Category: Hem/Onc Updates

Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer: ASCO Guideline Update

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

Approximately 20% of cancer patients develop VTE and 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.

Since the first publication of a VTE guideline by ASCO in 2007, there have been 3 updates, with the last update in 2023. ASCO convened an Expert Panel to review the evidence and revise previous recommendations as needed. The 2019 guideline update included a systematic review of 35 publications on VTE prophylaxis and treatment, and 18 publications on VTE risk assessment published from August 1, 2014, through December 4, 2018. After publication of five potentially practice-changing randomized clinical trials between November 1, 2018, and June 6, 2022, an updated systematic review was performed by the ASCO Expert Panel for two guideline questions: perioperative thromboprophylaxis and treatment of VTE.

The purpose of this guideline update is to provide updated recommendations about prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer. The term direct factor Xa inhibitors is used in this update, rather than the previously used direct oral anticoagulants, for increased specificity.

Guideline Question
How should venous thromboembolism (VTE) be prevented and treated in patients with cancer?

CLINICAL QUESTION 1.
Should hospitalized patients with cancer receive anticoagulation for VTE prophylaxis?
Recommendation 1.1.
Hospitalized patients who have active malignancy and acute medical illness or reduced mobility should be offered pharmacologic thromboprophylaxis in the absence of bleeding or other contraindications
Recommendation 1.2.
Hospitalized patients who have active malignancy without additional risk factors may be offered pharmacologic thromboprophylaxis in the absence of bleeding or other contraindications
Recommendation 1.3.
Routine pharmacologic thromboprophylaxis should not be offered to patients admitted for the sole purpose of minor procedures or chemotherapy infusion, nor to patients undergoing stem-cell/bone marrow transplantation

CLINICAL QUESTION 2.
Should ambulatory patients with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy?
Recommendation 2.1.
Routine pharmacologic thromboprophylaxis should not be offered to all outpatients with cancer
Recommendation 2.2.
High-risk outpatients with cancer (Khorana score of 2 or higher prior to starting a new systemic chemotherapy regimen) may be offered thromboprophylaxis with apixaban, rivaroxaban, or low-molecular-weight heparin (LMWH) provided there are no significant risk factors for bleeding and no drug interactions. Consideration of such therapy should be accompanied by a discussion with the patient about the relative benefits and harms, drug cost, and duration of prophylaxis in this setting
Recommendation 2.3.
Patients with multiple myeloma receiving thalidomide- or lenalidomide-based regimens with chemotherapy and/or dexamethasone should be offered pharmacologic thromboprophylaxis with either aspirin or LMWH for lower-risk patients and LMWH for higher-risk patients

CLINICAL QUESTION 3.
Should patients with cancer undergoing surgery receive perioperative VTE prophylaxis?
Recommendation 3.1.
All patients with malignant disease undergoing major surgical intervention should be offered pharmacologic thromboprophylaxis with either unfractionated heparin (UFH) or LMWH unless contraindicated because of active bleeding, or high bleeding risk, or other contraindications
Recommendation 3.2.
Prophylaxis should be commenced preoperatively
Recommendation 3.3.
Mechanical methods may be added to pharmacologic thromboprophylaxis but should not be used as monotherapy for VTE prevention unless pharmacologic methods are contraindicated because of active bleeding or high bleeding risk
Recommendation 3.4.
A combined regimen of pharmacologic and mechanical prophylaxis may improve efficacy, especially in the highest-risk patients
Recommendation 3.5.
Pharmacologic thromboprophylaxis for patients undergoing major surgery for cancer should be continued for at least 7 to 10 days.
Recommendation 3.6.
Extended prophylaxis with LMWH for up to 4 weeks postoperatively is recommended for patients undergoing major open or laparoscopic abdominal or pelvic surgery for cancer who have high-risk features, such as restricted mobility, obesity, history of VTE, or with additional risk factors. In lower-risk surgical settings, the decision on appropriate duration of thromboprophylaxis should be made on a case-by-case basis
Recommendation 3.7. (UPDATED ASCO RECOMMENDATION FROM 2023)
Patients who are candidates for extended pharmacologic thromboprophylaxis after surgery may be offered prophylactic doses of low molecular weight heparin (LMWH). Alternatively, patients may be offered prophylactic doses of rivaroxaban or apixaban after an initial period of LMWH or unfractionated heparin (UFH)
Qualifying statement: Evidence for rivaroxaban and apixaban in this setting remains limited. The two available trials differed with respect to type of cancer, type of surgery, and timing of rivaroxaban or apixaban initiation after surgery.

CLINICAL QUESTION 4.
What is the best method for treatment of patients with cancer with established VTE to prevent recurrence?
Recommendation 4.1. (UPDATED ASCO RECOMMENDATION FROM 2023)
Initial anticoagulation may involve LMWH, UFH, fondaparinux, or rivaroxaban. For patients initiating treatment with parenteral anticoagulation, LMWH is preferred over UFH for the initial 5 to 10 days of anticoagulation for the patient with cancer with newly diagnosed VTE who does not have severe renal impairment (defined as creatinine clearance less than 30 mL/min)
Recommendation 4.2. (UPDATED ASCO RECOMMENDATION FROM 2023)
For long-term anticoagulation, LMWH, edoxaban, or rivaroxaban for at least 6 months are preferred because of improved efficacy over vitamin K antagonists (VKAs). VKAs are inferior but may be used if LMWH or direct oral anticoagulants (DOACs) are not accessible. There is an increase in major bleeding risk with DOACs, particularly observed in GI and potentially genitourinary malignancies. Caution with DOACs is also warranted in other settings with high risk for mucosal bleeding. Drug-drug interaction should be checked prior to using a DOAC.
Recommendation 4.3.
Anticoagulation with LMWH, DOACs, or VKAs beyond the initial 6 months should be offered to select patients with active cancer, such as those with metastatic disease or those receiving chemotherapy. Anticoagulation beyond 6 months needs to be assessed on an intermittent basis to ensure a continued favorable risk-benefit profile
Recommendation 4.4.
Based on expert opinion in the absence of randomized trial data, uncertain short-term benefit, and mounting evidence of long-term harm from filters, the insertion of a vena cava filter should not be offered to patients with established or chronic thrombosis (VTE diagnosis more than 4 weeks ago), nor to patients with temporary contraindications to anticoagulant therapy (eg, surgery). There also is no role for filter insertion for primary prevention or prophylaxis of pulmonary embolism (PE) or deep vein thrombosis due to its long-term harm concerns. It may be offered to patients with absolute contraindications to anticoagulant therapy in the acute treatment setting (VTE diagnosis within the past 4 weeks) if the thrombus burden was considered life-threatening. Further research is needed
Recommendation 4.5.
The insertion of a vena cava filter may be offered as an adjunct to anticoagulation in patients with progression of thrombosis (recurrent VTE or extension of existing thrombus) despite optimal anticoagulant therapy. This is based on the panel’s expert opinion given the absence of a survival improvement, a limited short-term benefit, but mounting evidence of the long-term increased risk for VTE
Recommendation 4.6.
For patients with primary or metastatic CNS malignancies and established VTE, anticoagulation as described for other patients with cancer should be offered, although uncertainties remain about choice of agents and selection of patients most likely to benefit
Recommendation 4.7.
Incidental PE and deep vein thrombosis should be treated in the same manner as symptomatic VTE, given their similar clinical outcomes compared with patients with cancer with symptomatic events
Recommendation 4.8.
Treatment of isolated subsegmental PE or splanchnic or visceral vein thrombi diagnosed incidentally should be offered on a case-by-case basis, considering potential benefits and risks of anticoagulation

CLINICAL QUESTION 5.
Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival?
Recommendation 5.
Anticoagulant use is not recommended to improve survival in patients with cancer without VTE

CLINICAL DECISION 6.
What is known about risk prediction and awareness of VTE among patients with cancer?
Recommendation 6.1.
There is substantial variation in risk of VTE between individual patients with cancer and cancer settings. Patients with cancer should be assessed for VTE risk initially and periodically thereafter, particularly when starting systemic antineoplastic therapy or at the time of hospitalization. Individual risk factors, including biomarkers or cancer site, do not reliably identify patients with cancer at high risk of VTE. In the ambulatory setting among patients with solid tumors treated with systemic therapy, risk assessment can be conducted based on a validated risk assessment tool (Khorana score)
Recommendation 6.2.
Oncologists and members of the oncology team should educate patients regarding VTE, particularly in settings that increase risk, such as major surgery, hospitalization, and while receiving systemic antineoplastic therapy

Notes regarding off-label use in guideline recommendations: Apixaban, rivaroxaban, and LMWH have not been US FDA–approved for thromboprophylaxis in outpatients with cancer (recommendation 2.2 for apixaban and rivaroxaban; recommendations 2.2 and 2.3 for LMWH). Dalteparin is the only LMWH with US Food and Drug Administration approval for extended therapy to prevent recurrent thrombosis in patients with cancer (recommendation 4.2).

Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Guideline Update.Key NS , Khorana AA , Kuderer NM, et al. J Clin Oncol 2023; 41:3063-3071.

Whole Exome Sequencing Identifies Cancer Predisposition Syndromes Missed by Current Screening Guidelines

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SUMMARY: Hereditary factors play an important role in the risk of developing several cancers. Therefore, identification of a germline predisposition can have important implications for treatment decision making, risk-reducing interventions, cancer screening for early diagnosis, germline testing and targeted surveillance of unaffected relatives. Previously published studies have been biased by estimating the prevalence of germline cancer susceptibility in patients with breast, prostate, and colorectal cancer from registry populations, genetic testing companies, and high-risk cancer clinics.

With the widespread adoption of Next Generation Sequencing (NGS), multiple genes can be tested simultaneously (MultiGene Panel Testing-MGPT), rather than sequential single-gene testing, making MultiGene Panel Testing cheaper, faster and more efficient. Further, single-test multigene multiplexing strategy analyzes numerous cancer susceptibility genes and frequently detects highly penetrant, clinically actionable Pathogenic Germline Variants (PGV) in individuals whose clinical histories fail to fulfill syndrome-specific testing criteria. This is clinically relevant, as it has become increasingly complex to determine which individuals warrant germline testing. Several risk assessment models have been developed to provide probability of an individual carrying a germline mutation. These models provide syndrome-specific risk assessment for Lynch Syndrome, Hereditary Breast and Ovarian Cancer syndrome (HBOC)), etc.

The Genomics and Population Health Action Collaborative was formed in 2015 with the goal of identifying challenges and potential best practices for the widespread integration of evidence-based genomics applications in population health programs. They endorsed 11 genes associated with the three CDC Tier 1 inherited Autosomal Dominant cancer predisposition conditions – Hereditary Breast and Ovarian Cancer syndrome, Lynch syndrome, and Familial Hypercholesterolemia, as being a reasonable starting point for primary genomic screening in the general population.

Tapestry study is collaboration between Mayo Clinic and Helix, a population genomics company. The Tapestry trial included 44,306 patients who received treatment across Mayo Clinic sites in Minnesota, Arizona and Florida. Researchers gathered and evaluated saliva samples for pathogenic mutations in BRCA1 and BRCA2 (denoting Hereditary Breast and Ovarian Cancer), as well as MLH1, MSH2, MSH6, PMS2 and EPCAM (denoting Lynch syndrome). The mean age was 55 years, 63% were women and 90% were Caucasian. The aim of this study was to evaluate whether screening in a multisite tertiary medical center using Whole Exome Sequencing (WES) could efficiently identify carriers of two conditions, Hereditary Breast and Ovarian Cancers and Lynch syndrome, and determine the frequency of incremental carriers identified outside of traditional clinical practice guidelines.

The researchers identified 550 carriers of pathogenic mutations, including 387 individuals with Hereditary Breast and Ovarian Cancer syndrome (HBOC) and 163 with Lynch syndrome. Of these individuals with pathogenic mutations, 52.1% had no knowledge prior to this study that they carried cancer predisposition genes, and 39.2% of CARRIERS did not meet NCCN criteria for genetic testing, including 56.2% of those with Lynch syndrome and 32% of those with HBOC. Among the patients who were NEWLY DIAGNOSED with Lynch syndrome and HBOC syndrome during this study, 60% were ineligible for genetic testing per the current guidelines. They included 78% of those with Lynch syndrome and 51% of those with HBOC syndrome. Some of the reasons for not meeting NCCN criteria included having no personal history of cancer (63.3%), an insufficient number of relatives who had cancer (60.5%) and a cancer type or types not related to a genetic syndrome (58.6%). Among those who met NCCN guidelines for testing, 34.2% reported not knowing their diagnosis prior to the study. The researchers also noted that patients with HBOC or Lynch syndrome from racial and ethnic minority groups were significantly more likely than white patients to not meet NCCN screening criteria (49% versus 32%, respectively).

It was concluded that genomic screening in the broad general population for CDC Tier 1 genetic conditions has the potential to identify 50% of at-risk carriers who are otherwise not detected in current medical practice. Early diagnosis and intervention could have a positive impact on public health, and a systemic bias in the current guidelines could potentially be overcome by universal genetic testing. The authors added that the limitation of this study is that the patient population in this study may not reflect the demographics of the general population.

Exome sequencing identifies individuals with cancer predisposition syndromes missed by current screening guidelines (AACR press release). Available at: www.aacr.org/about-the-aacr/newsroom/news-releases/exome-sequencing-identifies-individuals-with-cancer-predisposition-syndromes-missed-by-current-screening-guidelines/. Published April 18, 2023.

FDA Approves BiSpecific Antibody EPKINLY® for Aggressive Non Hodgkin Lymphomas

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SUMMARY: The FDA on May 19, 2023, granted accelerated approval to Epcoritamab-bysp (EPKINLY®) for relapsed or refractory Diffuse Large B-Cell Lymphoma (DLBCL) not otherwise specified, including DLBCL arising from indolent lymphoma, and High-Grade B-Cell Lymphoma after two or more lines of systemic therapy. The American Cancer Society estimates that in 2023, about 80,550 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,180 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphomas in the United States, and the incidence has steadily increased 3-4% each year. More than half of patients are 65 or older at the time of diagnosis and the incidence is likely to increase with aging of the American population. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), UltraViolet radiation, pesticides, hair dyes, and diet.

DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using Gene Expression Profiling: Germinal Center B-cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher 5-year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless, R-CHOP regimen (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL, regardless of molecular subtype. Approximately 30-40% of patients experience disease progression or relapse, during the first 2 years and attempts to improve on R-CHOP regimen have not been successful. Maintenance treatment strategy following R-CHOP, to better control the disease, delay disease progression and improve long term survival, have included Autologous Stem Cell Transplantation, CAR T-cell therapy, maintenance treatment with agents such as oral protein kinase inhibitor Enzastaurin and Everolimus. Outcomes for transplant-ineligible patients with Relapsed/Refractory DLBCL patients remain poor.

Epcoritamab is a CD20-directed CD3 T-cell engager bispecific antibody, designed to target CD20 on the surface of B cells and CD3 on the surface of T cells. This dual targeting activates and redirects a patient’s existing T cells to engage and eliminate target B cells by releasing cytotoxic proteins into the B cells.

EPCORE NHL-1 is an ongoing, open-label, multi-cohort, multicenter, Phase 1/2b, single-arm trial in which the safety, tolerability, pharmacokinetics and preliminary efficacy of Epcoritamab in combination with standard-of-care (SOC) agents are being examined in patients with relapsed, progressive or refractory CD20+ mature B-cell Non-Hodgkin Lymphoma (NHL), including Diffuse Large B-Cell Lymphoma. Phase 1 of the trial consists of a first-in-human, dose-escalation portion, and Phase 2 is the expansion and optimization part.

The Phase 2 expansion cohort included 157 patients with relapsed/refractory Large B-Cell Lymphoma who were previously treated with a median of 3 lines of prior therapy. The median age was 64 years and median time from initial diagnosis was 1.6 yrs. Approximately 39% of patients had received prior CAR T-cell therapy, 20% had prior Autologous Stem Cell Transplantation, 61% had Primary refractory disease and 14% of patients with Diffuse Large B-Cell Lymphoma were confirmed Double Hit/Triple Hit by central FISH. Epcoritamab was administered subcutaneously in 28-day cycles until disease progression or unacceptable toxicity. Mitigation of Cytokine Release Syndrome included step-up dosing and corticosteroid prophylaxis in the first cycle alone. Step-up dosing was 0.16 mg on Day 1, 0.8 mg on Day 8, and 48 mg on Day 15 and Day 22 in Cycle 1, followed by fixed dosing of 48 mg weekly dosing during Cycles 2-3, every other week during Cycle 4-9, and then every four weeks on Day 1 of subsequent cycles. Per protocol, 24-hour hospitalization was required only for the first full dose (48 mg) to ensure close observation of patients. The Primary endpoint was Overall Response Rate (ORR) by Independent Review Committee. Key Secondary endpoints included the Duration of Response (DOR), time to response, Progression Free Survival (PFS), Overall Survival (OS), Complete Response (CR) rate, Safety, and tolerability.

At a median follow-up of 10.7 months, the Overall Response Rate for the total population was 63%, with a Complete Response Rate of 39%. The median Duration of Response was 12.0 months and was Not Reached among complete responders. Overall and Complete Response rates were similar across key prespecified subgroups. The median time to response was 1.4 months. MRD negativity was assessed by a ctDNA NGS assay and 46.4% were MRD negative at any time point on treatment. MRD negativity was reached at a median of 8 weeks for complete responders, and high MRD negativity rates were observed across all prespecified subgroups. MRD-negative responses were durable and correlated with PFS. The most common adverse events were Cytokine Release Syndrome (majority were Grade 1 or 2, with most events occurring after the first full dose), fever and fatigue. Immune effector Cell-Associated Neurotoxicity Syndrome occurred in 6.4% of patients.

It was concluded that subcutaneous single agent Epcoritamab is a convenient, off-the-shelf therapy that resulted in deep and durable responses, including high MRD negativity rates, with manageable safety, in highly refractory patients with Large B-cell lymphoma, including those with prior CAR T-cell exposure.

Epcoritamab, a Novel, Subcutaneous CD3xCD20 Bispecific T-Cell-Engaging Antibody, in Relapsed or Refractory Large B-Cell Lymphoma: Dose Expansion in a Phase I/II Trial. Thieblemont C, Phillips T, Ghesquieres H, et al. J Clin Oncol. 2023;;41:2238-2247.

Breast-Conserving Surgery with or without Irradiation in Early 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. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 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, adjuvant chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment.

The median age at the time of breast cancer diagnosis in the US is 62 years and approximately 26% of breast cancer diagnoses are in women 65 to 74 years of age. Patient undergoing breast conserving surgery, often receive adjuvant breast radiation therapy to reduce the risk of local recurrence. Radiation therapy however is inconvenient, expensive and is associated with acute and late toxicities. Avoidance of radiation in elderly patients with low risk disease has remained controversial due to the lack of long term Level 1 evidence. In the LUMINA trial and PRIME II study of women over 55 years of age with low risk breast cancer, after a median follow up of 5 years, 5-year rate of ipsilateral breast tumor recurrence was low at 2-4% among those women who did not receive adjuvant whole-breast radiotherapy after breast-conserving surgery. The researchers herein reported the 10-year outcomes of the PRIME II trial.

PRIME II is a Phase III randomized clinical trial of the omission of breast irradiation, designed by the Scottish Cancer Trials Breast Group (SCTBG). This study included women 65 years of age or older, who had Hormone Receptor (HR)-positive, node-negative, T1 or T2 primary breast cancer (with tumors 3 cm or less in the largest dimension), treated with breast-conserving surgery with clear excision margins and adjuvant endocrine therapy. Patients were eligible if they had either cancer with Grade 3 histologic features or lymphovascular invasion but not both. A total of 1326 women were randomly assigned to receive 40-50 Gy whole-breast irradiation (N=658) or no radiation therapy (N=668). Both treatment groups were well balanced. The median patient age was 70 years and less than 10% of patients had ER-low tumors. The Primary end point was local breast cancer recurrence. Regional recurrence, breast cancer–specific survival, distant recurrence as the first event, and Overall Survival were also assessed. The median follow up was 9.1 years.

The cumulative incidence of local breast cancer recurrence after 10 years of follow up was 9.5% in the no-radiotherapy group and 0.9% in the radiotherapy group (HR=10.4; P<0.001). Even though local recurrence was more common in the group that did not receive radiotherapy, there was no substantial difference in the 10-year incidence of distant recurrence as the first event between the two treatment groups (1.6% without radiotherapy and 3.0% with radiotherapy). Overall Survival at 10 years was almost identical in the two groups, at 80.8% with no radiotherapy and 80.7% with radiotherapy. The incidence of regional recurrence and breast cancer–specific survival also did not differ substantially between the two groups.

The authors concluded that omission of radiotherapy was associated with an increased incidence of local recurrence but had no detrimental effect on distant recurrence as the first event, or Overall Survival, among women 65 years of age or older, with Grade 1 or 2, Estrogen Receptor-high breast cancers, treated with breast-conserving surgery and 5 years of adjuvant endocrine therapy.

Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer. Kunkler IH, Williams LJ, Jack WJL, et al. N Engl J Med 2023; 388:585-594.

First-Line Time Limited Venetoclax Combinations in Chronic Lymphocytic Leukemia

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SUMMARY: The American Cancer Society estimates that for 2023, about 18,740 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4490 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitor, time limited therapy with BCL2 inhibitor Venetoclax, given along with anti-CD20 antibody Obinutuzumab or under certain circumstances, chemoimmunotherapy.

Brutons Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor, and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation, and promote programmed cell death (Apoptosis) by blocking B-cell activation and signaling. Three BTK inhibitors are presently approved by the FDA. They include first generation Ibrutinib (IMBRUVICA®) and second generation agents such as Acalabrutinib (CALQUENCE®) and Zanubrutinib (BRUKINSA®).

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by CLL cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death). Venetoclax (VENCLEXTA®) is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells.

In previously published studies, Venetoclax in combination with Obinutuzumab or Rituximab as first-line therapy led to a high incidence of undetectable Minimal Residual Disease (MRD) and long Progression-Free Survival, among patients who are not fit, and patients with relapsed disease. However, there is no data from prospective, randomized clinical trials evaluating the safety and efficacy of Venetoclax-Obinutuzumab combination in fit patients with CLL with normal renal function. Combining BCL2 inhibitors with BTK inhibitors have induced undetectable Minimal Residual Disease and improved disease control.

GAIA-CLL13 trial is a prospective, open-label, multicenter, four-group, Phase III trial, designed to evaluate the efficacy and safety of two fixed-duration regimens and one time-limited combination of Venetoclax plus anti-CD20 antibodies (Venetoclax-Rituximab, Venetoclax-Obinutuzumab, and Venetoclax-Obinutuzumab-Ibrutinib), as compared with chemoimmunotherapy, in the first-line treatment of young patients with CLL who are fit (low burden of coexisting conditions with no TP53 aberrations).

In this study, a total of 926 patients (N=926) were randomly assigned in a 1:1:1:1 ratio to receive six cycles of chemoimmunotherapy (N=229) or 12 cycles of treatment with either Venetoclax-Rituximab (N=237), Venetoclax-Obinutuzumab (N=229), or Venetoclax-Obinutuzumab-Ibrutinib (N=231). Chemoimmunotherapy consisted of Fludarabine 25 mg/m2 IV and Cyclophosphamide 250 mg/m2 IV, given on day 1-3 of each cycle, and patients older than 65 years of age received Bendamustine 90 mg/m2 IV on day 1 and 2 of each cycle. Rituximab 375 mg/m2 IV was added to chemotherapy on day 1 of cycle 1, and at a dose of 500 mg/m2 IV on day 1 of each of the next five cycles.

The three experimental regimens contained Venetoclax 400 mg orally daily for ten 28-day cycles after a 5-week ramp-up phase from day 22 in cycle 1 until the end of cycle 2. In the Venetoclax-Rituximab group, Rituximab was administered at a dose of 375 mg/m2 IV on day 1 of cycle 1 and at a dose of 500 mg/m2 on day 1 of each of the next five cycles. In the Obinutuzumab-containing regimens, Obinutuzumab was administered at a dose of 100 mg IV on day 1, 900 mg IV on day 2, and then 1000 mg IV on day 8 and 15 of cycle 1. On day 1 of the subsequent five cycles, Obinutuzumab was administered at a dose of 1000 mg IV. In the triple-combination regimen (Venetoclax-Obinutuzumab-Ibrutinib), Ibrutinib 420 mg orally daily was initiated along with the first Obinutuzumab infusion on day 1 of cycle 1 and was continued throughout the 12 treatment cycles, to which Venetoclax was added as described for the Venetoclax-Obinutuzumab regimen above. Ibrutinib was discontinued after two consecutive measurements of undetectable MRD or could be extended. The median patient age was 61 years and all the treatment groups were well balanced with respect to patient characteristics. The Primary end points were undetectable MRD ( less than 10−4, which meant less than 1 CLL cell in 10,000 leukocytes]) as assessed by flow cytometry in peripheral blood at month 15, and Progression Free Survival.

At 15 months, the percentage of patients with undetectable MRD, the Primary endpoint, was significantly higher in the Venetoclax-Obinutuzumab group (86.5%) and the Venetoclax-Obinutuzumab–Ibrutinib group (92.2%), compared to the chemoimmunotherapy group (52.0%), P<0.001 for both comparisons. However, the Primary endpoint of undetectable MRD was not significantly higher in the Venetoclax-Rituximab group compared to the chemoimmunotherapy group (57% versus 52%; P=0.32).

At a median follow up of 38.8 months, the interim analysis of 3-year Progression Free Survival (the second Primary end point) was superior in the Venetoclax-Obinutuzumab-Ibrutinib group (90.5%; HR=0.32; P<0.001) and the Venetoclax-Obinutuzumab group (87.7%; HR=0.42; P<0.001), compared to the chemoimmunotherapy group (75.5%). This PFS benefit was not seen in the in the Venetoclax-Rituximab group when compared to chemoimmunotherapy (80.8%; HR=0.79, P=0.18). Grade 3 and 4 infections were more common with chemoimmunotherapy (18.5%) and Venetoclax-Obinutuzumab–Ibrutinib (21.2%) than with Venetoclax-Obinutuzumab (13.2%) and Venetoclax-Rituximab (10.5%).

It was concluded that Venetoclax-Obinutuzumab combination with or without Ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL, with higher rates of undetectable MRD and Progression Free Survival.

First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. Eichhorst B, Niemann CU, Kater AP, et al., for the GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. N Engl J Med 2023; 388:1739-1754

Interrupting Endocrine Therapy to Attempt Pregnancy after 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. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 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, adjuvant chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment.

The median age at the time of breast cancer diagnosis in the US is 62 years. However approximately 5% of new diagnoses each year occur in those who are under 40 years. These young patients with Hormone Receptor (HR)-positive breast cancer receive modern adjuvant endocrine therapy and have excellent long-term outcomes. Nonetheless, 40-60% of patients who are diagnosed with breast cancer at age 40 or younger are concerned about their future fertility and pregnancy, as many have not completed their family planning at diagnosis due to delay in childbearing. Pregnancy is contraindicated during endocrine therapy and a delay in pregnancy for 5-10 years can further reduce the chance of a subsequent live birth due to age related declines in fertility.

The POSITIVE (Pregnancy Outcome and Safety of Interrupting Therapy for Women with Endocrine Responsive Breast Cancer) trial is a multicenter, global, single-arm prospective study, designed to evaluate whether temporary interruption of adjuvant endocrine therapy to attempt pregnancy is associated with a higher risk of breast cancer recurrence. This study included 516 women with Stage I-III Hormone Receptor (HR)-positive early breast cancer, 42 years or less, who had received 18-30 months of adjuvant endocrine therapy and wished to interrupt endocrine therapy for pregnancy. The study permitted treatment interruption for up to 2 years (after a 3 month endocrine therapy washout period) to allow pregnancy, delivery and breastfeeding, followed by endocrine therapy resumption to complete the planned duration of 5-10 of adjuvant endocrine therapy. The median time from breast cancer diagnosis to enrollment was 29 months. The median age was 37 years, 75% were nulliparous, fertility preservation was used by 51% of women, 93% had Stage I/II disease, 66% were node negative and 62% had received neo/adjuvant chemotherapy. Tamoxifen alone was the most prescribed endocrine therapy (42%), followed by Tamoxifen plus Ovarian Function Suppression (OFS) (35%).

The Primary endpoint of the study was Breast Cancer-Free Interval (BCFI), defined as the time from study enrollment to the first invasive breast cancer event (local/regional/distant recurrence or contralateral breast cancer). Three interim safety analyses were conducted by a Data Safety Monitoring Committee, and determined that the trial would be suspended if there were more than 46 breast cancer recurrences within approximately 3 years of average follow-up. This threshold however was not reached.

At a median follow up of 41 months, of the 497 patients evaluated for pregnancy status, 74% (N=368) had at least one pregnancy, with 70% of the pregnancies occurring within 2 years. Additionally, 63.8% (N=317) had at least one live birth, with a total of 365 babies born. Birth defects were low at 2% and the rates of conception and childbirth were similar to rates in the general public. The 3-year breast cancer recurrence rate among patients who halted therapy was 8.9%, similar to the 9.2% rate in an external control cohort from the SOFT/TEXT trials, which examined adjuvant endocrine therapy in premenopausal patients. Long term follow up is ongoing to assess recurrence risk over time, and trial participants were strongly recommended to resume endocrine therapy following their pregnancy attempts or success.

The authors concluded that among select women with previous Hormone Receptor–positive early breast cancer, temporary interruption of endocrine therapy to attempt pregnancy did not confer a greater short-term risk of breast cancer events, including distant recurrence, than that in the external control cohort. These data provide guidance to younger patients diagnosed with early breast cancer on endocrine therapy, who may be hoping to have children, and such decisions should be made in close consultation with health professionals.

Interrupting Endocrine Therapy to Attempt Pregnancy after Breast Cancer. Partridge AH, Niman SM, Ruggeri M, et al., for the International Breast Cancer Study Group, and the POSITIVE Trial Collaborators. N Engl J Med 2023; 388:1645-1656.

LONSURF® Plus Bevacizumab Improves Overall Survival in Advanced Refractory Colorectal Cancer

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 153,020 new cases of CRC will be diagnosed in the United States in 2023 and about 52,550 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. First line treatment of metastatic CRC include Oxaliplatin or Irinotecan, in combination with a Fluoropyrimidine and Leucovorin (FOLFOX or FOLFIRI), along with a VEGF targeting agent such as Bevacizumab or EGFR targeting agents such as Cetuximab and Panitumumab. Patients with Stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy. Patients who progress following these therapies are considered to have refractory disease. These patients sometimes are rechallenged with previously administered chemotherapeutic agents, but often receive STIVARGA® (Regorafenib), an oral multikinase inhibitor with antiangiogenic activity, or LONSURF® (a fixed dose combination of Trifluridine and Tipiracil).

LONSURF® is a combination of two agents – a novel thymidine-based nucleoside analogue, Trifluridine and a thymidine phosphorylase inhibitor, Tipiracil. Trifluridine incorporates into DNA resulting in DNA damage and cell death. Trifluridine however is rapidly metabolized when taken orally and this is prevented by Tipiracil, which increases the bioavailability of Trifluridine. LONSURF® was approved by the FDA in 2015 for the treatment of patients with metastatic CRC, who have been previously treated with Fluoropyrimidine, Oxaliplatin and Irinotecan-based chemotherapy, an anti-VEGF biological therapy and if RAS wild-type, an anti-EGFR therapy. This approval was based on the RECOURSE study, which is a pivotal, global, phase III trial in which LONSURF® significantly improved Overall Survival as well as Progression Free Survival, when compared to placebo in this patient population.

Bevacizumab is a humanized monoclonal antibody that targets VEGF, a cytokine secreted by tumor cells and tumor-associated macrophages. VEGF is responsible for neoangiogenesis, proliferation, and metastasis, through its effects on endothelial cells. Bevacizumab was approved for the treatment of CRC in 2004. Maintenance of VEGF inhibition with Bevacizumab beyond disease progression has shown clinical activity in patients with metastatic CRC. A combination of LONSURF® in combination with Bevacizumab improved Overall Survival in several single-group and randomized Phase II trials.

SUNLIGHT trial is a multinational, multicenter, randomized Phase III study, designed to assess the efficacy and safety of LONSURF® in combination with Bevacizumab, as compared with LONSURF® alone, in patients with refractory metastatic CRC. In this study, a total of 492 patients with refractory metastatic CRC were randomly assigned in a 1:1 ratio to receive LONSURF® along with Bevacizumab (N=246) or LONSURF® alone (N=246). Patients received LONSURF® 35 mg/m2 orally, twice daily, on days 1-5 and on days 8-12 every 28 days. Bevacizumab was administered at a dose of 5 mg/kg IV on days 1 and 15. The 28-day treatment cycle was continued until disease progression or unacceptable toxicities. Bevacizumab monotherapy was not allowed. The two treatment groups were well balanced. Most patients (92%) had received two previous treatment regimens for metastatic disease, all patients had received previous Fluoropyrimidine-based therapy, 72% had received previous anti-VEGF therapy, 94% of the patients with RAS wild-type disease had received previous anti-EGFR therapy, and 30% had RAS wild-type disease. The Primary end point was Overall Survival. Secondary end points included Progression Free Survival, Objective Response and Disease Control Rate, Quality of Life and Safety. The median follow up was 14.2 months in the LONSURF® combination group and 13.6 months in the LONSURF® alone group.

The median Overall Survival was 10.8 months in the combination group and 7.5 months in the LONSURF® alone group (HR=0.61; P<0.001), suggesting a 39% reduction in the risk of death with the combination regimen. The median Progression Free Survival was 5.6 months in the combination group and 2.4 months in the LONSURF® alone group (HR=0.44; P<0.001). These benefits of LONSURF® plus Bevacizumab with respect to Overall Survival and Progression Free Survival were observed in all subgroups examined, including patients with poor prognostic factors. Survival benefits with the combination regimen were observed regardless of age, sex, location of primary disease, number of metastatic sites, RAS mutation status and previous treatment with Bevacizumab. The Objective Response Rate was 6.1% in the combination group versus 1.2% in the LONSURF® alone group. The median time to worsening of the ECOG PS from 0 or 1 to 2 or more was 9.3 months in the combination group and 6.3 months in the LONSURF® alone group (HR=0.54). The addition of Bevacizumab to LONSURF® did not increase the risk of serious adverse events or treatment discontinuation. The most common adverse events in both groups were neutropenia, nausea, and anemia.

It was concluded from this study that among patients with refractory metastatic colorectal cancer, treatment with LONSURF® plus Bevacizumab resulted in longer Overall Survival and Progression Free Survival, compared to LONSURF® alone, and this benefit was noted in all subgroups of patients.

Trifluridine–Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. Prager GW, Taieb J, Fakih M, et al., for the SUNLIGHT Investigators. N Engl J Med 2023; 388:1657-1667

HER2DX Genomic Assay Predicts Pathological Response in Early Stage HER2-Positive 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. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence.

The HER or ERBB family of receptors, consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with HER2-positive 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.

HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2. It binds to the extracellular subdomain IV of the receptor and disrupts ligand independent HER2 downstream cell signaling pathways. PERJETA® (Pertuzumab) is a recombinant, humanized, monoclonal antibody that binds to the HER2 subdomain II and blocks ligand dependent HER2 heterodimerization with other HER receptors, ie., HER3, HER1 and HER4. Thus Trastuzumab along with Pertuzumab provide a more comprehensive blockade of HER2 driven signaling pathways, which has been attributed to differing mechanisms of action and synergistic interaction.

In the NeoSphere Phase II trial, among patients with locally advanced, inflammatory, or early HER2-positive breast cancer, the addition of Pertuzumab to Trastuzumab and Docetaxel led to a statistically significant and clinically meaningful 16.8% increase in pathologic Complete Response rate (pCR) in the breast and a 17.8% increase in total pCR in the breast and axilla. Further, the addition of one year of Pertuzumab to Trastuzumab-based chemotherapy improved invasive Disease Free Survival, but this benefit was restricted to patients with node-positive disease and no Overall Survival benefit was observed. The benefits of Pertuzumab in early-stage HER2-positive disease were modest. Biomarkers beyond HER2 status are therefore needed, to guide the use of Pertuzumab in the treatment of early-stage HER2-positive breast cancer.

HER2DX (Reveal Genomics) is a novel clinically available genomic test that measures the expression of 27 genes from Formalin-Fixed, Paraffin-Embedded (FFPE) breast cancer tissues. This assay integrates biologic information such as Immune infiltration, luminal differentiation, tumor cell proliferation and HER2 amplicon expression from 4 gene signatures, with clinical data such as tumor stage and nodal stage.

The present study was conducted to determine if the use of HER2DX genomic assay in pretreatment baseline tissue samples of patients with early-stage ERBB2-positive breast cancer, predicted response to neoadjuvant Trastuzumab-based chemotherapy with or without Pertuzumab. This analysis is a retrospective, multicenter, observational study conducted in Spain from 2018 to 2022. In addition, a combined analysis with 2 previously reported trials of neoadjuvant cohorts, with results from the assay (DAPHNe and I-SPY2) was performed. All patients had Stage I-III ERBB2 (HER2) positive breast cancer, and clinical T1- T2 and node-positive disease was present in 72.9% and 63.9% patients, respectively, and 67.7% tumors were hormone receptor positive. The mean age was 50 years and all patients had Formalin-Fixed Paraffin-Embedded tumor specimens available prior to starting therapy. Patients received Trastuzumab, 8 mg/kg IV as a loading dose, followed by 6 mg/kg IV every 3 weeks in combination with Docetaxel, 75 mg/m2 IV every 3 weeks and Carboplatin AUC of 6 IV every 3 weeks for 6 cycles, or this regimen plus Pertuzumab, 840 mg IV as a loading dose, followed by an 420 mg IV every 3 weeks for 6 cycles. HER2DX genomic assay was evaluated in 155 patients with ERBB2-positive breast cancer. The main outcome measures were the association of baseline assay-reported pathologic Complete Response (pCR) score with pCR in the breast and axilla, as well as association of baseline assay-reported pCR score with response to Pertuzumab.

The overall pCR rate was 57.4%. The assay-reported pathologic Complete Response (pCR) score showed statistically significant association with pCR in the breast and axilla following Trastuzumab-based chemotherapy independent of Pertuzumab use. The pCR rates in the breast and axilla in the assay-reported pCR-high and pCR-low groups were 75.0% and 28.3%, respectively (Odds Ratio=7.85; P<0.001). In the combined analysis of DAPHNe and I-SPY2 trials (N=282), assay-reported pCR-high tumors had an increase in pCR rate in the breast and axilla with the use of Pertuzumab (Odds Ratio=5.36; P<0.001), and this benefit was not seen in the assay-reported pCR-low tumors (Odds Ratio=0.86; P=0.77). A statistically significant interaction was observed between the assay-reported pCR score and the effect of Pertuzumab on pCR in the breast and axilla.

It was concluded that HER2DX genomic assay provides clinically meaningful information to guide therapeutic decisions, and can predict pCR following neoadjuvant Trastuzumab-based chemotherapy with or without Pertuzumab, independent of known clinical-pathological variables and intrinsic subtype. This assay could guide therapeutic decisions regarding the use of neoadjuvant Pertuzumab and can reliably identify patients who might be ideal candidates for neoadjuvant taxane, Trastuzumab and Pertuzumab.

Assessment of a Genomic Assay in Patients With ERBB2-Positive Breast Cancer Following Neoadjuvant Trastuzumab-Based Chemotherapy With or Without Pertuzumab. Bueno-Muiño C, Echavarría I, López-Tarruella S, et al. JAMA Oncol. Published online April 27, 2023. doi:10.1001/jamaoncol.2023.0187

Treatment of Oligometastatic Non-Small Cell Lung Cancer: An ASTRO/ESTRO Clinical Practice Guideline

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SUMMARY: The American Society for Radiation Oncology (ASTRO) and European Society for Radiotherapy and Oncology (ESTRO) convened a task force to review evidence and provide recommendations on the use of local therapy in the management of extracranial oligometastatic Non Small Cell Lung Cancer (NSCLC). Local therapy is defined as definitive comprehensive treatment of all known cancer (primary tumor, regional nodal metastases, and metastases). This joint guideline by ASTRO and ESTRO addressed 5 important questions focused on the use of local (radiation, surgery, other ablative methods) and systemic therapy in the management of oligometastatic NSCLC. The questions addressed clinical scenarios for using local therapy, sequencing and timing when integrating local with systemic therapies, radiation techniques critical for oligometastatic disease targeting and treatment delivery, and the role of local therapy for oligoprogression or recurrent disease.

Oligorecurrence refers to the general growth of limited numbers of metastatic deposits in patients off systemic therapy. For patients with oligometastates receiving active systemic treatment, they are considered as having oligoprogressive disease if current imaging establishes progression of disease in a limited number of existing and/or new sites, and oligopersistent disease if current imaging establishes stable disease or partial response to therapy, of the existing limited disease. The following recommendations were based on a systematic literature review, and created using ASTRO guidelines methodology. These recommendations focus on the management of extracranial disease with local therapy. This guideline and its recommendations with respect to the multimodally treatment strategy do not differentiate between patients with and without brain metastases.

Key Questions and Recommendations
What are the optimal patient/disease characteristics to select patients with oligometastatic NSCLC for definitive treatment combining systemic and local therapies?
1. Treatment decisions should be made using a patient-centered multidisciplinary team approach.
2. The integration of definitive local therapy is only recommended if technically feasible and clinically safe for all disease sites.
3. A discussion of definitive local therapy as a component of multimodality treatment approach is recommended irrespective of presence of activating driver mutations.
4. Definitive local therapy is recommended only for patients having up to 5 distant metastases, diagnosed with appropriate imaging. Implementation remark: Despite some prospective trials including patients with up to 5 extracranial metastases, most patients enrolled had 1-2 treated oligometastatic lesions, which should be factored into decision-making.
5. For patients with synchronous oligometastatic NSCLC, definitive local therapy to all cancer sites in addition to standard of care systemic therapy is conditionally recommended.
6. For patients with metachronous oligorecurrent NSCLC, definitive local therapy to all oligorecurrent cancer sites in addition to standard of care systemic therapy is conditionally recommended.
7. For patients with induced oligopersistent NSCLC, definitive local therapy to all persistent cancer sites in addition to standard of care systemic therapy is conditionally recommended.
8. For patients with induced oligoprogressive NSCLC receiving systemic therapy, definitive local therapy to all progressive cancer sites is conditionally recommended while continuing the current line of systemic therapy.

What are the selection criteria for choice of local treatment modality in the management of patients with oligometastatic NSCLC?
1. A patient-centered multidisciplinary discussion of the most appropriate local treatment strategy of RT and/or surgery, either alone or in combination, is recommended.
2. RT and/or surgery are recommended as definitive local treatment modalities for the locoregional primary and all oligometastases.
3. Highly conformal RT approaches and minimally invasive techniques for surgery are recommended to minimize morbidity.
4. Deciding between RT and surgery as the definitive local treatment modality should a) Favor RT when multiple organ systems are being treated b) Favor RT when the clinical prioritization is to minimize breaks from systemic therapy c) Favor surgery when large tissue sampling is needed for molecular testing, to guide systemic therapy.

What are the appropriate sequencing and timing of systemic therapy and definitive local therapies for patients with oligometastatic NSCLC?
1. For patients with synchronous oligometastatic NSCLC, 3 months or more of systemic therapy is recommended prior to definitive local therapy.
2. For patients with oligometastatic NSCLC, up-front definitive local treatment for symptomatic lesions should be prioritized. Implementation remark: Symptomatic disease sites (eg, brain metastases) are treated with up-front definitive local therapy.
3. For patients with synchronous oligometastatic NSCLC, the temporary pause of systemic therapy during definitive local therapy versus concomitant treatment should be discussed using a multidisciplinary team approach.
4. For patients with synchronous oligometastatic NSCLC, maintenance systemic therapy is conditionally recommended after completion of definitive local therapy.

What are the optimal dose-fractionation regimens, planning, and delivery technique of RT for patients with oligometastatic NSCLC?
1. Appropriate staging with FDG PET, cranial MRI, and MRI in cases of suspect or proven spine or liver metastases are recommended.
2. Individual assessment of respiratory motion for targets in the lungs and upper abdomen using 4-D CT, fluoroscopy, or MR-cine with appropriate motion compensation is recommended.
3. Highly conformal RT using inverse dose planning, appropriate motion management strategies and image-guided RT delivery are recommended.
4. A risk adapted approach using stereotactic RT (preferred), hypofractionated RT, or alternatively definitive chemoradiation based on the location and burden of disease is recommended.
5. Definitive local RT should use doses and fractionations which achieve durable local control.
Implementation remarks: a) Durable local control defined as minimum 85% local control at 2 years b) Higher BED10 (typically >75 Gy) with SBRT alone is associated with optimal local control c) Lower BED10 (50-75 Gy range) is associated with acceptable local control, typically in the setting of combination systemic therapy and SBRT.

After a definitive local therapy approach for oligometastatic NSCLC, what are the indications for additional local therapy upon disease progression?
1. Systemic therapy is recommended as the preferred treatment option.
2. Additional local therapy should be discussed using a multidisciplinary team approach.
3. Local therapy is conditionally recommended.
4. In patients previously treated with definitive local therapy for oligometastatic NSCLC who subsequently develop repeat oligoprogression or recurrence at sites previously treated with local therapy, re-treatment is conditionally recommended if systemic treatment options are limited, and local therapy can be delivered with toxicity acceptable to the multidisciplinary team and patient.

Treatment of Oligometastatic Non-Small Cell Lung Cancer: An ASTRO/ESTRO Clinical Practice Guideline. Iyengar P, All S, Berry MF, et al. Published:April 25, 2023. https://doi.org/10.1016/j.prro.2023.04.004

ORSERDU® for ESR-1 Mutated Advanced 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. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 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-negative metastatic breast cancer, as first line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression, including the development of ESR1 (Estrogen Receptor gene alpha) mutations.

ESR1 (Estrogen Receptor 1) gene mutation 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-positive 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 previously 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%). It is estimated that 40% of ER-positive, HER2-negative advanced or metastatic breast cancer patients have tumors that harbor ESR1 mutations. It is best to test for ESR1 mutations with a liquid biopsy following progression on an AI and CDK 4/6 inhibitor.

Fulvestrant (FASLODEX®) 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.

ORSERDU® (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 ORSERDU® in the HR-positive 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, ORSERDU® was noted to have an acceptable safety profile and demonstrated single-agent activity with confirmed Partial Responses in heavily pretreated patients with HR-positive metastatic breast cancer.

EMERALD trial is a multicenter, International, randomized, open-label, Phase III study, designed to evaluate the benefit of ORSERDU® in patients with ER+/HER2- advanced or metastatic breast cancer. In this study, 478 postmenopausal women with ER+/HER2- metastatic breast cancer were randomly assigned 1:1 to receive either ORSERDU® 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=239). 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. ESR1 mutational status was determined by blood circulating tumor deoxyribonucleic acid (ctDNA) using the Guardant360 CDx assay and was limited to ESR1 missense mutations in the ligand binding domain. In the study, 48% (N=228) had tumors with mutated ESR1 and 43% received two prior endocrine therapies. 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.

This study met both co-Primary endpoints and treatment with ORSERDU® resulted in a statistically significant and clinically meaningful improvement in PFS, compared with Standard of Care treatment. In the group of patients whose tumors had ESR1 mutations, the median PFS was 3.8 months in the ORSERDU® group and 1.9 months in the Standard of Care group (HR=0.55; P=0.0005), reducing the risk of progression or death by 45%. A post-hoc analysis of the PFS results based on the duration of prior CDK4/6 inhibitors usage was presented at San Antonio Breast Cancer Symposium (SABCS) in December 2022. The median PFS was 8.6 months in the ORSERDU® group versus 1.9 months in the Standard of Care group, in those patients whose tumors harbored ESR1 mutations and had been treated with a CDK4/6 inhibitors for at least 12 months.

It can be concluded from this study that ORSERDU® is the first oral Selective Estrogen Receptor Degrader for ER-positive, HER2-negative advanced breast cancer patients with ESR1 mutations, and offers a novel therapeutic option for this patient group.

Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. Bidard F-C, Kaklamani VG, Neven P, et al. J Clin Oncol, 1;40(28):3246-3256. DOI:10.1200/JCO.22.00338.