Category: Meeting Updates

IBM Artificial Intelligence Platform Highly Concordant with Physician Recommendations

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SUMMARY: Watson for Oncology, is an Artificial Intelligence (AI) computer developed by IBM in collaboration with Memorial Sloan Kettering Cancer Center. This revolutionary tool has the advanced ability to analyze the meaning and context of structured and unstructured data in the patients chart and is able to assimilate key patient information and then deliver evidence based treatment recommendations, through analytical approaches. The authors conducted this study to assess concordance between the Artificial Intelligence platform, Watson for Oncology (WFO) and their own multidisciplinary tumor board, which comprised of a group of 12 to 15 oncologists, who met weekly to review cases from their hospital system. The goal of the study was to understand how Watson for Oncology would impact oncologists day-to-day practice, and how Watson’s recommendations compared to the decisions of their team of experts.

The researchers studied 638 patients with breast cancer treated at Manipal Comprehensive Cancer Center in Bengaluru, India. Patient data was entered into the Watson for Oncology (WFO) computer system and the degree of concordance between WFO’s recommendations and those of the tumor board were analyzed, in addition to the time it took for each group to come up with their recommendations. In this study, WFO analyzed more than 100 patient attributes for breast cancer and provided treatment options ranked as follows – Recommended Standard Treatment (REC), For Consideration (FC) and Not Recommended (NREC). These recommendations provided by WFO were evidence based and the computer system allowed the treating physicians to learn more about the recommendations and the rationale behind those recommendations.

It was noted that 90% of WFO’s Recommendations for Standard Treatment (REC) and For Consideration (FC) were concordant with the recommendations of the tumor board. WFO recommendations were concordant nearly 80% of the time in non-metastatic breast cancer, but only 45% of the time in metastatic disease. In patients with triple-negative breast cancer, WFO agreed with the physicians 68% of the time, but in HER-2 negative cases, WFO’s recommendations matched the physician’s recommendations only 35% of the time. The authors attributed the difference in concordance to fewer treatment options for triple-negative breast cancer, compared to HER-2 negative breast cancer. Further, including HER-2 patients made more treatment options available and this would increase the demands on human thinking capacity. Additionally, more complicated cases lead to more divergent opinions on the recommended treatment.

This study also compared the amount of time it took to provide recommendations, after the data was captured and analyzed. It took an average of 20 minutes when done manually, but after gaining more familiarity with the cases, the time decreased to about 12 minutes. Watson for Oncology by comparison, took a median time of 40 seconds to capture and analyze data and give a treatment recommendation.

It was concluded that while Artificial Intelligence is a step towards personalized medicine, it should not be viewed as a replacement for a physician, but rather as a complement. In the end, the best treatment option for the patient should be determined together by the treating physician and the patient. Double blinded validation study to assess performance of IBM artificial intelligence platform Watson for oncology in comparison with Manipal multidisciplinary tumor board—first study of 638 breast cancer cases. Somashekhar SP, Kumar R, Rauthan A, et al. Presented at: San Antonio Breast Cancer Symposium, Friday, Dec. 9, 2016; San Antonio, TX. Abstract S6-07

Dual Inhibition Improves Outcomes for Patients with BRAF-Mutated Colorectal Tumors

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 135,430 new cases of ColoRectal Cancer will be diagnosed in the United States in 2017 and over 50,260 patients are expected to die of the disease. The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, triggering an enhanced antitumor immune response. MSI (Micro Satellite Instability) is therefore a hallmark of defective/deficient DNA MisMatchRepair (MMR) system and occurs in 15% of all colorectal cancers. Defective MisMatchRepair can be a sporadic or heritable event. Approximately 65% of the MSI tumors are sporadic and MSI-High tumors tend to have better outcomes. Patients with stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to Epidermal Growth Factor Receptor (EGFR) targeted therapy. Approximately 5-10% of all metastatic CRC tumors present with BRAF V600 mutations and BRAF V600 is recognized as a marker of poor prognosis in this patient group. These patients tend to have aggressive disease with a higher rate of peritoneal metastasis and do not respond well to standard treatment intervention. Approximately 25% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group.

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. The BRAF V600 mutations results in constitutive activation of the MAP kinase pathway. Inhibiting BRAF can transiently reduce MAP kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR.

ZELBORAF® (Vemurafenib), is a selective oral inhibitor of mutated BRAF whereas ERBITUX® (Cetuximab) is a monoclonal antibody targeting Epidermal Growth Factor Receptor (EGFR). Preclinical studies have shown that adding CAMPTOSAR® (Irinotecan) to ZELBORAF® and ERBITUX®, in patients with refractory BRAF V600E metastatic CRC, led to a durable responses and this combination was safe and tolerable. However, both single agent ZELBORAF® and ERBITUX® were shown to have limited activity in this patient group.

Based on this scientific rationale, a phase II trial was conducted (SWOG 1406), in which 106 metastatic ColoRectal Cancer patients, with mutations in BRAF V600 and extended RAS wild-type, were enrolled. Patients were randomized to receive CAMPTOSAR® 180 mg/m2 IV every 14 days and ERBITUX® 500 mg/m2 IV every 14 days, with or without ZELBORAF® 960 mg orally twice daily. The median age was 62 years and about 50% of patients had received 1 prior regimen for metastatic or locally advanced unresectable metastatic CRC, and 39% had received prior treatment with CAMPTOSAR® . Prior therapy with anti-EGFR agent or RAF or MEK inhibitors was not allowed. Crossover from the control arm to the experimental group was allowed, after documented disease progression. The primary endpoint was Progression Free Survival.

The median Progression Free Survival was 4.4 months with the triplet, versus 2.0 months with CAMPTOSAR® plus ERBITUX® (HR=0.42; P =0.0002). The response rate was 16% versus 4%, and the Disease Control Rate was 67% versus 22% (P =0.001), with a higher Duration of Response with the addition of ZELBORAF® to CAMPTOSAR® and ERBITUX® (Triplet). Approximately 50% of the patients in the control group crossed over to the experimental group at the time of disease progression. Overall Survival data and efficacy at cross-over, data, remain immature. Patients in the experimental group (Triplet group) experienced more grade 3/4 toxicities such as neutropenia, anemia and nausea, and this increase was attributed to increased duration of exposure to therapy.

The authors concluded that the addition of ZELBORAF® to the combination of CAMPTOSAR® and ERBITUX® resulted in a 58% reduction in the risk of disease progression and a higher Disease Control Rate, suggesting that simultaneous EGFR and BRAF inhibition (Dual Inhibition) is effective in BRAF V600 mutated ColoRectal Cancer. Subgroup analysis will examine the role of CAMPTOSAR® pre-treatment and the outcomes of patients based on tumor MicroSatellite Instability. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). Kopetz S, McDonough SL, Morris VK, et al. J Clin Oncol 35, 2017 (suppl 4S; abstract 520)

FDA Approves OPDIVO® for Bladder Cancer

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SUMMARY: The FDA on February 2, 2017 granted accelerated approval to OPDIVO® (Nivolumab), for the treatment of patients with locally advanced or metastatic urothelial carcinoma, who have disease progression during or following platinum containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy. Urothelial carcinoma accounts for 90 percent of all bladder cancers and can originate in the renal pelvis, ureter and urethra. The American Cancer Society’s estimates that in 2017, approximately 79,030 new cases of Bladder Cancer will be diagnosed and 16,870 patients will die of the disease. Treatment options for patients who progress after platinum based chemotherapy are limited, with poor outcomes. The response rates with standard chemotherapy in this patient population, is about 10%.

The treatment paradigm for solid tumors has been rapidly evolving, with a better understanding of the Immune checkpoints or gate keepers. 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. 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), as well as Programmed cell Death Ligands (PD-L1) that are expressed by cells in the tumor micro environment. By inhibiting checkpoint proteins and their ligands, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response.

OPDIVO® is an immune checkpoint PD-1 (Programmed cell Death 1) targeted, fully human, immunoglobulin G4 monoclonal antibody that has demonstrated antitumor efficacy in multiple tumor types. The FDA approval of OPDIVO® for patients with previously treated locally advanced or metastatic urothelial carcinoma, was based on CheckMate-275 trial which is an international, multicenter, phase II study, in which 270 patients with metastatic or surgically unresectable locally advanced urothelial carcinoma received OPDIVO® 3 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity. All patients had prior platinum based therapy. The median age was 66 years. The primary endpoint was overall Objective Response Rate confirmed by blinded independent review committee, in all treated patients and by tumor PD-L1 expression (5% or more and 1% or more). The follow up for this study is still ongoing. The median follow up for overall survival was 7 months.

The Objective Response Rate across all treated patients was 19.6% and the responses were durable and the median duration of response has not been reached. There was a higher likelihood of response with increasing tumor PD-L1 expression. The Objective Response Rate was 28.4% in patients with PD-L1 expression of 5% or greater, 23.8% in patients with PD-L1 expression of 1% or greater and 16.1% in those with PD-L1 expression of less than 1%. The most common adverse events were fatigue, musculoskeletal pain, nausea, and decreased appetite.

The authors concluded that single agent therapy with OPDIVO® in previously treated patients with metastatic or surgically unresectable urothelial carcinoma, resulted in durable response rate, irrespective of PD-L1 expression and was associated with an acceptable safety profile. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Sharma P, Retz M, Siefker-Radtke A, et al. The Lancet Oncology. Published: 25 January 2017, DOI: http://dx.doi.org/10.1016/S1470-2045(17)30065-7

Deep Clinical Responses and MRD Negativity with DARZALEX® in Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, about 30,280 new cases will be diagnosed in 2017 and 12,590 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. With a record number of regulatory approvals for Myeloma treatment over the past 12 years, the median survival for patients with Myeloma is over 10 years. The recent new drugs approved for the treatment of relapsed/refractory Multiple Myeloma include a Histone Decetylase inhibitor (FARYDAK®) and 2 monoclonal antibodies, Daratumumab (DARZALEX®) and Elotuzumab (EMPLICITI®).

Testing for MRD (Minimal Residual Disease) is standard practice in hematological malignancies such as Chronic Myeloid Leukemia (CML) which is characterized by a defined genetic abnormality ie. Philadelphia Chromosome, and CML also has very effective therapies. Unlike CML, multiple myeloma is a heterogeneous disorder and very effective therapies are only now becoming available. Effective combination regimens for myeloma has resulted in high response rates and therefore achievement of MRD negativity may be a primary endpoint in the near future. MRD negativity has been associated with prolonged Progression Free Survival (PFS) and Overall Survival (OS), in several meta-analyses.

Daratumumab (DARZALEX®) is a human IgG1 antibody that targets CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Mediated Cytotoxicity and direct apoptosis. Additionally, DARZALEX® may have a role in immunomodulation by depleting CD38-positive regulator Immune suppressor cells, and thereby expanding T cells, in patients responding to therapy.

The authors in this publication prospectively evaluated Minimal Residual Disease (MRD) status of patients enrolled in two large phase III trials, the POLLUX and CASTOR studies, and assessed the ability of DARZALEX® to yield deep clinical responses beyond complete remission. In the POLLUX study, 569 patients with relapsed or refractory multiple myeloma were randomized in a 1:1 ratio to receive either DARZALEX®, REVLIMID® (Lenalidomide) and Dexamethasone or REVLIMID® and Dexamethasone. In the CASTOR study, 498 patients with relapsed or refractory multiple myeloma were randomized in a 1:1 ratio to receive either DARZALEX®, VELCADE® (Bortezomib) and Dexamethasone or VELCADE® and Dexamethasone. In both these studies, the addition of DARZALEX® resulted in significant improvements in median PFS (HR=0.37; P<0.001 in the POLLUX study and HR=0.39; P<0.0001) in the CASTOR study), compared to the control group.

The researchers in this study, assessed MRD of bone marrow aspirate samples using ClonoSEQ next-generation sequencing–based assay. In the POLLUX study, MRD was assessed at the time of suspected Complete Response (CR), and at 3 and 6 months after. In the CASTOR study, MRD was assessed at the time of suspected CR, and at 6 months and 12 months after the first dose. The MRD sensitivity thresholds were 0.01% (1 cancer cell per 10,000 nucleated cells, or 10-4), 0.001% (10-5), and 0.0001% (10-6). The MRD negativity rate was defined as the proportion of patients with negative MRD results at any point during the studies. The median follow-up was 13.5 months for the POLLUX study and 7.4 months for the CASTOR study.

In the POLLUX study, the addition of DARZALEX® to REVLIMID® and Dexamethasone improved the MRD-negative status rates from 8.8% to 31.8% at the 10-4 threshold, from 5.7% to 24.8% at the 10-5 threshold, and from 2.5% to 11.9% at the 10-6 threshold. In the CASTOR study, the addition of DARZALEX® to VELCADE® and Dexamethasone improved the MRD-negative status rates from 3.6% to 18.3% at the 10-4 threshold, from 2.4% to 10.4% at the 10-5 threshold, and from 0.8% to 4.4% at the 10-6 threshold. It was noted that the MRD negativity was consistently higher in patients treated with DARZALEX® and DARZALEX® induced MRD negativity in three times as many patients as those treated with standard regimens. Further, MRD negativity was noted as soon as 3 months, with many patients continuing to achieve MRD negativity over time. High risk patients {t(4;14), t(14;16), del17p} benefited as well, with 18% of high risk patients in the POLLUX study and 14% of those in the CASTOR study achieving MRD negativity. Patients with sustained MRD negativity following treatment with DARZALEX®, had a significantly longer PFS compared with the control group.

It was concluded that the addition of DARZALEX®, in relapsed/refractory multiple myeloma, to standard treatment regimens, induced MRD negativity in three times as many patients as those treated with standard regimens. Evaluation of minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) patients treated with daratumumab in combination with lenalidomide plus dexamethasone or bortezomib plus dexamethasone. Avet-Loisseau H, Casneuf T, Chiu C, et al. Presented at: American Society of Hematology 58th Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract 246

XARELTO® for Heparin Induced Thrombocytopenia

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SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality. Heparin Induced Thrombocytopenia (HIT) is a prothrombotic disorder caused by antibodies to complexes of Platelet Factor 4 (PF4), a protein present in the platelet alpha granules and heparin and the incidence of HIT varies from 3-5% in patients treated with unfractionated heparin. The frequency of thromboemboli in HIT patients is 30-50% and women diagnosed with HIT are at a 1.7 times greater risk for thrombotic manifestations than men.

There are two types of HIT. Type 1 HIT is a non-immune disorder that results from the direct effect of heparin on platelet activation and manifests within the first 2 days after heparin exposure to heparin, and the platelet count normalizes with continued heparin therapy. Type 2 HIT however is an immune-mediated disorder that typically occurs 4-10 days after exposure to heparin and can result in life threatening thrombotic complications. Patients with HIT more often experience thrombotic events such as Deep Venous Thrombosis, Pulmonary Embolism and sometimes Arterial thrombosis rather than bleeding episodes. The 4 T’s that raise clinical suspicion for HIT include Thrombocytopenia, Timing of thrombocytopenia, Thrombosis and ruling out oTher causes of thrombocytopenia. Once a diagnosis of HIT is established, all heparin products should be stopped and alternative anticoagulants should be considered such as ARGATROBAN®, REFLUDAN® (Lepirudin), ANGIOMAXreg; (Bivalirudin) and ARIXTRA® (Fondaparinux). Warfarin may cause microthrombosis in patients with HIT and should be avoided and should be started only after the platelet count exceeds 150 x 109/L. IVC filters should be avoided as well.

The currently approved therapies for the treatment of HIT however are parenteral preparations and require laboratory coagulation monitoring. XARELTO® is a direct oral anti-Xa inhibitor and is presently approved by the FDA for the prevention and treatment of Deep Vein Thrombosis and Pulmonary Embolism as well as prevention of thromboembolic events in patients with Atrial Fibrillation. XARELTO® could be an ideal agent for patients with HIT, as it can be administered orally at a fixed dose and does not require routine coagulation monitoring.

The purpose of this study was to determine the safety and efficacy of XARELTO® in patients suspected or confirmed to have HIT. The authors in this multicenter, single-arm, prospective cohort study, reviewed the data of 22 consecutive adults with suspected or confirmed HIT. Patients received XARELTO® 15 mg PO BID until a local HIT assay result was available. Patients with a positive local assay result continued XARELTO® 15 mg PO BID until platelet recovery (or until day 21 if they had acute thrombosis at the time of entry into the study). The dose of XARELTO® was then changed to 20 mg PO daily, until day 30. This study was slated to enroll 200 patients but the study was terminated early after 22 patients were enrolled, because of difficulty in recruitment.

It was noted that the incidence of new, symptomatic, objectively confirmed, venous or arterial thromboembolism at 30 days in the HIT positive group (Primary endpoint), was 4.5% and one HIT-positive patient required limb amputation despite platelet recovery. Nine out of 10 HIT-positive patients with thrombocytopenia had platelet recovery.

It was concluded that based on this small study, XARELTO® was effective for treating patients with confirmed HIT, and also facilitated platelet recovery. This first prospective study of XARELTO® in HIT patients has a limited number of patients and the 22 patients in this study were enrolled over a 2.5 year period, which demonstrated the difficulty in enrolling patients in this study. Nonetheless, it is unlikely that larger studies will be designed to compare XARELTO® to one of the parenteral preparations. Based on the available data, XARELTO® may fulfill an unmet need for the management of patients with Heparin Induced Thrombocytopenia. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. Linkins LA, Warkentin TE, Pai M, et al. J Thromb Haemost 2016;14:1206-1210.

First Line KEYTRUDA® Superior to Chemotherapy in Advanced NSCLC

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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. The American Cancer Society estimates that for 2017 about 222,500 new cases of lung cancer will be diagnosed and over 155,000 patients will die of the disease. Non Small Cell Lung Cancer accounts for approximately 85% of all lung cancers. The FDA in October, 2016 approved KEYTRUDA® (Pembrolizumab) for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC), whose tumors have high PD-L1 expression (Tumor Proportion Score greater than or equal to 50%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and no prior systemic chemotherapy treatment for metastatic NSCLC.

KEYTRUDA® 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. High level of Programmed Death-Ligand 1 (PD-L1) expression is defined as membranous PD-L1 expression on at least 50% of the tumor cells, regardless of the staining intensity. It is estimated that based on observations from previous studies, approximately 25% of the patients with advanced Non Small Cell Lung Cancer (NSCLC) have a high level of PD-L1 expression and high level of PD-L1 expression has been associated with significantly increased response rates to KEYTRUDA®.

KEYNOTE-024 is an open-label, randomized, phase III trial in which KEYTRUDA® administered at a fixed dose was compared with investigator’s choice of cytotoxic chemotherapy, as first line therapy, for patients with advanced NSCLC, with tumor PD-L1 expression of 50% or greater. Three hundred and five (N=305) treatment naïve patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, were randomly assigned in a 1:1 ratio to receive either KEYTRUDA® (N=154) or chemotherapy (N=151). Enrolled patients had no sensitizing EGFR mutations or ALK translocations. Treatment consisted of KEYTRUDA® administered at a fixed dose of 200 mg IV every 3 weeks for 35 cycles or the investigator’s choice of platinum-based chemotherapy for 4-6 cycles. Pemetrexed (ALIMTA®) based therapy was permitted only for patients who had non-squamous tumors and these patients could receive ALIMTA® maintenance therapy after the completion of combination chemotherapy. The primary end point was Progression Free Survival and secondary end points included Overall Survival, Objective Response Rate and safety.

The median PFS was 10.3 months in the KEYTRUDA® group versus 6.0 months in the chemotherapy group (HR=0.50; P<0.001). This benefit was observed across all patient subgroups including tumor histologic type and chemotherapy regimen administered. The estimated Overall Survival at 6 months was 80.2% in the KEYTRUDA® group versus 72.4% in the chemotherapy group (HR=0.60; P=0.005). Patients in the KEYTRUDA® group experienced higher Response Rates than in the chemotherapy group (44.8% vs. 27.8%) as well as longer median duration of response (Not Reached versus 6.3 months). These benefits were realized even after 43.7% of the patients in the chemotherapy group following progression, had crossed over to receive KEYTRUDA®. Adverse events of any grade were less frequent in the KEYTRUDA® group compared to the chemotherapy group, with diarrhea, fatigue and pyrexia being more common in the KEYTRUDA® group whereas anemia, nausea and fatigue were more often noted in the chemotherapy group. As expected, immune-mediated adverse events (including pneumonitis) occurred more frequently with KEYTRUDA® whereas cytopenias occurred more frequently with chemotherapy.

It was concluded that in treatment naïve patients with advanced NSCLC and a PD-L1 tumor proportion score of 50% or greater, KEYTRUDA® was associated with significantly longer Progression Free and Overall Survival and with fewer adverse events, compared with platinum-based chemotherapy. This landmark trial is practice changing for advanced NSCLC. Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer. Reck M, Rodríguez-Abreu D, Robinson AG, et al. for the KEYNOTE-024 Investigators. October 9, 2016DOI: 10.1056/NEJMoa1606774

Late Breaking Abstract – ASCO 2016 ROVA-T, First Targeted Treatment for Small Cell lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and the American Cancer Society estimates that for 2016, about 224,390 new cases of lung cancer will be diagnosed and over 158,000 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Small cell lung cancer (SCLC) accounts for approximately 13-15 percent of all lung cancers and is aggressive. The five year survival rate for extensive stage SCLC is less than 5% with a median survival of 9 to 10 months from the time of diagnosis. Patients are often treated with chemotherapy and radiation in the first and second line setting. The Overall Response Rate (ORR) in the third line setting is approximately 18% and the one year Overall Survival is approximately 12%. These patients typically have a poor prognosis with limited treatment options. Delta-like protein 3 also known as DLL3, is encoded by the DLL3 gene and is expressed on the surface of tumor cells but not in normal adult tissues. Patients with high-grade pulmonary NeuroEndocrine Tumors, Small Cell Lung Cancer (SCLC) and Large Cell NeuroEndocrine Carcinoma (LCNEC) have increased expression of DLL3 protein (increased expression seen in approximately 80% of the tumors).

Rovalpituzumab Tesirine (Rova-T) is a first-in-class DLL3-targeted Antibody-Drug Conjugate (ADC) comprised of a humanized anti-DLL3 monoclonal antibody, conjugated to a DNA-damaging PyrroloBenzoDiazepine (PBD) dimer toxin. Rova-T delivers the cytotoxin directly to the DLL3-expressing cancer cells while minimizing toxicity to healthy cells.

The authors in this open-label, Phase 1a/1b, multicenter study, included seventy four (N=74) patients with SCLC who had progressed after at least one previous systemic therapy. Previous therapies included Platinum/Etoposide (96%) and radiation therapy (82%). The majority of patients (76%) had extensive disease at presentation, with 28% having CNS metastases. Over 85% of patients had DLL3 expression on 1% or more of tumor cells and 67% of the patients had DLL3 expression on 50% or more of tumor cells (DLL3-high expression). Patients received Rova-T at doses ranging from 0.05 to 0.8 mg/kg every 3 or 6 weeks. The median age was 61 years. The primary endpoints of the study were Overall Response Rate (ORR) and Maximum Tolerated Dose and secondary endpoints included Overall Survival (OS) and Progression Free Survival (PFS).

Rova-T demonstrated an Overall Response Rate of 39% and Clinical Benefit Rate (stable disease or better) of 89%, in patients with recurrent or refractory Small Cell Lung Cancer identified with high expression of DLL3. The one year Overall Survival rate was 32% in the patient group identified with high expression of DLL3. The most common adverse events were rash, fatigue, nausea, decreased appetite, pleural effusion, peripheral edema and thrombocytopenia.

The authors concluded that Rovalpituzumab Tesirine (Rova-T) has significant single-agent anti-tumor activity with manageable toxicity, in recurrent or refractory SCLC, and is the first biomarker-directed therapy to be defined, for the treatment of Small Cell Lung Cancer. Safety and efficacy of single-agent rovalpituzumab tesirine (SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate (ADC) in recurrent or refractory small cell lung cancer (SCLC). Rudin CM, Pietanza MC, Bauer TM, et al. J Clin Oncol 34, 2016 (suppl; abstr LBA8505)

Late Breaking Abstract – ASH 2016 Dramatic Responses in Patients with Refractory Diffuse Large B-Cell Lymphoma (DLBCL) with anti-CD19 CAR T Cells

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SUMMARY: The American Cancer Society estimates that in 2016, about 72,580 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,150 individuals will die of this disease. Patients with refractory DLBCL have poor outcomes with chemotherapy, and have a response rate of 20%-30% and median overall survival of approximately 6 months (J Clin Oncol 34, 2016, suppl; abstr. 7516), and thus represents a significant unmet medical need. Chimeric Antigen Receptor (CAR) T-cell therapy is a type of immunotherapy in which T cells are collected from the patient’s own blood and are genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR’s). The cytotoxic T cells with these chimeric antigen receptors on their surface are now able to recognize a specific antigen on tumor cells. These engineered CAR T-cells which are grown in the lab are then infused into the patient and they in turn proliferate in the patient’s body and the engineered receptor on their surface help recognize and kill cancer cells that expresses that specific antigen. CD19 antigen is expressed by majority of the B cell malignancies and therefore most studies using CAR T-cell therapy have focused on the treatment of advanced B-cell malignancies such as Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL) and Non Hodgkin lymphoma (NHL), such as Diffuse Large B-Cell Lymphoma (DLBCL).

The KTE-C19 (anti-CD19 Chimeric Antigen Receptor (CAR) T cells) construct consists of an extracellular domain which recognizes and targets the CD19 antigen on the surface of tumor cells, and the intracellular domains to avoid activation of hidden signals to the T-cells. ZUMA-1 is a multicenter phase I/II trial of anti-CD19 Chimeric Antigen Receptor (CAR) T cells (KTE-C19) in refractory, aggressive NHL and this study included patients with Diffuse Large B-Cell Lymphoma (DLBCL), Primary Mediastinal B-Cell Lymphoma (PMBCL), and Transformed Follicular Lymphoma (TFL). In the phase I component of this study, 43% of the patients had ongoing Complete Responses at 12 months.

Phase II of ZUMA-1 included 2 patient cohorts based on the tumor type. Cohort 1 included DLBCL and patients in cohort 2 had PMBCL or TFL. Refractory disease was defined as progressive or stable disease as best response to last line of therapy, or disease progression 12 months or less after Autologous Stem Cell Transplant (ASCT). All included patients received a prior anti-CD20 antibody and an Anthracycline-containing regimen. The median age was 58 years, 78% were refractory to 2 or more lines of therapy, 20% relapsed less than 12 months after ASCT. Patients received a low-dose conditioning regimen of Cyclophosphamide 500 mg/m2 IV and Fludarabine 30 mg/m2 IV, daily for 3 days followed by a target dose of 2 × 106 anti-CD19 CAR T cells/kg. The primary endpoint was Objective Response Rate (ORR) and secondary endpoints include Duration of Response, frequency of adverse events (AEs), and levels of CAR T cells and serum cytokines. The authors presented the results of a pre-specified interim analysis from cohort 1 and 51 patients in cohort 1 were eligible for analysis.

The study met its primary endpoint and with a minimal follow up of three months, the ORR was 76% compared with ORR of 20% in historical controls (P<0.0001). Complete Responses were noted in 47% of the patients and Partial Response rate was 29%. Majority of the responses (92%) occurred within the first month, and the Complete Response Rate at 3 months was 33% and 39% of the patients had ongoing responses at 3 months. The treatment benefit was consistent across all subgroups of patients. The most frequent more than grade 3 toxicities were cytopenias, encephalopathy and hypophosphatemia. Grade 3 or more Cytokine Release Syndrome (CRS) and neurologic events occurred in 20-30% of the patients.

The authors concluded that this is the first reported multicenter trial of CAR T cell therapy in patients with refractory aggressive NHL and therapy with KTE-C19 induced a nearly six fold higher Complete Response Rate compared to historical outcomes and efficacy was strongly associated with peak CAR T levels. KTE-C19 (anti-CD19 CAR T Cells) Induces Complete Remissions in Patients with Refractory Diffuse Large B-Cell Lymphoma (DLBCL): Results from the Pivotal Phase 2 ZUMA-1.Neelapu SS, Locke FL, Bartlett NL, et al. Presented at: American Society of Hematology 58th Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract LBA6.

Axillary Lymph Node Dissection Can Be Avoided in Some High Risk Breast Cancer Patients

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. Axillary lymph node evaluation is an important part of breast cancer staging and the presence of axillary lymph metastases decreases the 5-year survival rate by 28-40%. Axillary lymph node status remains the most powerful predictor of breast cancer recurrence and survival. Axillary Lymph Node Dissection (ALND) was first advocated in the 18th century as part of the treatment of invasive breast cancer and has been standard practice until 2 decades back. ALND can be associated with significant morbidities such as upper limb lymphedema, pain, and sensitivity disorders and this can have a major psychological impact on breast cancer patients. Sentinel Lymph Node Biopsy (SLNB) which was introduced into clinical practice in the mid 1990’s, however has now become a standard method of treatment for stage I and II breast cancer. This therapeutic surgical modality facilitates selective histopathological evaluation of the sentinel lymph nodes rather than routine lymphadenectomy, thereby sparing the patient from the morbidities associated with ALND. Several studies have shown no statistically significant difference in the axillary recurrence risk and survival rates, between these two therapeutic surgical modalities.

Neoadjuvant chemotherapy is considered standard practice in women with locally advanced breast cancer. This intervention increases the possibility of breast conserving surgery in women with locally advanced breast cancer and for tumors more than 3 cm in diameter, with good cosmetic outcomes. Close to half of the patients treated with neoadjuvant chemotherapy have no axillary lymph node involvement at the time of surgery. GANEA 2 trial was conducted to assess the feasibility and safety of SLNB, a less invasive procedure, for patients treated with neoadjuvant chemotherapy.

The researchers enrolled 590 patients with large, operable breast tumors who had no cancer in the lymph nodes as determined by axillary sonography with fine needle cytology. All patients received neoadjuvant chemotherapy, and then underwent surgery and Sentinel Lymph Node Biopsy. Cancer cells were detected in the Sentinel Lymph Node Biopsy specimens of 139 patients and these patients underwent Axillary Lymph Node Dissection.

No cancer cells were detected in the Sentinel Lymph Node Biopsy samples from 432 patients. Follow-up data was available for 416 of these patients. The median follow-up was 35.8 months. The Disease Free Survival at 3 years in the patient group who had no cancer cells in the Sentinel Lymph Node Biopsy sample, and therefore did not receive Axillary Lymph Node Dissection, was 94.8%. The Overall Survival rate was 98.7%.

The authors concluded that Axillary Lymph Node Dissection could be avoided in patients who have no signs of cancer involvement in the axillary lymph nodes, based on sonographic axillary assessment, prior to neoadjuvant chemotherapy and Sentinel Lymph Node Biopsy findings after neoadjuvant chemotherapy. In this study, the Disease Free Survival and Overall Survival rates for the patients who underwent only a Sentinel Lymph Node Biopsy after neoadjuvant chemotherapy, were comparable with the historical survival rates for patients in this situation who had Axillary Lymph Node Dissection rather than Sentinel Lymph Node Biopsy. Classe JM, Loaec C, Alran S, et al. Sentinel node detection after neoadjuvant chemotherapy in patient without previous axillary node involvement (GANEA 2 trial): follow-up of a prospective multi-institutional cohort. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract S2-07.

Late Breaking Abstract – ASH 2016 Superior Efficacy Data with Pacritinib in Myelofibrosis

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SUMMARY: Myelofibrosis is a MyeloProliferative Neoplasm (MPN) characterized by ineffective hematopoiesis, progressive fibrosis of the bone marrow and potential for leukemic transformation. This stem cell disorder is Philadelphia Chromosome negative and manifestations include anemia, splenomegaly and related symptoms such as abdominal distension and discomfort with early satiety. Cytokine driven debilitating symptoms such as fatigue, fever, night sweats, weight loss, pruritus and bone or muscle pain can further impact an individual’s quality of life. Myelofibrosis can be primary (PMF) or secondary to Polycythemia Vera (PV) or Essential Thrombocythemia (ET). The JAK-STAT signaling pathway has been implicated in the pathogenesis of Myelofibrosis. This pathway normally is responsible for passing information from outside the cell through the cell membrane to the DNA in the nucleus, for gene transcription. Janus Kinase (JAK) family of tyrosine kinases are cytoplasmic proteins and include JAK1, JAK2, JAK3 and TYK2. JAK1 helps propagate the signaling of inflammatory cytokines whereas JAK2 is essential for growth and differentiation of hematopoietic stem cells. These tyrosine kinases mediate cell signaling by recruiting STAT’s (Signal Transducer and Activator of Transcription), with resulting modulation of gene expression. In patients with MPN, the aberrant myeloproliferation is the result of dysregulated JAK2-STAT signaling as well as excess production of inflammatory cytokines associated with this abnormal signaling. These cytokines contribute to the symptoms often reported by patients with MF. JAK2 mutations such as JAK2 V617F are seen in approximately 60% of the patients with PMF and ET and 95% of patients with PV. Unlike CML where the BCR-ABL fusion gene triggers the disease, JAK2 mutations are not initiators of the disease and are not specific for MPN. Further, several other genetic events may contribute to the abnormal JAK2-STAT signaling.

Pacritinib is a potent JAK2 inhibitor, without significant JAK1 inhibition. It additionally targets FLT3, IRAK1, and CSF1R. Preliminary studies have shown minimal myelosuppression with Pacritinib. JAKAFI® (Ruxolitinib) is a potent JAK1 and JAK2 inhibitor approved by the FDA in 2011 to treat intermediate or high-risk Myelofibrosis. It is however not indicated for patients with platelet counts under 50,000/μl, and this group represents approximately one third of Myelofibrosis patients and have limited or no treatment options. Previously published PERSIST-1 trial showed that Pacritinib significantly reduced Spleen Volume and Myelofibrosis associated symptoms, in patients with low platelet count, when compared to Best Available Therapy (excluding JAKAFI®).

PERSIST-2 is an open label, phase III study in which the safety and efficacy of Pacritinib was compared with currently available therapies, including JAKAFI®, thus expanding the definition of Best Available Therapy (BAT). A total of 311 patients with platelet counts 100,000/μl or less were randomly assigned in a 1:1:1 ratio to receive Pacritinib 200 mg BID (N=107), 400 mg QD (N=104) or Best Available Therapy (N=100). The efficacy population in the Intent To Treat group included a total of 221 patients. Approximately half of the study population had platelet counts of less than 50,000/μl. Over 40% of the patients in both the treatment groups had prior therapy with JAKAFI®. About 60-70% of the patients had a diagnoses of Primary Myelofibrosis, and half of the patients fell in the International Prognostic Scoring System (IPSS) Intermediate-2 risk category. The two coprimary endpoints were the proportion of patients achieving 35% or greater reduction in Spleen Volume (SVR) as measured by MRI or CT scan and the proportion achieving a 50% or more improvement in symptoms such as fatigue, bone pain, itching, and abdominal pain after 24 weeks of follow up. The secondary objectives were to compare Pacritinib BID and Pacritinib QD, individually to BAT.

It was noted that 18% of patients who received Pacritinib achieved a 35% or greater reduction in Spleen Volume from baseline to week 24, compared to 3% of those in the BAT group (P=0.001). In the patient group who received Pacritinib twice daily, 32% reported a 50% or more reduction in symptoms compared with 14% in the BAT group (P=0.01). Further, patients treated with Pacritinib required fewer red blood cell transfusions and additionally, patients who received Pacritinib twice daily had substantially greater improvement in platelet count among those who had platelets counts 50,000/μl or less at enrollment. The most common adverse events related to Pacritinib included nausea, vomiting, diarrhea, anemia, and low platelets.

The authors concluded that this is the only randomized trial to date in patients with Myelofibrosis and thrombocytopenia that enrolled patients who had prior therapy with a JAK2 inhibitor. Regardless, Pacritinib was more effective at Spleen Volume Reduction than BAT and Pacritinib given BID was even more effective than QD dosing. Results of the Persist-2 Phase 3 Study of Pacritinib (PAC) Versus Best Available Therapy (BAT), Including Ruxolitinib (RUX), in Patients (pts) with Myelofibrosis (MF) and Platelet Counts <100,000/µl. Hoffman R, Talpaz M, Gerds AT, et al. 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract LBA-5.