Guideline for Human Papilloma Virus Testing in Head and Neck Carcinomas

SUMMARY: The Centers for Disease Control and Prevention estimates that in the US, there are more than 16,000 cases of Human PapillomaVirus (HPV)-positive OroPharyngeal Squamous Cell Carcinoma (OPSCC) per year and there has been a signifiant increase in incidence during the past several decades. They represent approximately 70% of all OPSCC in the United States and Canada. Patients with HPV-positive OPSCC tend to be younger males, who are former smokers or nonsmokers, with risk factors for exposure to High Risk HPV (HR-HPV). The HPV-positive primary Squamous Cell Carcinoma tend to be smaller in size, with early nodal metastases, and these patients have a better prognosis compared with patients with HPV-negative Head and Neck Squamous Cell Carcinoma (HNSCC), when treated similarly. Expression of tumor suppressor protein, known as p16, is highly correlated with infection with HPV in HNSCC. Accurate HPV assessment in head and neck cancers is becoming important as it significantly impacts clinical management.Molecular-Characteristics-of-HPV-Positive-Head-and-Neck-Carcinomas

There is currently no consensus on when to test oropharyngeal squamous cell carcinomas for HPV/p16, and which tests to choose. The College of American Pathologists convened a panel of experts and following review of evidence from over 400 peer reviewed articles, came up with the following Guideline. This guideline is recommended for all new Oropharyngeal Squamous cell carcinoma patients, but not routinely recommended for other head and neck carcinomas.

Summary of Guideline Statements

1) High-Risk (HR) HPV testing should be performed on all patients with newly diagnosed OPSCC, including all histologic subtypes and may be performed on the primary tumor or a regional lymph node metastasis when the clinical findings are consistent with an oropharyngeal primary. This test should not be routinely performed on nonsquamous carcinomas of the oropharynx, or nonoropharyngeal primary carcinomas of the head and neck.

2) For oropharyngeal tissue specimens (ie, noncytology), HR-HPV testing should be performed by surrogate marker p16 ImmunoHistoChemistry (IHC). Additional HPV-specific testing may be done at the discretion of the pathologist and/or treating clinician, or in the context of a clinical trial.

3) HR-HPV testing by surrogate marker p16 IHC should be routinely performed on patients with metastatic Squamous Cell Carcinoma of unknown primary in a cervical upper or mid jugular chain lymph node. An explanatory note on the significance of a positive HPV result is recommended.

4) HR-HPV testing should be performed on head and neck FNA (Fine Needle Aspiration) Squamous Cell Carcinoma samples from all patients with known OPSCC not previously tested for HR-HPV, with suspected OPSCC, or with metastatic SCC of unknown primary.

5) Pathologists should report p16 IHC positivity as a surrogate for HR-HPV in tissue specimens (ie, noncytology) when there is at least 70% nuclear and cytoplasmic expression with at least moderate to strong intensity.

6) Pathologists should not routinely perform low-risk HPV testing on patients with head and neck carcinomas.

7) For HPV-positive/p16 cases, tumor grade (or differentiation status) is not recommended.

8) HR-HPV testing strategy should not be altered based on patient smoking history.

9) Pathologists should report primary OPSCCs that test positive for HR-HPV or its surrogate marker p16 as HPV positive and/or p16 positive

Human Papillomavirus Testing in Head and Neck Carcinomas: Guideline From the College of American Pathologists. Lewis JS, Beadle B, Bishop JA, et al.

OPTUNE® Together with Temozolomide Significantly Improves Overall Survival in Newly Diagnosed Glioblastoma

SUMMARY: Glioblastoma Multiforme (GBM)) is the most common malignant tumor of the central nervous system in adults and originates in astrocytes which are specialized glial cells. It is estimated that approximately 12,500-18,000 new cases of GBM are diagnosed annually in the United States. The most frequent location for GBM is cerebral hemispheres and 95% of these tumors arise in supratentorial region. The etiology remains unclear and genetic predisposition has been observed in only 5-10 % of cases. GBM can be primary when arising de novo without clinical and histological evidences of a precursor lesion or secondary when they progress slowly from preexisting lower-grade astrocytoma. Primary GBMs are associated with hallmark genetic alterations and they include Epidermal Growth Factor Receptor (EGFR) gene mutation and amplification, over expression of Mouse Double Minute 2 (MDM2), deletion of p16 and Loss of Heterozygosity (LOH) of chromosome 10q holding Phosphatase and Tensin homolog (PTEN) and TERT promoter mutation.

GBM is not curable and management includes maximal safe debulking of the tumor followed by concurrent chemoradiation and then adjuvant chemotherapy. Current chemotherapy agents with FDA approval for treatment of GBM include Temozolomide, Bevacizumab (AVASTIN®), Lomustine (GLEOSTINE®), Carmustine (BiCNU®) and Carmustine Implant (GLIADEL® Wafer for intraoperative implantation). The median survival for GBM patients from diagnosis, with the current therapies, is about 15 months.Mechanism-of-Action-of-Tumor-Treating-Fields

Tumor-Treating Fields (TTFields) delivery system (OPTUNE®) is a novel external therapeutic device that slows and reverses tumor growth by inhibiting mitosis. The battery operated-TTF delivery system generates low intensity, intermediate frequency, alternating electrical fields to the brain. These electrical fields exert selective toxicity in dividing cells by interfering with organelle assembly in the cell and thereby facilitates apoptosis (programmed cell death), by preventing cell division. The non-dividing cells are not affected by these electrical fields. Tumor Treating Fields (TTFields) delivery system, OPTUNE®, along with Temozolomide is presently approved by the FDA for the treatment of adult patients with newly diagnosed, supratentorial Glioblastoma (GBM) following maximal debulking surgery and radiation with concurrent chemotherapy. It is also approved for the treatment of recurrent GBM as a monotherapy, after surgical and radiation options have been exhausted. Insulated ceramic discs (transducer arrays) are placed directly on the scalp and held by adhesive bandages. They deliver the electrical fields after they are connected to the TTFields delivery system, OPTUNE®. Patients wear the device for at least 18 hours a day and for at least four weeks.OPTUNE-is-Local-Delivery-System-and-Temozolomide-is-Systemic-Therapy

Previously published studies had shown that TTFields, in addition to its antimitotic effect on the dividing cell, can augment response to alkylator-based chemotherapy. These durable responses were sometimes delayed after an initial progression, and there was a high correlation between treatment compliance and survival. The EF-14 trial is a randomized, multicenter, open-label, phase III study, in which 695 patients with newly diagnosed grade IV GBM, who had completed standard treatment with surgery (resection or biopsy) and concurrent chemoradiation with Temozolomide, were randomized within 7 weeks of their last radiation dose, in a 2:1 ratio to TTFields plus maintenance Temozolomide chemotherapy (N=466) or Temozolomide alone (N=229). The TTFields, consisted of low-intensity, 200 kHz frequency, alternating electric fields and was delivered 18 hours/day or more, via 4 transducer arrays on the shaved scalp and connected to a portable device. Temozolomide was administered to both treatment groups at 150-200 mg/m2 PO for 5 days per 28 day cycle for 6-12 cycles. Patients had a Karnofsky Performance Score of 70 or more, with supratentorial tumor location and non-progressive disease. Patients were excluded if the tumor location was infratentorial and if there was evidence of increased intracranial pressure. The median age was 56 years, and majority of the patients were male. The Primary endpoint was Progression Free Survival (PFS) and the Secondary endpoint was Overall Survival (OS).

A preliminary report from this trial was published in 2015 and the authors now report the results of their final analysis. The median PFS from randomization was 6.7 months in the TTFields plus Temozolomide group and 4.0 months in the Temozolomide alone group (HR=0.63; P<0.001). The median OS was 20.9 months in the TTFields plus Temozolomide group versus 16.0 months in the Temozolomide alone group (HR=0.63; P< 0.001). This meant a 37% improvement in PFS and OS for patients who received TTFields plus Temozolomide compared to patients who received Temozolomide alone. The statistically significant benefit of TTFields with Temozolomide on Overall Survival, was seen in all pre-specified patient subgroups, regardless of prognostic factors such as age, performance status, MGMT promotor methylation and extent of resection. Mild to moderate skin toxicity underneath the transducer arrays occurred in 52% of patients in the TTFields plus Temozolomide group.

The authors concluded that the results in the final analysis were consistent with the previous interim analysis results, and for GBM patients who had received standard chemoradiation therapy, the addition of TTFields to maintenance Temozolomide chemotherapy, resulted in statistically significant improvement in PFS and OS, compared with maintenance Temozolomide alone. This is the first positive phase III trial in newly diagnosed GBM, since the efficacy of Temozolomide was established in 2005. Stupp R, Tailibert S, Kanner A, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: A randomized clinical trial. JAMA. 2017;318:2306-2316

LYNPARZA® (Olaparib)

The FDA on January 12, 2018, granted regular approval to LYNPARZA® tablets, a poly (ADP-ribose) polymerase (PARP) inhibitor, for the treatment of patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer, who have been treated with chemotherapy either in the neoadjuvant, adjuvant, or metastatic setting. LYNPARZA® is a product of AstraZeneca Pharmaceuticals LP.

FDA Approves LYNPARZA® for Germline BRCA-Mutated Metastatic Breast Cancer

SUMMARY: The FDA on January 12, 2018, granted regular approval to LYNPARZA® (Olaparib), a Poly ADP-Ribose Polymerase (PARP) inhibitor, for the treatment of patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer, who have been treated with chemotherapy either in the neoadjuvant, adjuvant, or metastatic setting. This is the first FDA-approved treatment for patients with gBRCAm HER2-negative metastatic breast cancer. Patients with Hormone Receptor (HR) positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine treatment. Patients must be selected for therapy based on an FDA-approved companion diagnostic for LYNPARZA®.

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, 266,120 new cases of invasive breast cancer are expected to be diagnosed in 2018 and about 40,920 women are expected to die of the disease. DNA can be damaged due to errors during its replication or as a result of environmental exposure to ultraviolet radiation from the sun or other toxins. The tumor suppressor genes such as BRCA1 (Breast Cancer 1) and BRCA2 help repair damaged DNA and thus play an important role in maintaining cellular genetic integrity, failing which these genetic aberrations can result in malignancies. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. 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. These mutations can be inherited from either of the parents and a child has a 50 percent chance of inheriting this mutation and the deleterious effects of the mutations are seen even when an individual’s second copy of the gene is normal.Mechanism-of-Action-of LYNPARZA

The PARP (Poly ADP Ribose Polymerase) family of enzymes, which include PARP1 and PARP2 repair damaged DNA. LYNPARZA® is a PARP enzyme inhibitor that causes cell death in tumors that already have a DNA repair defect, such as those with BRCA1 and BRCA2 mutations. The FDA approved LYNPARZA® in 2014 as monotherapy for the treatment of patients with deleterious or suspected deleterious germline BRCA mutated advanced ovarian cancer.

The present approval was based on data from OlympiAD, a randomized, open-label, phase III study that evaluated the efficacy and safety of LYNPARZA® compared with physician’s choice of standard single agent chemotherapy, in patients with HER2-negative metastatic breast cancer, with inherited, germline BRCA mutations. In this study, 302 patients were randomized in a 2:1 ratio to receive LYNPARZA® tablets 300 mg PO BID (N=205) or physician’s choice of standard chemotherapy (N=97). The later included 21-day cycles of either XELODA® (Capecitabine) 2500 mg/m2 orally on days 1-14, NAVELBINE® (Vinorelbine) 30 mg/m2 IV days 1 and 8 or HALAVEN® (Eribulin)1.4 mg/m2 IV days 1 and 8. Treatment was continued until disease progression or unacceptable toxicity. The median age was 44 years, and all patients had received prior chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients in this study were stratified based on prior use of chemotherapy for metastatic disease, Hormone Receptor status (HR positive versus triple negative), and previous use of platinum-based chemotherapy. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), time to second progression or death, Objective Response Rate (ORR) and effect on health-related Quality of Life.

At a median follow up of about 14 months, the median PFS was 7 months in the LYNPARZA® group versus 4.2 months with standard chemotherapy (HR=0.58; P=0.0009), suggesting a 42% reduced risk of cancer progression in the LYNPARZA® group compared to those who received chemotherapy. Following disease progression, the time to second progression (which meant duration of time before the cancer worsened again), was also longer in the LYNPARZA® group (HR 0.57), suggesting that recurrent disease was not more aggressive following progression on LYNPARZA®. The ORR was 60% and 29% in LYNPARZA® and chemotherapy groups respectively. Severe side effects were more common in chemotherapy treated patients (50%) compared with LYNPARZA® group (37%). The most common side effects in the LYNPARZA® group included nausea, fatigue and cytopenias, whereas rash on hands and feet were most common in the chemotherapy group.

The authors concluded that LYNPARZA® monotherapy significantly improved Progression Free Survival in HER2-negative metastatic breast cancer patients, with inherited germline BRCA mutations, compared to standard chemotherapy. This “proof of the principle” study demonstrated that breast cancers with defects in a specific DNA damage repair pathway are sensitive to targeted therapy and this is the first of several phase III studies with PARP inhibitors that are underway. OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm). Robson ME, Im S-A, Senkus E, et al. J Clin Oncol 35, 2017 (suppl; abstr LBA4).

KEYTRUDA® Doubles Overall Survival Compared with Chemotherapy in Advanced NSCLC

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers. The American Cancer Society estimates that for 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 patients will die of the disease. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers.

KEYTRUDA® is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor (immune checkpoint protein) and blocks its interaction with ligands PD-L1 and PD-L2. This leads to the undoing of the PD-1 pathway-mediated inhibition of the immune response and the tumor-specific effector T cells are unleashed. 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®.Unleashing-T cell-Function-with-KEYTRUDA-in-Advanced-Lung-Cancer

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. Patients in the chemotherapy group who experienced disease progression were allowed to cross over to the KEYTRUDA® group. The primary end point was Progression Free Survival (PFS) and secondary end points included Overall Survival (OS), Objective Response Rate (ORR) and safety.

It was previously reported that at a median follow up of 11.2 months, the median PFS was 10.3 months in the KEYTRUDA® group versus 6 months in the chemotherapy group (HR=0.50; P<0.001). However, median OS had not been reached in the KEYTRUDA® group at the time of that analysis. This publication is an updated analysis of the KEYNOTE-024 study, after a median follow-up of 25.2 months. Eighty two patients (N=82) assigned to chemotherapy, met criteria to cross over to the KEYTRUDA® group, upon progression. The median OS was 30 months in the KEYTRUDA® group and 14.2 months in the chemotherapy group (HR=0.63). Further, more patients in the KEYTRUDA® group achieved 12-month OS (70.3% vs. 54.8%) and an ORR response (45.5% vs. 29.8%), compared to the chemotherapy group. The ORR among patients who crossed over to KEYTRUDA®, was 20.7%. The median Duration of Response has not yet been reached for patients assigned to KEYTRUDA® and also for those who crossed over to KEYTRUDA®. For those assigned chemotherapy, the median Duration of Response was 7.1 months. Patients in the KEYTRUDA® group had lower rates of grade 3 to 5 adverse events compared to those in the chemotherapy group (31.2% vs 53.3%), as well as a lower rate of any-grade adverse events (76.6% vs 90%).

It was concluded that first-line treatment with KEYTRUDA® resulted in a significantly longer median OS with lower rates of Adverse Events, when compared to chemotherapy, among patients with metastatic NSCLC and high PD-L1 expression. Brahmer JR, Rodriguez-Abreu D, Robinson A, et al. Updated analysis of KEYNOTE-024: pembrolizumab vs platinum-based chemotherapy for advanced NSCLC with PD-L1 TPS>50%. Presented at: International Association for the Study of Lung Cancer 18th World Conference on Lung Cancer; Yokohama, Japan: October 15-18, 2017. Abstract OA 17.06.

FDA Approves OPDIVO® for Adjuvant Treatment of Malignant Melanoma

The FDA on December 20, 2017, granted regular approval to the anti-PD1 monoclonal antibody, OPDIVO® (Nivolumab) for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or in patients with metastatic disease who have undergone complete resection. The approved adjuvant therapies over the past two decades, for patients with high-risk melanoma have included high-dose INTRON® A (Interferon alfa-2b), SYLATRON® (peginterferon alfa-2b), and high-dose YERVOY® (Ipilimumab). The significant toxicities associated with these adjuvant interventions, precluded the wide spread use of adjuvant therapy in high risk melanoma.

OPDIVO® is a less toxic, better tolerated, adjuvant treatment option than YERVOY®, for patients with resected stage IIIB/C and IV melanoma, regardless of BRAF mutation. The Recurrence Free Survival rate at 18 months with OPDIVO® was 66.4% compared with 52.7% for YERVOY® and this meant a 35% reduction in the risk of recurrence or death with the OPDIVO® versus YERVOY®.  This will fulfill the unmet need  for adjuvant therapies, with improved benefit-risk ratio, for this patient group.

Late Breaking Abstract – ASH 2017 VENCLEXTA® plus RITUXAN® Superior to Bendamustine plus RITUXAN® in patients with Relapsed/Refractory Chronic Lymphocytic Leukemia

SUMMARY: The American Cancer Society estimates that for 2018, about 20,940 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4,510 patients will die of the disease. CLL accounts for about 25% of the new cases of leukemia and the average age at the time of diagnosis is around 71 years. B-cell CLL is the most common type of leukemia in adults.

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by CLL cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death). VENCLEXTA® (Venetoclax) is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. The FDA granted an accelerated approval to VENCLEXTA® in 2016, for the treatment of patients with CLL with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy.VENCLEXTA plus RITUXAN for CLL

MURANO trial is an open-label, international, multicenter, phase III study which included 389 patients with relapsed/refractory CLL who had received 1-3 prior lines of therapy, including at least one chemotherapy regimen. Patients were randomized 1:1 to receive a combination of either VR – VENCLEXTA® plus RITUXAN® (N=194) or BR – Bendamustine plus RITUXAN® (N=195). In the VR group, VENCLEXTA® tablets were given once daily with a weekly dose ramp-up schedule (20 mg for 1 week, followed by 1 week at each dose level of 50 mg, 100 mg, and 200 mg and then the recommended daily dose of 400 mg), over a period of 5 weeks, given along with Tumor Lysis Syndrome prophylaxis. Patients were treated with the 400 mg daily dosing for a maximum of 2 yrs or until disease progression. RITUXAN® (Rituximab) was given beginning week 6, and was administered at 375 mg/m2 on day 1, cycle 1, followed by 500 mg/m2 on day 1 of cycles 2 thru 6, of a 28 day cycle. In the BR group, Bendamustine was given at 70 mg/m2 on days 1 and 2 of each 28 day cycle for a total of 6 cycles along with RITUXAN®, using the same RITUXAN® dosing schedule as in the VR group. Patients were stratified based on del(17p) status and responsiveness to prior therapy. The median age was 65 years, 26% of the patients had del(17p) and 15% of the patients were refractory to Fludarabine. The Primary end point was Progression Free Survival (PFS) and Secondary end points included Overall Survival (OS), Overall Response Rate (ORR) and Complete Response (CR). The median follow up was 23.8 months.

Following recommendation from the Independent Data Monitoring Committee, the study arms were unblinded before the preplanned interim analysis. It was noted that the PFS was significantly superior in the VR group compared to BR (HR=0.17, P<0.0001; median Not Reached versus 17.0 months). This meant an 83% reduction in the risk of disease progression or death in the VR group compared with the BR group. The 24 month PFS estimates were 84.9% vs 36.3%, respectively favoring VENCLEXTA®. This PFS benefit was consistently seen in all subgroups assessed, including those with del(17p), p53 mutation and IgVH unmutated status. The ORR in the VR group was 93.3% versus 67.7% in the BR group (P<0.0001) and CR was achieved in 26.8% versus 8.2% of patients respectively. The rate of MRD (Minimal Residual Disease)-negativity, defined as less than 1 CLL cell in 10,000 leukocytes, attained at any time, was also higher with VR at 83.5% versus 23.1% with BR. Further, the MRD negativity was more durable in the VENCLEXTA® group. Overall Survival evaluation is ongoing. Grade 3/4 neutropenia was higher in VR group but there was no increase in febrile neutropenia or Grade 3/4 infection.

It was concluded from this primary analysis of MURANO trial that, VENCLEXTA® in combination with RITUXAN® resulted in a significant improvement in Progression Free Survival, Overall Response Rate, Complete Response rate, along with durable improvement in peripheral blood MRD negativity, when compared with Bendamustine and RITUXAN®, in patients with relapsed/refractory CLL. Venetoclax Plus Rituximab Is Superior to Bendamustine Plus Rituximab in Patients with Relapsed/ Refractory Chronic Lymphocytic Leukemia – Results from Pre-Planned Interim Analysis of the Randomized Phase 3 Murano Study. Seymour JF, Kipps TJ, Eichhorst BF, et al. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta, Georgia. Abstract LBA-2.

Late Breaking Abstract – ESMO 2017 FDA Approves OPDIVO® for Adjuvant Treatment of Malignant Melanoma

SUMMARY: The FDA on December 20, 2017, granted regular approval to the anti-PD1 monoclonal antibody, OPDIVO® (Nivolumab) for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or in patients with metastatic disease who have undergone complete resection. OPDIVO® was previously approved for the treatment of patients with unresectable or metastatic melanoma. It is estimated that in the US, approximately 91,270 new cases of melanoma will be diagnosed in 2018 and about 9,320 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades. Stage III malignant melanoma is a heterogeneous disease and the risk of recurrence is dependent on the number of positive nodes as well as presence of palpable versus microscopic nodal disease. Further, patients with a metastatic focus of more than 1 mm in greatest dimension in the affected lymph node, have a significantly higher risk of recurrence or death than those with a metastasis of 1 mm or less. Patients with stage IIIA disease have a disease-specific survival rate of 78%, whereas those with stage IIIB and stage IIIC disease have a disease specific survival rates of 59% and 40% respectively.Adjuvant OPDIVO for Melanoma

Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. Immune checkpoint proteins (“gate keepers”) suppress antitumor immunity. Antibodies targeting these, 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), etc., block the Immune checkpoint proteins and unleash T cells, resulting in T cell proliferation, activation and a therapeutic response.

The approved adjuvant therapies over the past two decades, for patients with high-risk melanoma have included high-dose INTRON® A (Interferon alfa-2b), SYLATRON® (peginterferon alfa-2b), and high-dose YERVOY® (Ipilimumab). The significant toxicities associated with these adjuvant interventions, precluded the wide spread use of adjuvant therapy in high risk melanoma. YERVOY® was approved by the FDA for the adjuvant treatment of patients with completely resected, Stage III melanoma, based on an improvement in Relapse Free Survival, when compared to placebo, in a randomized phase III trial. In this study however, over 50% of the patients treated with the recommended high dose YERVOY® experienced grade 3/4 toxicities. There is therefore an unmet need for adjuvant therapies, with improved benefit-risk ratio, for this patient group.

OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that targets PD-1 receptor. Monotherapy with OPDIVO®, in heavily pretreated advanced Melanoma patients can result in more than a third of patients (34%) being alive, 5 years after starting treatment. The present approval by the FDA was based on CheckMate 238 trial, which is a double-blind, phase III study that included 906 patients with completely resected, Stage IIIB/C or Stage IV melanoma. Patients were randomized in a 1:1 ratio to receive either OPDIVO® 3 mg/kg IV, every 2 weeks (N=453) or YERVOY® 10 mg/kg IV, every 3 weeks (N=453) for 4 doses, then every 12 weeks beginning at week 24, for up to 1 year. Both treatment groups were well balanced. The Primary end point was Recurrence Free Survival (RFS).

The Recurrence Free Survival rate at 18 months with OPDIVO® was 66.4% compared with 52.7% for YERVOY® (HR=0.65; P<0.0001). This meant a 35% reduction in the risk of recurrence or death with the OPDIVO® versus YERVOY®. The most common adverse reactions were headache, fatigue, nausea, diarrhea, abdominal discomfort, rash, pruritus and musculoskeletal pain. OPDIVO® was associated with significantly fewer treatment-related grade 3/4 toxicities compared to YERVOY® (14% versus 46%). Treatment was discontinued due to toxicities in approximately 10% of the patients in the OPDIVO® group, compared with 42% of patients in the YERVOY® group.

The authors concluded that OPDIVO® is a less toxic, better tolerated, adjuvant treatment option than YERVOY®, for patients with resected stage IIIB/C and IV melanoma, regardless of BRAF mutation, with a superior Relapse Free Survival rate. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: a randomized, double-blind, phase 3 trial (CheckMate 238). Presented at ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA8_PR.

Recombinant Hyaluronidase Significantly Improves Progression Free Survival in Metastatic Pancreatic Cancer

SUMMARY: The American Cancer Society estimates that in 2017, about 53,670 people will be diagnosed with pancreatic cancer in the United States and about 43,090 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. 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. The FDA approved ABRAXANE® ((Paclitaxel albumin-bound particles) for use, in combination with GEMZAR® (Gemcitabine), for the first line treatment of patients with metastatic adenocarcinoma of the pancreas. This approval was based on the demonstration of improved Overall Survival (OS) and Progression Free Survival (PFS) with this combination, when compared to single agent GEMZAR®, in a multicenter, international, open-label, randomized trial (MPACT study).

PEGPH20 is a PEGylated form of recombinant human Hyaluronidase, for the potential systemic treatment of tumors that accumulate Hyaluronan (HA). PEGPH20 is an enzyme that temporarily degrades Hyaluronan, a dense component of the tumor microenvironment that can accumulate in higher concentrations around certain cancer cells and potentially constrict blood vessels and there by impede treatment access to tumor tissue. It is estimated that 35% to 40% of patients with pancreatic cancer have high expression of Hyaluronan and this biomarker may predict response to PEGPH20.

HALO-202 is a phase 2 multicenter, randomized clinical trial, in which PEGPH20 in combination with ABRAXANE® and GEMZAR® (N=166) – PAG, was compared with ABRAXANE® and GEMZAR® – AG (N=113), in treatment-naive patients, with metastatic pancreatic carcinoma. In this study, following enrollment of 146 patients in the first stage of the trial, the study was placed on hold to address concerns regarding thromboembolic events, in the group receiving PEGPH20. The protocol was amended to exclude those at high risk for a thromboembolic event and prophylaxis with Low Molecular Weight Heparin was required. One hundred thirty-three patients (N=133) were enrolled into the second stage of the trial for a total of 279 patients. Patients enrolled in stage 2 received Low Molecular Weight Heparin at a starting dose of 40 mg/day or 1 mg/kg/day, to prevent thromboembolic events. Each 4-week treatment cycle consisted of 3 weekly treatments and 1 week off. PEGPH20 was administered at 3 µg/kg twice weekly for cycle 1 followed by weekly administration in subsequent cycles. ABRAXANE® and GEMZAR® were administered weekly at their standard FDA-approved doses of 125 mg/m2 and 1,000 mg mg/m2 respectively. Tumor biopsy samples for the Hyaluronan analysis were available for 138 patients treated with PEGPH20 and 79 patients treated in the control group, across both stages of the study. Overall, 49 patients in the PEGPH20 arm and 35 in the control group had Hyaluronan expression of 50% or more. The Primary endpoint of the study was Progression Free Survival (PFS) across the entire treatment group. Following change in the treatment protocol, a second Primary endpoint was added to assess thromboembolic event rate. Secondary endpoints included Objective Response Rate, PFS by Hyaluronan level, and Overall Survival. The second stage of this study was also utilized to validate a companion diagnostic for Hyaluronan (HA) levels.

It was noted that across the overall study population, there was a statistically significant increase in Progression Free Survival (PFS) in the PEGPH20 group compared to the control group (6 months versus 5.2 months; HR=0.73; P=0.49). In patients with high levels of Hyaluronan (HA-High), the PFS was 9.2 months among those treated with PEGPH20 plus ABRAXANE® and GEMZAR® versus 5.2 months among patients receiving ABRAXANE® and GEMZAR® alone (HR = 0.51, P = 0.048). The additional Primary endpoint of a reduction in the rate of thromboembolic events was achieved, in the PEGPH20 group. Across all patients, thromboembolic events were experienced by 14% of those in the PEGPH20 group versus 10% of those in the ABRAXANE® and GEMZAR® group. These events were lower in those receiving Low Molecular Weight Heparin at 1 mg/kg/day dose versus 40 mg/day (6% vs 10%, respectively). The most common adverse events were cytopenias.

The authors concluded that the addition of PEGPH20 to ABRAXANE® and GEMZAR® resulted in significant improvement in Progression Free Survival compared with ABRAXANE® plus GEMZAR® alone, in treatment naïve patients with advanced pancreatic cancer. Patients with high levels of expression of the biomarker Hyaluronan, had the best outcomes suggesting that a biopsy-based biomarker for hyaluronan content can potentially identify patients who will have a meaningfully greater response when PEGPH20 is added to standard chemotherapy. A phase III study is underway, evaluating PEGPH20 in combination with ABRAXANE® and GEMZAR® in patients with metastatic pancreatic cancer, with high Hyaluronan levels. HALO 202: Randomized Phase II Study of PEGPH20 Plus Nab-Paclitaxel/Gemcitabine Versus Nab-Paclitaxel/Gemcitabine in Patients With Untreated, Metastatic Pancreatic Ductal Adenocarcinoma. Hingorani SR, Zheng L, Bullock AJ, et al. DOI: 10.1200/JCO.2017.74.9564 Journal of Clinical Oncology – published online before print December 12, 2017

A Potential Cure for Hemophilia Using Gene Therapy

SUMMARY: Hemophilia A is an X-linked, recessive bleeding disorder caused by mutations in the gene encoding coagulation Factor VIII, resulting in deficiency of functional plasma clotting Factor VIII (FVIII). Hemophilia A can also arise from spontaneous mutation in the gene encoding coagulation Factor VIII. Patients with severe Hemophilia A (Factor VIII activity level less than 1 IU/dl) are at a high risk for spontaneous bleeding in joints and soft tissue, resulting in painful disabling arthropathy as well as increased risk of intracranial hemorrhage and early death. These patients often are on prophylactic Factor VIII therapy and may also require on-demand therapy with Factor VIII for breakthrough bleeding. In spite of the availability of Factor VIII concentrates with extended half-life, patients still require frequent infusions, to maintain adequate hemostasis. This can have a negative impact on quality of life and additionally can result in the development the alloantibodies (inhibitors) that can neutralize the effect of exogenously administered replacement clotting factors.Gene Therapy

Gene therapy enables the introduction of a normal copy of the gene into the cells and thereby restores the function of the abnormal or missing protein. Because a gene cannot be inserted directly into a cell, a carrier called a vector is genetically engineered to deliver the gene. Majority of gene therapy clinical trials employ viruses as vectors, as these viruses are able to deliver the new gene by infecting the cell and hijacking the cellular machinery for propagation. The viruses are modified to prevent them from causing disease. As vectors, the most extensively studied viruses are Retroviruses, Adenoviruses and Adeno-Associated Viruses (AAVs). Retroviruses integrate their genetic material (including the new gene) into a chromosome in the human cell, whereas Adenoviruses introduce their DNA into the nucleus of the cell, but the DNA is not integrated into a chromosome. The vector can be injected directly into a specific tissue in the body or given intravenously. Alternately, a sample of the patient’s cells can be exposed to the vector in the lab and the cells containing the vector can then be given back to the patient. If the treatment is successful, the new gene delivered by the vector, will start making a functioning protein.

The authors in this study developed AAV5-hFVIII-SQ (valoctocogene roxaparvovec), an AAV serotype 5 vector, in order to overcome specific challenges such as the large size of the Factor VIII coding region and inefficient expression of the human Factor VIII coding sequence. They then conducted a dose-escalation study involving nine patients. Eligible patients were adults with severe Hemophilia A, with no history of Factor VIII inhibitor development and without detectable immunity to the AAV5 capsid. Enrolled patients received a single IV infusion of AAV5-hFVIII-SQ and participants were enrolled sequentially into Low dose, Intermediate dose and High dose cohorts, and the follow up period was 52 weeks. All patients who had been receiving prophylactic Factor VIII therapy previously were withdrawn from prophylaxis. Patients were however permitted to self-administer Factor VIII therapy in the event of bleeding after gene transfer. The Primary end point was safety and the Primary efficacy goal was a Factor VIII activity level of at least 5 IU/dl, at week 16 after gene transfer. Secondary efficacy measures included the frequency of Factor VIII use and the number of bleeding episodes.

It was noted that in the High dose cohort (6×1013 vector genomes-vg/kg), the Factor VIII activity level was more than 5 IU/dl between weeks 2 and 9 after gene transfer and the level in six patients normalized (more than 50 IU/dl) and was maintained at 1 year after treatment with a single dose. Further in this high dose cohort, the median annualized bleeding rate among patients who had previously received prophylactic therapy decreased from 16 events before the study to 1 event after gene transfer, and by week 22, none of the patients in this cohort reported the use of Factor VIII for bleeding. The main adverse event was a slight elevation in the serum alanine aminotransferase (ALT) level. Neutralizing antibodies (inhibitors) to Factor VIII were not detected.

The authors concluded that gene therapy with a high dose infusion of AAV5-hFVIII-SQ was associated with the normalization of Factor VIII activity level over a period of 1 year with stabilization of hemostasis and a profound reduction in Factor VIII use. This landmark study has the potential to pave the way for a cure for Hemophilia patients. AAV5–Factor VIII Gene Transfer in Severe Hemophilia A. Rangarajan S, Walsh L, Lester W, et al. N Engl J Med 2017; 377:2519-2530