The FDA on July 31, 2017, granted accelerated approval to OPDIVO® (Nivolumab) for the treatment of patients 12 years and older with MisMatch Repair deficient (dMMR) and MicroSatellite Instability-High (MSI-H) metastatic ColoRectal Cancer, that has progressed following treatment with a Fluoropyrimidine, Oxaliplatin, and Irinotecan. NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer. Patients with metastatic ColoRectal Cancer who have dMMR or MSI-H tumors are less likely to respond to conventional chemotherapy and OPDIVO® demonstrated durable responses and disease control in this heavily pretreated patient group.
Author: RR
FDA Approves OPDIVO® for MSI-H or dMMR Metastatic Colorectal Cancer
SUMMARY: The FDA on July 31, 2017, granted accelerated approval to OPDIVO® (Nivolumab) for the treatment of patients 12 years and older with MisMatch Repair deficient (dMMR) and MicroSatellite Instability-High (MSI-H) metastatic ColoRectal Cancer, that has progressed following treatment with a Fluoropyrimidine, Oxaliplatin, and Irinotecan. 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 135,430 new cases of ColoRectal Cancer will be diagnosed in the United States in 2017 and over 50,260 patients are expected to die of the disease. The lifetime risk of developing ColoRectal Cancer is about 1 in 20 (5%).
The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, triggering an enhanced antitumor immune response. MSI (Micro Satellite Instability) is therefore a hallmark of defective/deficient DNA MisMatchRepair (MMR) system and occurs in 15% of all colorectal cancers. Defective MisMatchRepair can be a sporadic or heritable event. Approximately 65% of the MSI tumors are sporadic and when sporadic, the DNA MisMatchRepair gene is MLH1. Defective MisMatchRepair can also manifest as a germline mutation occurring in 1 of the 4 MisMatchRepair genes which include MLH1, MSH2, MSH6, PMS2. This produces Lynch Syndrome (Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC), an Autosomal Dominant disorder and is the most common form of hereditary colon cancer, accounting for 35% of the MSI colorectal cancers. MSI tumors tend to have better outcomes and this has been attributed to the abundance of tumor infiltrating lymphocytes in these tumors from increase immunogenicity. These tumors therefore are susceptible to PD-1 blockade with immune checkpoint inhibitors.
MSI (Micro Satellite Instability) testing is performed using a PCR based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MisMatchRepair genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC). MLH1 gene is often lost in association with PMS2. NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer.
This latest approval for OPDIVO® was based on results from the phase II CheckMate-142 trial, which is a multicenter, open label, single arm study, involving 53 patients with dMMR or MSI-H metastatic ColoRectal Cancer, who had disease progression during, after, or were intolerant to prior treatment with Fluoropyrimidine, Oxaliplatin, and Irinotecan-based chemotherapy. These 53 patients were a subset of the 74 patients who received at least one prior treatment regimen containing a Fluoropyrimidine with Oxaliplatin or Irinotecan for metastatic disease. All patients received OPDIVO® 3 mg/kg by intravenous infusion every 2 weeks until unacceptable toxicity or radiographic progression. The median age was 53 years. The Primary endpoint was Objective Response Rate (ORR) and exploratory endpoints included Safety, Progression Free Survival, Overall Survival and efficacy in biomarker-defined populations.
The Objective Response Rate as assessed by independent radiographic review committee, was 28% in the 53 patients who received prior Fluoropyrimidine, Oxaliplatin, and Irinotecan and responses lasted 6 months or more for the 67% of the responding patients. There was 1 complete response and 14 partial responses. The ORR was 32% among the 74 patients in the overall population. These responses and Clinical Benefit was seen regardless of PD-L1 expression, BRAF mutation status, KRAS mutation status, and clinical history of Lynch Syndrome. The most common adverse reactions related to OPDIVO® included fatigue, asthenia, rash, fever, nausea, diarrhea, musculoskeletal pain, cough and dyspnea.
The authors concluded that patients with metastatic ColoRectal Cancer who have dMMR or MSI-H tumors are less likely to respond to conventional chemotherapy and OPDIVO® demonstrated durable responses and disease control in this heavily pretreated patient group. Nivolumab in patients with DNA mismatch repair deficient/microsatellite instability high metastatic colorectal cancer: Update from CheckMate 142. Overman MJ, Lonardi S, Leone F, et al. J Clin Oncol 35, 2017 (suppl 4S; abstract 519).
FDA Approves DARZALEX® in Combination with POMALYST® and Dexamethasone for Relapsed or Refractory Multiple Myeloma
SUMMARY: The FDA on June 16, 2017 approved the use of DARZALEX® (Daratumumab) in combination with POMALYST® (Pomalidomide) and Dexamethasone for the treatment of patients with Multiple Myeloma who have received at least two prior therapies including REVLIMID® (Lenalidomide) and a Proteasome Inhibitor. Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, about 30,280 new cases will be diagnosed in 2017 and 12,590 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. With a record number of regulatory approvals for Myeloma treatment over the past 12 years, the median survival for patients with Myeloma is over 10 years.
DARZALEX® 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 Mediated Cytotoxicity 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. The FDA approved DARZALEX® in November 2015 as monotherapy for Myeloma patients who had received at least three prior lines of therapy including a Proteasome Inhibitor (PI) and an Immunomodulatory agent or who are double refractory to a PI and an Immunomodulatory agent. In November 2016, DARZALEX® was approved in combination with REVLIMID® and Dexamethasone, or VELCADE® (Bortezomib) and Dexamethasone, for the treatment of patients with Multiple Myeloma who have received at least one prior therapy. POMALYST® (Pomalidomide) is a novel, oral, immunomodulatory drug which is far more potent than THALOMID® (Thalidomide) and REVLIMID®, and has been shown to be active in REVLIMID® and VELCADE® refractory patients.
This new FDA approval was based on data from the phase Ib (MMY1001, EQUULEUS) study of DARZALEX® in combination with POMALYST® and Dexamethasone in relapsed or refractory Multiple Myeloma. This open-label study included 103 patients with Multiple Myeloma who had received prior treatment with a Proteasome Inhibitor and an Immunomodulatory agent. Treatment consisted of DARZALEX® 16 mg/kg IV on days 1, 8, 15, and 22 of a 28 day cycle for 8 weeks during cycles 1 and 2, every 2 weeks (on days 1 and 15) for 16 weeks (cycles 3 thru 6), and every 4 weeks thereafter until disease progression. POMALYST® 4 mg PO was administered daily for 21 days along with Dexamethasone 40 mg weekly (20 mg for patients over 75 years of age). The median patient age was 64 years and patients had received a median of 4 prior lines of therapy. About 75% of the patients had prior Autologous Stem Cell Transplant, 90% of patients were refractory to REVLIMID®, 70% were refractory to VELCADE®, and 64% were refractory to both agents.
The Overall Response Rate in this study was 59% with Very Good Partial Response (VGPR) noted in 28% of patients. Complete Response was achieved in 6% of patients and stringent Complete Response was achieved in 8% of patients. The median time to response was 1 month and the median duration of response was 13.6 months. The most common toxicities were infusion reactions, nausea, vomiting, diarrhea, fatigue, fever, upper respiratory tract infection, muscle spasms, cough and dyspnea. The most common grade 3/4 toxicities were cytopenias including lymphopenia.
It was concluded that DARZALEX® in combination with POMALYST® and Dexamethasone is a new combination therapy, with significant clinical benefit, for patients who relapse or become resistant to Proteasome Inhibitors and Immunomodulatory agents. This combination may be a viable option for patients who progress on a combination of REVLIMID®, VELCADE® and Dexamethasone (RVD) regimen, which is often given as first line therapy. A Study of JNJ-54767414 (HuMax CD38) (Anti-CD38 Monoclonal Antibody) in Combination With Backbone Treatments for the Treatment of Patients With Multiple Myeloma. ClinicalTrials.gov Identifier: NCT01998971 https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/761036orig1s005ltr.pdf.
VYXEOS ® (Liposome-encapsulated combination of Daunorubicin and Cytarabine)
The FDA on August 3, 2017 granted regular approval to VYXEOS ® for the treatment of adults with newly-diagnosed therapy-related AML (t-AML) or AML with Myelodysplasia-Related Changes (AML-MRC), two types of AML having a poor prognosis. VYXEOS ® is a product of Jazz Pharmaceuticals.
IMBRUVICA® (Ibrutinib)
The FDA on August 2, 2017 approved IMBRUVICA® for the treatment of adult patients with chronic Graft Versus Host Disease (cGVHD), after failure of one or more lines of systemic therapy. This is the first FDA-approved therapy for the treatment of cGVHD. IMBRUVICA® is a product of Pharmacyclics LLC.
IDHIFA® (Enasidenib)
The FDA on August 1, 2017 granted regular approval to IDHIFA®, for the treatment of adult patients with relapsed or refractory Acute Myeloid Leukemia with an Isocitrate DeHydrogenase-2 (IDH2) mutation, as detected by an FDA-approved test. IDHIFA® is a product of Celgene Corp.
OPDIVO® (Nivolumab)
The FDA on August 1, 2017 granted accelerated approval to OPDIVO®, for the treatment of patients 12 years and older with MisMatch Repair deficient (dMMR) and MicroSatellite Instability High (MSI-H) metastatic ColoRectal Cancer, that has progressed following treatment with a Fluoropyrimidine, Oxaliplatin, and Irinotecan. OPDIVO® is a product of Bristol-Myers Squibb Company.
Antiemetics American Society of Clinical Oncology Clinical Practice Guideline Update (Part II)
SUMMARY: Chemotherapy Induced Nausea and Vomiting (CINV) is quite common and occurs in about 80% of patients receiving chemotherapy. The following (Part II) is a continuation of the ASCO Antiemetics Clinical Practice Guideline Update.
KEY RECOMMENDATIONS (ctd) – PART II
Adult Patients
Breakthrough nausea and vomiting
• (No change) For patients with breakthrough nausea or vomiting, clinicians should re-evaluate emetic risk, disease status, concurrent illnesses, and medications, and ascertain that the best regimen is being administered for the emetic risk.
• (Updated) Adult patients who experience nausea or vomiting despite optimal prophylaxis, and who did not receive Olanzapine prophylactically, should be offered Olanzapine in addition to continuing the standard antiemetic regimen.
• (Updated) Adult patients who experience nausea or vomiting despite optimal prophylaxis, and who have already received Olanzapine, may be offered a drug of a different class—for example, an NK1 receptor antagonist, Lorazepam or Alprazolam, a dopamine receptor antagonist, Dronabinol, or Nabilone—in addition to continuing the standard antiemetic regimen.
Anticipatory nausea and vomiting
• (Reworded for clarity) All patients should receive the most active antiemetic regimen that is appropriate for the antineoplastic agents being administered. Clinicians should use such regimens with initial antineoplastic treatment, rather than assessing the patient’s emetic response with less effective antiemetic treatment. If a patient experiences anticipatory emesis, clinicians may offer behavioral therapy with systematic desensitization.
KEY RECOMMENDATIONS
High emetic risk Radiation Therapy
• (Updated) Adult patients who are treated with high-emetic-risk radiation therapy should be offered a two-drug combination of a 5-HT3 receptor antagonist and Dexamethasone before each fraction and on the day after each fraction if Radiation Therapy is not planned for that day.
Moderate-emetic-risk radiation therapy
• (Reworded for clarity) Adult patients who are treated with moderate-emetic-risk Radiation Therapy should be offered a 5-HT3 receptor antagonist before each fraction, with or without Dexamethasone before the first five fractions. Low-emetic-risk radiation therapy
• (Updated) Adult patients who are treated with Radiation Therapy to the brain should be offered rescue Dexamethasone therapy. Patients who are treated with Radiation Therapy to the head and neck, thorax, or pelvis should be offered rescue therapy with a 5-HT3 receptor antagonist, Dexamethasone, or a Dopamine receptor antagonist.
Minimal-emetic-risk radiation therapy
• (Updated) Adult patients who are treated with minimal-emetic-risk radiation therapy should be offered rescue therapy with a 5-HT3 receptor antagonist, Dexamethasone, or a Dopamine receptor antagonist.
Concurrent radiation and antineoplastic agent therapy
• (Updated) Adult patients who are treated with concurrent radiation and antineoplastic agents should receive antiemetic therapy that is appropriate for the emetic risk level of antineoplastic agents, unless the risk level of the radiation therapy is higher. During periods when prophylactic antiemetic therapy for antineoplastic agents has ended and ongoing radiation therapy would normally be managed with its own prophylactic therapy, patients should receive prophylactic therapy that is appropriate for the emetic risk of the radiation therapy until the next period of antineoplastic therapy, rather than receiving rescue therapy for antineoplastic agents as needed.
Pediatric Patients
High-emetic-risk antineoplastic agents
• (Updated) Pediatric patients who are treated with high-emetic-risk antineoplastic agents should be offered a three-drug combination of a 5-HT3receptor antagonist, Dexamethasone, and Aprepitant.
• (New) Pediatric patients who are treated with high-emetic-risk antineoplastic agents who are unable to receive Aprepitant should be offered a two-drug combination of a 5-HT3 receptor antagonist and Dexamethasone.
• (New) Pediatric patients who are treated with high-emetic-risk antineoplastic agents who are unable to receive Dexamethasone should be offered a two-drug combination of Palonosetron and Aprepitant.
Moderate-emetic-risk antineoplastic agents
• (Reworded for clarity) Pediatric patients who are treated with moderate-emetic-risk antineoplastic agents should be offered a two-drug combination of a 5-HT3receptor antagonist and Dexamethasone.
• (New) Pediatric patients who are treated with moderate-emetic-risk antineoplastic agents who are unable to receive Dexamethasone should be offered a two-drug combination of a 5-HT3 receptor antagonist and Aprepitant.
Low-emetic-risk antineoplastic agents
• (New) Pediatric patients who are treated with low-emetic-risk antineoplastic agents should be offered Ondansetron or Granisetron.
Minimal emetic risk antineoplastic agents
• (New) Pediatric patients who are treated with minimal-emetic-risk antineoplastic agents should not be offered routine antiemetic prophylaxis.
Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. Hesketh PJ, Kris MG, Basch E, et al. DOI: 10.1200/JCO.2017.74.4789 Journal of Clinical Oncology – published online before print July 31, 2017
Antiemetics American Society of Clinical Oncology Clinical Practice Guideline Update
SUMMARY: The ASCO guideline for Antiemetics in oncology was updated by the ASCO Expert Panel following a systematic review of 41publications from November 2009 thru June 2016. The recommendations in this guideline are most definitive for adults who are treated with single-day IV chemotherapy. This topic has been divided into Part I and Part II for easy reading. Part II is continued in the second article of this e NewsLetter.
Guideline Question: What are the most effective strategies for preventing or managing nausea and vomiting due to antineoplastic agents or radiation therapy?
Target Population: Adults and children who receive antineoplastic agents and adults who undergo radiation therapy for cancer.
Target Audience: Medical and Radiation Oncologists, Oncology Nurses, Nurse Practitioners, Physician Assistants, Oncology Pharmacists, and Patients with cancer
KEY RECOMMENDATIONS – PART I
Adult Patients
High-emetic-risk antineoplastic agents
• (Updated) Adult patients who are treated with Cisplatin and other high-emetic-risk single agents should be offered a four-drug combination of a Neurokinin 1 (NK1) receptor antagonist, a Serotonin (5-HT3) receptor antagonist, Dexamethasone, and Olanzapine. Dexamethasone and Olanzapine should be continued on days 2 to 4.
• (Updated) Adult patients who are treated with an Anthracycline combined with Cyclophosphamide should be offered a four-drug combination of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, Dexamethasone, and Olanzapine. Olanzapine should be continued on days 2 to 4.
Moderate-emetic-risk antineoplastic agents
• (Updated) Adult patients who are treated with Carboplatin AUC 4 or more should be offered a three-drug combination of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, and Dexamethasone.
• (Updated) Adult patients who are treated with moderate-emetic-risk antineoplastic agents, excluding Carboplatin AUC 4 or more, should be offered a two-drug combination of a 5-HT3 receptor antagonist (day 1) and Dexamethasone (day 1).
• (Updated) Adult patients who are treated with Cyclophosphamide, Doxorubicin, Oxaliplatin, and other moderate-emetic-risk antineoplastic agents that are known to cause delayed nausea and vomiting may be offered Dexamethasone on days 2 to 3.
Low-emetic-risk antineoplastic agents
• (Updated) Adult patients who are treated with low-emetic-risk antineoplastic agents should be offered a single dose of a 5-HT3 receptor antagonist or a single 8-mg dose of Dexamethasone before antineoplastic treatment.
Minimal-emetic-risk antineoplastic agents
• (Reworded for clarity) Adult patients who are treated with minimal-emetic-risk antineoplastic agents should not be offered routine antiemetic prophylaxis.
Antineoplastic combinations
• (Reworded for clarity) Adult patients who are treated with antineoplastic combinations should be offered antiemetics that are appropriate for the component antineoplastic agent of greatest emetic risk.
Adjunctive drugs
• (Updated) Lorazepam is a useful adjunct to antiemetic drugs, but is not recommended as a single-agent antiemetic.
Cannabinoids
• (New) Evidence remains insufficient for a recommendation regarding treatment with medical marijuana for the prevention of nausea and vomiting in patients with cancer who receive chemotherapy or radiation therapy. Evidence is also insufficient for a recommendation regarding the use of medical marijuana in place of the tested and US FDA-approved cannabinoids, Dronabinol and Nabilone, for the treatment of nausea and vomiting caused by chemotherapy or radiation therapy.
Complementary and alternative therapies
• (Reworded for clarity) Evidence remains insufficient for a recommendation for or against the use of ginger, acupuncture/acupressure, and other complementary or alternative therapies for the prevention of nausea and vomiting in patients with cancer.
High-dose chemotherapy with stem cell or bone marrow transplantation
• (Updated) Adult patients who are treated with high-dose chemotherapy and stem cell or bone marrow transplantation should be offered a three-drug combination of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, and Dexamethasone.
Multiday antineoplastic therapy
• (Reworded for clarity) Adult patients who are treated with multiday antineoplastic agents should be offered antiemetics before treatment that are appropriate for the emetic risk of the antineoplastic agent administered on each day of the antineoplastic treatment and for 2 days after the completion of the antineoplastic regimen.
• (Strengthened) Adult patients who are treated with 4- or 5-day Cisplatin regimens should be offered a three-drug combination of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, and Dexamethasone.
Continued….. in Article 2 of this e NewsLetter
Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. Hesketh PJ, Kris MG, Basch E, et al. DOI: 10.1200/JCO.2017.74.4789 Journal of Clinical Oncology – published online before print July 31, 2017
FDA Approves RYDAPT® for FLT3-Mutated Acute Myeloid Leukemia
The FDA on April 28, 2017 approved RYDAPT® (Midostaurin), a multikinase inhibitor, for the treatment of adult patients with newly diagnosed Acute Myeloid Leukemia (AML), who are FLT3 mutation-positive (FLT3+), as detected by an FDA-approved test, in combination with standard Cytarabine and Daunorubicin induction and Cytarabine consolidation. Activating mutations in the FLT3 receptor is the most common genetic abnormality in AML and is detected in approximately 30% of the patients. RYDAPT® along with chemotherapy significantly improved Overall Survival and represents a new standard of care for FLT3-mutated AML patients.