and about 50% of HER2-positive breast cancers are Hormone Receptor positive. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. Not all HER2-positive, Hormone Receptor positive metastatic breast cancer patients, are candidates for chemotherapy. These patients however may benefit from anti-HER2 targeted therapy given along with endocrine therapy.

Approximately 6% of newly diagnosed breast cancer patients present with Stage IV disease. Systemic therapy has been the cornerstone of treatment for patients with metastatic breast cancer. Breast surgery is often not a consideration for patients with metastatic breast cancer. However, breast surgery can be offered for palliation of symptoms, taking into consideration the risks and benefits of such intervention, in a patient with an ulcerated, bleeding, or a fungating tumor mass, that cannot be controlled with systemic therapy.

Surgical resection of metastatic disease is not a new concept. Previously published results from randomized controlled trials among patients with metastatic breast cancer concluded that there was no survival advantage with surgical intervention. However these results have been questioned because of the small number of participants, and did not take into account either the Hormone Receptor, HER-2 status or the sequence of chemotherapy in relation to the surgical intervention. It therefore remains unclear whether surgery, in addition to systemic treatments and radiation therapy, improves survival for certain patients with metastatic breast cancer.

The authors in this real-world study identified 12,838 patients with HER-2 overexpressing and Hormone Receptor positive, Stage IV breast cancer, from the NCI database. They then studied patients who had either systemic therapy alone, systemic therapy and surgery, or had systemic therapy, surgery and radiation, and evaluated whether certain biologic subtypes and timing of chemotherapy were associated with survival advantages. Specifically, they evaluated whether the Hormone Receptor status had an influence on surgical benefit, in these treatment-responsive breast cancer patients, understanding that triple negative breast cancers are not very responsive to treatment. The researchers excluded patients who died within six months of their diagnoses, in order to ensure that only treatment-responsive cancers were being studied. The goal of this study was to understand if surgery made a difference in metastatic breast cancers that were responsive to treatment.

The researchers noted that patients with a surgical intervention tended to have a longer survival, compared to patients with other treatment plans. Patients whose cancers were HER2-positive saw prolonged survival, especially when their treatment plan included surgery. Further, in addition to the benefit of surgery among treatment-responsive metastatic breast cancer patients, the authors noted that systemic therapy before surgery (preoperative systemic therapy which included chemotherapy and targeted therapies) had the greatest survival advantage in patients with positive HER-2 and Estrogen and Progesterone Receptor status.

It was concluded from this study that patients with Stage IV breast cancer responsive to systemic therapy may be able to benefit from the addition of surgery, regardless of their biologic subtype. The authors added that clinicians should evaluate real-world evidence, including this study, when choosing the optimal treatment for their patients with metastatic breast cancer, as it may be difficult to conduct randomized clinical trials in this patient population.

ASO Author Reflections: Surgery Offers Survival Advantage in Treatment-Responsive Metastatic Breast Cancer. Stahl K, Dodge D, and Shen C. Annals of Surgical Oncology, 2020; DOI: 10.1245/s10434-020-09286-9