Author: RR

FDA Approves BALVERSA® for Metastatic Urothelial Carcinoma

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SUMMARY: The FDA on April 12, 2019 granted accelerated approval to BALVERSA® (Erdafitinib) for patients with locally advanced or metastatic Urothelial Carcinoma, with susceptible FGFR3 or FGFR2 genetic alterations,that has progressed during or following platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Patients should be selected for therapy based on an FDA-approved companion diagnostic for BALVERSA®. The FDA also simultaneously approved the THERASCREEN® FGFR RGQ RT-PCR Kit, developed by QIAGEN, for use as a companion diagnostic for this therapeutic indication.

FGFR-Signaling-PathwayFGFRs are a family of Receptor Tyrosine Kinases, which may be upregulated in a variety of malignancies. The Fibroblast Growth Factor/Fibroblast Growth Factor Receptor (FGF/FGFR) signaling pathway regulates embryogenesis, adult tissue homeostasis, angiogenesis and wound repair, and is also pivotal in cell functions, including proliferation, differentiation, apoptosis and migration. Deregulated FGF/FGFR activations have been associated with developmental disorders and cancer progression. Following binding with a ligand, FGFRs activate downstream signaling pathways such as the Mitogen Activated Protein Kinase (MAPK), Signal Transducer and Activator of Transcription (STAT), the PhosphoInositide-3-Kinase (PI3K)/Akt pathways, and PLC-DAG-PKC pathway. FGFR isoforms have been shown to result in oncogenic FGFR signaling, which in turn promotes tumorigenesis. FGFR3 mutations have been described in approximately 75% of low-grade papillary bladder cancers, and FGFR3 overexpression has been noted in 42% of muscle-invasive bladder cancers. FGFR1 amplification has also been found in 3% of urinary bladder cancers. Patients with FGFR alterations have poor outcomes when treated with available therapies and these alterations occur in 20% of patients with metastatic Urothelial Carcinoma.

BALVERSA® (Erdafitinib) is a once-daily, oral, pan-Fibroblast Growth Factor Receptor (FGFR) Tyrosine Kinase Inhibitor. The approval of BALVERSA® was based on data from a cohort of 87 patients, enrolled in Study BLC2001, which is a multicenter, open-label, single-arm trial. Enrolled patients had locally advanced or metastatic Urothelial Carcinoma that had progressed during, or following at least one prior chemotherapy regimen, and had FGFR genomic alterations such as FGFR3 gene mutations or FGFR2 or FGFR3 gene fusions. Ten percent of patients were chemo naïve, 47% percent of patients had received two or more prior lines of therapy and 80% of patients had visceral metastases. Approximately 97% patients had prior Platinum based therapy and 24% of patients had received anti–PD-1/PD-L1 treatment. The median patient age was 67 years. Patients received BALVERSA® at a starting dose of 8 mg PO once daily. Patients whose serum phosphate levels were below the target of 5.5 mg/dL between days 14 and 17 (41% of the patients) had their dose increased to 9 mg once daily. Treatment was continued until disease progression or unacceptable toxicity. The Primary end point was Objective Response Rate (ORR).

The ORR was 32.2%, with Complete Responses in 2.3% and Partial Responses in 29.9%. Median response duration was 5.4 months. Responding patients included those patients who had previously not responded to anti PD-L1 or PD-1 treatment. The most common adverse reactions were increased serum phosphate, stomatitis, fatigue, increased serum creatinine, diarrhea, onycholysis, increased liver function studies and hyponatremia.

The authors concluded that treatment with BALVERSA® resulted in high Response Rates among patients with chemorefractory metastatic Urothelial Carcinoma with FGFR genomic alterations. BALVERSA® is the first approved personalized treatment, targeting susceptible FGFR genetic alterations, fulfilling an unmet need for these poor prognosis patients. First results from the primary analysis population of the phase 2 study of erdafitinib (ERDA; JNJ-42756493) in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRalt). Siefker-Radtke AO, Necchi A, Park SH, et al. J Clin Oncol 36, 2018 (suppl; abstr 4503)

BALVERSA® (Erdafitinib)

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The FDA on April 12, 2019 granted accelerated approval to BALVERSA® (Erdafitinib) for patients with locally advanced or metastatic Urothelial Carcinoma, with susceptible FGFR3 or FGFR2 genetic alterations,that has progressed during or following Platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant Platinum-containing chemotherapy. Patients should be selected for therapy based on an FDA-approved companion diagnostic for BALVERSA®. The FDA also simultaneously approved the THERASCREEN® FGFR RGQ RT-PCR Kit, developed by QIAGEN, for use as a companion diagnostic for this therapeutic indication. BALVERSA® is a product of Janssen Pharmaceutical Companies.

KEYTRUDA® (Pembrolizumab)

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The FDA on April 11, 2019, approved KEYTRUDA® (Pembrolizumab) for the first-line treatment of patients with Stage III Non-Small Cell Lung Cancer (NSCLC) who are not candidates for surgical resection or definitive chemoradiation, as well as those with metastatic NSCLC. Patients’ tumors must have no EGFR or ALK genomic aberrations and express PD-L1 (Tumor Proportion Score-TPS of 1% or more), as determined by an FDA-approved test. KEYTRUDA® was previously approved as a single agent for the first-line treatment of patients with metastatic NSCLC whose tumors express PD-L1 TPS of 50% or more. KEYTRUDA® is a product of Merck Inc.

AACR Late-Breaking Research Predicting Response to Anti-PD1/PDL1 Therapy beyond Tumor Mutational Burden

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SUMMARY: Immunotherapy with checkpoint inhibitors such as anti-PD1/PDL1 antibodies, is rapidly moving to the forefront of cancer treatment. These agents include PD1 targeted therapies such as KEYTRUDA® (Pembrolizumab), OPDIVO® (Nivolumab) and LIBTAYO® (Cemiplimab-rwlc) and PDL1 targeted therapies such as TECENTRIQ® (Atezolizumab), IMFINZI® (Durvalumab) and BAVENCIO® (Avelumab). Treatment with checkpoint inhibitors given as a single agent or in combination with chemotherapy has resulted in significant survival benefit in a variety of solid tumors, as well as hematologic malignancies. The efficacy of checkpoint inhibitors however varies considerably across different cancer types. Understanding tumors and their microenvironment and identifying the underlying variables that predict response to anti-PD1/PDL1 antibodies, has been challenging.

Tumor Mutational Burden (TMB) has recently emerged as a potential biomarker for immunotherapy with anti PD-1/PDL1 antibodies. TMB can be measured using Next-Generation Sequencing (NGS) and is defined as the number of somatic coding base substitutions and short insertions and deletions (indels), per megabase of genome examined. Several studies have incorporated Tumor Mutational Burden (TMB) as a biomarker, using the validated cutoff of TMB of 10 or more mutations/megabase as High, and less than 10 mutations/megabase, as Low. Drawbacks with TMB include sample consumption, higher attrition rate due to sample quality and quantity, and lack of standardization for the different TMB testing assays, with the definition of High TMB varying across studies from 7.4 or more to 20 mutations/megabase.

The Cancer Genome Atlas (TCGA), a landmark cancer genomics program, is a joint effort between the National Cancer Institute and the National Human Genome Research Institute. This program began in 2006 and has molecularly characterized over 20,000 primary cancers and matched normal samples, across 33 different cancer types. After 12 years and contributions from over 11,000 patients, TCGA has deepened our understanding of the molecular basis of cancer, changed the way cancer patients are managed in the clinic, established a rich genomics data resource for the research community and helped advance health and science technologies.

The authors in this study systematically analyzed Whole Exome Sequencing (WES) and RNA sequencing (RNAseq) data of 10,000 patients from the Cancer Genome Atlas, and the Overall Response Rate (ORR) to anti-PD1/PDL1 therapy of 21 different cancer types obtained from previous clinical trials. The researchers took into consideration more than 30 different variables belonging to three distinct classes: a) those associated with tumor neoantigen landscape (Tumor Mutational Burden-TMB) b) tumor microenvironment and inflammation, and c) the checkpoint inhibitor targets (PD1/PDL1). The performance of each of these variables and their combinations was then evaluated in predicting the ORR to anti-PD1/PDL1 therapy.

It was noted that the most important predictor of response to anti-PD1/PDL1 therapy across cancer types was CD8+ T-cell abundance in the tumor microenvironment, followed by the Tumor Mutational Burden, and a high PD1 gene expression in each cancer type in a fraction of samples. These three top predictors encompassed the three distinct classes considered in this analysis, and their combination was highly predictive of the ORR to anti-PD1/PDL1 therapy, and was able to explain more than 80% of the variance observed across different tumor types.

The authors concluded that in this first systemic evaluation of the different variables associated with PD1/PDL1 therapy response across different tumor types, the three top predictors mentioned above can explain most of the observed cross-cancer response variability. Combining tumor mutational burden, CD8+ T-cell abundance and PD1 mRNA expression accurately predicts response to anti-PD1/PDL1 therapy across cancers. Lee JS and Ruppin E. Presented at: 2019 AACR Annual Meeting; March 29 to April 3, 2019; Atlanta, GA.LB-017/9

2019 NCCN Pancreatic Cancer Guideline Update Draw Attention to Germline Testing and Molecular Profiling

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SUMMARY: 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 outcomes 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.

At the 2019 NCCN Annual Conference, three important pancreatic cancer guideline updates were discussed. They included germline testing, molecular analysis of tumors and a new adjuvant chemotherapy option for pancreatic adenocarcinoma.

Germline Testing

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.

1) Lynch Syndrome (Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC) is a Autosomal Dominant disorder caused by germline mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 or PMS2 and most often predisposes to colorectal cancer. Patients with Lynch Syndrome also have a 9-11 fold increase in the risk for pancreatic cancer. Consider testing for MSI and/or MMR for patients with locally advanced or metastatic pancreatic adenocarcinoma.

2) 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.

3) Mutations in Fanconi Anemia/BRCA pathway genes including PALB, FANCC and FANCG have also been identified as increasing pancreatic cancer risk.

4) Germline mutations in ATM gene has been identified in approximately 4% of individuals with familial pancreatic cancer.

5) Germline mutations in STK11 gene resulting in Peutz-Jeghers syndrome (associated with GI polyps) increases the risk of developing pancreatic cancer 132 fold. In approximately 5% of pancreatic cancers, somatic mutations in STK11 has been noted.

6) Similar to non-hereditary forms of pancreatitis, familial pancreatitis is also associated with increased risk of pancreatic cancer. Those with familial pancreatitis have been noted to have mutations in the PRSS1, SPINK1 and CFTR genes, increasing the risk of developing pancreatic cancer by 26-87 fold.

7) Familial malignant melanoma syndrome, also known as melanoma–pancreatic cancer syndrome or Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome, is associated with a 20-47 fold increased risk of pancreatic cancer. This has been attributed to germline mutation of CDKN2A gene.

Molecular Profiling

Molecular analysis of tumors should be considered for patients with metastatic disease, for treatment guidance

1) In the phase III POLO trial, patients with germline BRCA-mutated metastatic adenocarcinoma of the pancreas, benefited with PARP inhibitor, LYNPARZA® (Olaparib), which when given as frontline maintenance therapy, significantly reduced the risk of disease progression or death, when compared to placebo.

2) Patients with unresectable or metastatic MSI-High or MMR deficient (dMMR) solid tumors who had progressed on prior therapies, have significant responses with KEYTRUDA® (Pembrolizumab), and has been approved by the FDA for this indication.

3) For those patients with PALB2 mutation, Gemcitabine along with Cisplatin is a treatment option.

4) The presence of P16 alterations in resected tumors of patients with pancreatic adenocarcinoma is associated with a worse prognosis and may therefore benefit from adjuvant chemotherapy.

Adjuvant mFOLFIRINOX

In a large phase III multicenter, randomized clinical trial, adjuvant mFOLFIRINOX significantly improved Disease Free Survival, Metastasis Free Survival and Overall Survival, compared to Gemcitabine, after pancreatic cancer resection. The median OS was nearly 20 months longer with a mFOLFIRINOX regimen than with Gemcitabine (54.4 months versus 35 months), representing a 34% reduction in the risk of death with mFOLFIRINOX.

NCCN Guidelines Updates: Tempero MA. Treatment of Pancreatic Cancer. Presented at: 2019 NCCN Annual Conference; March 21-23, 2019; Orlando, FL.

FDA Approves TECENTRIQ® and ABRAXANE® Combination for Advanced Triple Negative Breast Cancer

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Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. Those with metastatic disease have one of the worst prognosis of all cancers with a median Overall Survival of 13 months.

TECENTRIQ® (Atezolizumab) an anti PD-L1 monoclonal antibody given along with ABRAXANE® (Nanoparticle Albumin-Bound – nab Paclitaxel) improved the Progression Free Survival (PFS) by 20%, when compared with ABRAXANE® alone. This benefit was even more significant among patients with PD-L1–positive tumors with PFS improvement of 38%. The combination of TECENTRIQ® plus ABRAXANE® could potentially change how we manage patients with Triple Negative Breast Cancer.

Immune Checkpoint Inhibitor Combination Efficacious in High-Grade Neuroendocrine Tumors

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SUMMARY: It is estimated that in the United States, more than 12,000 people are diagnosed with a Neuroendocrine tumor each year. NeuroEndocrine Tumors (NETs) arise from cells of the endocrine and nervous systems and produce biogenic amines and polypeptide hormones. NETs can be clinically symptomatic (functioning) or silent (nonfunctioning). The incidence is higher in African-Americans and is most frequently diagnosed in the small intestine, appendix, rectum, lungs and bronchi. The most common type of malignant gastrointestinal NETs originate in the midgut (jejunoileum and the proximal colon) and often metastasize to the mesentery, peritoneum and liver. NETs may be sporadic or may be a component of inherited genetic syndromes such as Multiple Endocrine Neoplasia (MEN) types 1 and 2. Majority of the NETs are nonfunctioning and are diagnosed incidentally but are clinically symptomatic following spread to the liver. Most NETs are classified based on tumor differentiation into 1) Well-differentiated, Low-grade (G1) 2) Well-differentiated, Intermediate-grade (G2) and 3) Poorly differentiated, High-grade (G3). Tumor differentiation and tumor grade often correlate with mitotic count and Ki-67 proliferation index. Even though surgery is curative when the tumor is detected early, this is often not the case, as most patients present with metastatic disease at the time of diagnosis.

OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, whereas YERVOY® (Ipilimumab) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152). Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. Immune checkpoint blockade with monoclonal antibodies such as OPDIVO® and YERVOY® has revolutionized the treatment of multiple cancers. Previously published studies have demonstrated successful patient outcomes across various tumor types, when treated with a combination of CTLA-4 and PD-1 inhibitors. However, it has remained unclear whether these agents can benefit those with rare, metastatic solid tumors. The investigators therefore launched the DART trial to fulfill this unmet need.

SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) is the first NCI-funded prospective, open-label, rare tumor immunotherapy basket study. Basket trials involve single treatment and single biomarker, different histologies, placed in multiple groups or baskets. These trials are an efficient way for screening experimental therapeutics across multiple patient populations.

In this phase II trial which included 37 different types of rare tumors, patients received YERVOY® 1 mg/kg IV every 6 weeks along with OPDIVO® 240 mg IV every 2 weeks. The Primary endpoint was Overall Response Rate (ORR) and Secondary endpoints included Progression Free Survival (PFS), Overall Survival (OS), Stable disease more than 6 months, and toxicity. This publication included a cohort of 33 eligible patients with Neuroendocrine tumors. Pancreatic Neuroendocrine tumors are currently being evaluated in a separate cohort within the trial. More than half of the patients (58%) had high-grade disease, and the most common tumor sites were gastrointestinal-non pancreatic (45%) and lung (18%). Enrolled patients had received a median of 2 prior lines of therapy.

The Overall Response Rate was 24% with 3% Complete Responses and 21% Partial Responses. Patients with high-grade Neuroendocrine cancer had a 42% Response Rate, whereas the Response Rate was 0% in low/intermediate grade tumors (P=0.01), independent of primary site. The authors hypothesized that the high response rate among those with high-grade Neuroendocrine carcinomas may be related to a higher Tumor Mutational Burden, which is an indicator of better response to immunotherapy. The 6-month PFS was 30% and the median OS was 11 months (historically, it has been around 10% and 3 months respectively). The most common toxicities were fatigue (30% of patients) and nausea (27%) and the most common grade 3/4 immune-related Adverse Events were ALT elevation in 9% of patients.

It was concluded that YERVOY® plus OPDIVO® combination was well tolerated with a 42% ORR in patients with high-grade Neuroendocrine cancer, regardless of primary site. The authors based on this study pointed out that, clinical trials are feasible even in rare tumors. A Phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) S1609: The neuroendocrine cohort. Patel SP, Othus M, Chae YK, et al. Presented at: 2019 AACR Annual Meeting; March 29 to April 3, 2019; Atlanta, GA.

AR-V7 in the Peripheral Blood (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 174,650 new cases of Prostate cancer will be diagnosed in 2019 and 31,620 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 (AR). Upon progression, (described as Castrate Resistant Prostate Cancer-CRPC, as these tumors are not androgen independent and continue to rely on Androgen Receptor), therapies directed at the Androgen Receptor , 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 therapies directed at the AR, and even those who respond will invariably develop resistance to these drugs.Androgen-Receptor-Variant-7-and-Drug-Resistance

ZYTIGA® and XTANDI® 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 one of these agents receive the alternative agent, as there are no formal guidelines on how best to sequence these agents after progression on first-line AR signaling inhibition. Resistance to ZYTIGA® and XTANDI® 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 affected by androgen depleting agents including ZYTIGA®. A critical unmet need is an assay that can detect AR-V7 protein in the peripheral blood (liquid biopsy), and accurately identify patients who are resistant to AR targeted therapies and who should instead switch to chemotherapy.

PROPHECY is a multicenter, prospective-blinded study, which evaluated the ability of baseline/pretreatment AR-V7 status in CTCs, to predict treatment outcomes with ZYTIGA® or XTANDI®. The researchers enrolled 118 men with high-risk mCRPC starting ZYTIGA® or XTANDI® treatment, from five academic medical centers. Prior exposure to XTANDI® or ZYTIGA® was permitted for men who were planning to receive the alternative agent. Among the study patients, 55 were treated with ZYTIGA®, 58 were treated with XTANDI®, and five received both therapies concurrently. The median age was 73 years, 58% had a Gleason score sum of 8-10 and the median number of high-risk features was six.

Peripheral blood samples were obtained for CTCs analysis at baseline, and at the time of clinical, radiographic, or biochemical progression, and analyzed at two central laboratories, each blinded to the results of the other. AR-V7 in CTCs was detected using two blood-based assays, including the Epic Sciences CTC nuclear-specific AR-V7 protein assay and The Johns Hopkins University (JHU) modified-AdnaTest CTC AR-V7 mRNA assay. One of the unique aspects of this multicenter study was that laboratory investigators were blinded to the clinical results, and clinicians were blinded to the laboratory results, and the definitions of a positive test for AR-V7 were defined in advance, and thus prospectively validated. In this study, approximately 10-24% of men with high-risk mCRPC were AR-V7 positive at baseline, depending on the assay used. The Primary endpoint was Progression Free Survival (PFS) on the basis of radiographic or clinical progression and Secondary clinical end points included 50% or greater decline in PSA and Overall Survival (OS). The Primary objective was to validate the prognostic significance of baseline CTC AR-V7 on the basis of radiographic or clinical progression free-survival (PFS). The median follow up was 19.6 months.

It was noted that AR-V7 detection in CTCs by either of two different assays was independently associated with shorter PFS and OS, after adjusting for CTC number and clinical prognostic factors. There was very little evidence of clinical benefit from ZYTIGA® or XTANDI® in AR-V7 positive patients, with a very low probability of confirmed PSA decline (0-11%) or soft tissue responses (0-6%). The concordance between the two AR-V7 assays utilized in this study was 82%.

The authors concluded that among patients with high-risk mCRPC , detection of AR-V7 in Circulating Tumor Cells (CTCs) by two blood-based assays is independently associated with shorter PFS and OS, when treated with ZYTIGA® or XTANDI®. These high risk patients who test positive for AR-V7 should be offered alternative, more effective treatments, such as Taxane chemotherapy or a clinical trial of an investigational therapy. Testing for AR-V7 can be undertaken utilizing either modified-AdnaTest CTC AR-V7 mRNA assay or Epic Sciences CTC nuclear-specific AR-V7 protein assay. The later assay is commercially available as Oncotype DX® AR-V7 Nucleus Detect® test, and is covered by Medicare. Prospective Multicenter Validation of Androgen Receptor Splice Variant 7 and Hormone Therapy Resistance in High-Risk Castration-Resistant Prostate Cancer: The PROPHECY Study. Armstrong AJ, Halabi S, Luo J, et al. Published online March 13, 2019. DOI: 10.1200/JCO.18.01731 Journal of Clinical Oncology

NCCN Establishes TKI Discontinuation Criteria in Updated CML Guideline

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SUMMARY: Chronic Myeloid Leukemia (CML) constitutes about 15% of all new cases of leukemia. The American Cancer Society estimates that about 8,990 new CML cases will be diagnosed in the United States in 2019 and about 1,140 patients 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.Treatment-of-Chronic-Myeloid-Leukemia

The presently available Tyrosine Kinase Inhibitors (TKI’s) approved in the United States including GLEEVEC® (Imatinib), share the same therapeutic target, which is BCR-ABL kinase. Resistance to TKI’s can occur as a result of mutations in the BCR-ABL kinase domain or amplification of the BCR-ABL gene. With the availability of newer therapies for CML, monitoring response to treatment is important. This is best accomplished by measuring the amount of residual disease using Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Molecular response in CML is expressed using the International Scale (IS) as BCR-ABL%, which is the ratio between BCR-ABL and a control gene. BCR-ABL kinase domain point mutations are detected using the mutational analysis by Sanger sequencing. Majority of the patients receiving a TKI following diagnosis of CML achieve a Complete Cytogenetic Response (CCyR) within 12 months following commencement of therapy and these patients have a life expectancy similar to that of their healthy counterparts. Previously published studies have shown that Deep Molecular Response (BCR-ABL <0.01% on the International Scale – MR4) is a new molecular predictor of long term survival in CML patients, and this was achieved in a majority of patients treated with optimized dose of GLEEVEC®. Further, it has been shown on previous observations, that a subgroup of CML patients experiencing deeper responses (MR3, MR4, and MR4.5), may stay in unmaintained remission even after treatment discontinuation. Despite this observation, precise criteria for stopping CML therapy have not been clearly defined.Monitoring-Molecular-Response-in-CML

Discontinuing TKI therapy after a Deep Molecular Response among patients with CML can potentially improve quality of life, minimize long term toxicities as well as drug-drug interactions, and reduce financial burden. Two important studies, STIM (Stop Imatinib) and EURO-SKI have set the stage for TKI discontinuation of TKI therapy in CML patients, who are in deep molecular remission, taking into consideration Sokal score at diagnosis, duration on TKI therapy and molecular response based on BCR-ABL transcripts log reduction. Sokal score is calculated using a formula that includes Age, Spleen size, Platelet count and percentage of Myeloblasts and has three risk groups: Low-risk (Sokal score<0.8), Intermediate-risk (Sokal score 0.8-1.2) and High-risk (Sokal score >1.2).

Stopping TKI therapy among CML patients appears to be safe and feasible in over 50% of the patients, although about 20% of these patients experience TKI withdrawal syndrome manifesting as musculoskeletal symptoms. Discontinuation of TKI therapy should only be considered in consenting patients after a thorough discussion of the potential risks and benefits.

Criteria for TKI Discontinuation: Outside of a clinical trial, TKI discontinuation should be considered only if a patient meets ALL the criteria listed below-

1) Age 18 years or older.

2) Chronic phase CML with no prior history of Accelerated or Blast phase.

3) On approved TKI therapy for at least 3 years.

4) Prior evidence of quantifiable BCR-ABL1 transcript.

5) Stable molecular response defined as MR4, (BCR-ABL equal to 0.01% or less IS), for 2 or more years as documented on at least 4 tests, performed at least 3 months apart.

6) Access to qPCR test that can reliably detect at least MR4.5 (BCR-ABL equal to 0.0032% or less IS), with results available within 2 weeks.

7) For patients who remain in Major Molecular Remission or MMR (MR3, BCR-ABL equal to 0.1% or less IS) after discontinuation of TKI therapy, the recommendations are monthly molecular monitoring the first year, every 6 weeks the second year and every 12 weeks thereafter, indefinitely.

8) TKI therapy should be promptly resumed within 4 weeks of a loss of MMR, with molecular monitoring every 4 weeks until MMR is re-established and then every 12 weeks thereafter, indefinitely. If a patient fails to achieve MMR after 3 months of TKI resumption, BCR-ABL kinase domain mutation testing should be performed, and monthly molecular monitoring should be continued for an additional 6 months.

9) Consultation with a CML Specialty Center is recommended regarding the appropriateness for TKI discontinuation, and potential risks and benefits of discontinuing therapy, including TKI withdrawal syndrome.

10) It is strongly encouraged to report the following to an NCCN CML Panel Member-

a) Any significant adverse event thought to be related to therapy discontinuation.

b) Progression to Accelerated or Blast phase at any time.

c) Failure to regain MMR after 3 months following treatment reinitiation.

NCCN guidelines updates: discontinuing TKI therapy in the treatment of chronic myeloid leukemia. Shah NP. Presented at 2019 NCCN Annual Conference; March 21-23, 2019; Orlando, FL.

Liquid Biopsy Accurate, Reliable and Rapid in Identifying Biomarker Mutations in Newly Diagnosed Advanced Lung Cancer

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SUMMARY: The American Cancer Society estimates that for 2019 about 228,150 new cases of lung cancer will be diagnosed and 142,670 patients will die of the disease. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Patients with newly diagnosed metastatic NSCLC are often tested for guideline-recommended genomic biomarkers which include both predictive biomarker mutations such as EGFR, ALK, ROS1, BRAF, RET, MET, ERBB2, as well as prognostic biomarker mutation such as KRAS.

The application of precision medicine with targeted therapy requires detection of molecular abnormalities in a tissue biopsy specimen. However, if testing is not done with a comprehensive assay, such as Next-Generation Sequencing and is done in successive steps one test after another, tissue sample can be depleted, with not enough tissue left for testing of all biomarkers. Following progression or recurrence, archived biopsy specimens may not be helpful, as it is important to identify additional mutations in the tumor at the time of recurrence or progression, in order to plan appropriate therapy. Further, recurrent tumors may be inaccessible for a safe biopsy procedure or the clinical condition of the patient may not permit a repeat biopsy. Additionally, the biopsy itself may be subject to sampling error due to tumor heterogeneity. Genotyping circulating cell-free tumor DNA (cfDNA) in the plasma can potentially overcome the shortcomings of repeat biopsies and tissue genotyping, allowing the detection of many more targetable gene mutations, thus resulting in better evaluation of the tumor genome landscape.

The Noninvasive versus Invasive Lung Evaluation (NILE) trial is a prospective, multicenter study conducted to demonstrate the noninferiority of comprehensive cell-free DNA (cfDNA) relative to standard-of-care traditional tissue genotyping tests, to identify guideline-recommended genomic biomarkers, in patients with metastatic NSCLC. The authors in this study enrolled 282 newly diagnosed patients at 28 North American centers, with previously untreated, nonsquamous, metastatic NSCLC undergoing standard-of-care tissue genotyping. Enrolled patients submitted a pretreatment blood sample for cfDNA analysis utilizing a CLIA-certified comprehensive 73-gene next generation sequencing panel (Guardant360®). Over 80% of the enrolled patients were white and over 50% were female.

The liquid biopsy utilizing Guardant360®, detected biomarker mutations at a rate similar to standard-of-care tissue genotyping tests, in the enrolled patients, meeting the Primary study objective. At least one of the guideline-recommended genomic biomarkers was detected in 60 patients (21.3%) using tissue-based tests and in 77 patients (27.3%) by cfDNA utilizing Guardant360® (P<0.0001). The detection rate was increased by 48% when Guardant360® was utilized for cfDNA analysis and this included those with negative, not assessed, or Quantity Not Sufficient (QNS) results in tissue. In addition, the Positive Predictive Value was 100% for cfDNA versus tissue genotyping, for FDA approved targets such as EGFR, ALK, ROS1, and BRAF mutations. There are agents already approved by the FDA to treat this patient population. The median turnaround time was significantly lower for cfDNA, compared to tissue genotyping (9 versus 15 days; P <0.0001).

The authors concluded that in this largest cfDNA study among patients with previously untreated advanced NSCLC, cfDNA successfully detected seven biomarker mutations noninvasively, significantly faster than tissue genotype testing, and was also able to rescue biomarker mutation positive patients who had non-diagnostic tissue results. They added that the findings in this study confirms similar findings from Europe and demonstrates the clinical utility of cfDNA in newly diagnosed metastatic NSCLC. Clinical utility of comprehensive cell-free DNA (cfDNA) analysis to identify genomic biomarkers in newly diagnosed metastatic non-small cell lung cancer (mNSCLC). Leighl N, Page RD, Raymond VM, et al. Presented at: AACR Annual Meeting April 2, 2019; Philadelphia, USA.