Author: RR

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

RR

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

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

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

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

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

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

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

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

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

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

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

Approximately 20% of cancer patients develop VTE and about 20% of all VTE cases occur in patients with cancer. There is a two-fold increase in the risk of recurrent thrombosis in patients with cancer, compared with those without cancer, and patients with cancer and VTE are at a markedly increased risk for morbidity and mortality. The high risk of recurrent VTE, as well as bleeding in this patient group, makes anticoagulant treatment challenging. Treatment with parenteral Low Molecular Weight Heparin (LMWH) preparations is often recommended for this patient group, based on efficacy data. LMWH activates antithrombin, which in turn accelerates the inactivation of coagulation enzymes thrombin (Factor IIa), Factor Xa and Factor IXa. Parenteral LMWH however can be inconvenient and expensive, leading to premature discontinuation of treatment.

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

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

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

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

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

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

Targeting ESR1 Mutations in Estrogen-Positive Advanced Breast Cancer

RR

Written By: Debra Patt, MD, PhD, MBA

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

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

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

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

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

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

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

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

FDA Approves LONSURF® with Bevacizumab for Advanced Refractory Colorectal Cancer

RR

SUMMARY: The FDA on August 2, 2023, approved LONSURF® (Trifluridine and Tipiracil with Bevacizumab, for metastatic ColoRectal Cancer (mCRC) previously treated with Fluoropyrimidine, Oxaliplatin and Irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 153,020 new cases of CRC will be diagnosed in the United States in 2023 and about 52,550 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23.

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

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

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

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

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

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

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

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

RR

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