Author: RR

POMALYST® Combination Significantly Improves Progression Free Survival in Relapsed/Refractory Myeloma

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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, 30,770 new cases will be diagnosed in 2018 and 12,770 patients are expected to die of the disease. Multiple Myeloma in 2018 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). POMALYST® (Pomalidomide) is a novel, oral, immunomodulatory drug which is far more potent than THALOMID® (Thalidomide) and REVLIMID® (Lenalidomide), and has been shown to be active in REVLIMID® and VELCADE® (Bortezomib) refractory patients. POMALYST® is approved by the FDA for use in combination with Dexamethasone for the treatment of patients with Multiple Myeloma who have received at least 2 prior therapies including REVLIMID® and a Proteasome Inhibitor, and have had disease progression on or within 60 days of completing their last therapy.

POMALYST® has demonstrated synergistic anti-myeloma activity with Dexamethasone and Proteasome Inhibitors. It has been shown to inhibit proliferation of REVLIMID® resistant cells in preclinical studies. With the increasing use of REVLIMID® as first line treatment for patients with Multiple Myeloma, there is a clinically relevant unmet medical need for patients who have progressed on REVLIMID®. The authors herein report the outcomes of a first phase III trial, comparing a combination of POMALYST®, VELCADE® and low dose Dexamethasone (PVd) with VELCADE® and Dexamethasone (Vd), in an entirely post-REVLIMID® treated population.

OPTIMISMM is an international, open label phase III study in which 559 patients with Relapsed/Refractory Multiple Myeloma were randomized in a 1:1 ratio to receive POMALYST® in combination with VELCADE® and low dose Dexamethasone (PVd – N=281) or VELCADE® and Dexamethasone (Vd – N=278). Patients in both treatment groups received VELCADE® 1.3 mg/m² SC, on days 1, 4, 8, and 11 of cycles 1 thru 8, and on days 1 and 8 of cycle 9 and beyond, of each 21 day cycle. Dexamethasone was given to all patients at 20 mg orally daily (10 mg/day if more than 75 years of age) on the days of and after VELCADE® treatment. In the experimental arm, patients received POMALYST® 4 mg orally daily on days 1 thru 14, of each 21 day cycle. The median age was 67.5 years and both treatment groups were well balanced. All patients had prior treatment with REVLIMID® and 70% were refractory to this agent, whereas 72% of the patients had prior treatment with VELCADE® and 68% were refractory to the last treatment. The median number of prior treatment lines was 2 and approximately 40% of the patients in both treatment groups had one prior line of therapy. The percentage of patients with high-risk cytogenetics such as del(17p), t(4;14), and or t(14;16]), was similar in both treatment groups. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Duration of Response, and Safety.

At a median follow up of 16 months, the median PFS was 11.2 months with PVd compared with 7.1 months with Vd alone (HR=0.61; P<0.0001). This meant a 39% reduction in the risk of progression or death with POMALYST®, VELCADE® and low dose Dexamethasone combination, compared with VELCADE® and low dose Dexamethasone alone. This PFS benefit was noted regardless of age, performance status, high-risk cytogenetics, number of prior therapies, and types of prior therapy. The OS data are not mature. The most common side effects of the drug combinations were neutropenia, infections, and thrombocytopenia, which were manageable.

It was concluded that in the treatment of Multiple Myeloma, there remains an unmet medical need for those patients who have received REVLIMID® based therapies and are in early relapse. OPTIMISMM is the only phase III study to date in early Relapsed/Refractory Multiple Myeloma, that has demonstrated a significant and clinically meaningful PFS improvement in patients who have previously received REVLIMID® and especially those who are refractory to REVLIMID®, suggesting that the combination of POMALYST®, VELCADE® and low dose Dexamethasone may be a new standard of care in patients with Relapsed/Refractory Multiple Myeloma, with prior exposure to REVLIMID®. Pomalidomide (POM), bortezomib, and low‐dose dexamethasone (PVd) vs bortezomib and low-dose dexamethasone (Vd) in lenalidomide (LEN)-exposed patients (pts) with relapsed or refractory multiple myeloma (RRMM): Phase 3 OPTIMISMM trial. Richardson PG, Rocafiguera AO, Beksac M, et al. J Clin Oncol 36, 2018 (suppl; abstr 8001)

Late Breaking Abstract – ASCO 2018 Broad Range of MSI-H tumors Linked with Lynch Syndrome

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SUMMARY: The FDA in 2017 granted accelerated approval to KEYTRUDA® (Pembrolizumab), a PD-1 blocking antibody, for adult and pediatric patients with unresectable or metastatic, MicroSatellite Instability-High (MSI-H) or MisMatch Repair Deficient (dMMR) solid tumors that have progressed following prior treatment, and who have no satisfactory alternative treatment options. This has led to routine MSI-H/dMMR testing in advanced solid tumors. 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 is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system and occurs in 15% of all colorectal cancers.Testing-for-MicroSatellite-Instability-and-MisMatch-Repair-Deficiency

Defective MisMatchRepair can be a sporadic or heritable event. Defective MisMatchRepair can manifest as a germline mutation occurring in MisMatchRepair genes including MLH1, MSH2, MSH6, PMS2 and EPCAM. This produces Lynch Syndrome often called Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC, an Autosomal Dominant disorder, that is often associated with a high risk for Colorectal and Endometrial carcinoma, as well as several other malignancies including Ovary, Stomach, Small bowel, Hepatobiliary tract, Brain and Skin. MSI is a hallmark of Lynch Syndrome-associated 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 blockade with immune checkpoint inhibitors. MSI 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). NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer. Unlike Colorectal and Endometrial cancer, where MSI-H/dMMR testing is routinely undertaken, the characterization of Lynch Syndrome across heterogeneous MSI-H/dMMR tumors is unknown.

The aim of the study was to determine the prevalence of germline mutations in the DNA mismatch repair genes diagnostic of Lynch Syndrome, across MSI-H tumors. The researchers in this study analyzed 15,045 tumor samples collected from patients with more than 50 different types of cancer using a comprehensive genomic test called MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), a next-generation sequencing platform. The MSK-IMPACT assay is a qualitative in-vitro diagnostic test that uses targeted next-generation sequencing of Formalin Fixed Paraffin-Embedded (FFPE) tumor tissue matched with normal specimens, from patients with solid tumors, to detect tumor gene alterations in a broad multigene panel. It is the first multiplex tumor profiling test to receive FDA authorization. The MSK-IMPACT test can look for gene mutations and other errors in all solid tumors, regardless of their origin.

Scores of less than 3, 3-9 and 10 or more were designated MSS, MSI-Indeterminate (MSI-I) or MSI-H status, respectively. Germline mutations were assessed in MLH1, MSH2, MSH6, PMS2, EPCAM. ImmunoHistoChemical staining (IHC) for dMMR, and tumor signatures in Lynch Syndrome patients were assessed.

Of the tumor samples analyzed, 93.2% were MSS, 4.6% were MSI-I, and 2.2% were MSI-H. Germline mutations indicative of Lynch Syndrome were identified in 0.3% of microsatellite-stable tumors, 1.9% of MSI-I tumors, and 16.3% of MSI-H tumors (P<0.001). The authors noted that nearly 50% of patients with MSI-H/MSI-I tumors identified as having Lynch Syndrome, had cancers other than colorectal or endometrial carcinoma – the two malignancies that are typically seen with Lynch Syndrome. The cancer types identified that were previously not linked to or rarely, linked to the Lynch Syndrome, included Mesothelioma, Sarcoma, Adrenocortical cancer, Melanoma, Prostate and Ovarian germ cell cancer. Nearly 40% of these patients did not meet the genetic testing criteria for Lynch Syndrome. MMR-deficiency was found in 98.3% of MSI-I/MSI-H tumor samples.

It was concluded that MSI-H/dMMR tumors, regardless of cancer type and irrespective of the family history, should prompt germline testing for the evaluation of Lynch Syndrome. This will increase the ability to recognize Lynch Syndrome, not only in the patients tested, but also in at-risk family members, thus enabling the implementation of enhanced surveillance and risk reduction measures. Pan-cancer microsatellite instability to predict for presence of Lynch syndrome. Schwark AL, Srinivasan P, Kemel Y, et al. J Clin Oncol 36, 2018 (suppl; abstr LBA1509)

Late Breaking Abstract – ASCO 2018 Chemoprevention of Esophageal Cancer with NEXIUM® and Aspirin

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SUMMARY: The American Cancer Society estimates that in 2018, about 17,290 new cases of esophageal cancer will be diagnosed in the US and about 15,850 individuals will die of the disease. It is the sixth most common cause of global cancer death. Squamous Cell Carcinoma is the most common type of cancer of the esophagus among African Americans, while Adenocarcinoma is more common in caucasians. In those with esophageal adenocarcinoma detected through symptoms, 5-year survival is less than 10%.

Barrett esophagus, defined as intestinal metaplasia in the distal esophagus, is a complication of GastroEsophageal Reflux Disease (GERD) and affects 2% of the adult population in western countries. In patients with Barrett’s esophagus, a portion of the esophagus that is usually lined with squamous epithelium undergoes metaplastic change to become columnar mucosa. Barrett esophagus predisposes patients to esophageal adenocarcinoma through a series of pathological events which include esophagitis, metaplasia, dysplasia and subsequently adenocarcinoma. Patients with Barrett’s esophagus are often screened for early malignancy with endoscopic evaluation with modest benefit. This is unlike screening for colorectal cancer that has proved successful in reducing colorectal cancer deaths.

It has been shown in observational studies that powerful acid suppression with Proton Pump Inhibitors (PPIs) could reduce risk of neoplastic progression in patients with Barrett’s esophagus, by downregulating cylcogoxygenase-2 expression. Esomeprazole (NEXIUM®) is the most commonly used PPI in the USA, and allows the healing of esophagitis without promoting clonal expansion of Barrett’s esophagus. Aspirin use in observational studies has been associated with reduced risk of esophageal adenocarcinoma. Based on these findings, the authors evaluated the efficacy and safety of these two drugs in the Aspirin and Esomeprazole Chemoprevention in Barrett’s metaplasia Trial (AspECT).

AspECT is a prospective, factorial design, multicenter, randomized, phase III study of chemoprevention by Aspirin and NEXIUM®, in patients with Barrett’s esophagus. Patients with Barrett’s esophagus of 1 cm or more (N=2557) were randomised 1:1:1:1 to Low-dose NEXIUM® (20 mg qd) and no Aspirin (N=705), High-dose NEXIUM® (40 mg bid) and no Aspirin (N=704), Low-dose NEXIUM® with Aspirin 300 mg qd (N=571) and High-dose NEXIUM® with Aspirin (N=577). The median follow up and treatment duration was 8.9 years. The Primary composite endpoint was time to all-cause mortality, esophageal adenocarcinoma, or high-grade dysplasia. The co-primary end points were the efficacy of High-dose PPI versus Low-dose PPI, and the efficacy of Aspirin versus no Aspirin.

It was noted that High-dose PPI was superior to Low-dose PPI (P=0.038). Aspirin was not significantly better than no Aspirin (P=0.068). However, if patients using Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) were censored at the time of first use, Aspirin was significantly better than no Aspirin (P=0.043). The most benefit was noted when High-dose PPI was combined with Aspirin compared with Low-dose PPI without Aspirin (P=0.0068). It appeared that the use of Aspirin and NEXIUM® (Proton Pump Inhibitor) would improve outcomes in Barrett’s esophagus, if given for at least 9 years. Serious adverse events were reported in only 1% of the participants.

It was concluded that in this largest randomized, controlled, chemoprevention trial in patients with Barrett’s esophagus, High dose NEXIUM® (given twice daily) along with Aspirin significantly reduces rates of death, esophageal adenocarcinoma, or high-grade dysplasia, with twice-daily NEXIUM® producing more effective suppression of acid reflux than once-daily dosing. Chemoprevention of esophageal cancer with esomeprazole and aspirin therapy: Efficacy and safety in the phase III randomized factorial ASPECT trial. Jankowski J, de Caestecker J, Love S, et al. J Clin Oncol 36, 2018 (suppl; abstr LBA4008)

AR-V7 in Circulating Tumor Cells (Liquid Biopsy) Can Guide Treatment in Castrate Resistant Prostate Cancer

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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 164,690 new cases of prostate cancer will be diagnosed in 2018 and 29,430 men will die of the disease. Prostate cancer is driven by Androgen Receptor (AR) and its signaling pathways. Initial treatment strategies for patients with metastatic prostate cancer include lowering the levels of circulating androgens with medical or surgical castration or blocking the binding of androgens to the androgen receptor. Upon progression, {described as Castrate Resistant Prostate Cancer (CRPC), as these tumors are not androgen independent and continue to rely on Androgen Receptor signaling}, Androgen Receptor Signaling (ARS) inhibitors, such as ZYTIGA ® (Abiraterone acetate) and XTANDI® (Enzalutamide), and Taxanes such as TAXOTERE® (Docetaxel) and JEVTANA® (Cabazitaxel) are the most widely used drug classes in the United States. ZYTIGA® inhibits CYP17A1 enzyme and depletes adrenal and intratumoral androgens, thereby impairing AR signaling. XTANDI® competes with Testosterone and Dihydrotestosterone and avidly binds to the Androgen Receptor, thereby inhibiting AR signaling, and in addition inhibits translocation of the AR into the nucleus and thus inhibits the transcriptional activities of the AR. About 20-40% of the patients do not respond to these newer agents (ARS inhibitors), and even those who respond will invariably develop resistance to these drugs.Androgen-Receptor-Variant-7-and-Drug-Resistance

ARS inhibitors are often the preferred choice for the first-line treatment of metastatic CRPC (mCRPC). In clinical practice, the majority of patients with mCRPC who progress on first-line ARS inhibitor receive a second ARS inhibitor, as there are no formal guidelines on how best to sequence these agents after progression on first-line ARS inhibition. Resistance to ARS inhibitors has been attributed to persistent AR signaling by variant forms of Androgen Receptor, generated through somatic mutation or aberrant RNA splicing. Androgen Receptor splice Variant 7 (AR-V7) is the most widely studied and can be detected in the CTCs (Circulating Tumor Cells). AR-V7 does not have the domain to bind androgens and may be associated with resistance to XTANDI®. Further AR-V7 is constitutively active and can independently activate transcription factors and therefore is not effected by androgen depleting agents including ZYTIGA®.

A critical unmet need is a test that can provide guidance on selecting appropriate therapy in the second and later lines, for this patient group. Accurately detecting a splice variant of the Androgen Receptor protein (AR-V7) in the nucleus of Circulating Tumor Cells (CTCs) using peripheral blood (liquid biopsy), would enable treating physicians to confidently decide whether patients treated with an ARS inhibitor, upon progression, would benefit from a second ARS inhibitor or should be switched to chemotherapy. This study focused on the patients receiving second-line treatment, to determine if an assay for the nuclear-localized AR-V7 protein in CTCs can be used to determine treatment for mCRPC.

The authors conducted this independent, multicenter cohort study to determine whether a validated assay for the nuclear-localized Androgen Receptor splice Variant 7 (AR-V7) protein in Circulating Tumor Cells (CTCs) can be used as a treatment-selection marker for metastatic CRPC, and whether it can determine Overall Survival difference among patients with mCRPC treated with Taxanes versus ARS inhibitors. This blinded correlative study included 142 patients with histologically confirmed mCRPC. Blood samples were obtained prior to administration of ARS inhibitors (N=70) or Taxanes (N=72), as a second-line therapy or later, for progressing mCRPC . Mean age was 69.5 years. Seventy (N=70) patients were designated as high risk by conventional prognostic factors. The Primary outcome measure was Overall Survival after treatment with an ARS inhibitor or Taxane, in relation to pretreatment AR-V7 status.

It was noted that the presence of AR-V7 protein in CTCs was associated with a greater benefit from Taxane treatment whereas outcomes in AR-V7 negative patients were better with ARS inhibitor treatment. The median survival of patients with AR-V7 negative CTCs was 19.8 months for those treated with an ARS inhibitor and 12.8 months for those treated with a Taxane (P=0.05). In contrast, among patients with AR-V7 positive CTCs, those receiving Taxanes had longer observed median survival times compared to those treated with ARS inhibitors (14.3 vs 7.3 months; HR=0.62; P=0.25). The observed difference was not statistically significant and may have been attributable to the small sample size.

The authors concluded that this study suggests that nuclear-localized AR-V7 protein in Circulating Tumor Cells (liquid biopsy test) can identify patients who may live longer with Taxane chemotherapy versus ARS inhibitor treatment. This tailored treatment approach addresses a critical unmet need by predicting and enabling selection of therapy that can improve median survival. Assessment of the Validity of Nuclear-Localized Androgen Receptor Splice Variant 7 in Circulating Tumor Cells as a Predictive Biomarker for Castration-Resistant Prostate Cancer. Scher HI, Graf RP, Schreiber NA, et al. JAMA Oncol. Published online June 28, 2018. doi:10.1001/jamaoncol.2018.1621

First Line TECENTRIQ® plus Chemotherapy in Advanced Squamous NSCLC

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Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and 30% are Squamous Cell Carcinomas (SCC). Non Small Cell Lung Cancer patients with Squamous Cell histology have been a traditionally hard- to-treat, patient group, and less than 15% of patients with advanced Squamous NSCLC survive a year after diagnosis and less than 5% of patients survive for five years or longer. IMpower131 is a multicenter, open-label, phase III study, in which 1021 chemotherapy-naïve patients with stage IV Squamous NSCLC received TECENTRIQ® ((Atezolizumab)) along with Carboplatin, and Paclitaxel, TECENTRIQ® along with Carboplatin, and ABRAXANE® (nab-paclitaxel) or Carboplatin and ABRAXANE® (control group). The addition of  TECENTRIQ® to chemotherapy significantly improved median Progression Free Survival across all PD-L1 subgroups. This is the first phase III trial of an immunotherapy-based treatment regimen, to demonstrate a significant improvement in Progression Free Survival, in advanced Squamous NSCLC.

Six Months Adjuvant HERCEPTIN® Safer and Efficacious in Early Stage HER2+ Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 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. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2, and adjuvant chemotherapy given along with HERCEPTIN® reduces the risk of disease recurrence and death, among patients with HER2-positive, early stage breast cancer. The duration of adjuvant HERCEPTIN® therapy has been 12 months and this length of treatment was empirically adopted from the pivotal registration trials.HER2-Directed-Therapy

PERSEPHONE is a randomized, phase III, noninferiority trial in which a 6-month course of adjuvant HERCEPTIN® was compared with the standard 12-month course, among patients with HER2-positive early breast cancer. This study was conducted based on the hypothesis that shorter course of treatment with HERCEPTIN® could reduce cardiotoxicities as well as cost without compromising efficacy. This trial randomized 4089 patients across 152 sites in a 1:1 ratio to receive HERCEPTIN® for 6 months (N=2044) or 12 months (N=2045). In this trial, 69% of patients had ER-positive tumors, 41% received Anthracycline-based chemotherapy, 49% received Anthracycline and Taxane-based chemotherapy, 10% received Taxane-based chemotherapy, 85% received adjuvant chemotherapy, and sequential HERCEPTIN® was administered in 54% of patients. This study also included assessment of Left Ventricular Ejection Fraction (LVEF) every 3 months until month 12, as well as continued Quality of Life and health economic assessments at months 18 and 24. The Primary endpoint was Disease Free Survival (DFS) from the time of diagnosis.

At a median follow-up period of 5 years, the 4-year DFS rate was identical in both treatment groups. DFS was 89.8% with 12 months of HERCEPTIN® compared with 89.4% with the 6-month course, which met the criteria for noninferiority (P=0.01). Further, only 4% of the patients enrolled in the 6-month HERCEPTIN® group discontinued HERCEPTIN® treatment due to cardiotoxicities compared with 8% in the 12-month group (P<0.0001), suggesting that the number of patients stopping treatment due to cardiac toxicities was cut in half with the shorter duration of treatment with HERCEPTIN®. Patients receiving shorter course of HERCEPTIN® also had a more rapid recovery of their cardiac LVEF following treatment, compared with the standard of care group (P=0.02).

It was concluded from this largest, reduced duration, noninferiority trial that a shorter 6-month course of adjuvant HERCEPTIN® was noninferior for Disease Free Survival, compared with the standard 12-month schedule, among patients with HER2-positive early breast cancer, with an additional benefit of reduction in cardiac toxicities, as well as cost both to the patients and healthcare systems. Overall Survival data was not available at the time of this analysis. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): Randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results. Earl HM, Hiller L, Vallier A-L, et al. J Clin Oncol 36, 2018 (suppl; abstr 506)

FDA Approves TIBSOVO® for Patients with Relapsed or Refractory Acute Myeloid Leukemia

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SUMMARY: The FDA on July 20, 2018, approved TIBSOVO® (Ivosidenib) for adult patients with relapsed or refractory Acute Myeloid Leukemia (AML) with a susceptible Isocitrate DeHydrogenase-1 (IDH1) mutation, as detected by an FDA-approved test. The American Cancer Society estimates that in 2018, 19,520 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 10,670 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients, based on risk and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy alone.MOA-of-Ivosidenib

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.

TIBSOVO® is an oral, targeted, small-molecule inhibitor of mutant IDH1. IDHIFA® (Enasidenib), an oral, selective, small molecule inhibitor of mutated IDH2 protein was approved in the United States in August 2017 for adult patients with relapsed or refractory AML with an IDH2 mutation. The Complete Remission (CR) rate with the currently available non-targeted therapies for patients with relapsed or refractory AML is 15% or less and the median Overall Survival is less than 4 months, with 30-day mortality of approximately 15% and 60-day mortality of approximately 30%.

The approval of TIBSOVO® was based on an open-label, single arm, multicenter clinical trial that included 174 adult patients with relapsed or refractory AML with an IDH1 mutation. IDH1 mutations were confirmed by the Abbott RealTime® IDH1 assay, the FDA-approved test for selection of patients with AML for treatment with TIBSOVO®. TIBSOVO® was given orally at a starting dose of 500 mg daily until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation. The median treatment duration was 4.1 months. Twenty one of the 174 patients (12%) received a Stem Cell Transplant following treatment with TIBSOVO®. The median patient age was 67 years, patients had a median number of 2 prior therapies, 87% of the patients had intermediate or poor cytogenetic risk status, 33% had secondary AML and 59% were refractory to their previous therapy. The Primary endpoint was the combined rate of Complete Remission (CR) plus Complete Remission with partial hematologic recovery (CRh) and the rate of conversion from transfusion dependence to independence. CRh was defined as less than 5% of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets more than 50,000/μl and ANC more than 500/μl)

The use of TIBSOVO® was associated with a CR plus CRh rate of 32.8%. The median time to response was 2 months and the median response duration was 8.2 months. The CR and CRh rates were 24.7% and 8.0% respectively. Among the 110 patients who were dependent on Red Blood Cell and/or platelet transfusions at baseline, 37.3% became transfusion independent during any 56-day post-baseline period. Of the 64 patients who were independent of both RBC and platelet transfusions at baseline, 59.4% remained transfusion independent during any 56-day post-baseline period. The most common adverse reactions were fatigue, nausea, diarrhea, rash, pyrexia, arthralgia, leukocytosis and QT prolongation. One effect of the IDH inhibitors are induction of differentiation of the malignant cells, and in 10-20% of patients, a clinical syndrome known as the IDH differentiation syndrome can occur. The IDH differentiation syndrome should be promptly managed by dose interruption and treatment with glucocorticoids, oral hydroxyurea, or both.

It was concluded that in patients with advanced IDH1-mutated relapsed or refractory AML, TIBSOVO® fills an unmet need, with durable molecular remissions and reduction in the need for transfusion support. Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. DiNardo CD, Stein EM, de Botton S, et al. N Engl J Med 2018; 378:2386-2398

KISQALI® (Ribociclib)

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The FDA on July 18, 2018 expanded the indication for KISQALI® in combination with an Aromatase Inhibitor for pre and perimenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine-based therapy. KISQALI® is a product of Novartis Pharmaceuticals Corporation.

TIBSOVO® (Ivosidenib)

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The FDA on July 20, 2018 approved TIBSOVO® for adult patients with relapsed or refractory Acute Myeloid Leukemia (AML) with a susceptible IDH1 mutation, as detected by an FDA-approved test. TIBSOVO® is a product of Agios Pharmaceuticals, Inc.

XTANDI® (Enzalutamide)

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The FDA on July 13, 2018 approved XTANDI® for patients with Castration-Resistant Prostate Cancer (CRPC). This approval broadens the indicated patient population to include patients with both non-metastatic CRPC (NM-CRPC) and metastatic CRPC. XTANDI® was previously approved for the treatment of patients with metastatic CRPC. XTANDI® is a product of Astellas Pharma US, Inc.