Category: Meeting Updates

Late Breaking Abstract – ASCO 2018 mFOLFIRINOX Regimen Significantly Improves Overall Survival in Resected Pancreatic Cancer

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SUMMARY: The American Cancer Society estimates that in 2018, about 55,440 people will be diagnosed with pancreatic cancer and about 44,330 people will die of the disease. Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States and Western Europe. Curative surgical resection has been shown to significantly improve Overall Survival (OS) when compared to Chemoradiation, for resectable Pancreatic Cancer. The standard surgical procedure for tumors of the Pancreatic head is the Pancreaticoduodenectomy (Whipple procedure), whereas distal Pancreatectomy is performed for tumors of the body or tail of the Pancreas. Previously published studies concluded that 6 months of Gemcitabine based adjuvant therapy improves Overall Survival for patients with resectable Pancreatic Cancer. FOLFIRINOX chemotherapy regimen however, is more effective than Gemcitabine as first-line treatment, in metastatic pancreatic cancer, for patients with good Performance Status. The following study was conducted to assess the benefit of mFOLFIRINOX regimen in the adjuvant setting.

PRODIGE 24/CCTG PA.6 is a phase III multicenter, randomized clinical trial in which 493 patients were enrolled. Eligible patients had histologically proven, nonmetastatic, pancreatic ductal adenocarcinomas, and had undergone R0 (curative resection) or R1(microscopic residual tumor/positive margins) resection, with no residual tumor on a postoperative CT scan. Patients had a WHO Performance Status of 1 or less and were randomized in a 1:1 ratio, 3-12 weeks after surgery, to receive Gemcitabine on days 1, 8, and 15 every 28 days for 6 cycles (Group A, N=246)) or mFOLFIRINOX regimen, which consisted of Oxaliplatin 85 mg/m², Leucovorin 400 mg/m², Irinotecan 150 mg/m² D1, and 5-FU 2400mg/m² over 46 hours, all drugs given IV, every 14 days for 12 cycles (Group B, N=247). The Primary endpoint was Disease Free Survival (DFS) and Secondary endpoints included Overall Survival (OS), Metastasis Free Survival (MFS), and Adverse Events (AE).

After a median follow up of 33.6 months, patients who received mFOLFIRINOX had a median DFS of 21.6 months compared with 12.8 months with Gemcitabine (HR=0.59; P<0.001) and the 3-year DFS was 39.7% with mFOLFIRINOX and 21.4% with Gemcitabine. The median OS was nearly 20 months longer with a mFOLFIRINOX regimen than with Gemcitabine (54.4 months versus 35 months). This represented a 34% reduction in the risk of death with mFOLFIRINOX (HR=0.66; P=0.003). The median MFS with mFOLFIRINOX regimen was 30.4 months versus 17.7 months with Gemcitabine (HR =0.59). Patients receiving mFOLFIRINOX experienced higher rates of grade 3 or 4 Adverse Events than with Gemcitabine for vomiting, diarrhea, fatigue, mucositis and sensory peripheral neuropathy. In the Gemcitabine group, the rate of grade 3/4 Adverse Events was higher for thrombocytopenia and febrile neutropenia.

It was concluded that adjuvant mFOLFIRINOX significantly improves Disease Free Survival, Metastasis Free Survival and Overall Survival, compared to Gemcitabine, after pancreatic cancer resection, in good Performance Status patients and should therefore be considered the new standard of care. It should be noted that patients with pancreatic cancer who undergo surgical resection, are fit enough to undergo this procedure and these patients would be the most likely candidates for mFOLFIRINOX. For those patients whose Performance Status is poor 12 weeks after surgery, and in those with clear contraindications to mFOLFIRINOX regimen, single agent Gemcitabine is an alternative treatment option. Unicancer GI PRODIGE 24/CCTG PA.6 trial: A multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas. Conroy T, Hammel P, Hebbar M, et al. J Clin Oncol 36, 2018 (suppl; abstr LBA4001)

Late Breaking Abstract – ASCO 2018 Endocrine Therapy Alone is Adequate for Early Stage Breast Cancer Patients with Intermediate Risk Recurrence Score

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 women will die of the disease. Approximately 50% of all breast cancers are Estrogen Receptor (ER) positive, HER2-negative, axillary node-negative tumors. Patients with early stage breast cancer often receive adjuvant chemotherapy. The Oncotype DX breast cancer assay, is a multigene genomic test that analyzes the activity of a group of 21 genes and is able to predict the risk of breast cancer recurrence and likelihood of benefit from systemic chemotherapy, following surgery, in women with early stage breast cancer. Chemotherapy recommendations for early stage, hormone receptor positive, HER negative, early stage breast cancer patients, are often made based on tumor size, grade, ImmunoHistoChemical (IHC) markers such as Ki-67, nodal status and Oncotype DX Recurrence Score (RS) assay.

Oncotype Dx assay categorizes patients on the basis of Recurrence Scores into Low risk (less than 18), Intermediate risk (18-30), and High risk (31 or more). It has been unclear whether patients in the Intermediate risk group benefited from the addition of chemotherapy to endocrine therapy. TAILORx was specifically designed to address this question and provide a very definitive answer. In this study, the Intermediate risk Recurrent Score (18-30) was changed to 11-25, to account for exclusion of higher-risk patients with HER2-positive disease and to minimize the potential for under treatment.

TAILORx ((Trial Assigning Individualized Options for Treatment) is a phase III, randomized, prospective, non-inferiority trial, and is the largest breast cancer treatment trial ever conducted, and the first precision medicine trial ever done, according to the authors. In this study, 10,273 women, 18-75 years of age, with hormone receptor-positive, HER2-negative, axillary node-negative breast cancer were enrolled. Patients had tumors 1.1-5.0 cm in size (or 0.6-1.0 cm and intermediate/high grade). Patients were divided into three groups based on their Recurrence Score. Women with a Low Recurrence Score of 0-10 received endocrine therapy alone and those with a High Recurrence Score of 26-100 received endocrine therapy in combination with standard adjuvant chemotherapy. Patient with Intermediate Recurrence Score of 11-25 (N=6711) were randomly assigned to receive endocrine therapy alone or endocrine therapy and adjuvant chemotherapy. The Primary endpoint was invasive Disease Free Survival, defined as recurrence of cancer in the breast, regional lymph nodes, and/or distant organs, a second primary cancer in the opposite breast or another organ, or death from any cause.

At a median follow-up of 7.5 years, the study met its Primary endpoint, and it was noted that that endocrine therapy alone was non-inferior to chemotherapy plus endocrine therapy, in patients with Intermediate Recurrence Score of 11-25. At 9 years, patients with Intermediate Recurrence Scores receiving endocrine therapy or chemotherapy in combination with endocrine therapy showed similar invasive Disease Free Survival rates (83.3% vs 84.3%), distant Recurrence Free Interval (94.5% vs 95.0%), Recurrence Free Interval (92.2% vs 92.9%) and Overall Survival (93.9% vs 93.8%) respectively. These findings suggested that there was no benefit from adding chemotherapy to endocrine therapy, for this patient group.

The authors also conducted an exploratory analysis of patients in the Intermediate Risk group to determine which patients would benefit from added chemotherapy. They noted that there was no significant interaction between menopause, tumor size or grade, with Recurrence Score. There was however an interaction between age and Recurrence Score. In women 50 years or younger with a Recurrence Score of 16-20, there were 2% fewer distant recurrences, and in those with a recurrence score of 21-25, there were 7% fewer distant recurrences with the addition of chemotherapy, suggesting that younger women with a Recurrence Score of 16-25 had some benefit with the addition of chemotherapy to endocrine therapy.

It was concluded that women older than 50 years with hormone receptor-positive, HER2-negative, node-negative breast cancer and a Recurrence Score of 0-25, as well as women 50 years or younger with hormone receptor-positive, HER2-negative, node-negative breast cancer and a Recurrence Score of 0-15, could be spared from chemotherapy, based on this study. This study showed that chemotherapy could be avoided in about 70% of these patients, by allowing this test to tailor treatment. Further, this prospective study reflects outcomes with current modern chemotherapy and endocrine therapy regimens. The authors recommended that any patient 75 years or younger with early-stage breast cancer should therefore be offered Oncotype DX assay test, for guidance regarding chemotherapy recommendations after surgery. TAILORx: phase III trial of chemoendocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, node-negative breast cancer and an intermediate prognosis 21-gene recurrence score. Sparano JA, Gray RJ, Wood WC, et al. J Clin Oncol. 2018;36(suppl; abstr LBA1).

FDA Approves KYMRIAH® for Relapsed or Refractory Large B-Cell Lymphoma

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SUMMARY: The FDA on May 1, 2018 approved KYMRIAH®, a CD19-directed genetically modified autologous T-cell immunotherapy, for adult patients with Relapsed or Refractory Large B-Cell Lymphoma, after two or more lines of systemic therapy including Diffuse Large B-Cell Lymphoma (DLBCL) Not Otherwise Specified (NOS), High grade B-Cell Lymphoma and DLBCL arising from Follicular Lymphoma. The American Cancer Society estimates that in 2018, about 74,680 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,910 individuals will die of this disease. Diffuse Large B-Cell Lymphoma is the most common of the aggressive Non-Hodgkin lymphomas in the United States, and the incidence has steadily increased 3-4% each year. The etiology of DLBCL is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), ultraviolet radiation, pesticides, hair dyes, and diet.

What is (CAR) T-cell immunotherapy?

Chimeric Antigen Receptor (CAR) T-cell therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure, and genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR). These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patient’s body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen. KYMRIAH® (genetically engineered T-cells) seeks out cancer cells expressing the antigen CD19, which is found uniquely on B cells and destroy them. Patients, following treatment with CAR T-cells, develop B-cell aplasia (absence of CD19 positive cells) due to B-cell destruction and may need immunoglobin replacement. Hence, B-cell aplasia can be a useful therapeutic marker, as continued B-cell aplasia has been seen in all patients who had sustained remission, following CAR T-cell therapy. Cytokine Release Syndrome, an inflammatory process is the most common and serious side effect of CAR T-cell therapy and is associated with marked elevation of Interleukin-6. Cytokine release is important for T-cell activation and can result in high fevers and myalgias. This is usually self limiting although if severe can be associated with hypotension and respiratory insufficiency. Tocilizumab (ACTEMRA®), an Interleukin-6 receptor blocking antibody produces a rapid improvement in symptoms. This is however not recommended unless the symptoms are severe and life threatening, as blunting the cytokine response can in turn negate T-cell proliferation. Elevated serum Ferritin and C-reactive protein levels are surrogate markers for severe Cytokine Release Syndrome.Chimeric-Antigen-Receptor-T-Cell-Immunotherapy

The CAR T-cells have been shown to also access sanctuary sites such as the central nervous system and eradicate cancer cells. 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 approval of KYMRIAH® was based on a single-arm, open-label, multi-center, global, pivotal phase II trial (JULIET), in adults with Relapsed or Refractory DLBCL and DLBCL after transformation from Follicular lymphoma. The study enrolled 147 patients, 99 of whom received the CAR T-cell infusion with a single dose of KYMRIAH®, which was manufactured at 2 sites (United States and Germany). Eligible patients were 18 years or older with Relapsed or Refractory DLBCL and had progressed after receiving two or more lines of chemotherapy, including an Anthracycline and Rituximab, and were ineligible for or failed Autologous Stem Cell Transplant (auto-SCT). The median number of prior lines of therapy was 3 and 47% of patients had prior auto-SCT. Prior to infusion with KYMRIAH®, 90% of patients received bridging therapy, 93% received lymphodepleting chemotherapy, which in most patients consisted of Fludarabine/Cyclophosphamide. The median age was 56 years and 77% of patients had Stage III or IV disease at the time of enrollment. The median time from infusion to data cutoff was 5.6 months. The Primary endpoint was best Overall Response Rate-ORR (Complete Response-CR + Partial Response-PR), per independent review committee.

In this primary analysis, the authors reported the outcomes among 81 patients who received KYMRIAH® manufactured in the United States, with more than 3 months of follow up. The Objective Response Rate was 53%, the Complete Response rate was 39.5% and Partial Response rate 13.6%. At month 3, the CR rate was 32% and the PR rate 6%. Among patients evaluable at 6 months (N=46), the CR Rate was 30% and PR rate was 7%. Response rates were consistent across prognostic subgroups, including those who received prior auto-SCT and those with Double-Hit lymphoma. The median Duration of Response and the median Overall Survival were not reached. The 6-month probability of being relapse free was 73.5% and the 6-month probability of Overall Survival was 64.5%. Grade 3 or 4 adverse events were reported in 86% of the patients and Cytokine-Release Syndrome occurred in 58%. CRS was managed with ACTEMRA® in 15% of patients with good response and 11% of patients received corticosteroids. Neurologic adverse events were reported in 12% of patients. No deaths were attributed to KYMRIAH®.

It was concluded that KYMRIAH® produces high Response Rates with 95% of Complete Responses at 3 months being sustained at 6 months, in heavily pretreated adult patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL). This first global study of CAR T-cell therapy in DLBCL also demonstrated that centralized manufacturing of CAR T-cells is feasible. Schuster SJ, Bishop MR, Tam CS, et al. Primary Analysis of Juliet: A Global, Pivotal, Phase 2 trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta. Abstract 577.

Treatment Sequencing with STIVARGA® before ERBITUX® Improves Survival in Metastatic Colorectal Cancer

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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 140,250 new cases of CRC will be diagnosed in the United States in 2018 and about 50,630 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 21 (4.7%). Even though colon cancer localized to the bowel is potentially curable with surgery and adjuvant chemotherapy, advanced colon cancer is often incurable. Standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab) as well as anti VEGF agent AVASTIN® (Bevacizumab), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC, whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now also clear that even among the KRAS Wild Type patients, about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Therefore, pan RAS (expanded RAS) testing is now recommended.

STIVARGA® (Regorafenib), is an oral multi-kinase inhibitor approved by the FDA for the treatment of patients with metastatic CRC, who have progressed on 5FU, ELOXATIN® (Oxaliplatin), CAMPTOSAR® (Irinotecan), anti-VEGF and anti-EGFR therapies. STIVARGA® inhibits multiple kinases including VEGF1, VEGF2, VEGF3, PDGFR, FGFR involved in tumor angiogenesis and KIT, RET, RAF-1, BRAF involved in oncogenesis. The approval was based on a phase III trial in which patients receiving STIVARGA® had a statistically significant improvement in the Overall Survival and Progression Free Survival, compared to placebo.

Both STIVARGA® and ERBITUX® are approved for metastatic CRC. The optimal sequencing of these drugs however, has remained unclear. The current standard of care is to offer an ERBITUX® based regimen followed by STIVARGA®. STIVARGA® however has demonstrated activity in patients with metastatic CRC, when given earlier in the course of the disease. Further preclinical data suggests that downregulation of MAP kinase and Akt with STIVARGA® was shown to sensitize metastatic CRC cells to anti-EGFR therapies, such as ERBITUX®.

The REVERCE trial is a multicenter, randomized phase II trial which enrolled patients with KRAS wild-type metastatic CRC, after failure on combination chemotherapy with Fluoropyrimidine, Oxaliplatin, and Irinotecan. A total of 101 patients were randomized in a 1:1 ratio to receive sequential treatment with STIVARGA® followed by ERBITUX® with or without Irinotecan or reverse sequence of ERBITUX® with or without Irinotecan followed by STIVARGA®. Patients were stratified by prior use of AVASTIN® and intent to use ERBITUX® in combination with Irinotecan. Patients continued each sequence until disease progression or unacceptable toxicity, at which time patients switched to the alternative drug. The Primary endpoint was Overall Survival. Secondary endpoints included Progression Free Survival (PFS) with initial treatment (PFS1), PFS with second treatment (PFS2), Time to sequential Treatment Failure (TTF), Response Rate, Safety, and Quality of Life (QOL). The authors further investigated possible biomarkers including oncogenic mutations from circulating cell free DNA by liquid biopsy, with serial measurements.

It was noted that giving STIVARGA® before ERBITUX® resulted in a significantly longer median Overall Survival of 17.4 months, compared with 11.6 months with ERBITUX® followed by STIVARGA®. After a median follow up of 29 months, there was a 39% reduction in the risk of death with the STIVARGA®-ERBITUX® sequence (HR=0.61; P=0.029). The benefit with STIVARGA®-ERBITUX® sequence was consistently noted across all patient subgroups. In the subgroup of patients with left-sided primary tumors (N=81), patients who started treatment with STIVARGA® first followed by ERBITUX®, had a median Overall Survival of 20.5 months compared with 11.9 months for those receiving ERBITUX® first, and this meant a 49% reduction in mortality risk, which was statistically significant (P=0.01).

The first Progression Free Survival (PFS1) did not differ significantly according to the drug sequence, but the second PFS (PFS2) was more prolonged in those receiving ERBITUX® after STIVARGA®, with a 71% reduction in the risk of progression or death following the second treatment (HR=0.29; P<0.0001). The time to treatment failure was a median of 7.4 months with STIVARGA® followed by ERBITUX® and 6.1 months with ERBITUX® followed by STIVARGA® (HR=0.60; P=0.017). Safety and quality of life were comparable between the two treatment groups.

It was concluded that data from this study suggest that treatment with STIVARGA® first, followed by ERBITUX® resulted in longer survival than that of the current standard sequence and the longer Progression Free Survival following the second treatment period with ERBITUX® may have contributed to the improvement in Overall Survival with the STIVARGA®-ERBITUX® sequence. A biomarker analysis is still ongoing. Randomized phase II study of regorafenib followed by cetuximab versus reverse sequence for wild-type KRAS metastatic colorectal cancer previously treated with fluoropyrimidine, oxaliplatin, and irinotecan (REVERCE). Shitara K, Yamanaka T, Denda T, et al. DOI: 10.1200/JCO.2018.36.4_suppl.557 Journal of Clinical Oncology 36, no. 4_suppl (February 2018) 557-557.

FDA Approves ERLEADA® for Non-Metastatic Castrate Resistant Prostate Cancer

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SUMMARY: The FDA on February 14, 2018 approved ERLEADA® (Apalutamide) for patients with Non-Metastatic Castration Resistant Prostate Cancer (NM-CRPC). Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 164,690 new cases of Prostate cancer will be diagnosed in 2018 and 29,430 men will die of the 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 Castration Sensitive Prostate Cancer (CSPC). Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide). The median duration of response is approximately 1 year and majority of these patients progress to Castration Resistant Prostate Cancer (CRPC). The mechanism of resistance to Androgen Deprivation Therapy (ADT) include reactivation of Androgen Receptor signaling through persistent adrenal androgen production, modification of the biologic characteristics of Androgen Receptors, intratumoral testosterone production and parallel steroidogenic pathways. Progression to Castration Resistant Prostate Cancer (CRPC) often manifests itself with a rising PSA (Prostate Specific Antigen), and watchful waiting is recommended in men with non-metastatic CRPC. However, those with a rapidly rising PSA on ADT (doubling time of less than 8-10 months), are at significantly greater risk of developing metastases and death.

ERLEADA® is a next-generation, nonsteroidal, competitive inhibitor of the Androgen Receptor. ERLEADA® prevents binding of androgens to the Androgen Receptor by competitively binding directly to the ligand-binding domain of the Androgen Receptor, and prevents the translocation of the Androgen Receptor to the nucleus and thereby impedes Androgen Receptor mediated DNA transcription. ERLEADA® resulted in durable PSA responses in a phase II study, among men with non-metastatic CRPC, who were at high risk for disease progression (with a PSA level of 8 ng/ml or more or a PSA doubling time of 10 months or less). Based on this preliminary data, the authors evaluated the efficacy of ERLEADA® in men with non-metastatic CRPC, who were at a high risk for the development of metastasis.

SPARTAN (Selective Prostate Androgen Receptor Targeting with ARN-509) trial is an international, randomized, placebo-controlled, phase III study in which 1207 men were randomly assigned in a 2:1 ratio, to receive ERLEADA® 240 mg orally daily (N=806) or placebo (N=401). Eligible patients had non-metastatic CRPC and were at high risk for the development of metastasis, with a PSA doubling time of 10 months or less during continuous Androgen Deprivation Therapy (bilateral orchiectomy or treatment with Gonadotropin Releasing Hormone analogue agonists or antagonists).

All the patients at the time of screening for eligibility, underwent a technetium-99m bone scan and Computed Tomography (CT) of the head, chest, abdomen and pelvis, abdomen, and were excluded from the study if distant metastasis was detected. Androgen Deprivation Therapy was continued throughout the study period. Patients were eligible to receive treatment with sponsor-provided ZYTIGA® (Abiraterone acetate) plus Prednisone, after the first detection of distant metastasis. The Primary end point was Metastasis-Free Survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death. Secondary end points included time to metastasis, Progression Free Survival, time to symptomatic progression, Overall Survival, and time to the initiation of cytotoxic chemotherapy. For those patients who developed metastases, the time between randomization to the first treatment for metastatic CRPC and subsequent progression (second Progression Free Survival-PFS2), was also evaluated.

At the time of the planned primary analysis, the median Metastasis-Free Survival was 40.5 months in the ERLEADA® group as compared with 16.2 months in the placebo group (HR for metastasis or death =0.28; P<0.001). This meant a 72% reduction in the risk of metastasis and death in the ERLEADA® group and significantly prolonged median Metastasis-Free Survival by 2 years, compared with placebo. Further, ERLEADA® significantly improved the time to metastasis, Progression Free Survival and symptom progression, compared with placebo. The time to symptomatic progression was significantly longer with ERLEADA® than with placebo (HR=0.45; P<0.001), which meant a 55% risk reduction in the time to symptomatic disease progression. All prespecified subgroups consistently benefited from ERLEADA®.

In spite of subsequent approved treatment for metastatic CRPC in 78% of placebo recipients (most common subsequent treatment being ZYTIGA® plus Prednisone), the second Progression Free Survival was significantly longer in the ERLEADA® group, compared to the placebo group (Hazard Ratio for progression or death=0.49). A trend toward improved survival was observed in the ERLEADA® group. At a median follow up of 20.3 months, 61% in the ERLEADA® group and 30% in the placebo group were still on therapy. Treatment discontinuation due to adverse events was 10.6% in the ERLEADA® group and 7.0% in the placebo group, and patients in the ERLEADA® group had a higher incidence of rash, hypothyroidism and fractures.

It was concluded that among patients with non-metastatic Castration Resistant Prostate Cancer, ERLEADA® significantly prolonged Metastasis-Free Survival and time to symptomatic progression, when compared to placebo. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. Smith MR, Saad F, Chowdhury S, et al. for the SPARTAN Investigators. N Engl J Med. February 8, 2018. DOI: 10.1056/NEJMoa1715546

OPDIVO® and YERVOY® Combination Improves Survival in Metastatic Colorectal Cancer

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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 140,250 new cases of CRC will be diagnosed in the United States in 2018 and about 50,630 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 21 (4.7%).

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 (dMMR) 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 therefore are susceptible to PD-1 blockade with immune checkpoint inhibitors.Testing-for-MSI-and-MMR-Deficiency

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. NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer.

CheckMate 142 is a large, multi-center, open label, phase II trial which evaluated the efficacy and safety of PD-1 inhibitor treatment in patients with dMMR/MSI-H metastatic colorectal cancer. This study evaluated the benefit of OPDIVO® alone or in combination YERVOY® in this patient population. The rationale behind combining OPDIVO® a PD-1 inhibitor and YERVOY®, a CTLA-4 inhibitor, was based on the synergy between these two agents, to promote T-cell antitumor activity, thereby improving upon single-agent activity of OPDIVO®. The study enrolled 119 patients who received OPDIVO® as a single agent at 3 mg/kg IV every 2 weeks or OPDIVO® 3 mg/kg plus YERVOY® 1 mg/kg every 3 weeks for 4 doses, followed by OPDIVO® 3 mg/kg every 2 weeks. Treatment was continued until disease progression or unacceptable toxicities. The Primary endpoint was Objective Response Rate (ORR) and exploratory endpoints included Safety, Progression Free Survival (PFS), Overall Survival (OS) and efficacy in biomarker-defined populations. This study was not designed to compare the outcomes in these two treatment cohorts. Based on initial data from CheckMate-142, the FDA in July 2017 granted accelerated approval to OPDIVO® for the treatment of patients with MisMatch Repair deficient (dMMR) and MicroSatellite Instability-High (MSI-H) metastatic CRC, that has progressed, following treatment with a Fluoropyrimidine, Oxaliplatin, and Irinotecan.

This review provides an update on outcomes with monotherapy and immunotherapy combination. In the OPDIVO® monotherapy group which included 74 patients, the updated analysis at 21 months showed a response rate was 34%, with 9% being complete responses, and the disease control rate was 62%. The median duration of response has not been reached in the overall cohort of patients and among those responding, 64% had responses lasting at least 1 year. Longer follow up resulted in deepening response rates. The median Progression Free Survival (PFS) for the entire cohort was 6.6 months. Clinical Benefit was seen regardless of PD-L1 expression, BRAF mutation status, KRAS mutation status, and clinical history of Lynch Syndrome.

In the combination immunotherapy group, the median follow up was 13.4 months and the authors of this analysis, André, et al., compared the results of this cohort with those of the OPDIVO® monotherapy group, for the same 13.4 month median follow up period. The most common prior therapies included Fluoropyrimidine (99%), Oxaliplatin (93%) and Irinotecan (73%). Of the 119 patients who received this combination immunotherapy, 76% had 2 or more prior lines of therapy. The Objective Response Rate with a combination of OPDIVO® and YERVOY® was 55%, with 3.4% Complete Responses, and the Disease Control Rate was 80%. About 78% of the patients had reduction in tumor burden with combination immunotherapy. The median time to response was 2.8 months and the median Duration of Response has not yet been reached. Among patients who responded to the combination, 94% had ongoing responses at the time of data cutoff and 63% of the cohort receiving combination immunotherapy remained on treatment. These responses were noted regardless of PD-L1 expression, BRAF or KRAS mutation status, or clinical history of Lynch syndrome. The PFS and Overall Survival with combination immune checkpoint inhibitor therapy at 12 months were 71% and 85%, respectively. There were statistically significant and clinically meaningful improvements in quality-of-life measurements as well.

These data from the CheckMate-142 study support the use of OPDIVO® as a single agent or in combination with YERVOY®, for the treatment of patients with previously treated DNA MisMatch Repair-Deficient/MicroSatellite Instability-High (MSI-H) metastatic CRC.

1. Overman MJ, Bergamo F, McDermott RS, et al. Nivolumab in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): Long-term survival according to prior line of treatment from CheckMate-142. Overman MJ, Bergamo F, McDermott RS, et al. J Clin Oncol 36, 2018 (suppl 4S; abstr 554)

2. Nivolumab + ipilimumab combination in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): First report of the full cohort from CheckMate-142. André T, Lonardi S, Wong M, et al. J Clin Oncol 36, 2018 (suppl 4S; abstr 553)

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

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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.

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

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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.

A Potential Cure for Hemophilia Using Gene Therapy

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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

Direct Oral Anticoagulant SAVAYSA® Noninferior to Subcutaneous FRAGMIN® for Cancer-Associated Venous Thromboembolism

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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, after myocardial infarction and stroke.

Approximately 20% of cancer patients develop VTE and the current recommendations are treatment with parenteral Low Molecular Weight Heparin (LMWH) preparations, based on efficacy data. This however can be inconvenient and expensive, leading to premature discontinuation of treatment. Direct Oral Anticoagulant agents have been proven to be as effective as Warfarin, a Vitamin K antagonist, for the treatment of VTE, and are associated with less frequent and less severe bleeding and fewer drug interactions. However, the efficacy and safety of Direct Oral Anticoagulants for the treatment of cancer-associated VTE have not been established.Anticoagulants

SAVAYSA® (Edoxaban)‎ an oral Factor Xa inhibitor was compared with subcutaneous Low Molecular Weight Heparin FRAGMIN® (Dalteparin), for the treatment of patients with cancer-associated VTE in the Hokusai VTE Cancer trial. This open-label, noninferiority trial randomized 1050 patients in a 1:1 ratio to receive either SAVAYSA® or FRAGMIN®. SAVAYSA® was given after an initial course of physician’s choice of Low Molecular Weight Heparin, given subcutaneously in therapeutic doses, for at least 5 days. SAVAYSA® was administered orally at a fixed dose of 60 mg once daily. FRAGMIN® was given subcutaneously at a dose of 200 IU/kg once daily for 30 days and at a dose of 150 IU/kg once daily thereafter. This treatment was continued for up to 12 months. The median age was 64 years and 90% of the patients had solid tumors and were on various chemotherapy regimens. The primary endpoint was a composite of recurrent VTE or major bleeding during the 12 months after randomization, regardless of treatment duration.

It was noted that SAVAYSA® was noninferior to FRAGMIN® with regards to composite rates of recurrent VTE and bleeding, which occurred in 12.8% of those receiving SAVAYSA® and 13.5% of those receiving FRAGMIN®. The similarity between the two treatment groups met statistical criteria for demonstrating noninferiority for SAVAYSA® (P=0.006). The rate of recurrent VTE was numerically lower with SAVAYSA® compared with FRAGMIN® (7.9% vs 11.3%, HR=0.71; P=0.09). The rate of major bleeding was however significantly higher with SAVAYSA® compared with FRAGMIN® (6.9% vs 4.0%, HR=1.77; P=0.04). This difference was mainly due to higher rate of upper gastrointestinal bleeding with SAVAYSA® in patients with gastrointestinal cancers. The frequency of severe major bleeding (category 3 or 4) however was similar in both treatment groups.

It was concluded that Direct Oral Anticoagulant, SAVAYSA® was noninferior to subcutaneous Low Molecular Weight Heparin, FRAGMIN® with respect to the composite outcome of recurrent Venous ThromboEmbolism or major bleeding. The lower rate of recurrent VTE observed with SAVAYSA® was offset by a similar increase in the risk of major bleeding. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. Raskob GE, Van Es N, Verhamme P, et al. for the Hokusai VTE Cancer Investigators. December 12, 2017DOI: 10.1056/NEJMoa1711948