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

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.

Influence of Tumor Genetics (MSI) on Prognostic Effect of BRAF and KRAS Mutations in Patients with Colon Cancer

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 135,000 new cases of ColoRectal Cancer will be diagnosed in the United States in 2016 and over 49,000 patients are expected to die of the disease. The role of adjuvant chemotherapy in patients with Stage III ColoRectalCancer (CRC) has been well established, with improvement in Disease Free Survival (DFS) and Overall Survival (OS). However, not all patients equally benefit from this therapy. Patients with MSI (Micro Satellite Instability) tumor phenotype have better survival when cancer is at an earlier stage although this beneficial effect in Stage III colon cancer remains unclear.

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 when sporadic, the DNA MisMatchRepair gene is MLH1. Defective MisMatchRepair can also manifest as a germline mutation occurring in 1 of the 4 MisMatchRepair genes which include MLH1, MSH2, MSH6, PMS2. This produces Lynch Syndrome (Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC), an autosomal dominant disorder and is the most common form of hereditary colon cancer, accounting for 35% of the MSI colorectal cancers. MSI tumors tend to have better outcomes and this has been attributed to the abundance of tumor infiltrating lymphocytes in these tumors from increase immunogenicity. These tumors are susceptible to PD-1 blockade and respond to treatment with checkpoint inhibitors such as Pembrolizumab (N Engl J Med 372:2509-2520, 2015).

MSI (Micro Satellite Instability) testing is performed using a PCR based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MisMatchRepair genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC). MLH1 gene is often lost in association with PMS2.

Patients with stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations because KRAS mutations are predictive of resistance to EGFR targeted therapy and BRAF V600E is recognized as a marker of poor prognosis in this patient group. BRAF mutations occur in approximately 45% of patients with sporadic colorectal cancer with MSI but not seen in patients with Lynch syndrome. The prognostic effect of these mutations in early stage disease has however remained controversial. This publication is a Post Hoc Analysis of the PETACC-8 study, a randomized phase III trial, in which patients with resected Stage III colon cancer received treatment with adjuvant FOLFOX with or without Cetuximab. The authors in this publication examined the prognostic effect of BRAF and KRAS mutations in this patient population, as it relates to MSI of the tumor.

The PETACC-8 trial enrolled 2559 patients with surgically resected colon cancer, treated with adjuvant FOLFOX chemotherapy regimen. The median age was 60 years. MisMatch Repair, BRAF V600E, and KRAS exon 2 mutational status, were determined on tumor blocks that were collected prospectively from the enrolled patients. MSI phenotype was noted in 9.9% (N=177), KRAS mutations in 33.1% (N=588) and BRAF V600E mutations in 9% (N=148) of the patients. The primary end point was Disease Free Survival (DFS) and Overall Survival (OS), as it relates to these mutations.

In multivariate analysis, MSI and BRAF V600E mutations for DFS were not prognostic, whereas KRAS mutation was associated with significantly shorter DFS (P<0.001) and OS (P=0.008). The subgroup analysis showed that in patients with Micro Satellite Stable (MSS) tumors, DFS and OS was inferior among those with KRAS and BRAF V600E mutation and were independently associated with worse clinical outcomes. In patients with MSI tumors, KRAS status was not prognostic, whereas BRAF V600E mutation was associated with significantly longer DFS (P=0.04), but not OS (P=0.08).

The authors based on this large analysis of patients with Stage III colon cancer receiving FOFOX adjuvant chemotherapy, concluded that BRAF V600E and KRAS mutations were significantly associated with shorter DFS and OS in patients with Micro Satellite Stable (MSS) tumors, but not in patients with MSI tumors. Prognostic Effect of BRAF and KRAS Mutations in Patients With Stage III Colon Cancer Treated With Leucovorin, Fluorouracil, and Oxaliplatin With or Without Cetuximab. A Post Hoc Analysis of the PETACC-8 Trial. Taieb J, Zaanan A, Le Malicot, et al. JAMA Oncol. 2016;2:643-653.

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

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.

FDA Approves AVASTIN® for Platinum-Sensitive Ovarian Cancer

SUMMARY: The FDA on December 7, 2016 approved AVASTIN® (Bevacizumab), either in combination with Carboplatin and Paclitaxel or in combination with Carboplatin and Gemcitabine chemotherapy, followed by AVASTIN® alone, for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. Platinum-sensitive disease is defined as relapse occurring six months or longer following the last treatment with a platinum-based chemotherapy. The American Cancer Society estimates that over 22,280 women will be diagnosed with ovarian cancer in the United States for 2016 and over 14,240 will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. The FDA had approved AVASTIN® in combination with Paclitaxel, Pegylated Liposomal Doxorubicin, or Topotecan in 2014, for the treatment of patients with Platinum-resistant, recurrent epithelial Ovarian, Fallopian tube, or Primary Peritoneal cancer.

The present approval was based on results from two randomized, controlled Phase III studies, GOG-0213 and OCEANS trial. GOG-0213 is phase III study and was conducted by the Gynecologic Oncology Group (GOG) that enrolled 673 women with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. This study enrolled 673 patients with predominantly serous adenocarcinoma histology. The patients were randomly assigned to receive combination chemotherapy with Paclitaxel and Carboplatin (N=336) or the same chemotherapy along with Avastin 15 mg/kg IV every 3 weeks (N=337), followed by AVASTIN® maintenance. The median age was 60 years. The Primary endpoint of this study was Overall Survival (OS) and Secondary endpoints included Progression Free Survival (PFS) and Objective Response Rate (ORR).

There was a 5 month improvement in the median Overall Survival with the addition of AVASTIN® to chemotherapy compared with chemotherapy alone (42.6 months vs 37.3 months, respectively; HR=0.84). There was a 3.4 improvement in the median PFS in the AVASTIN® group compared to chemotherapy alone (13.8 months vs 10.4 months, respectively; HR=0.61). The Objective Response Rate (ORR) was 78% with the addition of AVASTIN® to chemotherapy versus 56% with chemotherapy alone.

OCEANS trial is a placebo-controlled, randomized, multicentre Phase III study that evaluated the safety and efficacy of AVASTIN® in combination with Carboplatin and Gemcitabine chemotherapy. This study included 484 patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who were randomly assigned to receive combination chemotherapy with Carboplatin and Gemcitabine along with placebo (N=242) or combination chemotherapy along with Avastin (N=242). The Primary endpoint of the study was Progression Free Survival and Secondary endpoints included Objective Response Rate, Overall Survival and safety.

The addition of AVASTIN® to chemotherapy significantly improved PFS compared to chemotherapy alone (12.4 months vs. 8.4 months; HR=0.46, P<0.0001). The ORR was 78% in the AVASTIN® group compared with 57% in the chemotherapy alone group.

These studies supports the use of AVASTIN® either in combination with Carboplatin and Paclitaxel or in combination with Carboplatin and Gemcitabine chemotherapy, followed by AVASTIN® alone, for patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. A phase III randomized controlled clinical trial of carboplatin and paclitaxel alone or in combination with bevacizumab followed by bevacizumab and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian, peritoneal primary and fallopian tube cancer (Gynecologic Oncology Group 0213). Coleman RL , Bradya MF, Herzog TJ, et al. Scientific Plenary (Late-Breaking Abstract). SGO 2015. Abstract 3. Presented March 28, 2015

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

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.

FDA Approves TECENTRIQ® for Non-Small Cell Lung Cancer

SUMMARY: The FDA on October 18, 2016, approved TECENTRIQ® (Atezolizumab) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose disease progressed during or following platinum-containing chemotherapy. 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 2016 about 224,390 new cases of lung cancer will be diagnosed and over 158,000 patients will die of the disease. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. The treatment paradigm for malignancies 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. Survival of cancer cells in the human body may be to a significant extent related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. The T cells of the immune system therefore play a very important role in modulating the immune system. Under normal circumstances, Immune checkpoints or gate keepers inhibit an intense immune response by switching off the T cells of the immune system. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are now available 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 targeting the Immune check point proteins or their ligands, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response.

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 and restoring tumor-specific T-cell immunity. The approval of TECENTRIQ® was based two international, clinical trials (OAK and POPLAR trials). TECENTRIQ® demonstrated survival benefit compared to Docetaxel in a multicenter, randomized, phase II study (POPLAR trial). In this study, the median Overall Survival was 12.6 months and 9.7 months (HR=0.69) for the TECENTRIQ® and Docetaxel groups respectively.

OAK trial is a global, multicentre, open-label, randomized, controlled Phase III study in which 1225 patients with locally advanced or metastatic NSCLC, whose disease had progressed following previous treatment with platinum-containing chemotherapy, were enrolled. Patients with both squamous and non-squamous histology were randomized in a 1:1 ratio to receive either TECENTRIQ® 1200 mg IV every 3 weeks or Docetaxel 75 mg/m2 IV every 3 weeks. Patients were stratified according to PD-L1 status, number of prior chemotherapy regimens and histology. The median age was 64 years, 25% had 2 prior lines of therapy and 26% had squamous histology. The co-primary endpoints were Overall Survival (OS) in all randomized patients and in a PD-L1 selected subgroup in the primary analysis population. Secondary endpoints included Progression Free Survival, Objective Response Rate, Duration of Response and Safety.

The primary efficacy analysis was conducted and reported in the first 850 of 1225 total enrolled patients. The median Overall Survival was 13.8 months in the TECENTRIQ® group compared to 9.6 months in the Docetaxel group (HR=0.74; P=0.0004), with a 26% improvement in Overall Survival in the patient group who received TECENTRIQ®. This benefit was seen regardless of their PD-L1 expression levels, including patients whose tumors displayed PD-L1 expression of less than 1%. Patients with high PD-L1 expression had more pronounced benefit with TECENTRIQ® with a 59% improvement in OS compared with Docetaxel (HR=0.41; P<0.0001). The OS benefit was similar in patients with squamous or non-squamous histology. The most common adverse reactions in patients in patients treated with TECENTRIQ® were fatigue, decreased appetite, dyspnea, cough, nausea, musculoskeletal pain, and constipation.

The authors concluded that TECENTRIQ® offers a new second-line therapeutic strategy for patients with Non Small Cell Lung Cancer, with Overall Survival benefit, regardless of the PD-L1 status of the tumor. Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in 2L/3L NSCLC. Barlesi F, Park K, Ciardiello F et al. Abstract LBA44_PR. Presented at: 2016 ESMO Congress; October 7–11 (2016) Copenhagen, Denmark.

ASH – 2016 Discontinuing Tyrosine Kinase Inhibitors is Feasible in Some Patients with CML

SUMMARY: Chronic Myeloid Leukemia (CML) constitutes a little over 10% of all new cases of leukemia. The American Cancer Society estimates that about 8,220 new CML cases will be diagnosed in the United States in 2016 and about 1,070 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. 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®. It has been hypothesized based 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, stopping CML therapy is currently not a clinical recommendation and should only be considered in the context of a clinical trial.

The European Stop TKI (EURO-SKI) trial was conducted to assess the safety of stopping Tyrosine Kinase Inhibitor therapy in patients with CML, whose leukemia was in Deep Molecular Response (DMR). This trial enrolled 821 patients with chronic phase CML without prior TKI failure, in DMR (BCR-ABL <0.01% on the International Scale – MR4) for at least one year, following treatment with either Imatinib, Nilotinib or Dasatinib. Following cessation of treatment with TKIs, patients were followed up testing by RQ-PCR (Real-time Quantitative Polymerase Chain Reaction) every 4 weeks for the first 6 months followed by every 6 weeks, the first year and every 3 months thereafter. Molecular recurrence was defined by the loss of the Major Molecular Response (BCR-ABL <0.1% IS – MR3) at any one point.

It was noted that after stopping TKI therapy, 62% showed no evidence of molecular recurrence at 6 months, and 52% showed no recurrence at 24 months. Patients who had taken a TKI for more than 5.8 years before stopping, were significantly less likely to experience relapse within the first 6 months and had a Molecular Relapse Free Survival at 6 months of 65.5% compared with 42.6% for those on treatment for 5.8 years or less. Further, each additional year of TKI therapy increased a patient’s chances of maintaining Major Molecular Response successfully at 6 months by 16%, after TKI therapy was discontinued. Most of the patients who experienced molecular recurrence were able to regain their previous remission level, after resuming TKI therapy and none of the patients in the study had progression to advanced stage.

The authors concluded that stopping TKI therapy of CML patients appeared safe and feasible in over 50% of the patients and longer duration of therapy with TKIs (5.8 years or more) prior to stopping therapy with TKIs, was associated with a higher probability of Molecular Recurrence Free Survival. Cessation of Tyrosine Kinase Inhibitors Treatment in Chronic Myeloid Leukemia Patients with Deep Molecular Response: Results of the Euro-Ski Trial. Mahon F-X, Richter J, Guilhot J, et al. 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 787.

Late Breaking Abstract – ESMO 2016 FASLODEX® Superior to ARIMIDEX® as Initial Therapy in Advanced Breast Cancer

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. Estrogen Receptor (ER) positive breast cancer cells are driven by estrogens. Approximately 60-65% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and this is a predictor of response to endocrine therapy. These patients are often treated with anti-estrogen therapy as first line treatment. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol, in extragonadal/peripheral tissues. NOLVADEX® (Tamoxifen) is a nonsteroidal Selective Estrogen Receptor Modulator (SERM) and works mainly by binding to the Estrogen Receptor and thus blocks the proliferative actions of estrogen on the mammary tissue. ARIMIDEX® (Anastrozole), FEMARA® (Letrozole) and AROMASIN® (Exemestane) are Aromatase Inhibitors (AIs) that binds to the Aromatase enzyme and inhibit the conversion of androgens to estrogens in the extra-gonadal tissues. FASLODEX® (Fulvestrant) is an estrogen antagonist and like NOLVADEX®, binds to estrogen receptors (ERs) competitively, but unlike NOLVADEX® causes rapid degradation and loss of ER protein (ER downregulator), and is devoid of ER agonist activity.

The superiority of ARIMIDEX® over NOLVADEX® was first established in the year 2000 following the publication of the results of a North American Multicenter Randomized Trial. In this study, ARIMIDEX® as first-line treatment in postmenopausal women with advanced breast cancer resulted in a significant increase in Time To Progression and a lower incidence of thromboembolic events and vaginal bleeding, compared to NOLVADEX®. In a previously reported phase II study (FIRST trial), first-line treatment with FASLODEX® significantly improved Time To disease Progression and Overall Survival compared with ARIMIDEX®, in patients with hormone receptor (HR) positive advanced breast cancer.

The FALCON trial is a phase III study conducted to confirm findings from the FIRST trial. This study included 462 postmenopausal women, with locally advanced or metastatic hormone receptor positive, HER2-negative, endocrine-therapy naive breast cancer. Patients were randomized to receive FASLODEX® IM at 500 mg on days 0, 1, and 28 and then every 28 days (N=230) or ARIMIDEX® 1 mg PO daily (N=232). Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint was Progression Free Survival (PFS), and secondary endpoints included Overall Survival, Objective Response Rate, Clinical Benefit Rate, Duration of Response, health-related Quality of Life, and safety.

It was noted that FASLODEX® provided better disease control with a median PFS of 16.6 months compared to 13.8 months with ARIMIDEX® (P=0.048). Subgroup analysis showed that FASLODEX® was markedly superior to ARIMIDEX® in patients with non-visceral disease with a median Progression Free Survival of 22.3 months compared with 13.8 months for ARIMIDEX®. There was no significant improvement in the Overall Response Rate between the treatment groups. However, the median Duration of Response was 20.0 months with FASLODEX® compared to 13.2 months with ARIMIDEX®. Expected Duration of response and expected Duration of Clinical Benefit were in favor of FASLODEX® (11.4 vs 7.5 months; P=0.001) and (21.9 vs 17.5 months; P=0.001), respectively. There was no difference in Overall Survival at the time of this analysis. Rates of adverse events were similar in both treatment groups.

The authors concluded that FASLODEX® was superior to ARIMIDEX® as initial treatment of hormone receptor positive, endocrine therapy naive, advanced breast cancer. Patients with non-visceral and low volume disease, as well as elderly patients, may benefit the most with FASLODEX®, as this therapy is well tolerated with a low toxicity profile. FALCON: a phase III randomised trial of fulvestrant 500 mg vs. anastrozole for hormone receptor-positive advanced breast cancer. Ellis MJ, Bondarenko I, Trishkina E, et al. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA14.

Prolonged Survival with FOLFIRINOX Regimen in Locally Advanced Pancreatic Cancer

SUMMARY: The American Cancer Society estimates that in 2016, over 53,000 people will be diagnosed with Pancreatic cancer in the United States and close to 42,000 patients will die of the disease. Some important risk factors for Pancreatic cancer include increasing age, obesity, smoking history, genetic predisposition, exposure to certain dyes and chemicals, heavy alcohol use and pancreatitis. The best chance for long term survival is complete surgical resection, although this may not be feasible in a majority of the patients, as they present with advanced disease at the time of diagnosis. Approximately 35% of patients with Pancreatic cancer have unresectable, locally advanced disease at diagnosis. Based on the National Cancer Data Base, the 5 year observed survival rate for patients diagnosed with exocrine cancer of the Pancreas is 14% for those with Stage IA disease and 1% for those with Stage IV disease.

In a previously published study (N Engl J Med 2011; 364:1817-1825), FOLFIRINOX regimen, a combination of Fluorouracil, Leucovorin, Irinotecan (CAMPTOSAR®) and Oxaliplatin (ELOXATIN®) was significantly superior to single agent Gemcitabine (GEMZAR®), as first-line therapy, in patients with metastatic Pancreatic cancer. FOLFIRINOX resulted in a significantly improved median Overall Survival (OS), median Progression Free Survival (PFS) and Objective Response Rate (ORR).

The researchers in this study evaluated the effectiveness of FOLFIRINOX as first-line treatment in patients with newly diagnosed, locally advanced, unresectable Pancreatic cancer. The authors searched large databases for studies which involved treatment-naive patients of any age, who had received FOLFIRINOX as first-line treatment for locally advanced Pancreatic cancer. They were able to include 689 patients from 13 studies, of whom 355 (52%) patients had locally advanced Pancreatic cancer. FOLFIRINOX regimen consisted of Oxaliplatin 85mg/m2 IV over 2 hours, followed by Leucovorin 400mg/m2 IV over 2 hours given concomitantly with Irinotecan 180mg/m2 IV over 90 minutes, followed by 5-FU 400 mg/m2 IV bolus and 5-FU 2400 mg/m2 given as a 46 hour continuous infusion, with this cycle repeated every 2 weeks. The median number of administered cycles ranged from 3-11 cycles. In his retrospective review, the authors looked at Overall Survival as the Primary outcome. Secondary outcomes were Progression Free Survival, rates of Grade 3 or 4 toxicities, proportion of patients who underwent Radiotherapy or Chemoradiotherapy, surgical resection after FOLFIRINOX and R0 resection (margin-negative resection microscopically, with no gross or microscopic tumor present in the primary tumor bed).

It was noted that across studies, the pooled median OS was 24.2 months, median PFS was 15 months, Grade 3 or 4 adverse events were 60 events per 100 patients and no deaths were attributed to FOLFIRINOX toxicity. The proportion of patients who underwent Radiotherapy or Chemoradiation after FOLFIRINOX ranged from 31% to 100% across studies and the pooled proportion of patients who received any Radiotherapy treatment was 63.5%. The pooled proportion of patients who had surgical resection was 25.9% and the pooled proportion of patients who had R0 resection was 78.4%. There was no significant correlation found across studies, between the median number of FOLFIRINOX cycles administered and median Overall Survival.

The authors concluded that patients with locally advanced Pancreatic cancer treated with FOLFIRINOX had a longer median Overall Survival (24.2 months), compared with single agent GEMZAR® (6-13 months) and future studies should establish which patients might benefit from Radiotherapy or Chemoradiotherapy or Surgical resection, following treatment with FOLFIRINOX. FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis. Suker M, Beumer BR, Sadot, F, et al. Lancet Oncol 2016;17:801-810.

Immediate Androgen Deprivation Therapy Confers Survival Benefit in Prostate Cancer Patients with Biochemical Recurrence

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 180,890 new cases of prostate cancer will be diagnosed in 2016 and over 26,000 men will die of the disease. The major source of PSA (Prostate Specific Antigen) is the prostate gland and the PSA levels are therefore undetectable within 6 weeks after Radical Prostatectomy. Similarly, following Radiation Therapy, there is a gradual decline in PSA before reaching a post treatment nadir. A detectable PSA level after Radical Prostatectomy, or a rising PSA level following Radiation Therapy, is considered PSA failure or biochemical recurrence. The American Urological Association suggested that a PSA of 0.2 ng/mL or higher after Radical Prostatectomy, defines PSA failure or relapse. A PSA rise 2 ng/ml or more above post Radiation Therapy nadir is considered PSA failure or relapse. Approximately 35% of the patients with prostate cancer will experience PSA only relapse within 10 years of their primary treatment and a third of these patients will develop documented metastatic disease within 8 years following PSA only relapse. Rising PSA is therefore a sign of recurrent disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention for Hormone Sensitive Prostate Cancer. The appropriate time (immediate versus delayed) to start Androgen Deprivation Therapy in patients with prostate cancer with rising PSA, as the only sign of relapse, has remained unclear. This has been partly due to lack of patient accruals and patient reluctance to be randomized, in these clinical trials.

The authors conducted a randomized, prospective, phase III trial, to determine if immediate intervention with Androgen Deprivation Therapy (ADT) would improve Overall Survival (OS), compared with delayed ADT, in prostate cancer patients with PSA relapse, following previous attempted curative therapy (radiotherapy or surgery with or without postoperative radiotherapy) or in those considered not suitable for curative treatment (because of age, comorbidity or locally advanced disease). This analysis combined prostate cancer patients with PSA relapse enrolled in two separate studies. Two hundred and ninety three (N=293) eligible patients were randomly assigned 1:1 to immediate Androgen Deprivation Therapy (N= 142) or delayed ADT (N=151). The primary endpoint was Overall Survival. Secondary endpoints included Cancer-Specific Survival and Time to Clinical Progression. The median follow up was 5 years.

There was a statistically significant improvement in the Overall Survival, with a 45% reduction in the risk for death, for those receiving immediate ADT compared with the delayed treatment group (HR=0.55; P=0.05). Further, with immediate ADT, there was a statistically significant delay in the time to first local progression (HR= 0.51; P=0.001).

The authors concluded that immediate Androgen Deprivation Therapy significantly improved Overall Survival and Time to Clinical Progression for prostate cancer patients with PSA relapse, following immediate intervention with Androgen Deprivation Therapy. This benefit however must be weighed against the risks associated with long term Androgen Deprivation Therapy. Immediate ADT may be appropriate for patients with high risk features at the time of initial diagnosis, who present with early biochemical relapse after initial treatment and have a rapid PSA doubling time (less than 6 months). Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial. Duchesne GM, Woo HH, Bassett JK, et al. Lancet Oncol 2016;17:727-737