Category: Precision Oncology

TAILORx Long Term Update for Patients with Early Stage 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 50% of all breast cancers are Estrogen Receptor (ER) positive, HER2-negative, axillary node-negative tumors. Patients with early-stage breast cancer often receive adjuvant chemotherapy. The Oncotype DX breast cancer assay, is a multigene genomic test that analyzes the activity of a group of 21 genes and is able to predict the risk of breast cancer recurrence and likelihood of benefit from systemic chemotherapy, following surgery, in women with early-stage breast cancer. Chemotherapy recommendations for Hormone Receptor positive, HER negative, early-stage breast cancer patients, are often made based on tumor size, grade, ImmunoHistoChemical (IHC) markers such as Ki-67, nodal status and Oncotype DX Recurrence Score (RS) assay. Oncotype Dx assay categorizes patients based on Recurrence Scores into Low risk (0-10), Intermediate risk (11-25), and High risk (26-100). It has been unclear whether patients in the Intermediate risk group benefited from the addition of chemotherapy to endocrine therapy. TAILORx was specifically designed to address this question and provide a very definitive answer.

TAILORx ((Trial Assigning Individualized Options for Treatment) is a phase III, randomized, prospective, non-inferiority trial, and is the largest breast cancer treatment trial ever conducted, and the first precision medicine trial ever done, according to the authors. In this study, 10,273 women, 18-75 years of age, with hormone receptor-positive, HER2-negative, T1b-T2N0 early-stage axillary node-negative breast cancer were enrolled. Patients had tumors 1.1-5.0 cm in size (or 0.6-1.0 cm and intermediate/high grade). Patients were divided into three groups based on their Recurrence Score. Women with a Low Recurrence Score of 0-10 received endocrine therapy alone and those with a High Recurrence Score of 26-100 received endocrine therapy in combination with standard adjuvant chemotherapy. Patient with Intermediate Recurrence Score of 11-25 (N=6711) were randomly assigned to receive endocrine therapy alone (N=3399) or endocrine therapy and adjuvant chemotherapy (N=3312). The Primary endpoint was invasive Disease-Free Survival, defined as recurrence of cancer in the breast, regional lymph nodes, and/or distant organs, a second primary cancer in the opposite breast or another organ, or death from any cause. The researchers conducted an updated analysis, in which patients were followed for an additional 3.5 years, for an average of 11 years. The Primary endpoint in the updated analysis was invasive Disease-Free Survival (DFS) at a median follow-up of 11.0 years in the randomized population and 10.4 years in the overall population.

The previous TAILORx study conclusions remain unchanged. Among patients with a Recurrence Score of 11-25, endocrine therapy alone was non-inferior to chemotherapy plus endocrine therapy. The 5-year invasive DFS with endocrine therapy alone was 92.8% versus 93.1% with chemotherapy plus endocrine (HR=1.08; P=0.26). The 12-year invasive DFS with endocrine therapy alone was 76.8% versus 77.4% with chemotherapy plus endocrine therapy (HR =1.08). Although among those patients with a Recurrence Score of 0-25, less than 10% of patients had disease recurrence by 12 years, late recurrence events beyond 5 years exceeded earlier recurrence, regardless of treatment. There was also a higher risk of early recurrence in Black women.

It was concluded that with longer follow-up, the main TAILORx study findings remain unchanged, and clinicians should continue to use the 21-gene recurrence score results to guide decisions about the use of chemotherapy.

Trial Assigning Individualized Options for Treatment (TAILORx): An update including 12-year event rates. Sparano J, Gray RJ, Makower D, et al. Presented at SABCS 2022. December 6-10, 2022. Abstract GS1-05.

TUKYSA® Combination in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence.

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 metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. HER2-targeted therapies include HERCEPTIN® (Trastuzumab), TYKERB® (Lapatinib), PERJETA® (Pertuzumab), KADCYLA® (ado-Trastuzumab emtansine), ENHERTU® (Trastuzumab deruxtecan) and MARGENZA® (Margetuximab). Dual HER2 blockade with HERCEPTIN® and PERJETA®, given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2-positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival (OS). The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies. Patients progressing on Dual HER2 blockade often receive KADCYLA® which results in an Objective Response Rate (ORR) of 44% and a median PFS of 9.6 months, when administered after HERCEPTIN® and a taxane. There is however no standard treatment option for this patient population following progression on KADCYLA®.

With advances in systemic therapies for this patient population, the incidence of brain metastases as a sanctuary site has increased. Approximately 50% of patients with HER2-positive metastatic breast cancer develop brain metastases. However, systemic HER2-targeted agents, including Tyrosine Kinase Inhibitors, as well as chemotherapy have limited antitumor activity in the brain. Local therapeutic interventions for brain metastases include neurosurgical resection and Stereotactic or Whole-Brain Radiation Therapy. There is a high unmet need for systemic treatment options to treat established brain metastases and reduce the risk for progression in the Central Nervous System (CNS).

TUKYSA® (Tucatinib) is an oral Tyrosine Kinase Inhibitor that is highly selective for the kinase domain of HER2 with minimal inhibition of Epidermal Growth Factor Receptor. In a Phase 1b dose-escalation trial, TUKYSA® in combination with HERCEPTIN® and XELODA® (Capecitabine) showed encouraging antitumor activity in patients with HER2-positive metastatic breast cancer, including those with brain metastases.

HER2CLIMB is an international, randomized, double-blind, placebo-controlled trial in which the combination of TUKYSA® plus HERCEPTIN® and XELODA® was compared with placebo plus HERCEPTIN® and XELODA®. A total of 612 patients with unresectable locally advanced or metastatic HER2-positive breast cancer, who were previously treated with HERCEPTIN®, PERJETA® (Pertuzumab) and KADCYLA® (ado-Trastuzumab emtansine) were enrolled. Patients were randomly assigned in a 2:1 ratio to receive either TUKYSA® 300 mg orally twice daily throughout the treatment period (N=410) or placebo orally twice daily (N=201), in combination with HERCEPTIN® 6 mg/kg IV once every 21 days, following an initial loading dose of 8 mg/kg, and XELODA® 1000 mg/m2 orally twice daily on days 1 to 14 of each 21-day cycle. Stratification factors included presence or absence of brain metastases, ECOG Performance Status and geographic region. The median patient age was 52 years and patient demographics as well as disease characteristics at baseline were well balanced between the two treatment groups. In the total treatment population, 47.5% had brain metastases at baseline, 48.3% in the TUKYSA® combination group and 46% in the placebo combination group. The Primary endpoint was Progression Free Survival (PFS). Secondary end points included Overall Survival (OS), PFS among patients with brain metastases, confirmed Objective Response Rate (ORR), and Safety.

At median follow-up of 29.6 months, median OS in all patients with brain metastases at baseline was 9.1 months longer in the TUKYSA® combination group compared to the placebo combination group (21.6 versus 12.5 months, HR=0.60; P<0.001), with a 40% reduction in the risk of death with the TUKYSA® combination. The estimated 1-year OS was 70.0% for the TUKYSA® combination group and 50.6% for the placebo combination group and the estimated 2-year OS was 48.5% and 25.1% respectively.

The researchers in this exploratory subgroup analyses reported efficacy outcomes for patients with brain metastases, as well as time to new brain lesion(s) as the site of first progression or death, in all patients enrolled in HER2CLIMB trial, at a median follow up of 29.6 months.

There was greater CNS Progression Free Survival in the TUKYSA® combination group compared with the placebo combination group and was 5.7 months longer (9.9 versus 4.2 months, HR=0.39; P<0.001), with a 61% reduction in the risk of CNS progression with the TUKYSA® combination. The estimated 1 and 2-year CNS Progression Free Survivals were 38.4% versus 7.9% and 19.3% versus 0%, respectively.

Among those with active brain metastases and measurable disease at baseline, the intracranial Objective Response Rates for the TUKYSA® combination group were 47.3% versus 20.0% for the placebo combination group, with a median duration of intra cranial response of 8.6 versus 3.0 months, respectively.

The risk of developing new brain lesions as the site of first progression or death was reduced by 45% in the TUKYSA® combination group versus the placebo-combination group (HR=0.55; P =0.006).

The authors concluded that in this exploratory subgroup analysis, TUKYSA® in combination with HERCEPTIN® and XELODA® provided a clinically meaningful survival benefit, while reducing the risk of developing new brain lesions. The authors added that HER2CLIMB is currently the only double-blind, randomized, controlled clinical trial for patients with HER2-positive metastatic breast cancer, that prospectively included patients with both active and stable brain metastases.

Tucatinib vs Placebo, Both in Combination with Trastuzumab and Capecitabine, for Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer in Patients With Brain Metastases: Updated Exploratory Analysis of the HER2CLIMB Randomized Clinical Trial. Lin NU, Murthy RK, Abramson V, et al. JAMA Oncol. Published online December 1, 2022. doi:10.1001/jamaoncol.2022.5610

FDA Grants Accelerated Approval to KRAZATI® for KRAS G12C-mutated NSCLC

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SUMMARY: The FDA on December 12, 2022, granted accelerated approval to KRAZATI® (Adagrasib), a RAS GTPase family inhibitor, for adult patients with KRAS G12C-mutated locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy. FDA also approved the QIAGEN therascreen KRAS RGQ PCR kit (tissue) and the Agilent Resolution ctDx FIRST Assay (plasma) as companion diagnostics for KRAZATI®. If no mutation is detected in a plasma specimen, the tumor tissue should be tested.

The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

The KRAS (kirsten rat sarcoma viral oncogene homologue) proto-oncogene encodes a protein that is a member of the small GTPase super family. The KRAS gene provides instructions for making the KRAS protein, which is a part of a signaling pathway known as the RAS/MAPK pathway. By relaying signals from outside the cell to the cell nucleus, the protein instructs the cell to grow, divide and differentiate. The KRAS protein is a GTPase and converts GTP into GDP. To transmit signals, the KRAS protein must be turned on by binding to a molecule of GTP. When GTP is converted to GDP, the KRAS protein is turned off or inactivated, and when the KRAS protein is bound to GDP, it does not relay signals to the cell nucleus. The KRAS gene is in the Ras family of oncogenes, which also includes two other genes, HRAS and NRAS. When mutated, oncogenes have the potential to change normal cells cancerous.

KRAS is the most frequently mutated oncogene in human cancers and are often associated with resistance to targeted therapies and poor outcomes. The KRAS G12C mutation occurs in approximately 25% of Non-Small Cell Lung Cancers (NSCLC) and in 3-5% of colorectal cancers and other solid cancers. KRAS G12C is one of the most prevalent driver mutations in NSCLC and accounts for a greater number of patients than those with ALK, ROS1, RET, and TRK 1/2/3 mutations combined. KRAS G12C cancers are genomically more heterogeneous and occur more frequently in current or former smokers and are likely to be more complex genomically than EGFR mutant or ALK rearranged cancers. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, resulting in a predominantly GTP-bound KRAS oncoprotein, amplifying signaling pathways that lead to oncogenesis.

KRAZATI® (Adagrasib) is a potent, orally available, small molecule covalent inhibitor of KRAS G12C. This drug irreversibly and selectively binds KRAS G12C in its inactive, GDP-bound state. Unlike LUMAKRAS® (Sotorasib), which is also a selective covalent inhibitor of KRAS G12C, KRAZATI® has a longer drug half-life of 23 hours, as compared to 5 hours for LUMAKRAS®, has dose-dependent extended exposure, and can penetrate the CNS. Approximately, 27-42% of patients with NSCLC harboring KRAS G12C mutations have CNS metastases, with poor outcomes. KRYSTAL-1 is a Phase I/II multiple expansion cohort trial involving patients with advanced solid tumors harboring a KRAS G12C mutation. KRAZATI® demonstrated clinical activity in patients with KRAS G12C-mutated solid tumors, including colorectal, pancreatic, and biliary tract cancers. Further, preliminary data from two patients with untreated CNS metastases from a Phase 1b cohort showed antitumor activity against CNS metastases, with satisfactory concentrations of KRAZATI® in the CSF.

The present FDA approval was based on the results from Cohort A, a Phase 2 cohort of the KRYSTAL-1 study in which KRAZATI® at a dose of 600 mg orally twice daily was evaluated in patients with KRAS G12C-mutated NSCLC, previously treated with chemotherapy and anti-Programmed Death 1 (PD-1) or Programmed Death Ligand 1 (PD-L1) therapy. This registration study included a total of 116 unresectable or metastatic NSCLC patients, with histologically confirmed diagnosis, with KRAS G12C mutation (detected in tumor tissue at a local or central laboratory), who had previously received treatment with at least one platinum-containing chemotherapy regimen and checkpoint inhibitor therapy (in sequence or concurrently), and who had measurable tumor lesions. Enrolled patients received KRAZATI® 600 mg capsule twice daily, and treatment was continued until disease progression or unacceptable toxicities. The median patient age was 64 years, 97% had adenocarcinoma histology, 98% had both platinum-based therapy and checkpoint inhibitor therapy, and 21% of patients had CNS metastases. Key exclusion criteria included active CNS metastases (patients were eligible if CNS metastases were adequately treated and neurologically stable), carcinomatous meningitis, and previous treatment with a KRAS G12C inhibitor. Exploratory Biomarker Analyses included candidate biomarkers (PD-L1 Tumor Proportion Score and mutational status of STK11, KEAP1, TP53, and CDKN2A on tumor-tissue specimens, blood specimens, or both, for their association with tumor response. The Primary end point was Objective Response Rate as assessed by blinded Independent Central Review. Secondary end points included the Duration of Response, Progression Free Survival, Overall Survival, and safety. The median follow up was 12.9 months and the median duration of treatment was 5.7 months.

Of 112 patients with measurable disease at baseline, the confirmed Objective Response Rate was 42.9% and the median Duration of Response was 8.5 months. The median Progression Free Survival was 6.5 months, and the median Overall Survival was 12.6 months, at a median follow up of 15.6 months. Among 33 patients with previously treated, stable CNS metastases, the intracranial confirmed Objective Response Rate was 33.3%. Treatment-related adverse events occurred in 97.4% of the patients and 53% were Grade 1 or 2 toxicities. KRAZATI® was discontinued in 6.9% of patients due to adverse events.

It was concluded that among patients with previously treated KRAS G12C-mutated NSCLC, KRAZATI® showed significant clinical efficacy without new safety signals and encouraging intracranial activity. The researchers added that these are the first clinical data demonstrating CNS-specific activity of a KRAS G12C inhibitor in this patient population.

Adagrasib in Non–Small-Cell Lung Cancer Harboring a KRASG12C Mutation. Jänne PA, Riely GJ, Gadgeel SM, et al. N Engl J Med 2022; 387:1238-1239

FDA Approves REZLIDHIA® for Acute Myeloid Leukemia

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SUMMARY: The FDA on December 1, 2022, approved REZLIDHIA® (Olutasidenib) capsules for adult patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) with a susceptible IDH1 mutation, as detected by an FDA-approved test. The FDA on the same day also approved the Abbott RealTime IDH1 Assay to select patients for REZLIDHIA®.

The American Cancer Society estimates that for 2022, about 20,050 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,540 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients, based on risk and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high risk features such as unfavorable cytogenetics, molecular abnormalities, prior Myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy alone. AML mainly affects older adults and the median age at diagnosis is 68 years. A significant majority of patients with AML are unable to receive intensive induction chemotherapy due to comorbidities and therefore receive less intensive, noncurative regimens, with poor outcomes.

Isocitrate DeHydrogenase (IDH) is a metabolic enzyme that helps generate energy from glucose and other metabolites, by catalyzing the conversion of Isocitrate to Alpha-Ketoglutarate. Alpha-ketoglutarate is required to properly regulate DNA and histone methylation, which in turn is important for gene expression and cellular differentiation. IDH mutations lead to aberrant DNA methylation and altered gene expression, thereby preventing cellular differentiation, with resulting immature undifferentiated cells. IDH mutations can thus promote leukemogenesis in Acute Myeloid Leukemia and tumorigenesis in solid tumors and can result in inferior outcomes. There are three isoforms of IDH. IDH1 is mainly found in the cytoplasm, as well as in peroxisomes, whereas IDH2 and IDH3 are found in the mitochondria, and are a part of the Krebs cycle.

Approximately 20-25% of patients with AML, 70% of patients with Low-grade Glioma and secondary Glioblastoma, 50% of patients with Chondrosarcoma, 20% of patients with Intrahepatic Cholangiocarcinoma, 30% of patients with Angioimmunoblastic T-Cell Lymphoma and 8% of patients with Myelodysplastic syndromes/Myeloproliferative neoplasms, are associated with IDH mutations. IDH2 mutations are more common than IDH1 mutations, occurring in approximately 15% to 20% of patients with AML. The presence of IDH mutations has both prognostic and predictive value. Patients with an IDH mutation and a Nucleo¬phosmin (NPM1) mutation usually have a better prognosis whereas patients with mutations in IDH and FMS-like tyrosine kinase 3 (FLT3) do not. Further IDH mutations predict response to specific IDH1 and IDH2 inhibitors in the Relapsed and Refractory setting. The presence of an IDH mutation is therefore not only prognostic, but also predictive of response to certain therapies.

The two IDH inhibitors presently available in the US include IDHIFA® (Enasidenib), approved for the treatment of patients with Relapsed or Refractory AML with IDH2 mutation and TIBSOVO® (Ivosidenib), approved for AML patients with the IDH1 mutation who have Relapsed/Refractory disease, as well as monotherapy for newly diagnosed AML patients 75 years or older with comorbidities that preclude the use of intensive induction chemotherapy. IDHIFA® can be associated with indirect hyperbilirubinemia, which is of no clinical consequence, whereas with TIBSOVO® there is a small risk of QT interval prolongation. Both agents can lead to Differentiation Syndrome in 10-15% of patients which requires systemic steroids and hemodynamic monitoring for at least 3 days.

REZLIDHIA® is a potent, selective, oral, brain-penetrant, small molecule inhibitor of mutant IDH1, that has exhibited favorable tolerability and clinical activity in high-risk AML patients in a Phase 1 trial (Watts JM, et al. Blood 2019). The present FDA approval was based on the Phase 1/2 Study 2102-HEM-101 trial (NCT02719574), which included 147 adult patients with Relapsed or Refractory AML with an IDH1 mutation, confirmed using the above now approved assay. Enrolled patients had pathologically proven AML, except those with Acute Promyelocytic Leukemia with the t(15;17) translocation, or intermediate high, or very high-risk MDS as defined by the WHO criteria or Revised International Prognostic Scoring System. REZLIDHIA® 150 mg was given orally, twice daily, until disease progression, unacceptable toxicity, or Hematopoietic Stem Cell Transplantation. The median treatment duration was 4.7 months. Sixteen (11%) patients underwent Hematopoietic Stem Cell Transplantation following treatment with REZLIDHIA®. The Primary end points included the rate of Complete Remission (CR) plus Complete Remission with partial hematologic recovery (CRh). Secondary end points included time to response, Duration of Response, Event-Free Survival, Overall Survival, and Relapse-Free Survival.

The Complete Remission plus Complete Remission with partial hematologic recovery rate with REZLIDHIA® was 35%, with 32% CR and 2.7% CRh. The median time to CR+CRh was 1.9 months and the median duration of CR+CRh was 25.9 months. Among the 86 patients who were Red Blood Cell (RBC) and/or platelet transfusions dependent at baseline, 34% became RBC and platelet transfusion independent during any 56-day post-baseline period. Of the 61 patients who were RBC and platelet transfusions independent at baseline, 64% remained transfusion independent during any 56-day post-baseline period. The most common adverse reactions were nausea, diarrhea, constipation, mucositis, fatigue/malaise, arthralgia, fever, rash, leukocytosis, dyspnea, and transaminitis. Health care professionals and patients should be aware of the risk of Differentiation Syndrome, which can be fatal.

REZLIDHIA® is the third IDH inhibitor currently approved for the treatment of Acute Myeloid Leukemia.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olutasidenib-relapsed-or-refractory-acute-myeloid-leukemia-susceptible-idh1-mutation.

FDA Approves Biomarker-Driven ELAHERE® for Platinum-Resistant Ovarian Cancer

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SUMMARY: The FDA on November 14, 2022, granted accelerated approval to ELAHERE® (mirvetuximab soravtansine-gynx) for adult patients with Folate Receptor alpha (FR alpha) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens. The FDA also on the same day approved the VENTANA FOLR1 (FOLR-2.1) RxDx Assay (Ventana Medical Systems, Inc.), as a companion diagnostic device to select patients for the above indication.

It is estimated that in the United States, approximately 19,880 women will be diagnosed with ovarian cancer in 2022, and 12,810 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, and accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Approximately 85% of all ovarian cancers are epithelial in origin, and approximately 70% of all epithelial ovarian cancers are High-Grade Serous adenocarcinomas. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum-based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5-year Overall Survival rate of about 20-30%. Treatment options for patients with platinum-resistant ovarian cancer are limited, and patients are often treated with single-agent chemotherapy, with an Overall Response Rate of between 4% and 13%, short duration of response, and significant toxicities.

Approximately 35-40% of ovarian cancer patients express high levels of Folate Receptor alpha, and this expression correlates with advanced stages of disease and more malignant phenotypes. There is limited expression of Folate Receptor alpha in normal tissues and is limited to the choroid plexus, proximal renal tubules, placenta, and endometrium. Testing for Folate Receptor alpha can be performed on fresh or archived tissue.

ELAHERE® (mirvetuximab soravtansine-gynx) is a first-in-class Antibody Drug Conjugate (ADC), directed against FR alpha, a cell-surface protein highly expressed in ovarian cancer. It is comprised of a Folate Receptor alpha-binding antibody, cleavable linker, and the maytansinoid payload DM4, which is a potent tubulin inhibitor, disrupting microtubule formation, and thereby designed to kill the targeted cancer cells. Microtubules are major components of the cytoskeleton that give shape and structure to cells. ELAHERE® is the first FDA approved ADC for platinum-resistant disease.

The FDA approval was based on the pivotal SORAYA trial, which is a single-arm study in 106 patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, whose tumors expressed high levels of Folate Receptor alpha, and who had been treated with 1-3 prior lines of systemic treatment regimens. All patients were required to have received prior treatment with AVASTIN® (Bevacizumab). Enrolled patient’s tumors were positive for FR alpha expression as determined by the above-mentioned FDA approved assay. Patients were eligible for the study if at least 75% of cells had 2+ staining intensity or greater, based on immunohistochemistry-based scoring. Patients were excluded if they had corneal disorders, ocular conditions requiring ongoing treatment, more than Grade 1 peripheral neuropathy, or noninfectious interstitial lung disease. Patients received ELAHERE® 6 mg/kg (based on adjusted ideal body weight) IV infusion every three weeks, until disease progression or unacceptable toxicity. Assessments were made for tumor response every six weeks for the first 36 weeks, and every 12 weeks thereafter. The Primary endpoint was investigator-assessed Overall Response Rate (ORR), and key Secondary endpoint was Duration of Response (DOR).

The confirmed ORR was 31.7% including five Complete Responses, and the median Duration of Response was 6.9 months. Response rates were consistently seen regardless of the number of prior therapies or the use of a prior PARP inhibitor. The most common adverse reactions including laboratory abnormalities, were vision impairment, keratopathy, fatigue, nausea, peripheral neuropathy, increase in ALT and AST and cytopenias. Product labeling includes a boxed warning for ocular toxicity. The authors reported that the ocular events were reversible and primarily included low-grade blurred vision and keratopathy, which were managed with protocol-defined dose modifications. Approximately 60% of patients with symptoms had resolution prior to their next cycle of treatment, and less than 1% of patients discontinued therapy due to an ocular event.

It was concluded that ELAHERE® had impressive anti-tumor activity, durability of response, and overall tolerability, and may be a new therapeutic option for patients with Folate Receptor alpha-positive platinum-resistant ovarian cancer.

Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: Results from the SORAYA study. Matulonis UA, Lorusso D, Oaknin A, et al: 2022 SGO Annual Meeting on Women’s Cancer. Abstract 242. Presented March 19, 2022.

TAFINLAR® and MEKINIST® versus OPDIVO® plus YERVOY® for Patients with Advanced BRAF-Mutant Melanoma: The DREAMseq Trial

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

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been detected in 6-8% of all malignancies. The most common BRAF mutation in melanoma is at the V600E/K site and is detected in approximately 50% of melanomas, and results in constitutive activation of the MAPK pathway.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate (ORR) and prolongation of survival across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Over 50% of patients treated with a combination of PD-1 and CTLA-4 inhibitors are alive after five years.

TAFINLAR® (Dabrafenib), is a selective oral BRAF inhibitor and MEKINIST® (Trametinib) is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway. TAFINLAR® plus MEKINIST® led to long-term survival benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, from two randomized Phase III COMBI-d and COMBI-v trials.

A combination of OPDIVO® (Nivolumab) plus YERVOY® (Ipilimumab) showed durable improved outcomes among patients with unresectable or metastatic melanoma and approximately 50% of patients were alive at 6.5 years (J Clin Oncol 39, 2021. suppl 15; abstr 9506). The FDA granted approval for this combination in 2015 for the treatment of patients with metastatic melanoma, regardless of tumor BRAF mutation status.

It has been noted that BRAF/MEK inhibitor therapy tends to produce high tumor response rates and prolonged median Progression Free Survival (PFS), whereas OPDIVO® /YERVOY® tends to have its major impact on Duration of Response. However, the optimal treatment sequence for patients with treatment-naive BRAFV600-mutant metastatic melanoma, between combination OPDIVO®/YERVOY® checkpoint inhibitor immunotherapy and combination TAFINLAR® plus MEKINIST® molecularly targeted therapy, has remained unclear. Recently published tumor biology studies have suggested that resistance to BRAF/MEK-inhibitor therapy results in an immunosuppressive tumor microenvironment that is void of functional CD103+ dendritic cells, preventing effective antigen presentation to the immune system, and that immunotherapy may enhance BRAF-mutated melanoma responsiveness to targeted therapy.

DREAMseq (EA6134) is a two-arm, two-step, open-label, randomized Phase III trial, which investigated the anti PD-1/CLTA-4 immunotherapy combination of OPDIVO® plus YERVOY® followed by the anti-BRAF/MEK targeted therapy combination of TAFINLAR® plus MEKINIST®, versus the reverse sequence, in patients with advanced BRAF V600-mutant melanoma. This study was conducted to determine which treatment sequence produced the best efficacy.

In this study, 265 patients with treatment-naive BRAF V600-mutant metastatic melanoma were randomly assigned to receive either combination OPDIVO® plus YERVOY® (arm A=133) or TAFINLAR® plus MEKINIST® (arm B=132) in step 1, and at disease progression were enrolled in step 2 to receive the alternate therapy, TAFINLAR® plus MEKINIST® (arm C=27) or OPDIVO® plus YERVOY® (arm D=46). The two initial treatment arms were balanced and more patients on arm B had BRAF V600K-mutant tumors than those on arm A (25.2% versus 12.1%). The median patient age was 61 years and eligible patients had histologically confirmed, BRAF V600-mutant unresectable Stage III or IV melanoma with measurable disease. The Primary end point was 2-year Overall Survival (OS). Secondary end points included 3-year OS, Objective Response Rate (ORR), Duration of Response, Progression Free Survival (PFS), crossover feasibility, and Safety.

The study was stopped early by the Independent Data Safety Monitoring Committee because statistical significance was achieved for the Primary endpoint. The 2-year OS for those starting on arm A was 71.8% and arm B was 51.5% (P=0.01). Step 1 Progression Free Survival favored arm A (P=0.054). The Objective Response Rates were arm A: 46%, arm B: 43%, arm C: 47.8%, and arm D: 29.6%. The median Duration of Response was not reached for arm A, and 12.7 months for arm B (P<0.001). Crossover occurred in 52% of patients following documented disease progression. Grade 3 or more toxicities occurred with similar frequency between treatment groups and adverse events related to regimens were as expected.

It was concluded from this study that for patients with advanced BRAF V600-mutant metastatic melanoma, the treatment sequence beginning with the immune checkpoint inhibitor combination of OPDIVO® plus YERVOY® resulted in superior Overall Survival and longer Duration of Response, compared with the treatment sequence beginning with TAFINLAR® plus MEKINIST®, and should therefore be the preferred treatment sequence for most of these patients.

Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients with Advanced BRAF-Mutant Melanoma: The DREAMseq Trial—ECOG-ACRIN EA6134. Atkins MB, Lee SJ, Chmielowski B, et al. J Clin Oncol. Published online September 27, 2022. doi:10.1200/JCO.22.01763

RNF43 Mutations Predict Response to Anti-BRAF/EGFR Combination Therapy in BRAF V600E 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 151,030 new cases of CRC will be diagnosed in the United States in 2022 and about 52,580 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. Advanced colon cancer is often incurable and standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab) as well as anti VEGF agent AVASTIN® (Bevacizumab), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC (mCRC) whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now also clear that even among the KRAS Wild Type patient group about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Patients with Stage IV CRC are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy.

Approximately 8-15% of all metastatic CRC tumors present with BRAF V600E mutations, which is recognized as a marker of poor prognosis in this patient group. These patients predominantly present with right-sided proximal tumors, tend to have aggressive disease with a higher rate of peritoneal metastasis, and do not respond well to standard treatment intervention. Approximately 30% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group. Further, in striking contrast to patients with melanoma harboring BRAF V600E mutations in whom there is a 70% Objective Response Rate with BRAF inhibitor monotherapy, there is little or no clinical benefit with the same treatment among BRAF V600E mutant CRC patients.

Preclinical studies have shown that inhibiting BRAF in colorectal tumors can transiently reduce Mitogen-Activated Protein (MAP) kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR. In the Phase III BEACON Colorectal Cancer study, a combination of BRAF inhibitor BRAFTOVI® (Encorafenib) and EGFR antagonist ERBITUX® (Cetuximab), with or without concomitant MEK inhibition improved Response Rates, Overall Survival and Progression Free Survival in patients with metastatic CRC with a BRAF V600E mutation. The FDA approved this doublet therapy in 2020 for this patient group. Despite this improved efficacy, a significant percentage of patients do not respond this therapy and among those who respond, the responses noted in CRC are still not as robust as has been in BRAF-mutant metastatic melanomas treated with anti-BRAF therapy. This suggests that there may be other factors modulating treatment response, including molecular determinants, that need to be identified, to optimize clinical management of these patients.

BRAF V600E mutated tumors in CRC are also associated with specific molecular features, including a low frequency of APC mutations and a high rate of mutations in the tumor suppressor gene RNF43 (Ring Finger Protein 43). RNF43 is a E3 ubiquitin ligase which negatively regulates Wnt signaling by inducing degradation of the Wnt receptors. It has been postulated that the a cross-talk between the MAPK and WNT signaling pathways may modulate the antitumor activity of anti-BRAF/EGFR therapy.

The researchers in this study sought to explore which genes were enriched for somatic mutations in responder and non-responder groups, among patients with BRAF V600E mutant CRC, treated with anti-BRAF/EGFR combination therapy. This study included 166 patients (N=166) with BRAF V600E mutant CRC of whom 98 patients received treatment with anti-BRAF/EGFR combination therapy (N=46 in the Discovery cohort and N=52 in the Validation cohort). The Control cohort (N=68) consisted of BRAF V600E mutant CRC patients treated with chemotherapy with or without antiangiogenic therapy, and were not exposed to anti-BRAF therapy. Whole-Exome Sequencing (WES) and/or targeted gene sequencing was performed on baseline tumor and/or plasma cell-free DNA (cfDNA) samples of all included patients, and over 20,000 genes were analyzed.

It was noted that RNF43 mutations were identified in 29% of BRAF V600E-mutated MicroSatellite-Stable (MSS) metastatic CRC tumors, and this finding was strongly associated with a clinical response to anti-BRAF/EGFR-based combination therapy. When compared to BRAF V600E-mutated, MicroSatellite-Stable metastatic CRC patients without the RNF43 mutation (RNF43 wild-type), patients with BRAF V600E-mutated, MicroSatellite-Stable metastatic CRC carrying a RNF43 mutation had a Response Rate of 72.7% versus 30.8% (P=0.03), longer median Progression Free Survival (10.1 months versus 4.1 months, HR=0.30; P=0.01) and longer median Overall Survival (13.6 months versus 7 months, HR=0.26; P=0.008). Conversely, the predictive value of RNF43 mutations seen in MicroSatellite-Stable tumors was not observed in MicroSatellite Instability (MSI)-High tumors.

The researchers concluded that these findings suggest that RNF43 may be a potential stratification biomarker that could help with decision making, in patients with MicroSatellite-Stable, BRAF V600E–mutant metastatic Colorectal cancer. They added that RNF43 gene may be a predictive biomarker of a response to treatment with anti-BRAF/EGFR combination therapy in this patient group.

RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAF V600E metastatic colorectal cancer. Elez, E, Ros J, Fernandez J, et al. Nature Medicine 2022;28:2162–2170.

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

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

Fulvestrant (FASLODEX®) is an estrogen antagonist and like Tamoxifen binds to estrogen receptors (ERs) competitively, but unlike Tamoxifen causes rapid degradation and loss of ER protein (ER down regulator) and is devoid of ER agonist activity. Palbociclib (IBRANCE®) is a reversible, oral, selective, small molecule inhibitor of Cyclin Dependent Kinases, CDK4 and CDK6, and prevents RB1 phosphorylation. Palbociclib is the first CDK inhibitor approved by the FDA. It exhibits synergy when combined with endocrine therapies. The FDA in February 2016, approved Palbociclib in combination with Fulvestrant, for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer, with disease progression following endocrine therapy.

Patients with ESR1 mutations on Fulvestrant had improved Progression Free Survival (PFS) compared with Exemestane (AROMASIN®) in the SoFEA trial. The combination of Palbociclib and Fulvestrant improved PFS compared with Fulvestrant plus placebo in both ESR1 mutant and ESR1 wild-type patients, in the PALOMA3 trial.

The PADA-1 study aimed to show the efficacy of an early change in therapy based on a rising ESR1 mutation in the peripheral blood, while assessing the global safety of the combination Fulvestrant and Palbociclib. PADA-1 is a prospective, randomized, open-label, multicentre, Phase III trial in which 1017 patients with ER-positive, HER2-negative advanced breast cancer were included. These patients were monitored for a rising ESR1 mutation in the peripheral blood, while on first-line treatment with an Aromatase Inhibitor (Letrazole 2.5 mg, Anastrozole 1 mg or Exemestane 25 mg orally once daily, taken continuously) and Palbociclib 125 mg orally once daily on days 1-21 of a 28-day treatment cycle, at enrollment and every 2 months thereafter. Blood samples were monitored for several ESR1 mutations which included E380, P535, L536, Y537, and D538. The median time from trial enrollment to detection of the ESR1 mutation was 14.2 months. Patients with newly present or rising ESR1 mutation in the peripheral blood circulating tumor DNA and no synchronous disease progression (N=172) were randomly assigned (1:1) to continue with the same therapy (N=84) or to switch to Fulvestrant 500 mg IM on day 1 of each 28-day cycle and on day 15 of cycle 1, along with Palbociclib as previously dosed (N=88). Baseline characteristics were similar in both treatment groups. The median patient age was 61 years, and one-third of patients had prior treatment with an Aromatase Inhibitor. Patients were stratified according to visceral involvement (present or absent) and the time from inclusion to detection of ESR1 mutation in the peripheral blood (<12 months or 12 months or more). The co-Primary endpoints were Progression Free Survival and Grade 3 or more hematologic adverse events in all patients.

At a median follow up of 26.0 months from randomization, switching patients from an Aromatase Inhibitor to Fulvestrant, upon detection of ESR1 mutation in the peripheral blood was associated with a 39% reduction in the risk of disease progression or death. The median Progression Free Survival was 11.9 months in the Fulvestrant and Palbociclib group versus 5.7 months in the Aromatase Inhibitor and Palbociclib group (HR=0.61; P=0·004). The co-Primary endpoint of Grade 3 or more hematologic adverse events found no safety signals associated with switching from an Aromatase inhibitor to Fulvestrant. The most frequent Grade 3 or more hematological adverse events were neutropenia. lymphopenia, and thrombocytopenia. Dose reductions were similar in both randomized treatment groups.

The authors concluded that PADA-1 is the first prospective randomized trial to demonstrate that early therapeutic targeting of ESR1 mutation in the peripheral blood results in significant clinical benefit. The researchers added that the original design explored in PADA-1 might help with addressing acquired resistance to new drugs in future trials.

Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Bidard FC, Hardy-Bessard AC, Dalenc F, et al. The Lancet Oncology. Published: September 29, 2022.DOI:https://doi.org/10.1016/S1470-2045(22)00555-1

FDA Grants Accelerated Approval to LYTGOBI® for Cholangiocarcinoma

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SUMMARY: The FDA on September 30, 2022, granted accelerated approval to LYTGOBI® (Futibatinib) for adult patients with previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring Fibroblast Growth Factor Receptor 2 (FGFR2) gene fusions or other rearrangements. Bile Tract cancer (Cholangiocarcinoma) is a rare, heterogenous cancer, and comprises about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. Klatskin tumor is a type of Cholangiocarcinoma that begins in the hilum, at the junction of the left and right bile ducts. It is the most common type of Cholangiocarcinoma, accounting for more than half of all cases. About 8,000 people in the US are diagnosed with Cholangiocarcinoma each year and approximately 20% of the cases are suitable for surgical resection. The 5-year survival among those with advanced stage disease is less than 10%, with limited progress made over the past two decades.

Approximately 75% of patients are diagnosed with late-stage disease, and are often treated with Gemcitabine plus Cisplatin, based on the findings of the ABC-02 study. Second line treatment options include FOLFOX regimen, which is associated with a Response Rate of about 5%, median Progression Free Survival (PFS) of about 4 months, and median Overall Survival (OS) of about 6 months. There is therefore an unmet need for new effective therapies.

FGFRs (Fibroblast Growth Factor Receptors) play an important role in tumor cell proliferation and survival, migration, and angiogenesis. Activating fusions, rearrangements, translocations, and gene amplifications in FGFRs result in dysregulation of FGFR signaling, and may contribute to the pathogenesis of various cancers, including Cholangiocarcinoma. FGFR2 fusions or rearrangements occur almost exclusively in intrahepatic Cholangiocarcinoma, where they are observed in 10-20% of patients, and have been identified as oncogenic drivers. Futibatinib is a highly selective, irreversible FGFR1-4 inhibitor, and demonstrated tolerability and preliminary evidence of clinical efficacy in patients with intrahepatic cholangiocarcinoma.

The present FDA approval was based on the results from the pivotal FOENIX-CCA2 trial (NCT02052778), which is a global, multicenter, open-label, single-arm study that enrolled 103 patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma, harboring a FGFR2 gene fusion or other rearrangement. The presence of FGFR2 fusions or other rearrangements was determined using Next Generation Sequencing testing. Patients received Futibatinib 20 mg orally once daily until disease progression or unacceptable toxicity. The median age was 58 years, 53% had an ECOG Performance Status of 1, all patients had prior anticancer therapy, with 27% receiving prior radiotherapy. FGFR2 fusions were observed in 78% of patients and 22% had a rearrangement. The median time from prior anticancer therapy to the first Futibatinib dose was 1.5 months. The Primary endpoint was Objective Response Rate (ORR) by Independent Central Review. Secondary endpoints were Duration of Response (DOR), Disease Control Rate (DCR), Progression Free Survival (PFS), Overall Survival (OS), Safety, and Patient-Reported Outcomes. At the primary analysis of this trial, an Objective Response Rate of 41.7% was observed, with a median Duration of Response of 9.7 months. The researchers herein reported updated efficacy, including mature Overall Survival, and safety data from the final analysis, with an additional 8 months of follow up.

At a median follow up of 25 months, the median number of treatment cycles was 13.0 and the median treatment duration was 9.1 months. The confirmed Objective Response Rate was 41.7%, like what was noted at the time of primary analysis, and this benefit was consistent across patient subgroups. The Disease Control Rate of 82.5% and was similar as well. The median Duration of Response was 9.5 months, and 74% of responses lasted 6 months or more. The median PFS was 8.9 months, with a 12-month PFS rate of 35%. The median Overall Survival was 20 months, with a 12-month Overall Survival rate of 73%. The most common treatment-related adverse events included hyperphosphatemia (85%), alopecia (33%), dry mouth (30%), diarrhea (28%), dry skin (27%), and fatigue (25%). Approximately 4% of patients discontinued treatment due to adverse events.

The authors concluded that the final analysis of FOENIX-CCA2 study confirmed the results of the primary analysis and reinforced the durable efficacy and continued tolerability of Futibatinib in previously treated patients with advanced/metastatic intrahepatic cholangiocarcinoma harboring FGFR2 fusion/rearrangements. They added that the mature Overall Survival far exceeded historical data in this patient population.

Updated results of the FOENIX-CCA2 trial: Efficacy and safety of futibatinib in intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusions/rearrangements. Goyal L, Meric-Bernstam F, Hollebecque A, et al. J ClinOncol. 2022;40(suppl 16):4009. doi:10.1200/JCO.2022.40.16_suppl.4009

Expansion of Cancer Risk Profile beyond Breast and Ovarian Cancer for BRCA1 and BRCA2 Pathogenic Variants

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SUMMARY: 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 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 HR repair pathway.

BRCA1 and BRCA2 are tumor suppressor genes located on chromosome 17 and chromosome 13 respectively 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. Mutations in these genes predispose an individual to develop malignant tumors.

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.

Pathogenic Variants (PVs) in BRCA1 and BRCA2 (BRCA1/2) are well known to be associated with increased lifetime risk for breast and ovarian cancer in women, and reliable risk estimates are also available and can be as high as 85% and 40% respectively. However, the association of BRCA1 and BRCA2 Pathogenic Variants with cancers other than female breast and ovarian cancers remain uncertain, and these associations have been based on studies with relatively small sample sizes, resulting in imprecise cancer risk estimates. It is therefore important that precise risk estimates are available, in order to optimize clinical management strategies and guidelines for cancer risk management in female and male BRCA1/2 carriers. The NCCN and other guidelines recommend breast and ovarian cancer screening for BRCA1/2 carriers, prostate cancer screening for BRCA2 carriers. Screening is also recommended for pancreatic cancer in BRCA1/2 carriers, but only in the presence of a positive family history of the disease.

The researchers conducted this study to evaluate the association of BRCA1 and BRCA2 pathogenic variants, with additional cancer types and their clinical characteristics associated with pathogenic variant carrier status. For this study, a large-scale registry based sequencing study was performed across 14 common cancer types in 63, 828 patients and 37, 086 controls, whose data were drawn from a Japanese nationwide multi-institutional hospital-based biobank, between 2003 and 2018. In the study group, the median age was 64 years and 42% were female, whereas the median age was 62 years and 47% were female in the control group. Germline pathogenic variants were identified in the BRCA1 and BRCA2 genes by a multiplex Polymerase Chain Reaction-based target sequence method. Associations of (likely) pathogenic variants with each cancer type were assessed by comparing pathogenic variant carrier frequency between patients in each cancer type and controls. Compared with the researchers previous publications for breast, colorectal, pancreatic, and prostate cancers, this study included 14,448 additional controls and 8247 additional cancer cases. These data thus provided a broad view of cancer risks associated with pathogenic variants in BRCA1 and BRCA2 genes.

Pathogenic variants in BRCA1 were significantly associated with increased risk for three other types of cancer types, Biliary tract (Odds Ratio–OR=17.4), Gastric (OR=5.2), and Pancreatic cancer (OR=12.6), in addition to female Breast (OR=16.1) and Ovarian cancer (OR=75.6). Pathogenic variants in BRCA2 increased risk for seven cancer types which included female Breast (OR=10.9), male Breast (OR=67.9), Gastric (OR=4.7), Ovarian (OR=11.3), Pancreatic (OR=10.7), Prostate (OR=4.0), and Esophageal cancer (OR=5.6). Further, Biliary tract, female Breast, Ovarian, and Prostate cancers showed enrichment of carrier patients according to the increased number of reported cancer types in relatives.

The results of this large study suggested that pathogenic variants in BRCA1 and/or BRCA2 are associated with increased risk of biliary tract, gastric, and esophageal cancers, higher than for European populations, granted that these cancers are known to have a higher incidence rate in East Asian countries. Conversely in this study, the cumulative risk of prostate cancer for BRCA2 carriers was lower than that estimated in the UK and Ireland, suggesting that the cumulative risk for each cancer type may be associated with the different incidence rate in each country.

The authors concluded that this study suggested that pathogenic variants in BRCA1 and BRCA2 were associated with the risk of 7 cancer types and is likely broader than that determined from previous analysis of largely European ancestry cohorts. It would therefore be useful to expand indications for genetic testing of individuals with family history of these cancer types.

Expansion of Cancer Risk Profile for BRCA1 and BRCA2 Pathogenic Variants. Momozawa Y, Sasai R, Usui Y, et al. JAMA Oncol. 2022 Apr 14: e220476. doi: 10.1001/jamaoncol.2022.0476 [Epub ahead of print]