Category: Precision Oncology

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.

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

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.

FDA Approves Quizartinib for Newly Diagnosed Acute Myeloid Leukemia

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SUMMARY: The FDA on July 20, 2023 approved Quizartinib (VANFLYTA®) with standard Cytarabine and Anthracycline induction and Cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed Acute Myeloid Leukemia (AML) that is FLT3 Internal Tandem Duplication (ITD)-positive, as detected by an FDA-approved test. FDA also approved LeukoStrat CDx FLT3 Mutation Assay as a companion diagnostic for Quizartinib.

The American Cancer Society estimates that in 2023, 20,380 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,310 patients will die of the disease. AML is one of the most common types of leukemia in adults and can be considered as a group of molecularly heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy, or have disease that is refractory to standard chemotherapy. Even with the best available therapies, the 5-year Overall Survival in patients 65 years of age or older is less than 5%. 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. More importantly, with the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.

The Fms-Like Tyrosine kinase 3 (FLT3) protein is a receptor tyrosine kinase in the PDGF family of growth factor receptors located on the hematopoietic stem cell surface (transmembrane). FLT3 normally promote cell survival, growth, and differentiation. FLT3 plays an important role in both normal and malignant hematopoiesis by activating key signaling pathways. Activating mutations in the FLT3 receptor is the most common genetic abnormality in AML. Approximately 25% of patients with newly diagnosed AML have FLT3-ITD mutations and approximately 7% have point mutations in the Tyrosine Kinase Domain (TKD). FLT3-ITD (Internal Tandem Duplication) mutation is caused by tandem duplication within the coding region of the gene. The presence of FLT3-ITD mutations can negate the benefit of any other favorable molecular and cytogenetic features. Patients with FLT3-ITD mutations have poor outcomes with shorter remission duration and significantly decreased Leukemia Free and Overall Survival.

Quizartinib is an oral, highly potent, selective, Type 2 FLT3 inhibitor. This agent in combination with chemotherapy showed antitumor activity with an acceptable safety profile in patients with FLT3-ITD-positive newly diagnosed AML.

QuANTUM-First is a randomized, double-blind, placebo controlled, global, Phase III trial in which the efficacy of Quizartinib with chemotherapy was evaluated in patients with newly diagnosed FLT3-ITD positive AML aged 18–75 years. In this study, 539 patients (N=539) with newly diagnosed FLT3-ITD positive AML were randomly assigned 1:1 to receive chemotherapy plus Quizartinib (N=268) or placebo (N=271). Treatment consisted of induction with standard 7 plus 3 induction regimen of Cytarabine 100 mg/m2 daily (or 200 mg/m2 daily per institutional standard) by continuous IV from Days 1-7 and anthracycline (Daunorubicin 60 mg/m2 daily or Idarubicin 12 mg/m2 daily, by IV infusion on Days 1, 2, and 3, then Quizartinib 40 mg orally or placebo once daily, starting on day 8, for 14 days. Patients in complete remission or complete remission with incomplete neutrophil or platelet recovery received standard consolidation with high-dose Cytarabine plus Quizartinib (40 mg orally daily) or placebo, allo- Hematopoietic Stem Cell Transplantation (HSCT), or both as consolidation therapy, followed by continuation of single-agent Quizartinib or placebo for up to 3 years. There was no re-randomization at the initiation of post-consolidation therapy. Patients who proceeded to HSCT initiated maintenance therapy after HSCT recovery. FLT3-ITD status was determined prospectively with a clinical trial assay and verified retrospectively with the companion diagnostic LeukoStrat CDx FLT3 Mutation Assay. This study included patients aged 18 to 75 years, 55% male and 45% female, with newly diagnosed primary or secondary AML harboring a FLT3-ITD activating mutation, with an allelic ratio of 3% or more. The median age was 56 years. The aim of this study was to assess the effect of Quizartinib versus placebo on Overall Survival in patients with FLT3-ITD-positive newly diagnosed AML. The Primary end point of the trial was Overall Survival (OS). Secondary end points included Event-Free Survival (EFS), post induction rates of Complete Remission (CR) rate, composite CR (CRc) rate, Safety, and pharmacokinetics.

At a median follow up of 39.2 months, the median Overall Survival was 31.9 months for Quizartinib versus 15.1 months for placebo (HR=0.78; P=0.032), a 22% reduction in the risk of death. The CR rate in the Quizartinib group was 55%, with median response duration of 38.6 months, whereas the CR rate in those receiving placebo was 55% with median response duration of 12.4 months. Approximately 42% of patients treated with Quizartinib versus 38% treated with placebo were MRD negative at the time of Complete Remission or Complete Remission with incomplete neutrophil or platelet recovery. However, patients in both groups who were MRD negative had improved Overall Survival (HR 0.57), compared with those who remained MRD positive. The most common Grade 3 or 4 adverse events were febrile neutropenia, hypokalaemia, and pneumonia in both groups, and neutropenia in the Quizartinib group.

It was concluded that the addition of Quizartinib to standard chemotherapy with or without allo-HSCT, followed by continuation monotherapy for up to 3 years, resulted in improved Overall Survival in adults patients with FLT3-ITD-positive newly diagnosed AML, and provides a new, effective, and generally well tolerated treatment option for this patient group. The authors added that this is the first time a FLT3 inhibitor was studied in patients aged 18-75 years and is specifically approved for patients who have the worst FLT3 mutation, the ITD mutation.

Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Erba HP, Montesinos P, Kim H-J, et al. on behalf of the QuANTUM-First Study Group. The Lancet 2023;401:1571-1583.

Late Breaking Abstract – ASCO 2023: Biomarker-Driven ELAHERE® Improves Survival in Platinum-Resistant Ovarian Cancer

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SUMMARY: It is estimated that in the United States, approximately 19,710 women will be diagnosed with ovarian cancer in 2023, and 13,270 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. About 85% of all ovarian cancers are epithelial in origin, and 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 (OS) 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 (ORR) 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 (FR 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. In the single-arm SORAYA trial, ELAHERE® demonstrated an ORR of 31.7% and median Duration of Response of 6.9 months, in patients with platinum-resistant ovarian cancer and prior Bevacizumab exposure. These response rates were consistently seen regardless of the number of prior therapies or the use of a prior PARP inhibitor. As a result, the FDA in November 2022 granted accelerated approval to ELAHERE®.

MIRASOL is a confirmatory randomized Phase III trial, conducted to evaluate the efficacy and safety of ELAHERE® versus Standard-of-Care chemotherapy, in patients with pretreated, platinum-resistant ovarian, peritoneal, or fallopian tube cancer, whose tumors express high levels of FR alpha. In this study, 453 eligible patients (N=453) were randomized 1:1 to receive ELAHERE® 6 mg/kg (based on adjusted ideal body weight) IV infusion once every three weeks, until disease progression or unacceptable toxicity (N=227), or investigators choice of single-agent chemotherapy – Paclitaxel, Pegylated Liposomal Doxorubicin, or Topotecan (N=226)). Both treatment groups were well balanced. Approximately 13% of patients had BRCA mutations, 14% of patients had one prior line of therapy, 39% had two prior lines and 47% had three prior lines of therapy. About 62% received prior Bevacizumab and 55% received prior therapy with PARP inhibitors. The Primary efficacy endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Response Rate (ORR), Overall Survival (OS), and Patient-Reported Outcomes in hierarchical order, as well as Safety and tolerability. The median follow up was 13.1 months.

This study met its Primary and key Secondary endpoints with statistically significant improvement in PFS, ORR and OS. The PFS in the ELAHERE® group was 5.62 months compared to 3.98 months in the chemotherapy group (HR=0.65; P<0.0001). The ORR was also higher in the ELAHERE® group at 42% compared with 16% in the chemotherapy group (P<0.0001). The median Overall Survival rate was 16.46 months among patients who received ELAHERE® compared with 12.75 months among those who received single-agent chemotherapy (P=0.0046). The PFS and OS outcomes favored the ELAHERE® group, irrespective of prior exposure to Bevacizumab. Treatment with ELAHERE® was associated with a lower rate of Grade 3 or more Adverse Events and a lower discontinuation rate (9% compared with 16% for the chemotherapy group). The most common adverse reactions including laboratory abnormalities associated with ELAHERE® 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 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 treatment with ELAHERE® demonstrated a statistically significant improvement in Progression Free Survival and Overall survival, compared to chemotherapy, in patients with platinum-resistant ovarian cancer and high FR alpha expression, independent of Bevacizumab use, and may be the new standard-of-care for this patient group. ELAHERE® is the first FDA-approved Antibody Drug Conjugate and biomarker directed therapy for ovarian cancer, since the approval of PARP inhibitors.

Phase III MIRASOL (GOG 3045/ENGOT-ov55) study: Initial report of mirvetuximab soravtansine vs. investigator’s choice of chemotherapy in platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate receptor-alpha expression. Moore KN, Angelergues A, Konecny GE, et al. J Clin Oncol 41, 2023 (suppl 17; abstr LBA5507)

Late Breaking Abstract – ASCO 2023: Overall Survival with TAGRISSO® in Resected EGFR-Mutated NSCLC

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SUMMARY: 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 (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.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations and 90% of these mutations are either Exon 19 deletions or L858R substitution mutation in Exon 21. Approximately 25% of patients with EGFR mutated NSCLC have brain metastases at diagnosis, increasing to approximately 40% within two years of diagnosis. The presence of brain metastases often reduces median survival to less than eight months. EGFR-Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib), IRESSA® (Gefitinib) and GILOTRIF® (Afatinib), have demonstrated a 60-70% response rate as monotherapy when administered as first line treatment, in patients with metastatic NSCLC, who harbor the sensitizing EGFR mutations. However, majority of these patients experience disease progression within 9-14 months. This resistance to frontline EGFR TKI therapy has been attributed to the most common, acquired T790M “gatekeeper” point mutation in EGFR, identified in 50-60% of patients.

TAGRISSO® (Osimertinib) is a highly selective third-generation Epidermal Growth Factor Receptor (EGFR) TKI presently approved by the FDA, for the first-line treatment of patients with metastatic NSCLC, whose tumors have Exon 19 deletions or Exon 21 L858R mutations, as well as treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, whose disease has progressed on or after EGFR-TKI therapy. Further, TAGRISSO® has higher CNS penetration and is therefore able to induce responses in 70-90% of patients with brain metastases. Among patients with metastatic, EGFR-mutant NSCLC, first-line treatment with TAGRISSO® significantly improved median Overall Survival, compared with TARCEVA® and IRESSA®, and should therefore be considered the preferred regimen.

Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with platinum-based adjuvant chemotherapy to decrease the risk of recurrence. Nonetheless, 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

ADAURA is a global, double-blind, randomized Phase III study, which assessed the efficacy and safety of TAGRISSO® versus placebo in patients with Stage IB–IIIA EGFR mutated NSCLC, after complete tumor resection and adjuvant chemotherapy, when indicated. In this study, 682 patients with completely resected Stage IB, II, IIIA NSCLC, with or without postoperative adjuvant chemotherapy, were randomly assigned 1:1 to receive either TAGRISSO® 80 mg orally once daily (N=339) or placebo (N=343) once daily, for up to 3 years. Eligible patients had an ECOG Performance Status of 0 or 1, with confirmed EGFR mutations (Exon 19del or L858R). Treatment groups were well balanced and patients were stratified by Stage (IB/II/IIIA), mutation type (Exon 19del/L858R), and race (Asian/non-Asian). Most patients with Stage II to IIIA disease (76%) and approximately a quarter of the patients with Stage IB disease (26%) received adjuvant platinum-based chemotherapy. The Primary endpoint was Disease Free Survival (DFS) in Stage II–IIIA patients. Secondary endpoints included DFS in the overall population of patients with Stage IB to IIIA disease, Overall Survival (OS) and Safety. Following Independent Data Monitoring Committee recommendation, the trial was unblinded early, due to efficacy.

The FDA approved TAGRISSO® for use as adjuvant treatment in late 2020 based on the primary analysis data demonstrating that in the patients with Stage II/IIIA disease, the DFS had not been reached with TAGRISSO® versus 19.6 months with placebo (HR=0.17; P<0.001). This was equal to an 83% reduction in the risk of recurrence or death, indicating a significantly longer DFS among patients in the TAGRISSO® group, compared to those in the placebo group. The 2-year DFS rate in this patient group with TAGRISSO® was 90% versus 44% with placebo. In the overall population, which included Stage IB to IIIA disease, the median DFS was not reached with TAGRISSO® versus 27.5 months with placebo (HR=0.20; P<0.001). This Hazard Ratio equaled to an 80% reduction in the risk of disease recurrence or death among patients in the TAGRISSO® group compared to those in the placebo group. The 2-year DFS rate in the overall population was 89% with TAGRISSO® versus 52% with placebo. Updated data presented at the 2022 ESMO Congress showed that at a median follow up of 44.2 months, the DFS with TAGRISSO® was still robust at 77% in patients with Stage II/IIIA disease and 73% in the overall Stage IB-IIIA population.

The researchers herein reported the planned final Overall Survival (OS) analysis from ADAURA. Adjuvant TAGRISSO® significantly improved OS compared to placebo and reduced the risk of death by 51% compared to placebo in both Stages II-IIIA (HR for OS=0.49; P=0.0004), and in the overall Stages IB-IIIA trial population (HR=0.49; P<0.0001). This survival benefits with TAGRISSO® was seen, regardless of whether prior adjuvant chemotherapy was received. The 5-year OS rate was 88% in the TAGRISSO® group and 78% in the placebo group. Median OS was not reached in either population or treatment group. The safety profile with adjuvant TAGRISSO® was consistent with that in the primary analysis.

It was concluded that adjuvant TAGRISSO® demonstrated an unprecedented, highly statistically significant and clinically meaningful Overall Survival benefit in patients with EGFR mutated Stage IB–IIIA NSCLC after complete tumor resection, with or without adjuvant chemotherapy. The authors added that ADAURA is the first global Phase III study to demonstrate a statistically significant Disease Free Survival and Overall Survival benefit with targeted treatment for this patient group, reinforcing the importance of testing for biomarkers at the time of diagnosis and before starting therapy.

Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC. Tsuboi M, Herbst RS, John T, et al., for the ADAURA Investigators. June 4, 2023. DOI: 10.1056/NEJMoa2304594

HER2DX Genomic Assay Predicts Pathological Response in Early Stage HER2-Positive Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence.

The HER or ERBB family of receptors, consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with HER2-positive breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes.

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

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

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

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

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

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

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

ORSERDU® for ESR-1 Mutated Advanced Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay, for the management of ER+/HER2-negative metastatic breast cancer, as first line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression, including the development of ESR1 (Estrogen Receptor gene alpha) mutations.

ESR1 (Estrogen Receptor 1) gene mutation is the most common acquired mutation noted in breast tumors as they progress from primary to metastatic setting. These mutations promote ligand independent Estrogen Receptor activation and have been shown to promote resistance to estrogen deprivation therapy. It appears that ESR1 mutations are harbored in metastatic ER-positive breast cancers with prior Aromatase Inhibitor (AI) therapy, but not in primary breast cancers, suggesting that ESR1 mutations may be selected by prior therapy with an AI in advanced breast cancer. In a previously published study (JAMA Oncol.2016;2:1310-1315), ESR1 mutations Y537S and D538G mutations detected in baseline plasma samples from ER+/HER- advanced breast cancer patients, was associated with shorter Overall Survival. In this study it was noted that there was a three-fold increase in the prevalence of these mutations in patients who had failed first line hormonal therapy for metastatic disease, compared with those who were initiating first line therapy for advanced breast cancer (33% versus 11%). It is estimated that 40% of ER-positive, HER2-negative advanced or metastatic breast cancer patients have tumors that harbor ESR1 mutations. It is best to test for ESR1 mutations with a liquid biopsy following progression on an AI and CDK 4/6 inhibitor.

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

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

EMERALD trial is a multicenter, International, randomized, open-label, Phase III study, designed to evaluate the benefit of ORSERDU® in patients with ER+/HER2- advanced or metastatic breast cancer. In this study, 478 postmenopausal women with ER+/HER2- metastatic breast cancer were randomly assigned 1:1 to receive either ORSERDU® 400 mg orally daily (N=239) or the Standard of Care which included investigator’s choice of Fulvestrant or an Aromatase Inhibitor including Anastrozole, Letrozole, or Exemestane (N=239). Treatment was given until disease progression. Both treatment groups were well balanced. The median patient age was 63 years, and patients must have progressed or relapsed on or after 1 or 2 lines of endocrine therapy for advanced disease, one of which was given in combination with a CDK4/6 inhibitor, had 1 or fewer lines of chemotherapy for advanced disease, and had an ECOG performance status of 0 or 1. ESR1 mutational status was determined by blood circulating tumor deoxyribonucleic acid (ctDNA) using the Guardant360 CDx assay and was limited to ESR1 missense mutations in the ligand binding domain. In the study, 48% (N=228) had tumors with mutated ESR1 and 43% received two prior endocrine therapies. These patients were evenly distributed in both treatment groups. Patients were stratified by ESR1-mutation status, prior treatment with Fulvestrant, and visceral metastases. The co-Primary end points were Progression Free Survival (PFS) in the overall population, and in those with ESR1 mutations. Overall Survival (OS) was a Secondary end point.

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

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

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

 

ctDNA Analysis in Resectable Colorectal Cancer and Efficacy of Adjuvant Chemotherapy

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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.

It is estimated that approximately 30% of patients with Stage II or III CRC and 60–70% of patients after oligometastatic resection experience recurrence. Adjuvant chemotherapy for patients with resected, locally advanced, node-positive (Stage III) colon cancer has been the standard of care since the 1990s. However, not all patients with Stage III disease benefit from adjuvant chemotherapy. In the IDEA trial, the absolute Disease Free Survival benefit of adjuvant chemotherapy for the lowest-risk Stage III group and the highest-risk group was 8% and 20%, respectively, suggesting that a substantial number of patients with low-risk Stage III cancer can safely forgo adjuvant chemotherapy or be considered for treatment de-escalation. Even though 80% of patients with Stage II colon cancer are cured with surgery alone, adjuvant chemotherapy is recommended for patients who have Stage II colon cancer with high-risk clinicopathological features, including tumor penetration of the serosa (T4 disease). However, the benefit of adjuvant chemotherapy for patients with Stage II disease remains unclear, with less than 5% of patients benefiting from adjuvant chemotherapy. There is therefore an unmet need for more precise markers to predict risk of recurrence after surgery for resectable colon cancer, other than clinicopathological risk factors, and thus avoid exposure to unnecessary chemotherapy.

Circulating Tumor DNA (ctDNA) refers to DNA molecules that circulate in the bloodstream after cell apoptosis or necrosis, and can be detected in the cell-free component of peripheral blood samples (Liquid Biopsy) in almost all patients with advanced solid tumors including advanced colorectal cancer. ctDNA is a valuable biomarker and is directly evaluated for evidence of Minimal Residual Disease and allows early detection of relapse. Several studies have shown that detectable ctDNA following curative intent surgery for early stage cancers, including those with Stage II colon cancer, is associated with a very high risk of recurrence (more than 80%) without further adjuvant therapy. It has remained unclear whether adjuvant treatment is beneficial for these ctDNA-positive patients who are at high risk for recurrence.

The GALAXY study/cohort is a part of the CIRCULATE-Japan project, and is a large prospective, observational study that monitors ctDNA status for patients with clinical Stage II-IV or recurrent colorectal cancer following curative-intent surgery. In order to prospectively validate and build upon the previously published evidence, the authors conducted this cohort study to demonstrate that postsurgical ctDNA positivity is predictive of disease recurrence in early-stage CRC. In this publication the researchers reported on postsurgical ctDNA positivity and its associations with patient outcomes, as well as its implications for adjuvant chemotherapy selection, and the association between ctDNA dynamics and prognosis.

The GALAXY study/cohort included 1039 patients with clinical Stage II-III colon cancer or surgically resectable clinical Stage IV or recurrent colorectal cancer. Eligible patients had histologically confirmed colorectal adenocarcinoma, and curative resection planned for clinical Stage II or III, and R0 resection planned for relapsed or Stage IV colorectal cancer. The median age was 69 years. Formalin-Fixed, Paraffin-Embedded (FFPE) tumor tissue samples from surgical resection or biopsy were used for Whole Exome Sequencing (WES) to identify up to 16 patient-specific clonal, somatic Single-Nucleotide Variants (SNVs). These SNVs were then used to design personalized multiplex Polymerase Chain Reaction-based Next-Generation Sequencing assays (Signatera, Natera) for each study participant. Cell-free DNA was extracted from patient plasma at a given time point and was used to detect ctDNA. Plasma samples with at least 2 out of 16 tumor-specific variants detected above a predefined threshold were defined as ctDNA positive (tumor-informed ctDNA analysis. Overall, a total of 8,374 genes were selected for the 1,039 patients and the most frequently selected genes were TP53 (25.6%) and APC (17.5%). It was noted that more than 50% of genes were unique to each patient, suggesting large variability in the mutational landscape of colorectal cancer outside of known hotspot regions.

At a median follow-up of 16.74 months, postsurgical ctDNA positivity at 4 weeks after surgery was associated with higher recurrence risk compared to those patients who were ctDNA negative (61.4% versus 9.5%; HR=10.0, P< 0.0001) and the 18-month Disease Free Survival (DFS) was 38.4% versus 90.5%, respectively. This benefit was noted across all pathological stages. There was however no significant difference in recurrence risk by presurgical ctDNA status across all stages. In multivariate analysis for DFS in patients with pathological Stage II–III disease, ctDNA positivity 4 weeks after surgery was the most significant prognostic factor associated with increased risk for recurrence (HR=10.82, P< 0.001). Further, clinicopathological risk factors often used for staging and prognostication were nonsignificant. ctDNA was more valuable than CEA for relapse detection.

The researchers in this analysis examined the outcomes of ctDNA-positive and ctDNA-negative patients stratified by adjuvant chemotherapy status after adjusting for confounding variables such as age, sex, MSI status, pathological stage, and performance status in this analysis.

It was noted that patients with high-risk Stage II or Stage III disease and ctDNA-positive status 4 weeks after surgery derived significant benefit from adjuvant chemotherapy (adjusted HR=6.59; P< 0.001), and this trend was observed across all pathological stages. ctDNA-positive patients with Stage II–IV disease, not receiving adjuvant chemotherapy were noted to be at a higher risk for recurrence (adjusted HR=5.03; P< 0.001). Approximately 75% of ctDNA-positive patients with pathological Stage I or low-risk Stage II disease did not receive adjuvant chemotherapy and experienced recurrence.

Among the high-risk pathological Stage II or Stage III disease patients with ctDNA-negative status 4 weeks after surgery, there was no statistically significant benefit with adjuvant chemotherapy and the 18-month DFS was 94.9% and 91.5% for the adjuvant chemotherapy group and the observation group, respectively.

Among patients with available ctDNA status both 4 weeks and 12 weeks after surgery, there was a significantly higher risk of recurrence among patients who converted from ctDNA negative to positive, compared to those patients who were persistently negative (HR=14.0; P< 0.001).

Among the patients with ctDNA positivity 4 weeks after surgery, adjuvant chemotherapy was associated with a higher incidence of ctDNA clearance by week 24 after surgery compared with those who did not receive adjuvant therapy (68.48% versus 12.2%; adjusted HR=8.50, P< 0.0001). Among those who did not achieve ctDNA clearance, the DFS was inferior (adjusted HR=11; P< 0.0001).

Based on the results of this large and comprehensive prospective analysis of ctDNA in resectable colorectal cancer, the authors concluded that ctDNA status is a superior prognostic biomarker than the currently used high-risk clinicopathological features, and can identify patients who are at increased risk of recurrence and are likely to benefit from adjuvant chemotherapy.

Molecular residual disease and efficacy of adjuvant chemotherapy in patients with colorectal cancer. Kotani D, Oki E, Nakamura Y, et al. Nature Medicine 2023; 29:127–134.

Biomarkers May Predict Response to Enfortumab Vedotin in Advanced Urothelial Cancer

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SUMMARY: The American Cancer Society estimates that in 2023, approximately 82,290 new cases of Bladder Cancer will be diagnosed and 16,710 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. A third of the patients initially present with locally invasive or metastatic disease. Patients with urothelial carcinoma are currently treated in the first line setting with a Platinum based chemotherapy regimen and a checkpoint Inhibitor (PD-1 or PD-L1 inhibitor) in the second line setting. Treatment options for patients who progress after first and second line therapies are limited, with poor outcomes. The response rates with standard chemotherapy in this patient population, is about 10%. Approximately 50% of patients with advanced urothelial carcinoma are ineligible for Cisplatin-based chemotherapy. There is therefore a critical need for effective and tolerable first line treatment options in locally advanced or metastatic Urothelial Carcinoma.

Enfortumab vedotin-ejfv (PADCEV®) is an Antibody-Drug Conjugate (ADC) that targets Nectin-4, a cell adhesion molecule highly expressed in urothelial cancers and other solid tumors. Nectin-4 has been implicated in tumor cell growth and proliferation. Following binding to Nectin-4 on the cell surface, Enfortumab vedotin becomes internalized and is processed by lysosomes, with the liberation of its cytotoxic payload, Monomethyl auristatin E, which in turn disrupts microtubule assembly, leading to cell cycle arrest and apoptosis. Enfortumab vedotin resulted in significantly longer Overall Survival, Progression Free Survival, and a higher Overall Response Rate, than standard chemotherapy, in patients with locally advanced or metastatic urothelial carcinoma, who had previously received Platinum-based treatment and a PD-1 or PD-L1 inhibitor. However there are limited data available on biomarkers predictive of outcomes when treated with Enfortumab vedotin.

The researchers in this study investigated potential biomarkers of response to Enfortumab vedotin by analyzing data from the UNITE (Urothelial Cancer Network to Investigate Therapeutic Experiences) database. This analysis include 170 patients from 16 different sites, with available Next Generation Sequencing using institutional or commercial platforms, treated with Enfortumab vedotin alone, outside of a clinical trial setting, for whom outcomes were available. The median age was 70 years, 78% were men, 65% had pure urothelial histology, 69% had primary bladder tumor, and 68% had 2 or more lines of therapy before Enfortumab vedotin.

The following molecular biomarkers were assessed: Tumor Mutation Burden (TMB), PD-L1 status, presence of 1 or more DNA damage response mutations such as BRCA1, BRCA2, PALB2, ATM, CHEK2, CDK12, BARD1, PPP2R2A, or RAD51B, and somatic alterations such as TERTp, TP53, ARID1A, CDKN2A, CDKN2B, FGFR3, ERBB2, CCND1, KDM6A, MTAP, PIK3CA, RB1, TSC1, in 10% or more of patients. Investigators determined observed response to Enfortumab vedotin in patients with scans after one or more doses of the therapy.

For all patients included in this analysis, the Observed Response Rate was 47%, median Progression Free Survival was 6 months and median Overall Survival was 12 months. The Observed Response Rates were higher in patients with ERBB2 and TSC1 alterations versus wild-type (67% versus 44%; P=0.05 and 68% versus 25%; P=0.04, respectively). Shorter median Progression Free Survival was noted in patients with CDKN2A, CDKN2B, and MTAP alterations, whereas patients with high Tumor Mutation Burden (10 or more Mut/Mb) had longer median Overall Survival.

It was concluded that analysis of this large, multicenter, retrospective cohort of patients with advanced urothelial carcinoma, identified several potential biomarkers associated with differential outcomes to Enfortumab vedotin, and these findings may help inform clinical decision making and potential therapy sequencing.

Biomarkers of response to enfortumab vedotin (EV) in patients (pts) with advanced urothelial carcinoma (aUC): Analysis of the UNITE study. Jindal T, Kilari D, Alhalabi O, et al.DOI: 10.1200/JCO.2023.41.6_suppl.450 Journal of Clinical Oncology.