Late Breaking Abstract-ASCO 2015 Treating Cancer Based on Genomics Regardless of Tumor Type

SUMMARY: KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti–PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. The treatment paradigm for solid tumors has been rapidly evolving with a better understanding of the Immune checkpoints. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be to a significant extent, related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. The T cells of the immune system therefore play a very important role in modulating the immune system. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4), also known as CD152, PD-1(Programmed cell Death-1), etc. By doing so, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic respons

The FDA approves IRESSA® for metastatic Non Small Cell Lung Cancer

SUMMARY: The FDA on July 13, 2015 approved IRESSA® (Gefitinib) for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC), whose tumors have Epidermal Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA approved test. IRESSA was approved concurrently with a labeling expansion of the therascreen EGFR RGQ PCR Kit, a companion diagnostic test, for patient selection. Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. It is the leading cause of cancer death among both men and women. The American Cancer Society estimates that over 221,200 new cases of lung cancer will be diagnosed in the United States in 2015 and over 158,000 patients will die of the disease. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of Non Small Cell Lung Cancer (NSCLC), 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large cell carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer. Epidermal Growth Factor Receptor (EGFR) is frequently overexpressed in NSCLC. In 2004, the discovery of Epidermal Growth Factor Receptor (EGFR) mutations in some advanced Non Small Cell Lung Cancer (NSCLC) patients, with Adenocarcinoma histology, and the favorable responses with EGFR Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib), IRESSA® (Gefitinib) and GILOTRIF® (Afatinib), has changed the treatment paradigm, in favor of targeted therapy, for this patient subset. GILOTRIF® is an irreversible blocker of the ErbB family, which includes EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4. It is estimated that approximately 10% of Western patient population and 50% of Asian patients with NSCLC, harbor EGFR activating mutations. IRESSA® is an oral, EGFR Tyrosine Kinase Inhibitor (TKI), which works by blocking the activity of the EGFR tyrosine kinase enzyme responsible for regulating signaling pathways, implicated in the growth and survival of cancer cells. IRESSA® was granted Orphan Drug Designation by the FDA in August 2014 for the treatment of EGFR mutation positive NSCLC.

The approval of IRESSA® was based on the results of a Phase IV, single-arm, multicenter, open-label clinical study (IRESSA Follow-Up Measure or IFUM study) which included 106 treatment naïve-patients with metastatic EGFR mutation positive NSCLC who received IRESSA® 250mg PO daily. Treatment was given until disease progression or intolerable toxicity. Primary endpoint was Objective Response Rate (ORR). Secondary endpoints included Disease Control Rate (DCR), Progression Free Survival (PFS), Overall Survival (OS) and safety/tolerability. At the time of data cutoff, the investigator determined ORR was 70%, Duration of Response was 8.3 months, Disease Control Rate was 90.6%, median PFS was 9.7 months and median OS was19.2 months. This efficacy data was further supported by the IRESSA Pan-ASia Study (IPASS), a randomized phase III trial, which enrolled 1,217 treatment naïve advanced NSCLC patients with adenocarcinoma histology. Patients were randomized (1:1) to receive IRESSA® 250 mg PO daily or up to 6 cycles of combination chemotherapy with Carboplatin and Paclitaxel. The efficacy outcomes included Progression Free Survival (PFS) and Objective Response Rate (ORR). An exploratory analysis of a subset of 186 of 1217 patients (15%), who were determined to be EGFR mutation positive, had imaging studies available for evaluation (IRESSA® treated patients=88 and Carboplatin/Paclitaxel treated patients=98). The median PFS in the IRESSA® treated group was 10.9 months compared to 7.4 months for the Carboplatin/Paclitaxel treated patients (HR=0.54). The ORR was 67% with a Duration of Response (DoR) of 9.6 months for IRESSA® treated patients versus 41%, with a DoR of 5.5 months for Carboplatin/Paclitaxel treated patients. The most commonly reported adverse events for IRESSA® were diarrhea and skin toxicities including rash, acne, dry skin and pruritus. It was concluded that EGFR mutations are the strongest predictive biomarker for Progression Free Survival and tumor response to first line treatment with IRESSA®. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study. Douillard J-Y, Ostoros G, Cobo M, et al. Br J Cancer. 2014;110:55–62

GILOTRIF® Superior to TARCEVA® in Squamous Cell Carcinoma of the Lung

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. It is the leading cause of cancer death among both men and women. The American Cancer Society estimates that over 221,200 new cases of lung cancer will be diagnosed in the United States in 2015 and over 158,000 patients will die of the disease. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of Non Small Cell Lung Cancer (NSCLC), 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large cell carcinomas. Non Small Cell Lung Cancer patients with squamous cell histology have been a traditionally hard- to-treat patient group, with less than 5% of patients with advanced SCC, surviving for five years or longer. Some of the advanced NSCLC tumors are dependent on the Epidermal Growth Factor Receptor (EGFR) for cell proliferation and survival, regardless of EGFR mutation status. TARCEVA® (Erlotinib) is a reversible EGFR Tyrosine Kinase Inhibitor and is presently approved by the FDA for the treatment of locally advanced or metastatic NSCLC, after failure of at least one prior chemotherapy regimen. GILOTRIF® (Afatinib) is an oral, irreversible blocker of the ErbB family which includes EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4. This kinase inhibitor is indicated for the first line treatment of patients with metastatic NSCLC, whose tumors have Epidermal Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.

The LUX-Lung 8 is a phase III trial in which 795 patients with Stage IIIB/IV Squamous Cell Carcinoma of the lung who had progressed on first line platinum based doublet therapy, were randomized 1:1 to receive GILOTRIF 40 mg PO daily (N=398) or TARCEVA 150 mg PO daily (N=397). Treatment was given until disease progression. The median age was 65 years. Majority of the patients were male, caucasian and ex-smokers. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), Disease Control Rate (DCR), patient reported outcomes and safety. The Primary endpoint of Progression Free Survival (PFS) was met and reported in 2014 and favored GILOTRIF® over TARCEVA®. The authors in this analysis reported the Overall Survival data, as well as updated data on Progression Free Survival and other Secondary endpoints. The median Overall Survival was 7.9 months with GILOTRIF® and 6.8 months with TARCEVA® (HR=0.81; P=0.008). This meant a 19% reduction in the risk of death with GILOTRIF® when compared to TARCEVA® and this survival advantage was consistent across all time points. The updated median Progression Free Survival for GILOTRIF® was 2.6 months vs 1.9 months for TARCEVA® (HR=0.81; P=0.01). The Disease Control Rate was 50.5% for GILOTRIF® and 39.5% with TARCEVA® (P=0.002). Based on patient reported outcomes, symptoms including cough and dyspnea were better with GILOTRIF® compared to TARCEVA®. Incidence of severe adverse events was similar with both therapies, with patients on GILOTRIF® experiencing more grade 3 diarrhea and stomatitis and patients receiving TARCEVA® experiencing more grade 3 rash. The authors concluded that GILOTRIF® should be the TKI of choice in the second line treatment of patients with Squamous Cell Carcinoma of the lung, as it significantly improves Overall Survival, Progression Free Survival, Disease Control Rate and symptom control, with manageable toxicities, when compared to TARCEVA®. Afatinib (A) vs erlotinib (E) as second-line therapy of patients (pts) with advanced squamous cell carcinoma (SCC) of the lung following platinum-based chemotherapy: Overall survival (OS) analysis from the global phase III trial LUX-Lung 8 (LL8). Soria J, Felip E, Cobo M, et al. J Clin Oncol 33, 2015 (suppl; abstr 8002)

Choosing Appropriate Therapy in Chronic Myeloid Leukemia

SUMMARY: Chronic Myeloid Leukemia (CML) constitutes approximately 10% of all new cases of leukemia. The American Cancer Society estimates that 6,660 new CML cases will be diagnosed in the United States in 2015 and about 1,140 people will die of the disease. The hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9, fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells. Gleevec® (Imatinib) inhibits the BCR-ABL tyrosine kinase and is the standard first line treatment, of Ph chromosome positive (Ph+) leukemias. Lack of response due to resistance to GLEEVEC® and in some instances drug intolerance, has led to the development of newer agents including Second and Third generation Tyrosine Kinase Inhibitors (TKIs). Resistance to Gleevec® and other TKIs sharing the same therapeutic target (BCR-ABL kinase), has been attributed to point mutations in the ABL kinase domain, amplification of the BCR-ABL gene as well as other BCR- ABL independent mechanisms such as upregulation of SRC kinases. Mutation analysis at the time of TKI failure, utilizing high sensitivity sequencing techniques such as Next Generation Sequencing, can give clinically relevant information related to low level mutations and compound mutations and this information in turn, can dictate choice of second line therapy. The Second generation TKIs, TASIGNA® (Nilotinib) and SPRYCEL® (Dasatinib) although initially approved for second line treatment of CML after GLEEVEC® resistance or intolerance, are now FDA approved for the treatment of newly diagnosed Chronic Phase CML. This approval was based on the rapid and superior Major Molecular Responses (MMR) noted, when compared to GLEEVEC®. Now, that the Second generation TKIs are being used as first line therapy, the choice of second line therapy after failure with Second generation TKIs has become more nebulous. It is clear however that, patients with primary cytogenetic resistance to first and second line therapy do not benefit from sequential therapy with Second generation TKIs and BCR-ABL mutation analysis should be performed in all patients who develop TKI resistant disease. Before switching from a Second to a Third generation TKI such as Ponatinib, the following considerations should be taken into account

BCR-ABL Mutations and Sensitivity to Second Generation TKIs

1) Patients with F317L/V/I/C mutations are more sensitive to TASIGNA® (Nilotinib) or BOSULIF® (Bosutinib) than to SPRYEL® (Dasatinib)

2) Patients with V299L mutation are more sensitive to TASIGNA® than to BOSULIF® or SPRYCEL®

3) Patients with Y253F/H, E255K/V, and F359V/I/C mutations are more sensitive to SPRYCEL® or BOSULIF® than to TASIGNA®

Tolerability of Second Generation TKIs

1) Patients who experience pleural effusion during SPRYCEL® treatment might better tolerate TASIGNA® or BOSULIF®

2) Patients who experience rash during treatment with TASIGNA® or BOSULIF® could be switched to SPRYCEL®

3) Some toxicities common with other TKIs such as pleural effusion and cardiac toxicity are less common with BOSULIF® and this agent also has activity against many BCR-ABL kinase domain mutations resistant to GLEEVEC®, SPRYCEL® and TASIGNA®, with the exception of T315I mutation.

It should be noted that Second generation TKI as third line therapy has limited value in majority of the patients with CML. ICLUSIG® (Ponatinib) is a Third generation kinase inhibitor approved for the treatment of patients with T315I positive CML or T315I-positive Philadelphia Chromosome positive Acute Lymphoblastic Leukemia (Ph+ ALL) and for whom no other TKI is indicated. Other treatment options include SYNRIBO® (Omacetaxine Mepesuccinate), a first-in-class Cephalotaxine and a semi synthetic purified Homoharringtonine (HHT) compound. Unlike Tyrosine Kinase Inhibitors , SYNRIBO® is a protein synthesis inhibitor and reduces the levels of multiple Oncoproteins including BCR-ABL, BCL-2, MCL-1 and promotes apoptosis of leukemic stem cells. This agent is presently approved for the treatment of Chronic or Accelerated phase Chronic Myeloid Leukemia (CML) with resistance and/or intolerance to two or more Tyrosine Kinase Inhibitors, with cytopenias being the most common toxicity. Allogeneic Hematopoietic Stem Cell transplantation should be considered for eligible patients with T315I mutation not responding to ICLUSIG®, those with mutations resistance to second and third generation TKIs and patients with Accelerated or Blast phase CML, following remission with TKIs. Use of Second- and Third-Generation Tyrosine Kinase Inhibitors in the Treatment of Chronic Myeloid Leukemia: An Evolving Treatment Paradigm. Jabbour E, Kantarjian H and Cortes J. Clinical Lymphoma, Myeloma & Leukemia 2015;15:323-334

IRESSA® (Gefitinib)

The FDA on July 13, 2015 approved IRESSA® for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC), whose tumors have Epidermal Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA approved test. IRESSA® was approved concurrently with a labeling expansion of the therascreen EGFR RGQ PCR Kit, a companion diagnostic test, for patient selection. IRESSA® tablets are a product of AstraZeneca Pharmaceuticals LP.

Fish Oil and Certain Species of Fish May Negate the Effects of Chemotherapy

SUMMARY: It is estimated that approximately 20% of cancer patients in the US take Omega-3 fatty acids in the form of fish oil. Fish oil is a mixture of fatty acids produced from several species of fish and the two most abundant and important fatty acids in fish oil include EicosaPentaenoic Acid (EPA) and DocosaHexaenoic Acid (DHA). Fish oil content in presently available preparations is not standardized and does not require FDA approval. Preclinical studies have demonstrated that mouse tumors recruit mesenchymal stem cells that are specifically activated by platinum based chemotherapy and secrete 2 fatty acids, 12S-HHT and 16:4(n-3)). These fatty acids are called Platinum Induced Fatty Acids (PIFAs) and they have been shown to induce resistance to a broad range of chemotherapeutic agents, by activating a cytoprotective response in the tumor tissue. Fish oil has relevant levels of fatty acid 16:4(n-3) and preclinical models have shown that the fish oil neutralized the antitumor activity of chemotherapy, thus conferring drug resistance. With this preclinical information and given that cancer patients frequently use fish oil supplements, the authors evaluated the effect of fish oil intake in healthy volunteers, on the plasma levels of fatty acid 16:4(n-3), which has been shown to induce resistance to chemotherapeutic agents. The researchers first conducted a survey to determine what percentage of cancer patients undergoing treatment at a University Medical Center in the Netherlands were taking fish oil supplements. They also analyzed fatty acid 16:4(n-3) content, in 3 brands of fish oil supplements and 4 often consumed species of fish. The authors then randomly selected 30 healthy volunteers for the fish oil study and 20 healthy volunteers for the fish consumption study and the plasma levels of fatty acid 16:4(n-3) was measured after they consumed fish oil or fish, for a period of 2 weeks. They noted that 11% of the cancer patients in their study reported using omega-3 supplements. All fish oils tested contained amounts of fatty acid 16:4(n-3) ranging from 0.2 to 5.7 μM and this was adequate to induce chemoresistance to a variety of chemotherapeutic agents. They noted that there was a significant rise in the plasma 16:4(n-3) fatty acid levels in the healthy volunteers after they consumed fish oil supplements and fish, with high levels of fatty acid 16:4(n-3). Herring and Mackerel fish contained high levels of fatty acid 16:4(n-3), in contrast to Salmon and Tuna. The authors concluded that based on this preclinical data it is best to avoid fish oils and fish such as Herring and Mackerel in the 48 hours surrounding chemotherapy, as the high plasma 16:4(n-3) fatty acid levels may negate the effects of chemotherapy. These recommendations have been adopted by the Dutch Cancer Society and by the Dutch National Working Group for Oncologic Dieticians. Increased Plasma Levels of Chemoresistance-Inducing Fatty Acid 16:4(n-3) After Consumption of Fish and Fish Oil. Daenen LGM, Cirkel GA, Houthuijzen JM, et al. JAMA Oncol. 2015;1:350-358

Radiation Therapy Added to Androgen Deprivation Therapy Improves Overall Survival in Locally Advanced Prostate Cancer

SUMMARY:Prostate cancer is the most common cancer in American men with the exclusion of skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 220,800 new cases of prostate cancer will be diagnosed in 2015 and over 27,000 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention for hormone sensitive prostate cancer. This is accomplished by either surgical castration (bilateral orchiectomy) or medical castration using LHRH (GnRH- Gonadotropin-Releasing Hormone) agonists given along with 2 weeks of first generation anti-androgen agents such as EULEXIN® (Flutamide), CASODEX® (Bicalutamide) or NILANDRON® (Nilutamide), with the anti-androgen agents given to prevent testosterone flare. This large intergroup trial which was developed by the NCIC Clinical Trials Group in collaboration with the Medical Research Council and the National Cancer Institute US Cancer Therapy Evaluation Program, evaluated the benefits of adding Radiation Therapy (RT) to ADT, when compared to ADT alone, in patients with locally advanced prostate cancer. In this study, 1205 patients were randomly assigned to receive either ADT alone (N=602) or ADT plus RT (N=603). Eligible patients included those with T1-2 disease with either Prostate Specific Antigen (PSA) of more than 40 μg/L or PSA of 20-40 μg/L plus Gleason score of 8-10 or patients with T3-4, N0/NX, M0 prostate cancer. ADT consisted of either bilateral orchiectomy or LHRH agonists (plus 2 weeks of oral anti-androgen therapy to prevent testosterone flare), based on patient and physician preference, and ADT was continued for life. RT consisted of a dose of 64-69 Gy given in 35-39 fractions to the prostate gland and pelvis or prostate gland alone. The median age was 70 years and the median follow up was 8 years. Eighty seven percent of patients had T3-4 disease, 63% of patients had a PSA more than 20 μg/L and 18% had a Gleason score of more than 8. The Primary Endpoint was Overall Survival (OS), defined as the time from randomization to death from any cause. Secondary Endpoints included Time To Progression (TTP), improvement in Disease Specific Survival, quality of life and toxicity. The authors had previously reported the interim analysis findings of this intergroup trial and they noted that the addition of RT to ADT significantly improved overall survival, at a median follow up of 6 years (HR= 0.77; P=0.033). In this final analysis, at a median follow up of 8 years, the interim analysis findings were confirmed and the patients assigned to ADT plus RT had significantly improved Overall Survival compared to those who received ADT alone (HR=0.70; P<0.001), with a 30% reduction in the risk of death. Disease Specific Survival was also superior with ADT plus RT compared to ADT alone, with a 54% reduction in deaths from prostate cancer (HR=0.46; P <0 .001). There was a higher incidence of grade 1 and 2 bowel toxicities in patients who received ADT plus RT, but grade 3 bowel toxicities were rare and short term. The authors concluded that this long term follow up data suggests that the addition of Radiation Therapy to Androgen Deprivation Therapy significantly prolongs Overall and Disease Specific Survival, in patients with locally advanced prostate cancer. Final Report of the Intergroup Randomized Study of Combined Androgen-Deprivation Therapy Plus Radiotherapy Versus Androgen-Deprivation Therapy Alone in Locally Advanced Prostate Cancer. Mason MD, Parulekar WR, Sydes MR, et al. J Clin Oncol 2015; 33:2143-2150

Tumor genomics May Predict Outcomes with First Line Therapy in Metastatic Renal Cell Carcinoma

SUMMARY: The American Cancer Society estimates that about 61,560 new cases of kidney cancer will be diagnosed in the United States in 2015 and over 14,000 patients will die from this disease. The VHL (Von Hippel-Lindau) gene is the most frequently mutated gene (approximately 90%) in clear cell Renal Cell Carcinoma (ccRCC). The VHL gene is a tumor suppressor gene and under normal conditions with normal oxygen tension, binds to Hypoxia-Inducible Factor (HIF-1 alpha) and facilitates degradation of this factor. Under hypoxic conditions and in patients having biallelic loss of function and mutation of VHL genes, HIF-1alpha is not degraded. Build up of HIF-1 alpha results in increased angiogenesis, increased tumor cell proliferation and survival, as well as metastasis. SUTENT® (Sunitinib) is a MultiKinase Inhibitor(MKI) and simultaneously targets the tumor cell wall, vascular endothelial cell wall as well as the pericyte/fibroblast/vascular/ smooth vessel cell wall and is capable of specifically binding to tyrosine kinases, inhibiting the earlier signaling events and thereby inhibits phosphorylation of VEGF receptor, PDGF receptor, FLT-3 and c-KIT. AFINITOR® (Everolimus) unlike SUTENT® does not inhibit tyrosine kinases but is a specific inhibitor of mTOR(Mammalian Target of Rapamycin) which is a serine/threonine kinase, normally activated further downstream in the signaling cascade. With the inhibition of mTOR, protein synthesis is inhibited resulting in decreased angiogenesis, cell proliferation and survival as well as decreased levels of HIF-1 alpha. Besides VHL gene mutation, several novel relatively common mutations of histone modifying and chromatin remodeling genes have been identified in clear cell RCC, with the availability of Next Generation Sequencing (NGS). Next-generation sequencing (NGS) platforms or second-generation sequencing unlike the first-generation sequencing, known as Sanger sequencing, perform massively parallel sequencing, which allows sequencing of millions of fragments of DNA from a single sample. With this high-throughput sequencing, the entire genome can be sequenced in less than 24 hours. Some of the new genes identified include PBRM1, KDM5C, SETD2 and BAP1. These are tumor suppressor genes and are located on chromosome 3p, close to the VHL gene, at the 3p locus. Mutations involving these genes in clear cell RCC, results in loss of protein expression and has been associated with advanced tumor stage, grade and poor patient outcomes.

The authors in this study explored patient outcomes, based on somatic mutations and therapy given, amongst patients enrolled in the RECORD-3 trial. RECORD-3 is multicenter, randomized phase II trial which enrolled 471 treatment-naïve, metastatic, clear cell Renal Cell Carcinoma patients and compared first line AFINITOR® followed by SUTENT® at progression (N=238) with the standard sequence of first line SUTENT® followed by AFINITOR® (N=233). Using Next Generation Sequencing the authors were able to identify somatic mutations in the exons of 341 cancer related genes and associated the first line Progression Free Survival (PFS) with the tumor genotypes. They noted that 41% of the cohort of patients had PBRM1 mutations. In the group of patients receiving AFINITOR® as first line therapy, those with PBRM1 mutations had a longer median PFS compared to those who did not have PBRM1 mutations (11.1 vs 5.3 months; P=0.0031). Further, those with PBRM1 mutations, derived comparable PFS benefit from first line AFINITOR® or first line SUTENT®. In the group receiving SUTENT® as first line therapy, patients with KDM5C mutations had a longer PFS compared to those who did not have KDM5C mutations (mPFS 20.6 vs 8.4 months; P=0.0511). The authors concluded that PBRM1 and KDM5C gene mutations may predict sensitivity to mTOR or VEGFR inhibitors, in metastatic Renal Cell Carcinoma with different genomic profiles. Identification of efficacy biomarkers in a large metastatic renal cell carcinoma (mRCC) cohort through next generation sequencing (NGS): Results from RECORD-3. Hsieh J, Chen D, Wang P, et al. J Clin Oncol 33, 2015 (suppl; abstr 4509)

Late Breaking Abstract – ASCO 2015 Adjuvant Chemotherapy Improves Overall Survival in Localized High Risk Prostate Cancer

SUMMARY: Prostate cancer is the most common cancer in American men excluding skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 220,800 new cases of prostate cancer will be diagnosed in 2015 and over 27,000 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention for hormone sensitive prostate cancer. Chemotherapy is usually considered for patients who progress on hormone therapy and TAXOTERE® (Docetaxel) has been shown to improve Overall Survival (OS) of metastatic prostate cancer patients, who had progressed on Androgen Deprivation Therapy. Two previously published trials, STAMPEDE and CHAARTED have shown that TAXOTERE® in combination with Androgen Deprivaton Therapy significantly improved Overall Survival among men with newly diagnosed hormone naïve metastatic prostate cancer. Based on this information the authors hypothesized that if chemotherapy is beneficial in metastatic hormone sensitive prostate cancer, non-metastatic, hormone-sensitive, prostate cancer, should have improved outcomes with chemotherapy, as well.

RTOG 0521 is a randomized phase III trial which enrolled 612 high-risk with localized prostate cancer and 563 patients were eligible for evaluation. High risk prostate cancer was defined as 1) Patients with Gleason score of 7-8, any T-stage and PSA of 20 ng/ml or more or 2) Gleason score of 8, T2 or more and any PSA or 3) Gleason score of 9-10, any T stage and any PSA. All patients had a PSA of 150 ng/ml or less. This study was designed to detect a 51% relative reduction in the risk of death. Patients were randomized to receive Androgen Deprivation Therapy (ADT) with LHRH agonists and Radiation Therapy to a dose of 75.6 Gy (N=281) or ADT along with Radiation Therapy and TAXOTERE® (Docetaxel) 75 mg/m2 given on Day 1, every 3 weeks, for a total of 6 cycles, along with Prednisone, starting 4 weeks after the completion of Radiotherapy (N=282). Androgen Deprivation Therapy was given for 24 months and Radiation Therapy was delivered over an 8 week period. The median age was 66 years. The median PSA level was 15.1 ng/mL, 53% had Gleason scores between 9 and 10, 27% had prostate cancer with clinical T3-4 disease and 33% had node-negative disease. The primary endpoint was Overall Survival. With a median follow up of 5.5 yrs, the 4 year Overall Survival rates were 89% for those who received ADT and Radiation Therapy (RT) compared to 93% for men treated with ADT, RT, and TAXOTERE® chemotherapy (HR=0.68; P=0.03). The 5 year Disease Free Survival rates were 66% in the ADT plus RT versus 73% in the TAXOTERE® group (HR = 0.76; P=0.05) and there was associated reduction in the incidence of distant metastasis. There were more grade 3 and 4 hematologic toxicities in the chemotherapy arm as was expected and these toxicities were manageable. The authors concluded that this is the first phase III study to show Overall Survival benefit when TAXOTERE® is given as adjuvant chemotherapy in high risk, hormone sensitive, prostate cancer patients with localized disease. Longer follow up will determine if the role of adjuvant chemotherapy with TAXOTERE®, in this patient population will become more established. A phase III protocol of androgen suppression (AS) and 3DCRT/IMRT versus AS and 3DCRT/IMRT followed by chemotherapy (CT) with docetaxel and prednisone for localized, high-risk prostate cancer (RTOG 0521). Sandler HM, Hu C, Rosenthal SA, et al. J Clin Oncol 33, 2015 (suppl; abstr LBA5002)

Late Breaking Abstract – ASCO 2015 IBRANCE® More Than Doubles Progression Free Survival in Hormone Receptor Positive Advanced Breast Cancer

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, 231,840 new cases of invasive breast cancer will be diagnosed in 2015 and over 40,000 women will die of the disease. Estrogen Receptor (ER) positive breast cancer cells are driven by estrogens. Tamoxifen is a nonsteroidal Selective Estrogen Receptor Modulator (SERM) and works mainly by binding to the Estrogen Receptor and thus blocks the proliferative actions of estrogen on the mammary tissue. Anastrozole and Letrozole are nonsteroidal Aromatase Inhibitors that binds reversibly to the aromatase enzyme and inhibit the conversion of androgens to estrogens in the extra-gonadal tissues. Approximately 80% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and these patients are often treated with anti-estrogen therapy as first line treatment. 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. 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. 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. IBRANCE® (Palbociclib) is a reversible, oral, selective, small molecule inhibitor of Cyclin Dependent Kinases, CDK4 and CDK6, and prevent RB1 phosphorylation. IBRANCE® is the first CDK inhibitor approved by the FDA. It exhibits synergy when combined with endocrine therapies. In an open-label, randomized, phase II study, which included treatment naïve postmenopausal women with ER-positive, HER2-negative, advanced breast cancer, IBRANCE® given along with Aromatase Inhibitor FEMARA® (Letrozole) significantly prolonged Progression Free Survival, Overall Response rate and median duration of response, compared to FEMARA® alone. Based on this data, the U. S. Food and Drug Administration on February 3, 2015 granted accelerated approval to IBRANCE® (Palbociclib), for use in combination with FEMARA® (Letrozole) in this patient population. FASLODEX® (Fulvestrant) is a selective estrogen receptor down-regulator presently indicated for the treatment of hormone receptor positive metastatic breast cancer patients, with disease progression following antiestrogen therapy.

The PALOMA3 is double-blind, phase 3 study in which the efficacy and safety of the combination of IBRANCE® and FASLODEX® was evaluated, in premenopausal or postmenopausal women, with hormone receptor positive, HER-2 negative, advanced breast cancer, who had disease progression during prior endocrine therapy. Five hundred and twenty one (N=521) patients were randomly assigned in a 2:1 ratio to receive either FASLODEX® 500 mg IM on days 1 and 15 during cycle 1, of a 28 day cycle, and then on day 1 of each cycle thereafter, along with IBRANCE® 125 mg PO daily for 3 weeks, followed by 1 week off (N=347) or FASLODEX® and placebo (N=174). ZOLADEX® (Goserelin) was administered to premenopausal or perimenopausal patients for the duration of study treatment, starting at least 4 weeks before randomization and continuing every 28 days. The median age was 57 years. One previous line of chemotherapy for metastatic disease was allowed and 79% were post-menopausal, 60% had visceral disease and 33% of the patients had prior chemotherapy for advanced disease. The primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS), Response Rates, safety and tolerability. At the time of the preplanned interim analysis, the median Progression Free Survival was 9.2 months in the FASLODEX® / IBRANCE® group and 3.8 months in the FASLODEX® /placebo group (HR=0.422; P<0.000001). This PFS benefit was observed across all prespecified patient subgroups, regardless of menopausal status. The most common adverse events in the IBRANCE® group were neutropenia (78.8% vs 3.5%) and fatigue (38.0% vs 26.7%). The incidence of febrile neutropenia was very rare (0.6%) and similar in both treatment groups. Treatment discontinuation rate due to adverse events was 2% in the IBRANCE® group and 1.7% in the placebo group. The authors concluded that IBRANCE® in combination with FASLODEX® more than doubled the Progression Free Survival in advanced breast cancer patients, with hormone receptor positive and HER-2 negative disease, who had progressed on prior endocrine therapy. This study has reinforced the importance of CDK4 and CDK6, as key targets for hormone receptor positive breast cancer. Palbociclib in Hormone Receptor Positive Advanced Breast Cancer. Turner NC, Ro J, Andre F, et al. June 1, 2015DOI: 10.1056/NEJMoa1505270