Category: Meeting Updates

FDA Approves KISQALI® for First-Line Treatment of Hormone Receptor Positive Advanced Breast cancer

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SUMMARY: The FDA on March 13, 2017 approved KISQALI® (Ribociclib), a cyclin-dependent kinase 4/6 inhibitor, in combination with an Aromatase Inhibitor, as initial endocrine-based therapy for the treatment of postmenopausal women with Hormone Receptor (HR)-positive, Human Epidermal growth factor Receptor 2 (HER2)-negative advanced or metastatic breast cancer. Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop breast cancer during their life time. Approximately, 255,180 new cases of breast cancer will be diagnosed in 2017 and 41,070 women will die of the disease. Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients.

Cyclin Dependent Kinases (CDK) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. Cyclin Dependent Kinases 4 and 6 (CDK4 and CDK6), phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity and phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in hormone receptor positive breast cancer, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. The understanding of the role of Cyclin Dependent Kinases in the cell cycle, has paved the way for the development of CDK inhibitors.

KISQALI® is an orally bioavailable, selective, small-molecule inhibitor of CDK4/6 that blocks the phosphorylation of RetinoBlastoma protein, thereby preventing cell-cycle progression and inducing G1 phase arrest. In a phase 1b study involving postmenopausal women with ER positive, HER2-negative advanced breast cancer, KISQALI® in combination with FEMARA® (Letrozole) demonstrated an Overall Response Rate (ORR) of 46% and a Clinical Benefit Rate of 79%, in treatment-naïve patients with advanced breast cancer.

MONALEESA-2 trial is a randomized, double-blind, placebo-controlled, phase III study in which 668 patients were randomly assigned in a 1:1 ratio to receive either KISQALI® plus FEMARA® (Letrozole) or placebo plus FEMARA®. Eligible patients included post-menopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer who had received no prior therapy for advanced disease. Treatment consisted of oral KISQALI® 600 mg daily on a 3-weeks on and 1-week off schedule, in 28-day treatment cycles plus FEMARA® 2.5 mg orally daily on a continuous schedule or placebo plus FEMARA®. Patients were stratified according to the presence or absence of liver or lung metastases and treatment was continued until disease progression or unacceptable toxicity. No treatment crossover was allowed. The median age was 62 years and close to 60% of the patients had visceral metastases. The primary end point was Progression Free Survival (PFS) and secondary end points included Overall Survival (OS), Overall Response Rate (ORR), Clinical Benefit Rate (Overall Response plus stable disease lasting 24 weeks or more), safety, and Quality of Life assessments.

A pre-planned interim efficacy analysis demonstrated a significant improvement in the PFS amongst the KISQALI® group compared to the placebo group (HR=0.56; P<0.0001). The median duration of follow-up was 15.3 months. The estimated median PFS had not been reached in the KISQALI® group and was 14.7 months in the placebo containing arm. The Overall Response Rate (ORR) in patients with measurable disease was 52.7% in the KISQALI® group and 37.1% in the placebo plus FEMARA® group (P<0.001). Overall Survival data was mature at the time of this analysis. The rates of discontinuation because of adverse events were 7.5% in the KISQALI® group and 2.1% in the placebo group. The most common adverse reactions observed in patients taking KISQALI® were myelosuppression, nausea, vomiting, diarrhea and fatigue, as well as abnormal liver function tests. KISQALI® has been shown to prolong the QT interval in a dose-dependent manner and prolongation of the QT interval occurred in 3.3% of patients treated at the 600 mg dose, with changes mostly occurring within the first 4 weeks of treatment.

The authors concluded that among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the addition of KISQALI® to FEMARA® significantly prolonged PFS compared to FEMARA® alone, with a higher rate of myelosuppression noted in the KISQALI® group. Ribociclib as First-Line Therapy for HR-positive, Advanced Breast Cancer. Hortobagyi GN, Stemmer SM, Burris HA, et al. N Engl J Med 375:1738-1748, 2016.

FDA Approves IMBRUVICA® for Marginal Zone Lymphoma

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SUMMARY: The FDA on January 18, 2017 granted accelerated approval to IMBRUVICA® (Ibrutinib) for the treatment of patients with Marginal Zone Lymphoma (MZL), who require systemic therapy and have received at least one prior anti-CD20 based therapy. The American Cancer Society estimates that in 2017, about 72,240 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,140 individuals will die of this disease. Indolent Non Hodgkin Lymphomas are mature B-cell lymphoproliferative disorders and include Follicular Lymphomas, Small Lymphocytic Lymphomas (SLL), LymphoPlasmacytic Lymphomas (LPL) and Marginal Zone Lymphoma subtypes such as Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL)/Mucosa-Associated Lymphoid Tissue (MALT) lymphoma and Splenic Marginal Zone Lymphoma (SMZL). Marginal Zone Lymphoma is an indolent B-cell lymphoma originating in the lymph nodes as well as in organs including the stomach, salivary glands, thyroid gland, lungs and spleen. It accounts for approximately 10% of all cases of Non Hodgkin Lymphomas (NHL) in adults and is often linked to chronic infection. When treatment is indicated, patients are often treated with a RITUXAN® (Rituximab) based regimens with improved outcomes. Relapses however are common and there is presently no therapy, specifically approved for the treatment of Marginal Zone Lymphoma.

Normal B-cell activation and proliferation is dependent on B-Cell Receptor (BCR) signaling. This signaling is also important for initiation and progression of B-cell lymphoproliferative disorders. Bruton’s Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Following binding of antigen to the B-Cell Receptor, kinases such as Syk (Spleen Tyrosine Kinase), Lyn (member of the Src family of protein tyrosine kinases) and BTK (Bruton’s Tyrosine Kinase) are activated, with subsequent propagation through PI3K/Akt, MAPK, and NF-κB pathways. This results in B-cell activation and proliferation. IMBRUVICA® (Ibrutinib) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. IMBRUVICA® is presently approved by the FDA for the treatment of patients with Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma including those with del-17p, patients with Mantle Cell Lymphoma who had received at least one prior therapy, and patients with Waldenstrom’s Macroglobulinemia.

The approval of IMBRUVICA®, in MZL was based on results from a multicenter, open-label, single-arm, phase II trial, in which the safety and efficacy of IMBRUVICA® was evaluated in 63 patients with Marginal Zone Lymphoma. Enrolled patients had previously received one or more prior therapies including at least one anti-CD20 targeted monoclonal antibody -containing regimen or monotherapy RITUXAN®. The subtypes of Marginal Zone Lymphomas included, Extra Nodal MZL (N=32), Nodal MZL (N=17) and Splenic MZL (N=14). The median number of prior systemic therapies was 2 and 35% of the enrolled patients had 3 or more prior therapies. Treatment consisted of IMBRUVICA® 560 mg orally once daily until progression or unacceptable toxicity. The primary study endpoint was Overall Response Rate (ORR). Secondary endpoints included Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS), and safety.

The Overall Response Rate as assessed by an independent review committee was 46%,of whom with 3.2% of patients had a Complete Response and 42.9% achieved a Partial Response. This benefit was observed across all three subtypes of Marginal Zone Lymphomas (Overall Response Rate was 46.9%, 41.2%, and 50.0% for ENMZL/MALT, NMZL, and SMZL subtypes, respectively). The median time to response was 4.5 months and the median duration of response was not reached (range, 16.7 months – Not Reached). The most common adverse events were fatigue, diarrhea, cytopenias, nausea, peripheral edema, cough, arthralgia and dyspnea.

The authors concluded that single agent IMBRUVICA® achieved high Response Rates and durable responses in patients with Relapsed/Refractory Marginal Zone Lymphoma. IMBRUVICA® addresses an unmet need for previously treated Marginal Zone Lymphoma patients, who are in need of non-chemotherapy treatment options. Single-Agent Ibrutinib Demonstrates Efficacy and Safety in Patients with Relapsed/Refractory Marginal Zone Lymphoma: A Multicenter, Open-Label, Phase 2 Study. Noy A, de Vos S, Thieblemont C, et al. Presented at: ASH 2016 Annual Meeting and Exposition. Abstract 1213.

Chemoradiation Alone without Surgery does not Compromise Survival in Selected Patients with Rectal Cancer

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SUMMARY: The American Cancer Society estimates 39,910 new cases of Rectal Cancer will be diagnosed in the United States in 2017. Rectal cancer diagnosed at an early stage such as Stage II (T3-T4, N0) or Stage III (Node positive disease without distant metastases) is potentially curable and often treated with a combination of neoadjuvant (preoperative) chemoradiation and surgery and postoperative chemotherapy. Unlike colon cancer, the risk of locoregional recurrence is high in Rectal Cancer due to its close proximity to the surrounding pelvic organs and difficulty in obtaining a clear surgical margins. Further, there is no serosal tissue surrounding the rectum. For all these reasons, preoperative Radiation Therapy (RT) with concurrent Fluoropyrimidine based chemotherapy as a radiosensitizer, followed by postoperative chemotherapy, has been the standard intervention. Radiation consists of 45 Gy delivered in 25 fractions 5 days a week with a 5.4 Gy boost. Concurrent chemotherapy in the US has included 5-FU/Leucovorin, single agent 5-FU or single agent XELODA® (Capecitabine). Complete Response is seen in approximately 25% of the patients who receive chemoradiation. However, 15% to 25% of these patients develop local recurrence. Surgery following chemoradiation may result in long term complications and may necessitate temporary or permanent colostomy in addition to sexual and urinary dysfunction.

The International Watch & Wait Database Consortium was established in 2014 by EURECCA (the European Registration of Cancer Care) and the Champalimaud Foundation in Lisbon. This Consortium which includes 35 institutions in 11 countries was established mainly to collect all available data and expand knowledge on the benefits, risks and oncological safety of organ preserving strategies, in Rectal Cancer. This database as of August 2016 included 775 patients and majority of these patients had stage T2/3 disease (92%) with clinical N0/1 nodal status (75%). Ninety percent of these patients (N=679) had a clinical Complete Response following induction therapy with chemoradiation. These patients did not undergo surgery and were followed up for a median of 2.6 years.

It was noted that 25% of all patients had local recurrence and 84% of these occurred in the first 2 years of follow up. Local recurrence was endoluminal in 96% of the patients and in the loco-regional lymph nodes in 4%. Distant metastasis occurred in 7% of the patients. The 3-year Overall Survival rate was 91% among all patients, and was 87% for patients who experienced local recurrence. These findings are comparable to survival rates seen in patients with a Complete Response, who undergo standard surgery.

It was concluded that in this largest series of patients to date with Rectal Cancer, a “watch-and-wait” strategy to treating Rectal Cancer without surgery, following Complete Response to chemoradiation, resulted in outcomes comparable to historical controls. As more information is gathered, it is important that restaging be performed in all patients with Rectal Cancer who undergo chemoradiotherapy, to prevent unnecessary surgical procedures, and give patients the option for a watch-and-wait approach. The International Watch & Wait database (IWWD) for rectal cancer: An update. van der Valk M for the International Watch and Wait Database Consortium. J Clin Oncol 35, 2017 (suppl 4S; abstract 521)

Niraparib Maintenance Therapy Significantly Improves Progression Free Survival in Platinum-Sensitive Ovarian Cancer

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SUMMARY: It is estimated that in the United States, approximately 22,440 women will be diagnosed with ovarian cancer in 2017 and a little over 14,000 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 and the 5 year Overall Survival rate is about 20-30%. These patients are often treated with platinum based chemotherapy following primary surgical cytoreduction.

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 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers. They also account for 15 percent of ovarian cancers in addition to other cancers such as colon and prostate.

Homologous Recombination (HR) is an important pathway that allows repair of double-stranded DNA breaks and operates during the S and G2 phases of the cell cycle, relying on several proteins including BRCA1 and BRCA2. Deficiency of BRCA1 and BRCA2 results in non-functioning HR pathway (HR Deficiency), and other pathways then come in to play, which are less precise and error prone, resulting in the accumulation of additional mutations and chromosomal instability in the cell, with subsequent malignant transformation. Hereditary Epithelial Ovarian Cancer was thought to be caused almost exclusively by mutations in BRCA1 and BRCA2. It however now appears that about 50% of the high grade serous ovarian cancers have aberrations in HR repair pathway. 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, and loss of BRCA function due to frequent somatic aberrations in ovarian cancers likely deregulates 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 (HRD) have demonstrated sensitivity to PARP inhibitors. The two currently FDA approved PARP inhibitors include LYNPARZA® (Olaparib) for the treatment of ovarian cancer with gBRCA mutations after three lines of therapy and RUBRACA® (Rucaparib) for the treatment of ovarian cancer with gBRCA mutations and /or somatic mutations after two lines of therapy.

Niraparib is a highly selective PARP 1/2 inhibitor, that detects DNA damage and promotes its repair. Previously published studies demonstrated the antitumor activity of Niraparib in patients with ovarian cancer, at a maximum dose of 300 mg per day, with a low frequency of high grade adverse events. Based on this preliminary data, the authors conducted a randomized, placebo-controlled, phase III trial (ENGOT-OV16/NOVA) to evaluate the efficacy and safety of Niraparib versus placebo, as maintenance treatment in patients with platinum-sensitive, recurrent ovarian cancer.

This study enrolled two independent cohort of patients based on the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort), as determined on BRACAnalysis® testing (Myriad Genetics). All enrolled patients had tumors sensitive to platinum-based therapy and had received at least 2 lines of therapy. Enrolled patients (N=553) were randomly assigned in a 2:1 ratio to receive Niraparib 300 mg or placebo once daily. The gBRCA cohort included 203 patients (138 assigned to Niraparib and 65 to placebo) and the non-gBRCA cohort included 350 patients (234 assigned to Niraparib and 116 to placebo). The Primary end point was Progression Free Survival (PFS) and Secondary end points included chemotherapy-free interval, time to first subsequent therapy, Overall Survival and safety.

It was noted that patients in the Niraparib group had a significantly longer Progression Free Survival compared to those in the placebo group. In the gBRCA cohort, the PFS with Niraparib compared to placebo was 21.0 vs. 5.5 months (HR=0.27), in the non-gBRCA cohort for patients who had tumors with Homologous Recombination Deficiency (HRD), the PFS was 12.9 months vs. 3.8 months (HR=0.38) and for the overall non-gBRCA cohort, the PFS was 9.3 months vs. 3.9 months (HR=0.45). The P value was significant for all three comparisons (P<0.001). The most common grade 3 or 4 toxicities in the Niraparib group were thrombocytopenia (34%), anemia (25%), and neutropenia (20%), and this was managed with dose modifications.

The authors concluded that among patients with platinum-sensitive, recurrent ovarian cancer, Niraparib significantly prolonged Progression Free Survival compared to placebo and this benefit was achieved regardless of the presence or absence of gBRCA mutations or HRD status, with acceptable toxicities. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. Mirza MR, Monk BJ, Herrstedt J, et al. N Engl J Med 375:2154-2164, 2016

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