Month: March 2019

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.

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

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.

Substantial Benefit with Maintenance LYNPARZA® in Patients with Newly Diagnosed Advanced Ovarian Cancer

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SUMMARY: It is estimated that in the United States, approximately 22,530 women will be diagnosed with ovarian cancer in 2019 and 13,980 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, and accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5 year Overall Survival rate of about 20-30%.

BRCA1 and BRCA2 are tumor suppressor genes and functional BRCA proteins that repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. Mutations in BRCA1 and BRCA2 account for about 20-25% of hereditary breast cancers and about 5-10% of all breast cancers. They also account for 15% of ovarian cancers, in addition to other cancers such as colon and prostate. BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic). Somatic mutations account for a significant portion of overall BRCA1 and BRCA2 aberrations. Loss of BRCA function due to frequent somatic aberrations in ovarian cancers likely deregulates Homologous Recombination (HR) pathway and increases sensitivity to platinum drugs. Majority of the women with Germline BRCA mutations (gBRCA) are positive for HR deficiency. The PARP (Poly ADP Ribose Polymerase) family of enzymes which include PARP1 and PARP2, repair damaged DNA. PARP inhibitors kill tumors defective in the BRCA1 or BRCA2 genes through the concept of synthetic lethality. Epithelial ovarian cancers with Homologous Recombination Deficiency have demonstrated sensitivity to PARP inhibitors.MOA-of-LYNPARZA

SOLO1 is an international, randomized, double-blind, Phase III trial, conducted to evaluate the efficacy of maintenance therapy with a PARP inhibitor LYNPARZA® (Olaparib), in patients with newly diagnosed advanced ovarian cancer with a Germline or Somatic mutation in BRCA1, BRCA2, or both (BRCA1/2), who had a complete or partial clinical response after platinum-based chemotherapy. Patients (N=391) were randomly assigned in a 2:1 ratio, to receive LYNPARZA® tablets 300 mg PO twice daily (N=260) or placebo (N=131). Enrolled patients had international FIGO Stage III or IV high-grade Serous or Endometrioid ovarian cancer, Primary Peritoneal cancer, or Fallopian tube cancer (or a combination thereof), and majority of the enrolled patients (N=388) had a centrally confirmed Germline BRCA1/2 mutation, and 2 patients had a centrally confirmed Somatic BRCA1/2 mutation. Patients with Stage III disease had cytoreductive surgery attempted upfront before the start chemotherapy, or had interval cytoreductive surgery after the start but before the end of chemotherapy. Patients with Stage IV disease either had a biopsy for tissue diagnosis or underwent upfront or interval cytoreductive surgery. The Primary end point was Progression Free Survival (PFS) and Secondary end points included second PFS which was the time from randomization to second disease progression or death, and Overall Survival.

After a median follow up of 41 months, the risk of disease progression or death was 70% lower with LYNPARZA® when compared to placebo, with an estimated rate of freedom from disease progression and death at 3 years of 60% versus 27% (HR for disease progression or death= 0.30; P<0.001). The estimated rate of freedom from second disease progression and death at 3 years was 75% in the LYNPARZA® group, as compared with 60% in the placebo group (HR for second disease progression or death=0.50; P<0.001). Adverse events were consistent with the known toxic effects of LYNPARZA®, with anemia being the most common serious side effect. Adverse events were usually managed by dose interruption or dose reduction, rather than discontinuation of the study drug.

It was concluded that maintenance therapy with LYNPARZA® after platinum-based chemotherapy provided a substantial Progression Free Survival benefit, with a 70% lower risk of disease progression or death, when compared to placebo, among women with newly diagnosed advanced ovarian cancer and a BRCA1/2mutation. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. Moore K, Colombo N, Scambia G, et al. N Engl J Med 2018; 379:2495-2505

TECENTRIQ® (Atezolizumab)

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The FDA on March 18, 2019 approved TECENTRIQ® in combination with Carboplatin and Etoposide, for the first-line treatment of adult patients with Extensive-Stage Small Cell Lung Cancer (ES-SCLC). TECENTRIQ® is a product of Genentech Inc.

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

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SUMMARY: The FDA on March 8, 2019 granted accelerated approval to TECENTRIQ® (Atezolizumab) in combination with ABRAXANE® (Paclitaxel protein-bound) for adult patients with unresectable locally advanced or metastatic Triple Negative Breast Cancer (TNBC) whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] of any intensity covering 1% or more of the tumor area), as determined by an FDA-approved test. The FDA also approved the VENTANA PD-L1 (SP142) Assay as a companion diagnostic device for selecting TNBC patients for TECENTRIQ®. Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease.

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. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients. It is usually aggressive, and tumors tend to be high grade and patients with TNBC are at a higher risk of both local and distant recurrence. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers. The lack of known recurrent oncogenic drivers in patients with metastatic TNBC, presents a major therapeutic challenge. Nonetheless, patients with TNBC often receive chemotherapy in the neoadjuvant, adjuvant or metastatic settings and approximately 30-40% of patients achieve a pathological Complete Response (pCR) in the neoadjuvant setting. Those who do not achieve a pathological Complete Response tend to have a poor prognosis. It therefore appears that there are subsets of patients with TNBC who may be inherently insensitive to cytotoxic chemotherapy. Three treatment approaches appear to be promising and they include immune therapies, PARP inhibition and inhibition of PI3K pathway. Previously published studies have shown that tumor-infiltrating lymphocytes were associated with clinical benefit, when treated with chemotherapy and immunotherapy, in patients with TNBC, and improved clinical benefit was observed in patients with immune-enriched molecular subtypes of metastatic TNBC.

TECENTRIQ® (Atezolizumab) is an anti PD-L1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors, and thus enabling the activation of T cells. Single-agent TECENTRIQ® is presently approved for the treatment of metastatic Urothelial carcinoma and Non Small Cell Lung Cancer (NSCLC). TECENTRIQ® has also been shown to have clinical activity with acceptable safety profile in patients with other solid tumors including Triple Negative Breast Cancer. The premise for combining chemotherapy with immune checkpoint inhibitors is that chemotherapy may enhance release of tumor antigens and antitumor responses to immune checkpoint inhibition. Taxanes in particular may additionally activate toll-like receptor activity and promote dendritic-cell activity. ABRAXANE® (Nanoparticle Albumin-Bound – nab Paclitaxel) was selected as a chemotherapy partner in the present study because at the time that this trial was designed, the glucocorticoid premedication that is required with solvent-based Paclitaxel (TAXOL®), had been hypothesized to affect immunotherapy activity.

IMpassion130 is an international, randomized, double-blind, placebo-controlled phase III trial in which first-line treatment with TECENTRIQ® plus ABRAXANE®, was compared with placebo plus ABRAXANE®, in patients with locally advanced or metastatic Triple Negative Breast Cancer. Patients with untreated metastatic Triple Negative Breast Cancer (N=902) were randomly assigned in a 1:1 ratio and received TECENTRIQ® 840 mg IV or placebo on days 1 and 15 and ABRAXANE® 100 mg/m2 IV on days 1, 8, and 15 of every 28-day cycle. Treatment was continued until disease progression or unacceptable toxicity. Stratification factors included presence or absence of liver metastases, use or non-use of neoadjuvant or adjuvant taxane treatment, and PD-L1 expression on tumor-infiltrating immune cells as a percentage of tumor area (less than 1% was considered PD-L1 negative versus1% or more considered PD-L1 positive) according to ImmunoHistochemical testing (IHC). Both treatment groups were well balanced. Approximately 40% of the patients were PD-L1 positive. The two Primary end points were Progression Free Survival (PFS) and Overall Survival (OS).

At a median follow up of 12.9 months, the median PFS in the intent-to-treat population was 7.2 months with TECENTRIQ® plus ABRAXANE®, as compared with 5.5 months with placebo plus ABRAXANE® (HR=0.80; P=0.002). This suggested a 20% improvement in PFS with the TECENTRIQ® combination. At the time of the first interim analysis, the median overall survival was 21.3 months in the TECENTRIQ® plus ABRAXANE® group and 17.6 months in the placebo plus ABRAXANE® group (HR for death=0.84; P=0.08). The Objective Response Rate (ORR) in the intent-to-treat population was 56% in the TECENTRIQ® and ABRAXANE® group versus 45.9% in the placebo plus ABRAXANE® group.

Among patients with PD-L1–positive tumors, the benefit was even more significant. The addition of TECENTRIQ® improved PFS by 38% (HR=0.62; P<0.001) and similar benefit was noted in the OS, with a median OS of 25 months with the TECENTRIQ® combination and 15.5 months with placebo plus ABRAXANE® (HR=0.62). Grade 3 or 4 adverse events were 48.7% in the TECENTRIQ® and ABRAXANE® and 42.2% in the placebo plus ABRAXANE® group.

It was concluded that TECENTRIQ® plus ABRAXANE® significantly prolonged Progression Free Survival among patients with metastatic Triple Negative Breast Cancer in both the intent-to-treat population and the PD-L1 positive subgroup, and could potentially change how we manage patients with Triple Negative Breast Cancer. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. Schmid P, Adams S, Rugo HS, et al. N Engl J Med 2018; 379:2108-2121

Metastatic Pancreatic Cancer ASCO Clinical Practice Guideline Update

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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%.

The ASCO Expert Panel in 2016 published a guideline to assist in clinical decision making in metastatic pancreatic cancer for initial assessment after diagnosis, first and second-line treatment options, palliative and supportive care, and follow-up. This present update incorporated new evidence related to second-line therapy, published between June 2015 and January 2018, for patients who have experienced disease progression or intolerable toxicities during first-line therapy.

INITIAL ASSESSMENT

Recommendation 1.1: A multiphase CT scan of the Chest, Abdomen, and Pelvis should be performed to assess extent of disease. Other staging studies should be performed only as dictated by symptoms.

Recommendation 1.2: The baseline Performance Status, symptom burden, and comorbidity profile of a patient with metastatic pancreatic cancer should be evaluated carefully.

Recommendation 1.3: The goals of care including a discussion of an advance directive, patient preferences, as well as support systems, should be discussed with every patient with metastatic pancreatic cancer and his or her caregivers.

Recommendation 1.4: Multidisciplinary collaboration to formulate treatment and care plans and disease management for patients with metastatic pancreatic cancer should be the standard of care.

Recommendation 1.5: Every patient with pancreatic cancer should be offered information about clinical trials, which include therapeutic trials in all lines of treatment as well as palliative care, biorepository/biomarker, and observational studies.

FIRST-LINE TREATMENT

Recommendation 2.1: FOLFIRINOX (Leucovorin, Fluorouracil, Irinotecan, and Oxaliplatin) is recommended for patients who meet all of the following criteria: an ECOG PS of 0-1, favorable comorbidity profile, patient preference and a support system for aggressive medical therapy, and access to chemotherapy port and infusion pump management services.

Recommendation 2.2: Gemcitabine plus NAB-Paclitaxel is recommended for patients who meet all of the following criteria: an ECOG PS of 0-1, a relatively favorable comorbidity profile, and patient preference and a support system for relatively aggressive medical therapy.

Recommendation 2.3: Gemcitabine alone is recommended for patients who have either an ECOG PS of 2 or a comorbidity profile that precludes more aggressive regimens and who wish to pursue cancer-directed therapy. The addition of either Capecitabine or Erlotinib to Gemcitabine may be considered in this setting.

Recommendation 2.4: Patients with an ECOG PS 3 or more or with poorly controlled comorbid conditions despite ongoing active medical care should be offered cancer-directed therapy only on a case-by-case basis. The major emphasis should be on optimizing supportive care measures.

SECOND-LINE TREATMENT

Recommendation 3.1: Routine testing for dMMR or MSI-H is recommended, using IHC, PCR, or NGS for patients who are considered to be candidates for checkpoint inhibitor therapy.

Recommendation 3.2: PD-1 immune checkpoint inhibitor pembrolizumab is recommended as second-line therapy for patients who have tested positive for dMMR or MSI-H.

Recommendation 3.3: Gemcitabine plus NAB-Paclitaxel can be offered as second-line therapy to patients who had received first-line treatment with FOLFIRINOX, have an ECOG PS of 0-1, with a relatively favorable comorbidity profile, and patient preference and a support system for aggressive medical therapy.

Recommendation 3.4: Fluorouracil plus nanoliposomal Irinotecan, or Fluorouracil plus Irinotecan where the former combination is unavailable, is preferred as second-line therapy for patients who meet all of the following criteria: first-line treatment with Gemcitabine plus NAB-Paclitaxel, an ECOG PS of 0-1, a relatively favorable comorbidity profile, patient preference and a support system for aggressive medical therapy, and access to chemotherapy port and infusion pump management services.

Recommendation 3.5: Fluorouracil plus Oxaliplatin may be considered as second-line therapy for patients who meet all of the following criteria: first-line treatment with Gemcitabine plus NAB-Paclitaxel, an ECOG PS of 0-1, a relatively favorable comorbidity profile, patient preference and a support system for aggressive medical therapy, and access to chemotherapy port and infusion pump management services.

Qualifying statement for Recommendations 3.4 and 3.5: A recent phase III trial comparing mFOLFOX6 with FU + LV demonstrated a higher rate of grade 3 or 4 adverse events and significantly reduced OS within the mFOLFOX6 arm of the trial. However, previous phase III data have demonstrated a benefit with the OFF regimen compared with FU + LV. Considering the inconsistency of these results, although Fluorouracil plus nanoliposomal Irinotecan is preferred, the Expert Panel continues to support the use of Fluorouracil plus Oxaliplatin as an option where the availability of Fluorouracil plus nanoliposomal Irinotecan is limited or where residual toxicity from first-line therapy or comorbidities preclude the use of Fluorouracil plus nanoliposomal Irinotecan.

Recommendation 3.6: Gemcitabine or Fluorouracil can be considered as second-line therapy for patients who have either an ECOG PS of 2 or a comorbidity profile that precludes more aggressive regimens and who wish to pursue cancer-directed therapy.

Recommendation 3.7: No data are available to recommend third-line (or greater) therapy with a cytotoxic agent. Clinical trial participation is encouraged

PALLIATIVE CARE

Recommendation 4.1: Patients with metastatic pancreatic cancer should have a full assessment of symptom burden, psychological status, and social supports as early as possible, preferably at the first visit. In most cases, this assessment will indicate a need for a formal palliative care consult and services.

TREATMENT of PAIN and SYMPTOMS

Recommendation 5.1: Patients with metastatic pancreatic cancer should be offered aggressive treatment of the pain and symptoms of the cancer and/or the cancer-directed therapy.

FOLLOW-UP/SURVEILLANCE

Recommendation 6.1: For patients on active cancer-directed therapy outside a clinical trial, imaging to assess first response should be offered at 2-3 months from the initiation of therapy. CT scans with contrast are the preferred modality. Thereafter, clinical assessment, conducted frequently during visits for cancer-directed therapy, should supplant imaging assessment. The routine use of PET scans for the management of patients with pancreatic cancer is not recommended. CA19-9 is not considered an optimal substitute for imaging for the assessment of treatment response.

Recommendation 6.2: No data exist on the duration of cancer-directed therapy. An ongoing discussion of goals of care and assessment of treatment response and tolerability should guide decisions to continue or to hold or terminate cancer-directed therapy.

Metastatic Pancreatic Cancer: ASCO Clinical Practice Guideline Update. Sohal DPS, Kennedy EB, Khorana A, et al. J Clin Oncol. 2018;36:2545-2556.

TECENTRIQ® (Atezolizumab)

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The FDA on March 8, 2019 granted accelerated approval to TECENTRIQ® in combination with Paclitaxel protein-bound for adult patients with unresectable locally advanced or metastatic Triple Negative Breast Cancer (TNBC) whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] of any intensity covering 1% or more of the tumor area), as determined by an FDA-approved test. The FDA also approved the VENTANA PD-L1 (SP142) Assay as a companion diagnostic device for selecting TNBC patients for TECENTRIQ®. TECENTRIQ® is a product of Genentech Inc.

LONSURF® (Trifluridine/ Tipiracil)

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The FDA on February 22, 2019 approved LONSURF® tablets, a fixed combination of Trifluridine, a nucleoside metabolic inhibitor, and Tipiracil, a thymidine phosphorylase inhibitor, for adult patients with metastatic Gastric or GastroEsophageal Junction (GEJ) adenocarcinoma, previously treated with at least two prior lines of chemotherapy that included a Fluoropyrimidine, a Platinum, either a Taxane or Irinotecan, and if appropriate, HER2/neu-targeted therapy. LONSURF® is a product of Taiho Pharmaceutical Co., Ltd.