Medication-Related Osteonecrosis of the Jaw: MASCC/ISOO/ASCO Clinical Practice Guideline Summary

January 17th, 2020
SUMMARY: Medication-Related OsteoNecrosis of the Jaw (MRONJ) is defined as progressive bone destruction in the maxillofacial region resulting in exposed bone, or bone that can be probed through an intraoral or extraoral fistula (or fistulae) in the maxillofacial region and that does not heal within 8 weeks, occurring in a patient who has received a Bone-Modifying Agent (BMA) or an angiogenic inhibitor agent and with no history of head and neck radiation. The condition may involve the mandible or the maxilla and can be challenging to treat and can cause significant pain, impacting patients quality of life.
BMAs that have been linked with MRONJ principally include bisphosphonates such as Zoledronic acid and Pamidronate and Rank Ligand inhibitor, Denosumab. BMAs are an integral part of cancer management and have essential roles in supportive oncology for the treatment of hypercalcemia of malignancy and bone metastases, and prevention of skeletal-related events such as pathologic fractures and reduce the need for radiation or surgical intervention. BMAs disrupt the bone remodeling cycle by reducing osteoclast survival and function.
The incidence of MRONJ in the osteoporosis patient population is very low and majority of the MRONJ cases occur in the oncology patient population receiving high doses of BMAs and prevalence has been estimated to be as high as 18.6%. The incidence in cancer patients appears to be related to dose and duration of exposure to BMAs. Bisphosphonates-related ONJ occurs after a mean IV administration of 33 months in cancer patients, whereas Denosumab-related ONJ occurs early after treatment, independent of the number of previous administrations. Risk factors for ONJ while on BMAs include smoking, poor oral hygiene, ill-fitting dentures, invasive dental procedures, and uncontrolled diabetes. Chemotherapeutic agents such as angiogenesis inhibitors, Tyrosine Kinase Inhibitors, mTOR inhibitors and immunotherapeutic agents have also been implicated.
The expert panel including representatives from ASCO, the Multinational Association of Supportive Care in Cancer, and the International Society of Oral Oncology outlined best practice recommendations for the prevention and management of MRONJ in patients with cancer who receive BMAs for oncologic indications, following a systematic review of the medical literature. Given the paucity of high-quality evidence, a majority of the recommendations are based on consensus using ASCO’s formal consensus process. The guideline does not address BMAs used for osteoporosis, which are administered at a lower dose and carry a lower risk for MRONJ.
Medication-Related Osteonecrosis of the Jaw: MASCC/ISOO/ASCO Clinical Practice Guideline Summary
Guideline Question: What are the recommended best practices for preventing and managing medication-related osteonecrosis of the jaw (MRONJ) in patients with cancer?
Target Population: Adult patients with cancer who are receiving Bone-Modifying Agents (BMAs) for any oncologic indication.
Target Audience: Oncologists and other physicians, dentists, dental specialists, oncology nurses, clinical researchers, oncology pharmacists, advanced practitioners, and patients with cancer.
Clinical Question 1. What is the preferred terminology and definition for OsteoNecrosis of the Jaw (maxilla and mandible) associated with pharmacologic therapies in oncology patients?
Recommendation 1.1. It is recommended that the term Medication-Related OsteoNecrosis of the Jaw (MRONJ) be used when referring to bone necrosis associated with pharmacologic therapies.
Recommendation 1.2. Clinicians should confirm the presence of all three of the following criteria to establish a diagnosis of MRONJ – a) Current or previous treatment with a BMA or angiogenic inhibitor b) Exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region and that has persisted for longer than 8 weeks c) No history of radiation therapy to the jaws or metastatic disease to the jaws
Clinical Question 2. What steps should be taken to reduce the risk of MRONJ?
Recommendation 2.1. (Coordination of care.) For patients with cancer who are scheduled to receive a BMA in a non-urgent setting, oral care assessment (including a comprehensive dental, periodontal, and oral radiographic exam when feasible to do so) should be undertaken before initiating therapy. On the basis of the assessment, a dental care plan should be developed and implemented. The care plan should be coordinated between the dentist and the oncologist to ensure that medically necessary dental procedures are undertaken before initiation of the BMA. Follow-up by the dentist should then be performed on a routine schedule (eg, every 6 months) once therapy with a BMA has commenced.
Recommendation 2.2. (Modifiable risk factors.) Members of the multidisciplinary team should address modifiable risk factors for MRONJ with the patient as early as possible. These risk factors include poor oral health, invasive dental procedures, ill-fitting dentures, uncontrolled diabetes mellitus, and tobacco use.
Recommendation 2.3. (Elective dentoalveolar surgery.) Elective dentoalveolar surgical procedures (eg, non–medically necessary extractions, alveoloplasties, and implants) should not be performed during active therapy with a BMA at an oncologic dose. Exceptions may be considered when a dental specialist with expertise in prevention and treatment of MRONJ has reviewed the benefits and risks of the proposed invasive procedure with the patient and the oncology team.
Recommendation 2.4. (Dentoalveolar surgery follow-up.) If dentoalveolar surgery is performed, patients should be evaluated by the dental specialist on a systematic and frequently scheduled basis (eg, every 6 to 8 weeks) until full mucosal coverage of the surgical site has occurred. Communication with the oncologist regarding status of healing is encouraged, particularly when considering future use of BMA.
Recommendation 2.5. (Temporary discontinuation of BMAs before dentoalveolar surgery.) For patients with cancer who are receiving a BMA at an oncologic dose, there is insufficient evidence to support or refute the need for discontinuation of the BMA before dentoalveolar surgery. Administration of the BMA may be deferred at the discretion of the treating physician, in conjunction with discussion with the patient and the oral health provider.
Clinical Question 3. How should MRONJ be staged?
Recommendation 3.1. A well-established staging system should be used to quantify the severity and extent of MRONJ and to guide management decisions. Options include the 2014 American Association of Oral and Maxillofacial Surgeons staging system, the Common Terminology Criteria for Adverse Events version 5.0, and the 2017 International Task Force on Osteonecrosis of the Jaw staging system for MRONJ. The same system should be used throughout the patient’s MRONJ course of care. Diagnostic imaging may be used as an adjunct to these staging systems.
Recommendation 3.2. Optimally, staging should be performed by a clinician experienced with the management of MRONJ
Clinical Question 4. How should MRONJ be managed?
Recommendation 4.1. (Initial treatment of MRONJ.) Conservative measures compose the initial approach to treatment of MRONJ. Conservative measures may include antimicrobial mouth rinses, antibiotics if clinically indicated, effective oral hygiene, and conservative surgical interventions (eg, removal of a superficial bone spicule).
Recommendation 4.2. (Treatment of refractory MRONJ.) Aggressive surgical interventions (eg, mucosal flap elevation, block resection of necrotic bone, soft tissue closure) may be used if MRONJ results in persistent symptoms or affects function despite initial conservative treatment. Aggressive surgical intervention is not recommended for asymptomatic bone exposure. In advance of the aggressive surgical intervention, the multidisciplinary care team and the patient should thoroughly discuss the risks and benefits of the proposed intervention.
Clinical Question 5. Should BMAs be temporarily discontinued after a diagnosis of MRONJ has been established?
Recommendation 5. For patients diagnosed with MRONJ while being treated with BMAs, there is insufficient evidence to support or refute the discontinuation of the BMAs. Administration of the BMA may be deferred at the discretion of the treating physician, in conjunction with discussion with the patient and the oral health provider.
Clinical Question 6. What outcome measures should be used in clinical practice to describe the response of the MRONJ lesion to treatment?
Recommendation 6. During the course of MRONJ treatment, the dentist or dental specialist should communicate with the medical oncologist the objective and subjective status of the lesion (ie, resolved, improving, stable, or progressive). The clinical course of MRONJ may impact local and/or systemic treatment decisions with respect to cessation or recommencement of BMAs.
The Multinational Association of Supportive Care in Cancer, International Society of Oral Oncology, and ASCO believe that cancer clinical trials are vital to inform medical decisions and improve cancer care, and that all patients should have the opportunity to participate.
Medication-Related Osteonecrosis of the Jaw: MASCC/ISOO/ASCO Clinical Practice Guideline Summary. Shapiro CL, Yarom N, Peterson DE, et al. J Oncol Practice 2019;15: 603-606.

CDK4/6 Inhibitors May Replace Chemotherapy in HR-Positive, HER2-Negative Metastatic Breast Cancer

January 17th, 2020
SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 279,100 new cases of invasive breast cancer will be diagnosed in 2020 and about 42,690 individuals will die of the disease. Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and 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. Cyclin Dependent Kinases (CDK) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies.Cell-Cycle-Inhibition-by-CDK4/6-Inhibitors
Cyclin Dependent Kinases 4 and 6 (CDK4 and CDK6) phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity and phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in hormone receptor positive breast cancer, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. The understanding of the role of Cyclin Dependent Kinases in the cell cycle, has paved the way for the development of CDK inhibitors.
Even though major international oncology treatment guidelines recommend a sequence of endocrine based therapies with or without targeted therapies in postmenopausal women with HR-positive, HER2-negative metastatic breast cancer, Real-World Data suggests that upfront use of chemotherapy remains common even in the absence of visceral crisis. This treatment approach may partly be due to paucity of data directly comparing hormonal therapies with chemotherapy regimens, in this patient group. To provide guidance with additional evidence, the authors conducted a comprehensive systematic review and network meta-analysis to evaluate the efficacy and activity of several first or second line hormonal therapy and chemotherapy regimens that have been investigated in randomized controlled trials, and the researchers aimed to compare these two different approaches.
This analysis included all Phase II and III randomized controlled trials investigating chemotherapy with or without targeted therapies and hormone therapies with or without targeted therapies as first-line or second-line treatments, or both, in postmenopausal women with HR-positive, HER2-negative metastatic breast cancer. Relevant examples of new targeted therapies are mTOR inhibitor Everolimus (AFINITOR®), CDK4/6 inhibitors Palbociclib (IBRANCE®), Ribociclib (KISQALI®) and Abemaciclib (VERZENIO®), and PI3K inhibitor Alpelisib (PIQRAY®), which are used in combination with endocrine therapy. Following a literature search on PubMed, Embase, Cochrane Central Register of Clinical Trials, Web of Science, and online archives of the most relevant international oncology conferences published between Jan 1, 2000 and Dec 31, 2017, 140 studies were selected, comprising of 50,029 patients. Studies exclusively enrolling premenopausal patients and those with HER2-positive or triple-negative breast cancer were excluded from this analysis. The median age was 58 yrs and median follow up was 20 months. All treatments were compared to Anastrozole (ARIMIDEX®) and to CDK4/6 inhibitor Palbociclib (IBRANCE®) plus Letrozole (FEMARA®). The Primary outcome was Progression Free Survival (PFS) and the Secondary outcome was Overall Response Rate.
In this analysis, it was noted that CDK4/6 inhibitors and PIK3K inhibitor (in patients with PIK3CA mutation) along with endocrine therapy was superior to standard endocrine therapy such as Anastrozole alone or Fulvestrant (FASLODEX®) alone, with significantly better PFS. Chemotherapy regimens with or without targeted agents were not significantly better than CDK4/6 inhibitors plus endocrine therapy. Further, the combination of CDK4/6 inhibitors plus endocrine therapy was associated with a favorable toxicity profile compared to chemotherapy. There were no significant differences noted in PFS among the three CDK4/6 inhibitors in combination with an Aromatase Inhibitor or Fulvestrant.
The authors concluded that in the first and second line setting, CDK4/6 inhibitors plus endocrine therapies are superior to standard single agent endocrine therapies in terms of Progression Free Survival. Moreover, no chemotherapy regimen with or without targeted therapy is significantly better than CDK4/6 inhibitors plus endocrine therapies in terms of Progression Free Survival. The researchers added that this is the first study to directly compare all three CDK4/6 inhibitors combined with an Aromatase Inhibitor or Fulvestrant. Endocrine treatment versus chemotherapy in postmenopausal women with hormone receptor-positive, HER2-negative, metastatic breast cancer: a systematic review and network meta-analysis. Giuliano M, Schettini F, Rognoni C, et al. Lancet Oncol. 2019;20:1360-1369.

Circulating Tumor DNA in the Peripheral Blood Predicts Recurrence Risk After Surgery and Adjuvant Chemotherapy in Stage III Colon Cancer

January 10th, 2020
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 145,600 new cases of CRC were diagnosed in the United States in 2019 and about 51,020 patients died of the disease. The lifetime risk of developing CRC is about 1 in 23. Adjuvant chemotherapy for patients with resected, locally advanced, node-positive (Stage III) colon cancer has been the standard of care since the 1990s. Adjuvant treatment with an ELOXATIN® (Oxaliplatin) based chemotherapy regimen has been considered standard intervention since 2004, for patients with Stage III colon cancer, following surgical resection, and has been proven to decrease the chance of recurrent disease. Chemotherapy regimens have included (FOLFOX – Leucovorin, 5-FluoroUracil, ELOXATIN®) or CAPOX/XELOX (XELODA®/Capecitabine and ELOXATIN®), given over a period of 6 months. In spite of these advancements, defining patient subsets at high risk of recurrence following standard adjuvant therapy remains challenging and treatment failure can only be acknowledged when clinical recurrence is documented.
Cell-free DNA (cfDNA) refers to DNA molecules that circulate in the bloodstream after cell apoptosis or necrosis. A specific portion of cfDNA that originates from tumor cells is referred to as circulating tumor DNA (ctDNA), which can be detected in the cell-free component of peripheral blood samples in almost all patients with advanced solid tumors including advanced colorectal cancer. ctDNA is a valuable biomarker and allows early detection of relapse. Several studies have shown that detectable ctDNA following surgery for early stage cancers, is associated with a very high risk of recurrence. The authors in this publication report on the results of a correlative biomarker study in patients with Stage III colon cancer, undergoing standard adjuvant chemotherapy.
A multicenter, population-based, cohort study was conducted to determine whether serial post-surgical and post-chemotherapy ctDNA analysis could provide a real-time indication of efficacy of adjuvant therapy in Stage III colon cancer. In this study, 100 patients with newly diagnosed Stage III colon cancer who were planned to receive 24 weeks of adjuvant chemotherapy were enrolled. Patients had R0 resection with no evidence of metastatic disease on staging CT of the chest, abdomen, and pelvis before surgery. The chemotherapy regimen was chosen by the treating physician, who was blinded to the ctDNA result. High-risk patients were defined as those having pT4 and/or pN2 disease according to the pTNM staging system. Blood samples for ctDNA and CEA (CarcinoEmbryonic Antigen) analysis were collected 4-10 weeks after surgery prior to commencement of adjuvant chemotherapy and at the completion of adjuvant therapy, within 6 weeks of the final cycle of chemotherapy. All patients had a surveillance CT scan 4-8 weeks after completion of adjuvant chemotherapy. Follow up surveillance included clinical exam every 3 months along with CEA measurement and annual CT imaging for 3 years. Serial plasma samples were collected after surgery and after chemotherapy. Somatic mutations in individual patient tumors were identified by massively parallel sequencing of 15 genes commonly mutated in colorectal cancer, and personalized assays were designed to quantify ctDNA. For each patient, one mutation identified in the tumor tissue was assessed in the plasma for the presence of ctDNA. The median duration of follow up was 28.9 months and the primary aim of this study was to demonstrate the association between postsurgical and post-chemotherapy ctDNA detection and the risk of recurrence.
Among the 96 evaluable patients, circulating tumor DNA was detectable in 20 of 96 (21%) post-surgical samples and these patients had an increased risk of recurrence with associated inferior Recurrence-Free Survival, (HR=3.8; P<0.001). The estimated 3 year Recurrence Free Interval (RFI) for patients with positive ctDNA findings was 47% and for those with ctDNA-negative findings was 76%. Circulating tumor DNA was detectable in 15 of 88 (17%) post-chemotherapy samples. The estimated 3 year RFI was 30% when ctDNA was detectable after chemotherapy and 77% when ctDNA was undetectable (HR=6.8; P<0.001). Postsurgical ctDNA status was an independent predictor of disease recurrence after adjusting for known clinicopathologic risk factors (HR=7.5; P<0.001).
The authors concluded that post-surgical and post-chemotherapy circulating tumor DNA analyses is a promising prognostic marker in Stage III colon cancer, and may identify patients at high risk of recurrence, despite completing standard adjuvant treatment. This high-risk population presents a unique opportunity to explore additional therapeutic approaches. Circulating Tumor DNA Analyses as Markers of Recurrence Risk and Benefit of Adjuvant Therapy for Stage III Colon Cancer. Tie J, Cohen JD, Wang Y, et al. JAMA Oncol. 2019;5:1710-1717.

Association Between Pseudoprogression and Outcomes in Men with Metastatic Castration-Resistant Prostate Cancer Treated with XTANDI®

January 10th, 2020
SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 174,650 new cases of prostate cancer were diagnosed in 2019 and 31,620 men died 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, anti-androgen agents, which include, ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide), ERLEADA® (Apalutamide) and NUBEQA® (Darolutamide). 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 (mCRPC). Among those patients without metastases at CRPC diagnosis, 33% are likely to develop metastases within two years. The estimated mean survival of patients with CRPC is 9-36 months.
The skeletal system is the most common site for distant metastases among patients with prostate cancer and over 80% of patients with advanced prostate cancer develop bone metastases, which are osteoblastic (or sclerotic), characterized by deposition of new bone. Bone scan is the most common and cost effective modality for the diagnosis of bone metastases and Technetium (Tc) 99m-labeled methylene diphosphonate is the most widely used bone scanning agent. Bone scans are commonly used to both diagnose and monitor disease progression in the bone, among patients with advanced prostate cancer, with a sensitivity ranging from 60-90% but with lower specificity. Bone scan however is more sensitive and specific than plain films and CT scans, whereas MRI is superior in evaluating vertebral metastases. Bone scan provides information on osteoblastic activity and skeletal vascularity, with preferential uptake at sites of active bone formation, reflecting the metabolic reaction of bone to the disease activity, regardless of whether it is neoplastic, traumatic or inflammatory. It is for these reasons it has been well known that bone scans can be misleading in determining whether a patient with bone metastases is benefiting from a treatment, particularly endocrine therapy. The Prostate Cancer Working Group (PCWG) recommended that the assessment of disease progression in bone in the absence of other signs of progression, requires that new lesions detected on the first post-treatment scan be confirmed with the documentation of additional new lesions on the next follow-up scan, in the absence of other signs of disease progression. This is because the new lesions detected on the first post-treatment scan may either reflect true progression or can be the result of bone healing known as pseudoprogression (also known as bone scan flare) that can be misinterpreted as treatment failure, and lead to the premature discontinuation of an effective therapy. Even though the occurrence of pseudoprogression is well documented, its association with clinical outcomes in large prospective studies has not been evaluated.
The authors therefore conducted a post hoc retrospective analysis of the PREVAIL (A Safety and Efficacy Study of Oral MDV3100 in Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer) and AFFIRM (Safety and Efficacy Study of MDV3100 in Patients With Castration-Resistant Prostate Cancer Who Have Been Previously Treated With Docetaxel-based Chemotherapy) studies to determine the association between new unconfirmed lesions detected on a follow up bone scan, and clinical outcomes in XTANDI® (Enzalutamide)-treated men with mCRPC. The PREVAIL and AFFIRM trials were both designed in accordance with the PCWG guidelines. This analysis included 643 patients from the PREVAIL study who had not received Docetaxel and 404 men from the AFFIRM study who had previously received Docetaxel. Eligible patients had stable disease or response to therapy based on non-bone disease criteria, including assessment of PSA and soft-tissue disease response. Pseudoprogression was defined as detection of one or more lesions on a first post-treatment bone scan (at week 9 in PREVAIL or 13 in AFFIRM) or a second bone scan (at week 17 in PREVAIL or 25 in AFFIRM), without subsequent new lesions detected at later assessments. The authors evaluated the association of the new lesions detected on the first and second bone scans, with radiographic Progression Free Survival (rPFS), Overall Survival (OS), PSA decline, Objective Response in soft tissue, and Quality of Life.
In the PREVAIL study, new unconfirmed bone lesions were detected on bone scans in 27.5% of Docetaxel-naive patients. The rPFS, OS and time to PSA progression among these patients was similar to those without new lesions, suggesting pseudoprogression. In the AFFIRM study, new, unconfirmed lesions were detected in 18.1% of Docetaxel-treated patients and the rPFS, and time to PSA progression among these patients was similar to those without new lesions on bone scans. However, the OS was significantly worse among these patients, compared with those without new lesions on bone scan, suggesting true disease progression. Most lesions were detected on the first follow up bone scan and investigators were unable to identify any pretreatment factor associated with the development of new, unconfirmed lesions in patients responding to XTANDI®, in either clinical setting.
It was concluded that new unconfirmed lesions detected on follow up bone scans within the first 4 months of treatment initiation may represent pseudoprogression in men with mCRPC and are indicative of a favorable treatment response to XTANDI®. However, new unconfirmed bone lesions in men with mCRPC who were previously treated with Docetaxel may reflect disease heterogeneity and true progression with associated worse Overall Survival. Treatment discontinuation can be considered in this patient group, taking into consideration other disease manifestations such as changes in PSA level, finding on soft tissue imaging, symptoms, and patient preferences. These findings reinforce the importance of functional imaging for diagnosing bone metastases. Association Between New Unconfirmed Bone Lesions and Outcomes in Men With Metastatic Castration-Resistant Prostate Cancer Treated With Enzalutamide: Secondary Analysis of the PREVAIL and AFFIRM Randomized Clinical Trials. Armstrong AJ, Al-Adhami M, Lin P, et al. JAMA Oncol. 2019 Dec 12. doi: 10.1001/jamaoncol.2019.4636. [Epub ahead of print]

IDHIFA® plus VIDAZA® Significantly Improves Complete Remission and Overall Response in Newly Diagnosed IDH2-Mutated AML

January 3rd, 2020

SUMMARY: The American Cancer Society estimates that in 2019, 21,450 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 10,920 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive 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.

Isocitrate DeHydrogenase (IDH) is a metabolic enzyme that helps generate energy from glucose and other metabolites, by catalyzing the conversion of Isocitrate to Alpha-Ketoglutarate. Alpha-ketoglutarate is required to properly regulate DNA and histone methylation, which in turn is important for gene expression and cellular differentiation. IDH mutations lead to aberrant DNA methylation and altered gene expression thereby preventing cellular differentiation, with resulting immature undifferentiated cells. IDH mutations can thus promote leukemogenesis in Acute Myeloid Leukemia and tumorigenesis in solid tumors and can result in inferior outcomes. There are three isoforms of IDH. IDH1 is mainly found in the cytoplasm, as well as in peroxisomes, whereas IDH2 and IDH3 are found in the mitochondria, and are a part of the Krebs cycle. Approximately 20% of patients with AML, 70% of patients with Low-grade Glioma and secondary Glioblastoma, 50% of patients with Chondrosarcoma, 20% of patients with Intrahepatic cholangiocarcinoma, 30% of patients with Angioimmunoblastic T-cell lymphoma and 8% of patients with Myelodysplastic syndromes/Myeloproliferative neoplasms, are associated with IDH mutations.

IDHIFA® (Enasidenib) is a selective, oral, small molecule inhibitor of mutated IDH2 protein that promotes myeloid cell differentiation. IDHIFA® indirectly reduces DNA methylation by suppressing the oncometabolite, 2-HydroxyGlutarate, thereby restoring function to Alpha-Ketoglutarate-dependent TET family enzymes. IDHIFA® was approved in the US in 2017 for the treatment of adult patients with relapsed or refractory Acute Myeloid Leukemia (AML), with an IDH2 mutation. Further, treatment with single agent IDHIFA® resulted in an Overall Response Rate (ORR) of 31% and a Completer Response (CR) rate of 18% in patients with newly diagnosed AML. VIDAZA® (Azacitidine) is a hypomethylating agent that promotes DNA hypomethylation by inhibiting DNA methyltransferases. VIDAZA® has been shown to significantly improve Overall Survival (OS) when compared to conventional care regimens in elderly unfit patients with newly diagnosed AML, who are not candidates for intensive chemotherapy. In vitro studies demonstrated that a combination of IDHIFA® and VIDAZA® enhance cell differentiation and apoptosis.

Based on this preclinical data and early clinical trials, an open label, Phase I/II study was conducted comparing a combination of IDHIFA® and VIDAZA® with single agent VIDAZA® in patients with newly diagnosed IDH2 mutated AML, who are not candidates for intensive chemotherapy. The authors reported the first interim outcomes from the randomized, Phase II portion of this ongoing study. The Phase II portion of the trial enrolled 101 patients with newly diagnosed IDH2-mutant AML who were ineligible to receive intensive chemotherapy. Patients had an ECOG PS score of 2 or less and were randomized in a 2:1 ratio to receive IDHIFA® plus VIDAZA® or VIDAZA® alone in repeated 28-day cycles. All patients received VIDAZA® 75 mg/m2/day SC for the first 7 days of each treatment cycle, whereas patients randomized to IDHIFA® plus VIDAZA® also received IDHIFA® 100 mg orally QD continuously. The median patient age was 75 years, and 78% in the combination group and 90% in the VIDAZA® only group had intermediate-risk cytogenetics respectively, and 18% and 10% had poor-risk cytogenetics. The median number of treatment cycles was 8. The Primary endpoint was Overall Response Rate (ORR), which included Complete Remission (CR), CR with incomplete blood or platelet count recovery (CRi/CRp), Partial Remission (PR), and Morphologic Leukemia-Free State (MLFS), per modified IWG 2003 AML response criteria. Mutant IDH2 Variant Allele Frequencies (VAF) in bone marrow mononuclear cells was assessed by digital PCR.

It was noted that the ORR were significantly higher with combination treatment vs VIDAZA® alone (71% versus 42% respectively, P=0.0064) and the CR rates were 53% versus 12% (P=0.0001). The time to first response was about 2 months in each treatment group and the median Duration of Response was 24.1 months with the combination treatment and 12.1 months with VIDAZA® alone. Responses were observed in patients with RAS pathway co-mutations, which have been usually associated with resistance to IDHIFA® monotherapy. The maximal mutant IDH2 VAF suppression from baseline was significantly greater with the combination treatment versus single agent VIDAZA® (median –69.3% versus –14.1% respectively, P=0.0004). Treatment related Grade 3-4 Adverse Events occurring in 10% or more of patients in the combination group were neutropenia, thrombocytopenia, anemia, febrile neutropenia and IDH differentiation syndrome.

It was concluded that a combination of IDHIFA® plus VIDAZA® was associated with significantly improved Complete Remission and Overall Response Rates, with significant mutant IDH2 Variant Allele Frequencies reductions, compared with VIDAZA® alone, in patients with newly diagnosed IDH2-mutant AML. Further the combination treatment was generally well tolerated, with a safety profile similar to that reported for monotherapy with either of these two agents. Enasidenib Plus Azacitidine Significantly Improves Complete Remission and Overall Response Compared with Azacitidine Alone in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) with Isocitrate dehydrogenase 2 (IDH2) Mutations: Interim Phase II Results from an Ongoing, Randomized Study. DiNardo CD, Schuh AC, Stein EM, et al. Presented at 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 643.

FDA Approves LYNPARZA® for Germline BRCA-Mutated Metastatic Pancreatic Adenocarcinoma

January 3rd, 2020

SUMMARY: The FDA on December 27, 2019 approved LYNPARZA® (Olaparib) for the maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) metastatic pancreatic adenocarcinoma, as detected by an FDA-approved test, whose disease has not progressed on at least 16 weeks of a first-line Platinum-based chemotherapy regimen. The FDA also approved the BRACAnalysis CDx test (Myriad Genetic Laboratories, Inc.) as a companion diagnostic for the selection of patients with pancreatic cancer for treatment with LYNPARZA® based upon the identification of deleterious or suspected deleterious germline mutations in BRCA1 or BRCA2 genes.

The American Cancer Society estimates that for 2019, about 56,770 people will be diagnosed with pancreatic cancer and about 45,750 people will die of the disease. Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States and Western Europe. Unfortunately, unlike other malignancies, very little progress has been made and outcome for patients with advanced pancreatic cancer has been dismal, with a 5-year survival rate for metastatic pancreatic cancer of approximately 2%. Pancreatic cancer has surpassed breast cancer as the third leading cause of cancer death in the United States and is on track to surpass colorectal cancer, to move to the second leading cause of cancer related deaths in the United States around 2020.

BRCA1 and BRCA2 are tumor suppressor genes located on chromosome 17 and chromosome 13 respectively. They control cell growth by repairing DNA damage and thus prevent tumor development. Mutations in these genes predispose an individual to develop malignant tumors. It is well established that the presence of BRCA1 and BRCA2 mutations can significantly increase the lifetime risk for developing breast and ovarian cancer, as high as 85% and 40% respectively. BRCA1/2 mutations have been detected in 4-7% of patients with pancreatic cancer, with a 2-6 fold increase in risk, associated with these mutations. These patients tend to be younger. Among pancreatic cancer patients with Ashkenazi Jewish ancestry, the prevalence of BRCA1/2 mutations is 6-19%, with mutations more common for BRCA2. NCCN guideline recommends that germline testing should be considered for all patients with pancreatic cancer and is especially recommended for those with a personal history of cancer, family history or clinical suspicion of a family history of pancreatic cancer. Approximately 10% of pancreatic cancer cases have a familial component. When hereditary cancer syndrome is suspected in patients with pancreatic cancer, genetic counseling should be considered.

BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic). The BRCA gene plays an important role in DNA repair via Homologous Recombination (HR). Mutation of BRCA gene results in loss of BRCA function and likely deregulates Homologous Recombination (HR) pathway. Majority of patients with Germline BRCA mutations (gBRCA) have HR Deficiency (HRD) resulting in inability to repair double strand breaks. HRD can also occur due to other mechanisms, such as somatic mutations and epigenetic modifications of other genes involved in the HR pathway. Patients with HRD exhibit specific clinical behaviors, and improved responses to treatments, such as platinum-based chemotherapy and PARP Inhibitors. The PARP (Poly ADP Ribose Polymerase) family of enzymes, include PARP1 and PARP2, which repair damaged DNA. LYNPARZA® is a first-in-class PARP enzyme inhibitor that causes cell death in tumors that already have a DNA repair defect, such as those with BRCA1 and BRCA2 mutations, through the concept of synthetic lethality. Malignancies such as epithelial ovarian cancers with Homologous Recombination Deficiency, have demonstrated sensitivity to PARP inhibitors. Recent studies have confirmed that PARP inhibitors are effective not only in ovarian cancers displaying germline or somatic BRCA mutations but also in cancers with HRD caused by other underlying etiologies. LYNPARZA® in a Phase II trial demonstrated antitumor activity in heavily pretreated metastatic pancreatic cancer patients with a germline BRCA mutation. Maintenance treatment with LYNPARZA® in BRCA mutated ovarian cancer patients resulted in significant improvement in Progression Free Survival.

The POLO (Pancreas Cancer Olaparib Ongoing) trial was conducted to evaluate the efficacy of maintenance therapy with LYNPARZA® in metastatic pancreatic adenocarcinoma patients with a germline BRCA mutation whose disease had not progressed during first-line platinum-based chemotherapy. In this international, multicenter, randomized, double-blind, placebo-controlled Phase III study, 154 patients with BRCA mutant disease were randomly assigned in a 3:2 ratio, to receive maintenance LYNPARZA® tablets 300 mg twice daily (N=92) or matching placebo (N=62). The median patient age was 57 years. Eligible patients should have received at least 16 weeks of continuous first-line platinum-based chemotherapy for metastatic pancreatic cancer and maintenance treatment was initiated 4-8 weeks after the last dose of first-line chemotherapy had been administered. Maintenance intervention was continued until disease progression. Crossover to LYNPARZA® was not permitted during this trial. The Primary end point was Progression Free Survival (PFS) and Secondary end points included Objective Response Rate (ORR) and Quality of Life.

The median PFS was significantly longer in the LYNPARZA® group compared to the placebo group (7.4 months versus 3.8 months; HR for disease progression or death=0.53; P=0.004). This suggested a 47% reduction in the risk of disease progression or death. At 2 years, 22% of the patients in the LYNPARZA® group did not have disease progression compared with 9.6% of patients in the placebo group. The ORR among patients who had measurable disease at baseline was 23% in the LYNPARZA® group and 12% in the placebo group. The interim analysis of Overall Survival showed no significant difference, with a median 18.9 months for the LYNPARZA® group and 18.1 months for the placebo group (HR=0.91; P=0.68). Health-related Quality of Life scores were also not significantly different. Grade 3 or higher adverse events were 40% in the LYNPARZA® group and 23% in the placebo group and 5% and 2% of the patients, respectively, discontinued therapy because of an adverse event.

It was concluded that among metastatic pancreatic cancer patients with germline BRCA mutation and whose cancer has not progressed during platinum-based chemotherapy, Progression Free Survival was significantly longer with maintenance LYNPARZA® than with placebo. This study allows identifying patients with metastatic pancreatic cancer who will likely benefit from PARP inhibition. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. Golan T, Hammel P, Reni M, et al. N Engl J Med 2019; 381:317-327

FDA Approves ENHERTU® for Advanced HER2-Positive Breast Cancer

December 27th, 2019

SUMMARY: The FDA on December 20, 2019, granted accelerated approval to ENHERTU® (Trastuzumab deruxtecan) for patients with unresectable or metastatic HER2-positive breast cancer, who have received two or more prior anti-HER2-based regimens in the metastatic setting. Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 268,600 new cases of invasive breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. HER2-targeted therapies include HERCEPTIN® (Trastuzumab), TYKERB® (Lapatinib), PERJETA® (Pertuzumab) and KADCYLA® (ado-Trastuzumab emtansine). Dual HER2 blockade with HERCEPTIN® and PERJETA®, given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2 positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival (OS). The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies. Patients progressing on Dual HER2 blockade often receive KADCYLA® which results in an Objective Response Rate (ORR) of 44% and a median PFS of 9.6 months, when administered after HERCEPTIN® and a taxane. There is however no standard treatment option for this patient population following progression on KADCYLA®.Mechanism-of-Action - ENHERTU

ENHERTU® is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). ENHERTU® has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike KADCYLA®, ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, minimizing systemic exposure. In a Phase 1 dose-finding study involving patients with advanced HER2-positive breast cancer, treatment with ENHERTU® resulted in a confirmed response rate was 59.5%, and the median response duration was 20.7 months. However, the efficacy of ENHERTU® in patients with HER2-positive metastatic breast cancer, previously treated with KADCYLA® remained unclear.

The present FDA approval was based on DESTINY-Breast01 study, which is a multicenter, single-arm, Phase II trial, in which 184 patients with HER2-positive, metastatic breast cancer, who had received two or more prior HER2 targeted therapies including KADCYLA®, were enrolled. Patients received ENHERTU® 5.4 mg/kg IV every 3 weeks until disease progression or unacceptable toxicity. The median age was 55 years, 53% had Hormone Receptor-positive tumors and the median number of previous lines of therapy for metastatic disease was six and included KADCYLA® (100%), Trastuzumab (100%), Pertuzumab (66%), and other anti-HER2 therapies (54%). The Primary end point was Objective Response Rate (ORR) assessed by Independent Central Review and Secondary endpoints included Duration of Response, Progression Free Survival (PFS) and Overall Survival (OS). The median follow up was 11.1 months. The ORR was 60.9%, with 6% Complete Responses and 54.9% Partial Responses. The median time to response was 1.6 months and the median response duration was 14.8 months. The median PFS was 16.4 months the median OS was not reached at the time of this publication. The most Grade 3 or higher adverse events were cytopenias, nausea, diarrhea and Interstitial Lung Disease.

It was concluded that ENHERTU® has a high level of clinical efficacy with a durable antitumor activity in a pretreated patient population with HER2-positive metastatic breast cancer. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. Modi S, Saura C, Yamashita T, et al. for the DESTINY-Breast01 Investigators. N Engl J Med. 2019 Dec 11. doi: 10.1056/NEJMoa1914510. [Epub ahead of print]

FDA Grants Accelerated Approval to PADCEV® for Metastatic Urothelial Cancer

December 27th, 2019

SUMMARY: The FDA on December 18, 2019, granted accelerated approval to PADCEV® (Enfortumab vedotin-ejfv), for adult patients with locally advanced or metastatic urothelial cancer who have previously received a Programmed Death receptor-1 (PD-1) or Programmed Death-Ligand1 (PD-L1) inhibitor, and a Platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. The American Cancer Society estimates that in 2019, approximately 80,470 new cases of Bladder Cancer will be diagnosed and 17,670 patients will die of the disease. Patients with urothelial carcinoma are currently treated in the first line setting with a Platinum based chemotherapy regimen and a Check Point 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%.

PADCEV® is an Antibody-Drug Conjugate (ADC) that targets Nectin-4, a cell adhesion molecule highly expressed in urothelial cancers and other solid tumors. Following binding to Nectin-4 on the cell surface, PADCEV® 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. In a Phase I dose-finding study of PADCEV®, the Objective Response Rate (ORR) was 42% among patients with advanced urothelial cancer, who previously received treatment with a PD-1/PD-L1 inhibitor.

This FDA approval was based on the results from the pivotal Phase II EV-201 study, which is an open-label, single-arm, multicenter trial in which 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and Platinum-based chemotherapy were enrolled. Patients received PADCEV® 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle, until disease progression or unacceptable toxicity. The median age was 69 years. The Primary endpoint was ORR as assessed by blinded Independent Central Review. Secondary endpoints included Duration of Response, Progression Free Survival (PFS), Overall Survival (OS), Safety and Tolerability.

The ORR was 44%, with 12% Complete Responses and 32% Partial Responses. Overall, 84% of evaluable patients showed some degree of tumor shrinkage. The responses were noted at a median of 1.8 months after treatment initiation and the median Duration of Response was 7.6 months. These objective responses were seen in all patient subgroups evaluated, including those with poor prognostic features. The median PFS was 5.8 months, and the median Overall Survival was 11.7 months. The most common adverse reactions were fatigue, alopecia, decreased appetite and peripheral neuropathy. Blood glucose levels should be monitored closely in patients with, or at risk, for diabetes mellitus or hyperglycemia.

It was concluded from this study that treatment with PADCEV® demonstrated clinically meaningful Objective Response Rate, in patients with advanced metastatic urothelial cancer, who received prior treatment with a PD-1 or PD-L1 inhibitor and Platinum-based chemotherapy, thus fulfilling an unmet need. PADCEV® is the first Nectin-4-directed Antibody-Drug Conjugate to receive FDA approval, and a Phase III study is underway comparing PADCEV® against standard single-agent chemotherapy, in patients with advanced, previously treated metastatic urothelial cancer. EV-201: Results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer previously treated with platinum and immune checkpoint inhibitors. Petrylak DP, Balar AV, O'Donnell PH, et al. DOI: 10.1200/JCO.2019.37.18_suppl.LBA4505 Journal of Clinical Oncology 37, no. 18_suppl (June 20, 2019) 4505-4505.

Long-Term Breast Cancer Preventive Benefit with ARIMIDEX®

December 20th, 2019

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 268,600 new cases of invasive breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. Some high risk factors for the development of breast cancer include first-degree relative with breast cancer at any age, first-degree relative with bilateral breast cancer who developed the first breast cancer at 50 years of age or less, Lobular Carcinoma In Situ (LCIS), Atypical ductal or lobular hyperplasia in a benign lesion, and Ductal Carcinoma In-Situ (DCIS).

Previously published studies have shown a 38% reduction in all breast cancers and 50% reduction of ER-positive tumors with the use of SERMs (Selective Estrogen Receptor Modulators) such as Tamoxifen and Raloxifene for breast cancer prevention. Further it has been shown that the effects of Tamoxifen continue with a constant 29% annual preventive effect for at least 15 years after completion of treatment. A further improvement in breast cancer incidence short-term was seen in two trials using, two Aromatase Inhibitors, ARIMIDEX® (Anastrozole) in the International Breast Cancer Intervention Study II (IBIS-II) and AROMASIN® (Exemestane) in the MAP.3 trial. However in the MAP.3 study, the study was unblinded after the initial publication and a post-treatment effect, as was seen with Tamoxifen, was not possible.

The International Breast Cancer Intervention Study II (IBIS-II) is an international, randomized, double-blind, placebo-controlled trial, which was initiated in 2003. In this trial, 3864 postmenopausal women aged 40-70 years, at increased risk of developing breast cancer were recruited and were randomly assigned (1:1) to either ARIMIDEX® 1 mg orally daily (N=1920) or matching placebo (N=1944) daily for 5 years. After treatment completion, women were followed on a yearly basis and data was collected on breast cancer incidence, death, incidence of other cancers, and major adverse events (cardiovascular events and fractures). The median age at study entry was 59 years. The exclusion criteria for this study included premenopausal status, prior breast cancer including Ductal Carcinoma In Situ (DCIS) diagnosed more than 6 months before trial entry, current or previous Tamoxifen, Raloxifene, or other SERM use for more than 6 months, or previous or planned prophylactic mastectomy. Unblinding was only permitted if the participant developed breast cancer, when a clinician considered there to be valid medical or safety reasons. The Primary outcome was the development of histologically confirmed breast cancer, either invasive or non-invasive (DCIS), particularly during the post-5-year time period. Secondary outcomes were ER-positive breast cancer, breast cancer mortality, incidence of other cancers, cardiovascular disease, fractures, and all-cause mortality. The decision to analyze the data was made without looking at the results before hand. The first analysis after a median follow-up of 60 months showed a significant reduction (53%) in incidence for all breast cancer (including DCIS). The authors now report the results on the extended duration of benefit of ARIMIDEX® in preventing breast cancer, for up to 12 years after trial entry.

After a median follow up of 10.9 years for this analysis, women assigned to the ARIMIDEX® group were 49% less likely to develop breast cancer than women assigned to the placebo arm of the study ((HR=0.51, P<0.0001). The reduction in incidence in the first 5 years of follow up was 61% (HR=0.39; P<0.0001), and a smaller but still significant 36% reduction (HR=0.64; P=0•014) was seen in subsequent years, which was still larger than that seen for Tamoxifen in previous trials, and the effects in the two time periods was not significantly different (P=0.08). Invasive ER-positive breast cancer was reduced by 54% with ARIMIDEX® treatment (HR=0.46; P<0.0001), with a continued significant effect observed in the post-treatment follow up period. A 59% reduction in DCIS overall was observed (HR=0.41; P=0.0081), with a very large reduction noted in those cases known to be ER-positive (HR = 0.22; P<0.0001). A significant decrease in non-breast cancers was observed in the ARIMIDEX® group, primarily contributed by non-melanoma skin cancer (P=0.0042), and no excess rates of fractures or cardiovascular disease was observed.

The authors concluded that this updated analysis shows a continuing long-term effect of 5 years of ARIMIDEX® treatment, in preventing breast cancer, in high-risk postmenopausal women. These new results strongly suggest that ARIMIDEX® should be preferred therapy for breast cancer prevention in postmenopausal women at increased risk for the disease, with Tamoxifen used for women who experience severe side effects from ARIMIDEX®. Use of anastrozole for breast cancer prevention (IBIS-II): long-term results of a randomised controlled trial. Cuzick J, Sestak I, Forbes JF, et al. The Lancet. Published:December 12, 2019. DOI:

DARZALEX® Combination Improves Overall Survival in Transplant-Ineligible Myeloma Patients

December 20th, 2019

SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 32,110 new cases will be diagnosed in 2019 and 12,960 patients are expected to die of the disease. Multiple Myeloma (MM) in 2019 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile or refractory disease have the worst outcomes. The median survival for patients with myeloma is over 10 years.

Elderly patients with myeloma in the US are often treated with a combination of REVLIMID® (Lenalidomide) and Dexamethasone, whereas Melphalan, Prednisone, and Thalidomide (MPT) and VELCADE® (Bortezomib), Melphalan and Prednisone (VMP) are the most widely used regimens outside the US. These regimens are associated with a PFS of 18-24 months and an OS of 4-5 years. For patients with newly diagnosed multiple myeloma who are ineligible for ASCT, treatment with VMP regimen has been a standard effective regimen, based on the VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone) trial.Mechanism-of-Action-of-Daratumumab

DARZALEX® (Daratumumab) is a human IgG1 antibody that targets CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Dependent Cytotoxicity (CDC) and direct Apoptosis. Additionally, DARZALEX® may have a role in immunomodulation, by depleting CD38-positive regulator immune suppressor cells, and thereby expanding T cells, in patients responding to therapy.

ALCYONE is a multicenter, randomized, open-label, active-controlled, Phase III trial in which DARZALEX® given along with VELCADE®, Melphalan and Prednisone (D-VMP regimen) was compared with VMP alone (control group), in patients with newly diagnosed multiple myeloma, who were ineligible for Autologous Stem Cell Transplantation (ASCT). Of the 706 enrolled patients, 350 were assigned to the DARZALEX® group and 356 to the control group. The median age was 71 yrs. All the patients received up to nine 6 week cycles of VELCADE® 1.3 mg/m2 SQ, twice weekly on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5 of cycles 2-9), Melphalan 9 mg/m2 orally, once daily on days 1-4 of each cycle, and Prednisone 60 mg/m2 once daily on days 1-4 of each cycle. In the study group, patients received DARZALEX® 16 mg/kg IV administered with Dexamethasone 20 mg oral or IV (to manage infusion reactions), once weekly for a total of 6 doses, every 3 weeks for a total of 16 doses and every 4 weeks thereafter until disease progression or unacceptable toxicity. The Primary end point was Progression Free Survival (PFS). Secondary end points included Overall Response Rate (ORR), rates of Very Good Partial Response (VGPR), Complete Response (CR) rate, Minimal Residual Disease (MRD) negativity and Overall Survival (OS). The FDA in 2018 approved DARZALEX® in combination with VELCADE® (Bortezomib), a proteasome inhibitor, Melphalan, an alkylating agent and Prednisone VMP regimen), for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for Autologous Stem Cell Transplant (ASCT), based on the Progression Free Survival (PFS) benefit at 16.5 months, noted during the primary analysis of the ALCYONE study. The authors herein presented outcomes after more than 36 months of follow-up from the ALCYONE study, including analysis of Overall Survival (OS) from a prespecified interim analysis.

In this updated analysis, treatment with D-VMP continued to demonstrate a twofold greater median PFS at 36.4 months versus 19.3 months with VMP, after a median follow-up of 41months (HR=0.42; P<0.0001). Patients assigned to D-VMP also had significantly prolonged PFS on subsequent therapy (PFS-2). Median PFS-2 was not reached with D-VMP versus 42.3 months with VMP (HR=0.55; P<0.0001), representing a 45% reduction in the risk for progression or death. The median time to subsequent therapy had yet to be reached in the D-VMP group versus 25.9 months for the VMP group. The Overall Response Rate was 91% in the D-VMP group as compared with 74% in the control group and the rate of Complete Response or better (including stringent CR) was 46%, versus 24.4% in the control group. The MRD-negative rate (at a threshold of 1 tumor cell per 105 white cells) was 28% with D-VMP and 7% with VMP and D-VMP also led to higher rates of sustained MRD negativity. MRD negativity for 12 or more months was associated with improved PFS. The estimated 36 month OS rate was 78% with D-VMP versus 68% with VMP, with a significant benefit for OS observed for D-VMP versus VMP alone (HR=0.60; P=0.0003). This represented a 40% reduction in the risk of death, in favor of D-VMP.

The authors concluded that for the first time, this study demonstrated that the addition of DARZALEX® to VMP significantly prolonged Overall Survival in patients with transplant-ineligible newly diagnosed Multiple Myeloma, with a 40% reduction in the risk of death, when compared with VMP alone. They added that these findings, together with the Phase 3 MAIA study (DARZALEX® plus Lenalidomide and Dexamethasone versus Lenalidomide plus Dexamethasone), continue to support the addition of DARZALEX® to frontline treatment regimens for patients with Multiple Myeloma. Daratumumab Plus Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Patients with Transplant-Ineligible Newly Diagnosed Multiple Myeloma: Overall Survival in Alcyone. Mateos MV, Cavo M, Bladé J, et al. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 859.