Category: Hem/Onc Updates

Germline Testing to Identify 11 Genes Linked to Aggressive Prostate Cancer

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 288,300 new cases of Prostate cancer will be diagnosed in 2023 and 34,700 men will die of the disease. The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer, and is the first treatment intervention. Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. The malignant transformation of prostatic epithelial cell as well as the development of CRPC has been attributed to deleterious alterations in a variety of genes including loss-of-function alterations in Homologous Recombination Repair (HRR) genes.

DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 are tumor suppressor genes that recognize and repair double strand DNA breaks via Homologous Recombination Repair (HRR) pathway. Homologous Recombination is a type of genetic recombination, and is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway. At least 15 genes are involved in the Homologous Recombination Repair (HRR) pathway including BRCA1, BRCA2, PALB2, CHEK2 and ATM genes. Mutations in these genes predispose an individual to develop malignant tumors. Mutations in BRCA1 and BRCA2 account for about 20-25% of hereditary breast cancers and about 5-10% of all breast cancers. They also account for 15% of ovarian cancers, in addition to other cancers such as Colon and Prostate. BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic). Somatic mutations account for a significant portion of overall BRCA1 and BRCA2 aberrations. Loss of BRCA function due to frequent somatic aberrations likely deregulates HR pathway, and other pathways then come in to play, which are less precise and error prone, resulting in the accumulation of additional mutations and chromosomal instability in the cell, with subsequent malignant transformation. Homologous Recombination Deficiency therefore indicates an important loss of DNA repair function.

The current National Comprehensive Cancer Network (NCCN) guidelines for prostate cancer (version 1.2022) recommend germline testing for the subsets of patients with prostate cancer who are more likely to have germline DNA repair mutations. They include men with node positive, high-risk or very high-risk localized prostate cancer, men with metastatic prostate cancer, and men meeting family history criteria. NCCN recommends considering germline testing for men with personal history of prostate cancer and intermediate risk prostate cancer and intraductal/cribriform histology and personal history of exocrine pancreatic, colorectal, gastric, melanoma, pancreatic, upper tract urothelial, glioblastoma, biliary tract or small intestinal cancers. Germline testing panel sizes vary from dedicated BRCA1/2 testing to extended 91 plus-gene panels

The goal of this study was to investigate the association between rare deleterious variants and Variants of Unknown Significance (VUS) across the genome and in candidate genes, particularly DNA repair genes, and identify genes associated with aggressive prostate cancer.

The researchers conducted a two-stage exome-sequencing genetic association study, to identify rare genetic variants associated with aggressive prostate cancer. This analysis included 17,546 patients of European ancestry with prostate cancer from 18 epidemiological studies across the US, Europe and Australia. The study population included 9185 men with aggressive prostate cancer and 8361 men with nonaggressive prostate cancer. Aggressive prostate cancer was defined as at least one of the following: T4 disease, T3 plus a Gleason score of 8 or more, metastatic disease, or death from prostate cancer, while nonaggressive prostate cancer was defined as localized T1/T2 disease and a Gleason score of 6 or less. The researchers focused their study on 29 DNA repair pathway and cancer susceptibility genes previously linked with prostate cancer, in addition to a group of 167 genes thought to be related to DNA damage repair. They then looked for associations between deleterious genetic variants or Variants of Uncertain Significance (VUS) and aggressive versus nonaggressive prostate cancer, using a relatively modest threshold for significance.

The strongest evidence of association with aggressive or metastatic prostate cancer was noted for rare deleterious variants in known prostate cancer risk genes BRCA2 and ATM (P<0.0000019), followed by NBN (P=0.00017). This study found nominal evidence (P <0.05) of association with rare deleterious variants in MSH2, XRCC2, and MRE11A. Five other genes analyzed, TP53, RAD51D, BARD1, GEN1, and SLX4, had evidence of greater risk with an Odds Ratio (OR) of 2 or more, but carrier frequency differences between aggressive and nonaggressive prostate cancer were not statistically significant. Deleterious variants of the 11 candidate genes identified in the study were carried by 2.3% of patients with nonaggressive prostate cancer, 5.6% with aggressive prostate cancer, and 7.0% with metastatic prostate cancer.

In conclusion, the researchers from this analysis of the largest cohort of prostate cancer patients were able to identify DNA repair pathway gene variants, associated with aggressive prostate cancer. Testing should be extended to men without aggressive prostate cancer, as men carrying deleterious variants in these genes are likely to develop advanced disease.

Germline Sequencing Analysis to Inform Clinical Gene Panel Testing for Aggressive Prostate Cancer. Darst BF, Saunders E, Dadaev T, et al. JAMA Oncol. Published online September 21, 2023. doi:10.1001/jamaoncol.2023.3482

FDA Approves Pralsetinib for Non Small Cell Lung Cancer with RET gene fusions

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SUMMARY: The FDA on August 9, 2023, granted regular approval to Pralsetinib (GAVRETO®) for adult patients with metastatic Rearranged during Transfection (RET) fusion-positive Non-Small Cell Lung Cancer (NSCLC) as detected by an FDA approved test. Pralsetinib was previously granted accelerated approval for the NSCLC indication in Sept. 2020, based on initial Overall Response Rate (ORR) and Duration of Response (DOR) in 114 patients enrolled in the ARROW trial. The conversion to regular approval was based on data from an additional 123 patients and 25 months of additional follow up, to assess Durability of Response.

Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer accounts for approximately 85% of all lung cancers.

In addition to the well characterized gene fusions involving ALK and ROS1 in NSCLC, genetic alterations involving other kinases including EGFR, BRAF, RET, MET, KRAS, NTRK, are all additional established targetable drivers. These genetic alterations are generally mutually exclusive, with no more than one predominant driver in any given cancer. The hallmark of all of these genetic alterations is oncogene addiction, in which cancers are driven primarily, or even exclusively, by aberrant oncogene signaling, and are highly susceptible to small molecule inhibitors.

RET kinase is a transmembrane Receptor Tyrosine Kinase and plays an important role during the development and maintenance of a variety of tissues, including neural and genitourinary tissues. RET signaling activates downstream pathways such as JAK/STAT3 and RAS/RAF/MEK/ERK and leads to cellular proliferation, survival, invasion, and metastasis. Oncogenic alterations to the RET proto-oncogene results in uncontrolled cell growth and enhanced tumor invasiveness. RET alterations include RET rearrangements, leading to RET fusions, and activating point mutations occurring across multiple tumor types. RET fusions have been identified in approximately 2% of NSCLCs, 10-20% of non-medullary thyroid cancers. Activating RET point mutations account for approximately 60% of sporadic Medullary Thyroid Cancers (MTC) and more than 90% of inherited MTCs. Other cancers with documented RET alterations include colorectal, breast, and several hematologic malignancies.

Patients without a driver mutation are often treated with a platinum-doublet cytotoxic chemotherapy with/without Immune checkpoint inhibitors, or with Immune checkpoint inhibitor monotherapy. However, outcomes with immune checkpoint inhibitors remain poor in patients with RET fusion–positive NSCLC, regardless of PD-L1 expression.

Pralsetinib (GAVRETO®) is an oral, highly potent, selective RET kinase inhibitor targeting oncogenic RET alterations, including fusions and mutations, regardless of the tissue of origin. The efficacy of Pralsetinib was investigated in a multicenter, open-label, multi-cohort, Phase I/II basket clinical trial (ARROW), in patients with tumors showing RET alterations. Identification of RET gene alterations was prospectively determined in local laboratories using either, Next Generation Sequencing (NGS), Fluorescence In Situ Hybridization (FISH), or other tests. (In a basket trial, tumors with different histologies and single biomarker are placed in different baskets and receive a single treatment). Phase I Pralsetinib dose escalation study determined 400 mg QD as the recommended Phase II trial dose. Phase II trial evaluated Pralsetinib in multiple expansion groups, defined by disease type and treatment history.

The FDA regular approval was based on the efficacy of Pralsetinib in a total of 237 patients (N=237) with locally advanced or metastatic RET fusion-positive NSCLC. Patients received Pralsetinib 400 mg once daily until disease progression or unacceptable toxicity. Among the patients studied, 107 (N=107) were treatment-naïve and 130 patients (N=130) were previously treated with platinum-based chemotherapy. The main efficacy outcome measures were Overall Response Rate (ORR) and Duration of Response, as determined by a Blinded Independent Review Committee, using RECIST criteria.

The median age of the 107 patients in the treatment-naïve group was 63 years and 28% of patients had a history of or active CNS/brain metastases. The ORR in this group was 78%, with a Complete Response (CR) rate of 7%. The median Duration of Response was 13.4 months and 45% of patients experienced a Duration of Response of 12 months or longer.

The median age of the 130 patients in the group that was previously treated with platinum-based chemotherapy, was 59 years and 41% had a history of or active CNS/brain metastases. The ORR in this group was 63% with a CR rate of 6%. The median Duration of Response of 38.8 months and 66% of patients experienced a Duration of Response of at least 12 months.

In patients with measurable intracranial metastases, the intracranial response rate was 70%.

The most common adverse reactions were fever, fatigue, cough, constipation, diarrhea, musculoskeletal pain, hypertension and edema.

It was concluded from this study that treatment with Pralsetinib produced robust efficacy including intracranial activity, in patients with advanced RET fusion–positive NSCLC who are treatment-naive or are refractory to standard-of-care chemotherapy. Results from the confirmatory Phase III AcceleRET Lung study of Pralsetinib versus standard of care in the first-line setting are eagerly awaited and may further support the use of Pralsetinib for RET fusion-positive NSCLC in the first-line setting.

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pralsetinib-non-small-cell-lung-cancer-ret-gene-fusions

FDA Approves Momelotinib for Patients with Myelofibrosis and Anemia

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SUMMARY: The FDA on September 15, 2023 approved Momelotinib (OJJAARA®) for the treatment of adult patients with intermediate or high-risk myelofibrosis, including Primary myelofibrosis or Secondary myelofibrosis, and anemia. Myelofibrosis is a MyeloProliferative Neoplasm (MPN) characterized by ineffective hematopoiesis, progressive fibrosis of the bone marrow and potential for leukemic transformation. It affects approximately 25,000 patients in the United States. This stem cell disorder is Philadelphia Chromosome negative and manifestations include anemia, splenomegaly and related symptoms such as abdominal distension and discomfort with early satiety. Cytokine driven debilitating symptoms such as fatigue, fever, night sweats, weight loss, pruritus and bone or muscle pain can further impact an individual’s quality of life. Myelofibrosis can be Primary (PMF) or Secondary to Polycythemia Vera (PV) or Essential Thrombocythemia (ET).

The JAK-STAT signaling pathway has been implicated in the pathogenesis of myelofibrosis. This pathway normally is responsible for passing information from outside the cell through the cell membrane to the DNA in the nucleus, for gene transcription. Janus Kinase (JAK) family of tyrosine kinases are cytoplasmic proteins and include JAK1, JAK2, JAK3 and TYK2. JAK1 helps propagate the signaling of inflammatory cytokines whereas JAK2 is essential for growth and differentiation of hematopoietic stem cells. These tyrosine kinases mediate cell signaling by recruiting STATs (Signal Transducer and Activator of Transcription), with resulting modulation of gene expression.

In patients with MPN, the aberrant myeloproliferation is the result of dysregulated JAK2-STAT signaling as well as excess production of inflammatory cytokines associated with this abnormal signaling. These cytokines contribute to the systemic symptoms often reported by patients with myelofibrosis, in addition to bone marrow fibrosis, and clonal proliferation resulting in extramedullary hematopoiesis and splenomegaly. JAK2 mutations such as JAK2 V617F are seen in approximately 60% of the patients with PMF and ET and 95% of patients with PV. Unlike CML where the BCR-ABL fusion gene triggers the disease, JAK2 mutations are not initiators of the disease and are not specific for MPN. Further, several other genetic events may contribute to the abnormal JAK2-STAT signaling.
Chronic inflammation also drives hyperactivation of ACVR1 (Activin A receptor type 1), elevated hepcidin, dysregulated iron metabolism, and anemia of myelofibrosis. Approximately 40% of patients have moderate to severe anemia at the time of diagnosis of myelofibrosis, and almost all patients develop anemia over the course of the disease.

Momelotinib is a first-in-class inhibitor of three signaling pathways, Activin A receptor type 1 (ACVR1) as well as JAK1 and JAK2. Inhibition of ACVR1 leads to a decrease in circulating hepcidin, which is elevated in myelofibrosis and contributes to anemia, whereas inhibition of JAK1 and JAK2 may improve constitutional symptoms and splenomegaly.

The FDA approval was based on the findings from the pivotal Phase III MOMENTUM trial, and data from a subpopulation of adult patients with anemia enrolled in the SIMPLIFY-1 Phase III trial.

MOMENTUM is an ongoing Phase III, global, multicentre, randomized, double-blind study, conducted to evaluate the safety and efficacy of Momelotinib compared to Danazol, in patients with myelofibrosis who were symptomatic and anemic, and had been previously treated with an approved JAK inhibitor. This study was designed to evaluate the benefit of Momelotinib in reducing the key manifestations of myelofibrosis including constitutional symptoms, blood transfusion requirements due to anemia and splenomegaly. In this study, 195 eligible patients, with a confirmed diagnosis of Primary myelofibrosis, post-Polycythemia Vera (PV) myelofibrosis, or post–Essential Thrombocytopenia (ET) myelofibrosis were randomized 2:1 to receive Momelotinib 200 mg orally daily along with a placebo (N=130) or Danazol 600 mg orally daily along with a placebo (N=65). Enrolled patients were symptomatic with a Total Symptom Score (TSS) of at least 10, hemoglobin less than 10 gm/dL and platelet count 25,000/L or more. The median age was 70 years, approximately 50% of patients were Transfusion Dependent requiring 4 or more units of RBC transfusions in the 8 weeks before randomization and approximately 35% were Transfusion Requiring, who required RBC transfusions but did not meet the criteria for Transfusion Dependence. The Primary end point was achievement of a Myelofibrosis Symptom Assessment Form (MFSAF v4.0) TSS reduction of 50% or more at week 24 compared to baseline. Patients in the Danazol group were allowed to cross over to Momelotinib after week 24. It was noted that at week 24, 25% of patients in the Momelotinib group experienced a TSS reduction of 50% or more, compared with 9% in the Danazol group (P=0.0095). At week 24, 31% of patients who received Momelotinib achieved Transfusion Independence, compared with 20% in the Danazol group. Further, 39% of patients in the Momelotinib group experienced a splenic volume response of at least 25% by week 24, compared to 6% in the Danazol group (P<0.0001).

SIMPLIFY-1 was a multicentre, randomized, double-blind, Phase III study in which the efficacy and safety of Momelotinib was compared Ruxolitinib in patients with myelofibrosis who had not received prior treatment with a JAK inhibitor. In this study 432 eligible patients (N=432) received Momelotinib 200 mg orally once daily or Ruxolitinib (JAKAFI®) at an adjusted dose twice daily for 24 weeks. Subsequently, those in the Ruxolitinib arm were able to switch to open-label Momelotinib. Safety and efficacy results for SIMPLIFY-1 were based upon a subset of patients with anemia (hemoglobin less than 10 g/dL) at baseline. The efficacy of Momelotinib in the treatment of patients with myelofibrosis in SIMPLIFY-1 was based on spleen volume response (reduction by 35% or greater). In this study, Transfusion Independence was significantly improved at week 24 with Momelotinib compared to Ruxolitinib. Results in this study were mixed and Momelotinib offered less symptom control than Ruxolitinib, but there was comparable spleen volume reduction and a potential benefit in terms of anemia.

These findings support the potential use of Momelotinib as an effective treatment in patients with myelofibrosis, particularly in patients with anemia and thrombocytopenia, thus fulfilling an unmet need for these patients.

Ojjaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia. News release. GSK. September 15, 2023. Accessed September 15, 2023. https://www.gsk.com/en-gb/media/press-releases/ojjaara-momelotinib-approved-in-the-us-as-the-first-and-only-treatment-indicated-for-myelofibrosis-patients-with-anaemia/

FDA Approves AKEEGA® for Metastatic Castration Resistant Prostate Cancer with BRCA1/2 Mutations

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SUMMARY: The FDA on August 11, 2023, approved the fixed dose combination of Niraparib and Abiraterone acetate (AKEEGA®) with prednisone, for adult patients with deleterious or suspected deleterious BRCA-mutated Castration Resistant Prostate Cancer (mCRPC), as determined by an FDA-approved test. Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 288,300 new cases of Prostate cancer will be diagnosed in 2023 and 34,700 men will die of the disease.

The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide) or with second-generation Androgen-Receptor Pathway Inhibitors (ARPI), which include ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide) and ERLEADA® (Apalutamide). Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. The estimated mean survival of patients with CRPC is 9-36 months, and there is therefore an unmet need for new effective therapies.

DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 genes recognize and repair double strand DNA breaks via Homologous Recombination Repair (HRR) pathway. Homologous Recombination is a type of genetic recombination and is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HRR pathway. At least 15 genes are involved in the HRR pathway including BRCA1, BRCA2 and ATM genes. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. BRCA1 and BRCA2 are tumor suppressor genes and functional BRCA proteins repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. Recently published data has shown that deleterious Germline and/or Somatic mutations in BRCA1, BRCA2, ATM, or other Homologous Recombination DNA-repair genes, are present in about 30% of patients with advanced prostate cancer, including metastatic CRPC. Patients with metastatic CRPC harboring BRCA alterations and other HRR gene alterations have poor outcomes and earlier resistance to commonly used systemic therapies.

The PARP (Poly ADP Ribose Polymerase), family of enzymes include, PARP1and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. PARP inhibitors trap PARP onto DNA at sites of single-strand breaks, preventing their repair and generating double-strand breaks that cannot be repaired accurately in tumors harboring defects in HRR genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death. PARP inhibitors have demonstrated significant activity in patients with prostate cancer and HRR gene alterations, with the greatest clinical benefit noted in BRCA1/2 mutation carriers. Niraparib (ZEJULA®) is a highly selective PARP-1 and PARP-2 inhibitor approved for several indications, including ovarian, fallopian tube, and primary peritoneal cancers. When given along with Abiraterone and Prednisone, the combination targets two oncogenic drivers in patients with metastatic CRPC (mCRPC), which include alterations in the Androgen Receptor axis and BRCA1/2 in the HRR pathway.

MAGNITUDE is a multicenter, multicohort, placebo-controlled, randomized, double-blind, Phase III study, prospectively designed as a precision medicine study to identify the specific population of patients who would most benefit from Niraparib with Abiraterone Acetate plus Prednisone, and potentially increase the likelihood of treatment success. This study involved 3 cohorts of patients: Cohort 1: Participants with mCRPC and HRR Gene Alteration. Cohort 2: Participants with mCRPC and No HRR Gene Alteration. Cohort 3 (Open-label): Participants with mCRPC

The present FDA approval was based on the safety and efficacy data from Cohort 1 group of patients with metastatic CRPC with HRR gene mutation. In this cohort, 423 patients (N=423) with HRR gene-mutated mCRPC were randomized (1:1) to receive Niraparib 200 mg orally once daily along with Abiraterone acetate 1,000 mg plus Prednisone 10mg daily, or placebo and Abiraterone acetate plus Prednisone daily. Patients with HRR positive biomarker included those with ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2 gene alterations. Approximately 53% had BRCA gene mutations. Patients were required to have a prior orchiectomy or be receiving GnRH analogues. Patients with mCRPC were eligible if they had not received prior systemic therapy in the mCRPC setting except for a short duration of prior Abiraterone acetate plus Prednisone (up to four months) and ongoing ADT. Patients could have received prior chemotherapy with Docetaxel or Androgen-Receptor (AR) targeted therapies in earlier disease settings. Randomization was stratified by prior Docetaxel, prior AR targeted therapy, prior Abiraterone acetate plus Prednisone, and BRCA status. The Primary endpoint of this trial was radiographic Progression Free Survival (rPFS) assessed by blinded Independent Central Review. Secondary endpoints included time to initiation of cytotoxic chemotherapy, time to symptomatic progression and Overall Survival.

The combination of Niraparib and Abiraterone with Prednisone significantly improved rPFS in all HRR-positive patients (HR=0.73; P=0.022). This improvement was most pronounced in patients with BRCA1/2 gene mutations and the median rPFS was 16.6 months versus 10.9 months (HR=0.53; P=0.0014), with a 47% reduction in the risk of disease progression. With additional median follow up at 24.8 months in the BRCA subgroup, rPFS by Independent Central Review demonstrated a consistent and clinically meaningful treatment benefit favoring Niraparib plus Abiraterone, with a median rPFS of 19.5 months, compared with 10.9 months for placebo plus Abiraterone and Prednisone. Additionally, in the BRCA gene mutated patients, an exploratory OS analysis demonstrated a median of 30.4 versus 28.6 months favoring the Niraparib combination (HR=0.79). Further there was a strong improvement in time to symptomatic progression and clinically meaningful improvement in time to initiation of cytotoxic chemotherapy in the Niraparib combination group. The most common Grade 3 Adverse Events were anemia and hypertension, and the Niraparib combination also maintained overall quality of life, compared to placebo plus Abiraterone and Prednisone.

It was concluded from this study that Niraparib in combination with Abiraterone and Prednisone significantly improved radiographic Progression Free Survival and other clinically relevant end points compared to placebo plus Abiraterone and Prednisone, in patients with BRCA1/2 gene altered metastatic Castration Resistant Prostate Cancer. The authors added that MAGNITUDE study enrolled the largest cohort of BRCA1/2-positive patients for the first line treatment of metastatic Castration Resistant Prostate Cancer to date, emphasizing the importance of identifying patients with these molecular alterations.

Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial. Chi KN, Sandhu S, Smith MR, et al. Annals of Oncology 2023;34:772-782.

Duration of Anticoagulation Therapy in Cancer Patients with Isolated Distal Deep Vein Thrombosis

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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. Treatment with parenteral Low Molecular Weight Heparin (LMWH) preparations is often recommended for this patient group, based on efficacy data. LMWH activates antithrombin, which in turn accelerates the inactivation of coagulation enzymes thrombin (Factor IIa), Factor Xa and Factor IXa. Parenteral LMWH however can be inconvenient and expensive, leading to premature discontinuation of treatment.

Direct Oral Anticoagulant agents have been proven to be as effective as COUMADIN® (Warfarin), a Vitamin K antagonist, for the treatment of VTE, and are associated with less frequent and less severe bleeding, and fewer drug interactions. The Direct Oral AntiCoagulants (DOACs) include PRADAXA® (Dabigatran), which is a direct Thrombin inhibitor and XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Edoxaban), BEVYXXA® (Betrixaban), which are Factor Xa inhibitors. Compared to COUMADIN®, the New Oral Anticoagulants have a rapid onset of action, wider therapeutic window, shorter half-lives (7-14 hours in healthy individuals), require no laboratory monitoring and have a fixed dosing schedule.

Patients with cancer are often found to have distal DVTs. In patients with isolated distal DVT, the best treatment strategy remains unclear and evidence is lacking for the optimal duration of anticoagulation therapy. Further, prolonged anticoagulation therapy, beneficial as it may be, could increase the risk of bleeding.

The ONCO DVT study is a multicenter, open-label, adjudicator-blinded, randomized, clinical trial, conducted at 60 institutions in Japan. This study included 601 cancer patients with isolated distal DVT, who were randomly assigned in a 1:1 ratio, to receive either Edoxaban (SAVAYSA®) for 12 months (N=296) or 3 months (N=305). Edoxaban was given at a dose of 60 mg orally once daily but it was dose-reduced to 30 mg in 75% of patients due to either creatinine clearance of 30-50 mL/min or a body weight of 60 kg or less, or due to concomitant treatment with potent P-glycoprotein inhibitors. The researchers hypothesized that 12-month Edoxaban treatment was superior to a 3-month Edoxaban treatment for reducing thrombotic events, in cancer patients with isolated distal DVT. Eligible patients had active cancer and newly diagnosed isolated distal DVT confirmed by ultrasonography. The mean age was 71 years and 72% of the patients were women. The most common type of cancer was gynecologic cancer (27%), followed by lung cancer (11%), colon cancer (10%) and pancreatic cancer (8%). The most common reason for conducting ultrasonography was due to a high-risk status with elevated D-dimer levels (38%), followed by elevated D-dimer levels before surgery (24%) and suspected DVT based on the symptoms (20%). Patients were excluded from this study if they were on anticoagulation therapy at the time of the diagnosis, if they had pulmonary embolism, or if they were expected to have a life prognosis of 3 months or less by the treating physicians. The Primary endpoint was symptomatic recurrent Venous ThromboEmbolism (VTE) or VTE-related death at 12 months. The Secondary endpoint was major bleeding at 12 months, according to the criteria of the International Society on Thrombosis and Hemostasis.

The Primary endpoint of a symptomatic recurrent VTE event or VTE-related death occurred in 1% of patients in the 12-month Edoxaban group and in 7.2% of patients in the 3-month Edoxaban group (odds ratio, 0.13). The Secondary endpoint of major bleeding occurred in 9.5% of patients in the 12-month edoxaban group and in 7.2%of patients in the 3-month edoxaban group (Odds Ratio=1.34), and this was not statistically significant. There were no differences noted in prespecified subgroup analyses, stratified by age, body weight and renal function.

It was concluded that in cancer patients with symptomatic or asymptomatic isolated distal DVT, anticoagulation with Edoxaban for 12 months was superior to 3 months with respect to symptomatic recurrent VTE or VTE-related death, without increasing the risk of bleeding. The authors added that this is the first and only randomized clinical trial to show the superiority of longer duration, over shorter duration anticoagulation therapy, for reducing thrombotic events in cancer patients with isolated distal DVT. Since this study only included Japanese, it is unclear if this data would be applicable to people of other races and ethnicities.

Edoxaban for 12 Months Versus 3 Months in Cancer Patients with Isolated Distal Deep Vein Thrombosis (ONCO DVT study): An Open-label, Multicenter, Randomized Clinical Trial. Yamashita Y, Morimoto T, Muraoka N, et al., on behalf of the ONCO DVT Study Investigators. Originally published 28 Aug 2023. https://doi.org/10.1161/CIRCULATIONAHA.123.066360 Circulation. 2023;0

Targeting ESR1 Mutations in Estrogen-Positive Advanced Breast Cancer

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Written By: Debra Patt, MD, PhD, MBA

In the golden age of oncology, many patients can now live with cancer as a chronic disease. Understanding how to optimally block cancer growth and how cancers develop mechanisms of resistance is critical to improving therapy.

For most patients with advanced breast cancer, estrogen blockade is the mainstay of early cancer treatments. Optimizing estrogen blockade in combination with other targets has dramatically improved progression-free and overall survival in patients with advanced breast cancer. Optimizing endocrine blockade in patients with ER+ advanced breast cancer is not only an effective therapy that improves outcomes, but also delays other systemic therapy, like chemotherapy, which have a toxicity profile that is typically more severe than endocrine therapy alone. By delaying chemotherapy with effective endocrine therapy, patients can enjoy longer disease-free intervals and maintain a high quality of life. While estrogen-positive breast cancer can be targeted by many estrogen-targeted therapies, resistance to aromatase inhibition through the development of ESR1 mutations is an important mechanism of resistance that contributes to cancer progression via the endocrine blockade.1

As we continue to make progress in cancer care, becoming familiar with new therapies is critical. This article will review elacestrant, approved by the Food and Drug Administration (FDA) in January 2023 for patients with estrogen receptor-positive (ER+) advanced breast cancer with ESR1 mutations after at least one line of endocrine therapy.

The superior response among patients with ESR1 mutations led to FDA approval among patients with ESR1 mutations who had received at least one line of endocrine therapy. Because ESR1 mutation status is central to FDA approval and the basis of many coverage determinations from payers, assessing ESR1 mutation status accurately is an important aspect of treatment. ESR1 mutations can develop in patients with ER+ advanced breast cancer and can change over time. In patients with treatment naïve early-stage breast cancer, de novo ESR1 mutations are relatively rare, but as patients are exposed to therapy, ESR1 mutations are acquired, making them a common mechanism of resistance in patients with metastatic disease.2 Because mutations develop over time with the evolutionary pressure of therapy, a patient’s ESR1 mutation status, when they are initially diagnosed with ER+ metastatic disease, can later change after exposure to aromatase inhibition. If analysis for ESR1 mutations is conducted early in a patient’s treatment and is found negative, resistance may emerge and only be demonstrated with subsequent molecular testing. There is evidence that blood-based serial testing may be a useful way to identify patients who are eligible for treatment.3 In January 2023, Guardant Health, through the Guardant 360 CDx, was approved by the FDA as a tool to test the blood for ESR1 mutations to assess for eligibility for elacestrant. By using sequential serologic testing, patients can have an assessment of molecular characteristics without undergoing additional biopsy. Because such a small number of patients have ESR1 mutations when they are treatment naïve, but it becomes much more likely through the course of a patient’s disease, repeat testing is the primary way to assess if ESR1 mutations have evolved over time, and can be conducted via plasma assessment.

Elacestrant works by binding estrogen receptor alpha and acting as a Selective Estrogen Receptor Down regulator (SERD), allowing degradation of the estrogen receptor. The FDA approved elacestrant in 2023 based on the reporting of the phase III EMERALD trial showing that patients with ER-positive and HER2 negative advanced breast cancer who had had one to two lines of endocrine therapy, pretreatment with a cyclin-dependent kinase 4/6 inhibitor, and not more than one line of chemotherapy, achieved a significant progression-free survival advantage when treated with elacestrant in comparison to other therapy.4 The population was further stratified as the whole population vs. just those with ESR1 mutations. In the entire population treated with elacestrant, PFS was prolonged (HR=0.70; 95% CI=0.55-0.88), and the results were more striking in those with ESR1 mutations (HR=0.55; 95% CI=0.39-0.77). In this group of pretreated patients with advanced breast cancer, ESR1 mutations were detected in 47.8% of patients. The progression-free survival of patients in the EMERALD trial was 3.8 months among patients receiving elacestrant in comparison to 1.9 months for other commonly prescribed endocrine therapies.

Elecestrant was well tolerated with treatment-related grade 3/4 adverse events in 7.2% of patients receiving elecestrant in comparison to 3.1% in patients receiving standard-of-care. Nausea was the most common side effect occurring to any extent in 35% of patients receiving elecestrant (though grade 3 was 2.5% and grade 4 was 0.9%) in comparison to 18.8% in patients who were receiving standard-of-care treatment. Other common side effects include abdominal pain, vomiting, diarrhea, constipation, elevation of liver function tests, cytopenias, hyponatremia, and fatigue. To mitigate side effects, it can help to take the medication with food, administer it at the same time each day, and use supportive anti-nausea and anti-diarrheal guidance upfront, in addition to dose reductions as appropriate.

In our modern era of cancer treatment, optimizing the use of incremental therapy can benefit patients. Making sure we consider ESR1 mutations in patients with ER+ advanced breast cancer, offer appropriate testing as patients are exposed to different treatments, and anticipate and mitigate side effects as appropriate will help us manage patients with ER+ advanced breast cancer optimally.

References
1) Brett, J.O., Spring, L.M., Bardia, A. et al. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res 23, 85 (2021). https://doi.org/10.1186/s13058-021-01462-3.
2) Kinslow CJ, Tang A, Chaudhary KR, Cheng SK. Prevalence of Estrogen Receptor Alpha (ESR1) Somatic Mutations in Breast Cancer. JNCI Cancer Spectr. 2022 Sep 1;6(5):pkac060. doi: 10.1093/jncics/pkac060. PMID: 35959983; PMCID: PMC9438742.
3) Sundaresan TK, Dubash TD, Zheng Z, Bardia A, Wittner BS, Aceto N, Silva EJ, Fox DB, Liebers M, Kapur R, Iafrate J, Toner M, Maheswaran S, Haber DA. Evaluation of endocrine resistance using ESR1 genotyping of circulating tumor cells and plasma DNA. Breast Cancer Res Treat. 2021 Jul;188(1):43-52. doi: 10.1007/s10549-021-06270-z. Epub 2021 Jun 8. PMID: 34101078; PMCID: PMC8667563.
4) Bidard FC, Kaklamani VG, Neven P, Streich G, Montero AJ, Forget F, Mouret-Reynier MA, Sohn JH, Taylor D, Harnden KK, Khong H, Kocsis J, Dalenc F, Dillon PM, Babu S, Waters S, Deleu I, García Sáenz JA, Bria E, Cazzaniga M, Lu J, Aftimos P, Cortés J, Liu S, Tonini G, Laurent D, Habboubi N, Conlan MG, Bardia A. 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. J Clin Oncol. 2022 Oct 1;40(28):3246-3256. doi: 10.1200/JCO.22.00338. Epub 2022 May 18. Erratum in: J Clin Oncol. 2023 Aug 10;41(23):3962. PMID: 35584336; PMCID: PMC9553388.

FDA Approves LONSURF® with Bevacizumab for Advanced Refractory Colorectal Cancer

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SUMMARY: The FDA on August 2, 2023, approved LONSURF® (Trifluridine and Tipiracil with Bevacizumab, for metastatic ColoRectal Cancer (mCRC) previously treated with Fluoropyrimidine, Oxaliplatin and Irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. 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 includes Oxaliplatin or Irinotecan, in combination with a Fluoropyrimidine and Leucovorin (FOLFOX or FOLFIRI respectively), 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. Single agent 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.

The present FDA approval was based on SUNLIGHT trial, which 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

Late Breaking Abstract – ASCO 2023: Vorasidenib a Novel IDH1/2 Inhibitor May Be the New Standard of Care for Low-Grade Gliomas

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SUMMARY: Glioma is the most common neoplasm of the CNS in adults and originates from glial cells. It is estimated that in the US, 6 cases of gliomas are diagnosed per 100,000 people each year. Gliomas are very diffusely infiltrative tumors, with Glioblastoma being the most malignant type, where as Pilocytic astrocytomas are the least malignant brain tumors.

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 resulting in the accumulation of oncometabolite 2-hydroxyglutarate, which prevents cellular differentiation. IDH mutations can thus promote leukemogenesis in Acute Myeloid Leukemia 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.

Almost all Grade 2 diffuse gliomas in adults are associated with IDH mutations and in the most recent update to the WHO classification, gliomas that have a mutation in IDH1 or IDH2 and an unbalanced translocation between chromosomes 1 and 19 (1p/19q-codeleted) are defined as oligodendrogliomas, whereas IDH-mutant gliomas without 1p/19q codeletion (1p/19q–non-codeleted) are defined as astrocytomas. IDH-mutant Grade 2 oligodendrogliomas and astrocytomas are slow and continuous in their growth pattern, infiltrate normal brain tissue, and eventually transform to aggressive tumors with accelerated tumor growth and neovascularization, which is reflected by the appearance of enhancement on contrast MRI. Diffuse Grade 2 gliomas with IDH mutation represent the most common malignant primary brain tumors diagnosed in adults younger than 50 years of age and are not curable with current therapies. They affect approximately 30,000 adults in the US and the mean age at diagnosis is 41 years and the appropriate treatment regimen remains unclear.

Treatment options for patients with Grade 2 glioma include surgery, chemotherapy, and radiotherapy. Complete surgical resection may not be feasible due to the anatomical location and growth pattern of the tumor. The timing of adjuvant therapy after surgery remains controversial and patients with low risk of early disease progression are often monitored. Radiotherapy alone following surgery prolongs the time to recurrence but does not increase Overall Survival, and may be associated with a reduction in neurocognitive function. Chemotherapy with concurrent radiation treatment improves Overall Survival but these tumors will eventually recur.

Vorasidenib is a dual inhibitor of the mutant IDH1 and IDH2 enzymes that crosses the blood-brain barrier, and has a favorable safety profile. In a perioperative trial, treatment with Vorasidenib resulted in more than 90% reduction in the concentration of the oncometabolite 2-hydroxyglutarate in resected tumor, which in turn was associated with reversal of gene expression and epigenetic changes typically associated with IDH mutation in glioma

INDIGO is a global, randomized, double-blind Phase III trial, conducted to assess the efficacy of Vorasidenib in patients with recurrent or residual IDH-mutant glioma. In this study, a total of 331 patients (N=331) were randomly assigned to receive Vorasidenib 40 mg orally once daily (N=168) or a matching placebo (N=163) in 28-day cycles. Enrolled patients had residual or recurrent Grade 2 IDH-mutant glioma, and had undergone no previous treatment other than surgery, with the median interval between the last glioma surgery and randomization being 2.4 years. The two treatment groups were well balanced with respect to baseline characteristics. The median patient age was 40 years and all the patients had undergone brain tumor surgery previously, with 21.5% of the patients having undergone two or more tumor surgeries before enrollment. The numbers of astrocytomas and oligodendrogliomas were similar in the two treatment groups. The tumor size at baseline (determined on the basis of the longest diameter) was at least 2 cm in more than 80% of patients in each treatment group. Randomization was stratified according to locally determined chromosome 1p/19q status (codeleted or non-codeleted) and baseline tumor size (longest diameter 2 cm or more, or less than 2 cm). Patients with high-risk features (such as disease with contrast enhancement on MRI or brain-stem involvement) or uncontrolled disease-related symptoms were excluded. The Primary end point was imaging-based Progression Free Survival as assessed by Blinded Independent Review Committee. Key Secondary end point was the time to the next anticancer intervention. Crossover to Vorasidenib from placebo was permitted upon confirmation of imaging-based disease progression.

At a median follow-up of 14.2 months, 68.3% of patients were continuing to receive Vorasidenib or placebo. The PFS was significantly improved in the Vorasidenib group as compared with the placebo group, with a PFS of 27.7 months versus 11.1 months respectively (HR for disease progression or death=0.39; P<0.001). The Key Secondary end point of the time to the next intervention was also significantly improved in the Vorasidenib group as compared with the placebo group (HR=0.26; P<0.001). The benefit with Vorasidenib was seen across all subgroups independent of tumor type (astrocytoma or oligodendroglioma), and the time since the last surgery. Adverse events of Grade 3 or higher occurred in 23% of the patients who received Vorasidenib and in 13.5% of those who received placebo. Approximately 9% of the patients who received Vorasidenib had an increased hepatic alanine aminotransferase level of Grade 3 or higher.

It was concluded that in patients with Grade 2 IDH-mutant glioma, Vorasidenib significantly improved Progression Free Survival and delayed the time to the next intervention. The authors added that even though the current trial showed single-agent activity of Vorasidenib in patients with previously untreated WHO Grade 2 glioma, additional studies will be necessary to define the role of Vorasidenib, as a single agent, or as part of combination therapy regimens, in patients with glioma who have received cancer therapy previously or who present with WHO grade 3 or 4 disease.

Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma. Mellinghoff IK, van den Bent MJ, Blumenthal DT, et al. N Engl J Med 2023; 389:589-601

Omitting Radiotherapy after Breast-Conserving Surgery in Luminal A 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. Breast cancer is the second leading cause of cancer death in women, in the U.S.

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. Previously published study by Kunkler IH, et al. (Lancet Oncol. 2015;16:266-273) concluded that radiotherapy could be avoided in a subset of elderly patients with low risk breast cancer following breast conserving surgery. However, conventional clinical pathological factors have limited ability to identify breast cancer patients with low risk disease, who could avoid radiation therapy. Even though biomarker assays such as 21-gene recurrence score and the Prediction Analysis of Microarray [PAM] 50 assay are being evaluated for their usefulness in identifying patients in whom radiotherapy might be omitted, follow-up in these trials is short. Molecular defined intrinsic subtypes of breast cancer may be of help in providing additional prognostic information.

Breast cancer is heterogeneous malignancy and using global gene expression analyses, 5 breast cancer intrinsic subtypes have been established. They include Luminal A, Luminal B, HER2-enriched, Basal-like, and Normal breast-like group. Luminal A breast cancer overexpresses estrogen pathway genes and is the least proliferative, and patients have the lowest risk of recurrence with the best prognosis. In a retrospective analysis of women over age 60 years, with Luminal A, Grade 1-2, T1N0 breast cancer, treated with breast conserving surgery and endocrine therapy alone, the local recurrence rate was low (JCO 2015; 33:2035). However, the utility of combining molecular subtype (Luminal A subtype) with clinical pathological factors, to guide radiotherapy decision-making, has not been prospectively evaluated.Molecular-Subtypes-of-Breast-Cancer

LUMINA is a prospective multicenter single-arm, cohort study, in which 500 women, 55 years and older, who had undergone breast conserving surgery for breast cancer, were enrolled. Eligible patients had invasive ductal T1N0, Grade 1-2, Luminal A breast cancer, had undergone breast conserving surgery, with excision margins of at least 1 mm and sentinel lymph node biopsy, omitted radiotherapy, and had received adjuvant endocrine therapy for at least 5 years. Luminal A subtype was defined as ER 1% or more, PR more than 20%, HER2 negative and Ki67 13.25% or less. Ki67 immunohistochemistry was performed centrally in one of three Canadian laboratories using International Ki67 Working Group methods. The median patient age was 67 years, 66% had Grade 1 tumors, 88% of patients were less than 75 years, and the median tumor size was 1.1 cm. Patients were excluded if they had a lobular carcinoma (including mixed ductal-lobular carcinoma), clinical or pathological evidence of direct extension to the chest wall or skin, multifocal or multicentric disease, Grade 3 histologic features, extensive intraductal component, or evidence of lymphovascular invasion. Patients were followed every six months for the first two years and then yearly. The Primary outcome was local recurrence defined as time from enrollment to any invasive or non-invasive cancer in the ipsilateral breast. Secondary endpoints included contralateral breast cancer, Disease Free Survival, and Overall Survival.

At a median follow up of 5 years, the local recurrence rate was 2.3% and the rate of contralateral breast cancer was 1.9%. The 5-year Disease Free Survival was 89.9% and 5-year Overall Survival rate was 97.2%.

The authors concluded that among women 55 years of age and over, with low grade Luminal A breast cancer, omission of radiation therapy following breast conserving surgery and treatment with endocrine therapy alone for 5 years or more, resulted in very low rates of local recurrence at 5 years. The researchers added that approximately 30,000-40,000 women per year in North America, predominantly in the US, could avoid the morbidity, expense, and inconvenience of radiotherapy.

Omitting Radiotherapy after Breast-Conserving Surgery in Luminal A Breast Cancer. Whelan TJ, Smith S, parpia S, et al. for the LUMINA Study Investigators. N Engl J Med 2023; 389:612-619.

Tucatinib plus Trastuzumab for HER2-Positive Metastatic 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.

Human Epidermal Growth Factor Receptor 2 (HER2) is overexpressed in 3-5% of patients with RAS wild-type metastatic colorectal cancer. HER2-positive tumors are IHC3+ by Immunohistochemistry (IHC) or IHC2+/FISH [Fluorescence in Situ Hybridization] amplified. Previously published studies have indicated that patients with HER2-positive CRC have less benefit from EGFR targeted therapies. In the HERACLES trial, a combination of two HER2 targeted therapies prolonged Overall Survival (OS) in RAS wild-type metastatic colorectal cancer.

Tucatinib (TUKYSA®) is an oral Tyrosine Kinase Inhibitor that is highly selective for the kinase domain of HER2, with minimal inhibition of Epidermal Growth Factor Receptor. Trastuzumab (HERCEPTIN®) is a humanized monoclonal antibody targeting HER2/neu oncogene.

MOUNTAINEER is a U.S. and European multicenter, open-label, randomized, prospective, Phase II study, conducted among patients with previously treated HER2-positive metastatic colorectal cancer. This U.S. investigator-sponsored trial initially consisted of a single cohort (Cohort A) of patients who received Tucatinib 300 mg orally BID in combination with Trastuzumab 8 mg/kg IV given as a loading dose on Cycle 1, Day 1, followed by maintenance dose of Trastuzumab 6 mg/kg IV on Day 1 every three weeks thereafter. Patients were treated until disease progression or unacceptable toxicity. This trial was subsequently expanded globally to include patients who were randomized to receive Tucatinib plus Trastuzumab (Cohort B) or Tucatinib monotherapy (Cohort C). Eligible patients (N=114) were required to have HER2-positive, RAS wild-type, unresectable or metastatic colorectal cancer and prior treatment with Fluoropyrimidine, Oxaliplatin, Irinotecan, and an anti-Vascular Endothelial Growth Factor (VEGF) monoclonal antibody. Patients whose tumors were MisMatch Repair (dMMR) deficient or were MicroSatellite Instability-High (MSI-H) must also have received an anti PD-1 monoclonal antibody. Patients who received prior anti-HER2 targeted therapy were excluded. HER2 amplification was identified by Next Generation Sequencing in 61% of patients, by an IHC test score of 3+ in 40%, and by an IHC test score of 2+ and FISH amplification in 32%. The median age was 56 years, 58% were male, and 77% were Caucasian. Of patients who received combination therapy, 85% had left-sided primaries, 78% had received 2 or more lines of prior therapy, and 40% had received 3 or more lines of prior therapy. Over two thirds of the patients had liver or lung metastases. The Primary endpoint was Objective Response Rate (ORR) as assessed by blinded Independent Central Review (ICR) in patients receiving the combination of Tucatinib and Trastuzumab (Cohorts A and B). Secondary endpoints included Duration of Response, Progression Free Survival (PFS), Overall Survival (OS) and safety and tolerability of the combination regimen.

At a median follow up of 20.7 months, the ORR among Cohort A and B patients treated with a combination of Tucatinib and Trastuzumab (N=84) was 38.1% and the median Duration of Response was 12.4 months. The Disease Control Rate was 71.4%. The median Progression Free Survival was 8.2 months, and median Overall Survival was 24.1 months. In the Cohort C patients who received Tucatinib monotherapy (N=30), the ORR was only 3.3% and participants who did not respond to Tucatinib monotherapy by 12 weeks or had disease progressed at any time had the option to receive the combination of Tucatinib and Trastuzumab. Tucatinib in combination with Trastuzumab was well tolerated. Grade 1 or 2 diarrhea was the most common adverse event, followed by fatigue and nausea. Treatment discontinuation due to adverse events was low at 5.8%.

It was concluded that in this largest prospective trial to date among patients with chemotherapy-refractory HER2-positive, RAS wild-type metastatic colorectal cancer, Tucatinib in combination with Trastuzumab demonstrated durable and clinically meaningful antitumor activity and is a new chemotherapy-free treatment option for this group of patients. Based on these results, the FDA in January 2023, granted accelerated approval to Tucatinib in combination with Trastuzumab for RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that has progressed following Fluoropyrimidine, Oxaliplatin, and Irinotecan-based chemotherapy. Studies are underway investigating Tucatinib plus Trastuzumab in earlier lines of therapy.

Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study. Strickler JH, Cercek A, Siena S, et al. The Lancet Oncology 2023;24:496-508.