Anti-BCMA CAR T-Cell Therapy in Relapsed or Refractory Multiple Myeloma

SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 32,110 new cases will be diagnosed in 2019 and 12,960 patients are expected to die of the disease. Multiple Myeloma (MM) in 2019 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile or refractory disease have the worst outcomes.

Chimeric Antigen Receptor (CAR) T-cell therapy has been associated with long-term disease control in some hematologic malignancies and is emerging as a novel treatment for patients with Relapsed and Refractory Multiple Myeloma. B-cell Maturation Antigen (BCMA) is a member of the Tumor Necrosis Factor superfamily of proteins. It is a transmembrane signaling protein primarily expressed by malignant and normal plasma cells and some mature B cells. BCMA is involved in JNK and NF-kB signaling pathways that induce B-cell development and autoimmune responses. BCMA has been implicated in autoimmune disorders as well as B-lymphocyte malignancies, Leukemia, Lymphomas, and Multiple Myeloma.

Anti-BCMA CAR T-Cell Therapy bb2121 is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure. These T cells are then stimulated by treating with interleukin 2 (IL-2) and anti-CD3 antibodies in vitro, so that they will actively proliferate and expand to large numbers. These T cells are then genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR), by transducing with a gene encoding the engineered CAR, via a retroviral vector such as lentiviral vector. These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen such as BCMA 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 such as BCMA. The patient undergoes lymphodepletion chemotherapy with Fludarabine and Cytoxan prior to the introduction of the engineered CAR T-cells. By depleting the number of circulating leukocytes, cytokine production is upregulated and reduces competition for resources, which in turn promotes the expansion of the engineered CAR T-cells. In a mouse model of human Multiple Myeloma, a single-dose administration of bb2121 showed rapid and durable tumor responses, with 100% survival. On the basis of these findings, the authors conducted a Phase 1 clinical study (CRB-401) of bb2121 involving patients with Relapsed or Refractory Multiple Myeloma and reported the initial results from this ongoing study.Chimeric-Antigen-Receptor-T-Cell-Immunotherapy

A total of 36 consecutive patients were enrolled in the study and underwent leukapheresis. Patients received bb2121 as a single infusion at increasing doses in the dose-escalation phase (50×106, 150×106, 450×106, or 800×106 CAR T-cells) followed by a dose expansion phase. The median number of previous treatment regimens was 7, and most of the enrolled patients had received previous Autologous Stem-Cell Transplantation. Further, all the patients had previously received both VELCADE® (Bortezomib) and REVLIMID® (Lenalidomide), and more than 75% of patients were exposed to VELCADE®, KYPROLIS® (Carfilzomib), REVLIMID®, POMALYST® (Pomalidomide) and DARZALEX® (Daratumumab). The median patient age was 60 years and the median time from diagnosis was 5 years. Approximately two thirds of the patients had Stage II or III disease, 27% had extramedullary disease, and 45% had a high-risk cytogenetic profile, defined by the presence of del(17p), t(4;14), or t(14;16). The Primary end point was Safety. The median duration of follow up after bb2121 infusion was 11.3 months.

Hematologic Grade 3 Adverse Events manifesting as cytopenias were the most common. Approximately 70% of patients had Grade 1 or 2 Cytokine Release Syndrome (CRS) and 6% had Grade 3 CRS. Approximately 40% of patients had Grade 1 or 2 neurotoxicity.

The Objective Response Rate was 85%, with 45% Complete Responses. The median time to first Partial Response or better was 30 days. The median Duration of Response was 10.9 months. Response rates were independent of tumor BCMA expression. All patients who had a Partial Response or better and who could be evaluated for Minimal Residual Disease (MRD) had MRD-negative status (10−4 or less nucleated cells). CAR T-cells persisted for up to 1 year after the infusion and CAR T-cell expansion was associated with responses. The median Progression Free Survival was 11.8 months.

It was concluded that, CAR T-cell therapy with bb2121 showed promising efficacy at dose levels of 150×106 or more CAR T-Cells, in a heavily pretreated population of patients with Multiple Myeloma. The authors added that non-hematologic toxicities were grade 2 or lower. Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma. Raje N, Berdeja J, Lin Y, et al. N Engl J Med 2019;380:1726-1737

BRAFTOVI®, MEKTOVI® and ERBITUX® Triplet Therapy for Patients with BRAF V600E-Mutant Metastatic Colorectal Cancer

SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 145,600 new cases of CRC will be diagnosed in the United States in 2019 and about 51,020 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23. Advanced colon cancer is often incurable and 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 (mCRC), 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 patient group about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Patients with stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy. Approximately 8-15% of all metastatic CRC tumors present with BRAF V600E mutations and BRAF V600E is recognized as a marker of poor prognosis in this patient group. These patients tend to have aggressive disease with a higher rate of peritoneal metastasis and do not respond well to standard treatment intervention. Approximately 20% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group.BRAF-and-MEK-Inhibition-in-MAPK-Pathway

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. The BRAF V600E mutations results in constitutive activation of the MAP kinase pathway. Inhibiting BRAF can transiently reduce MAP kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR. However, BRAF V600E-mutated CRC is inherently less sensitive to BRAF inhibition than melanoma.

The FDA approved BRAFTOVI® (Encorafenib) and MEKTOVI® (Binimetinib) in combination for the first-line treatment of patients with BRAF V600-mutant melanoma, in June 2018. In a recent Phase II study among previously treated patients with BRAF V600E-mutant mCRC, treatment with a combination of BRAFTOVI® plus ERBITUX® resulted in an Objective Response Rate (ORR) of 24%, PFS of 4.2 months, and OS of 9.3 months. These results were significantly better than the standard of care, as well as other BRAF, MEK, and EGFR-inhibitor triplet combinations. Preclinical data suggests that BRAFTOVI® has target binding characteristics that differ from other BRAF inhibitors such as ZELBORAF® (Vemurafenib) and TAFINLAR® (Dabrafenib), with a prolonged target dissociation half-life and higher potency. This may explain the superior efficacy of BRAFTOVI® over other BRAF inhibitors in BRAF V600E-mutated CRC. These encouraging results with the BRAFTOVI® plus ERBITUX® doublet led to the initiation of the Phase III BEACON CRC study.

The BEACON Colorectal Cancer trial is an open-label, randomized, three-arm, Phase III study in which the efficacy and safety of BRAFTOVI® plus ERBITUX® with or without MEKTOVI® was compared with the investigators’ choice of ERBITUX® combined with either Irinotecan or Fluorouracil, Folinic acid, and Irinotecan, in patients with BRAF V600E-mutant mCRC whose disease has progressed after one or two prior regimens. At the time BEACON CRC was initiated, the triplet combination of MEKTOVI®, BRAFTOVI®, and ERBITUX® had not been clinically evaluated. The authors therefore conducted a Safety Lead-In (SLI) to determine the Safety, tolerability, and preliminary efficacy of this triplet combination at the same doses planned for the randomized portion of the trial.

The randomized portion of the trial was ongoing at the time of this analysis. The BEACON trial included patients with mCRC whose tumor tissue was positive for the presence of BRAF V600E mutation. Majority of the patients had right-sided disease as is characteristic of BRAF V600E-mutant mCRC, with a high frequency of nodal and peritoneal metastasis. Liver however, was the most frequent site of metastasis. Enrolled patients must have had progressive disease on one, but no more than two prior treatment regimens, in the metastatic setting. Enrolled patients received BRAFTOVI® 300 mg PO daily plus MEKTOVI® 45 mg PO BID along with ERBITUX® 400 mg/m2 IV, followed by 250 mg/m2 IV weekly every 28 days. The Safety Lead-In was initiated before the randomized portion of the BEACON trial and included 30 patients with disease characteristics and treatment schedule as described above. The Primary end point was Safety, including the incidence of dose-limiting toxicities. Efficacy end points included Overall Response Rate, Progression Free Survival, and Overall Survival.

The median follow up was 18.2 months, and the median time on study drug was 7.9 months. The confirmed Overall Response Rate was 48%, median Duration of Response was 5.5 months, median Progression Free Survival was 8.0 months, and median Overall Survival was 15.3 months. Approximately 79% of responding patients achieved a response within 2 months. The most common adverse events were nausea, diarrhea, fatigue and dermatitis. Approximately 6% of patients experienced serous retinopathy without loss of visual acuity.

It was concluded that in this Safety Lead-In, the combination regimen of BRAFTOVI®, MEKTOVI® and ERBITUX® resulted in promising results compared with available therapies, among patients with previously treated BRAF V600E-mutant mCRC, and if confirmed in the randomized portion of the trial, could become the new standard of care in this patient group. Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients With BRAF V600E–Mutant Metastatic Colorectal Cancer: Safety Lead-In Results From the Phase III BEACON Colorectal Cancer Study. Van Cutsem E, Huijberts S, Grothey A, et al. Journal of Clinical Oncology 2019; 37:1460-1469.

Late Breaking Abstract – ASCO 2019 Front-Line Keytruda® Monotherapy for Patients with Advanced Gastric or Gastroesophageal Junction Adenocarcinoma

SUMMARY: The American Cancer Society estimates that in the US, about 27,510 cases of Gastric Cancer will be diagnosed in 2019 and about 11,140 people will die of the disease. The average age at diagnosis is 68 years and Gastric Cancer is one of the leading causes of cancer-related deaths in the world. Risk factors for gastric cancer include age, gender, ethnicity, geography and infection with Helicobacter pylori. Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with Gastric and GastroEsophageal (GE) Adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. These patients frequently are treated with Platinum containing chemotherapy along with a Fluoropyrimidine and, if appropriate, HER2/neu-targeted therapy. This can however be associated with significant toxicities impacting patient’s quality of life.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. KEYTRUDA® in the Phase II KEYNOTE-059 trial demonstrated promising antitumor activity and durable responses in patients with advanced Gastric/GastroEsophageal Junction cancer, who had progressed on more than 2 lines of therapy, with higher Objective Response Rates noted in patients with PD-L1-positive tumors.

KEYNOTE-062 is a randomized, phase III controlled study in which KEYTRUDA® monotherapy was compared to standard chemotherapy as first line treatment, in select patients with advanced Gastric or GastroEsophageal Junction (GEJ) Adenocarcinoma. This trial enrolled 763 newly diagnosed patients of whom 69% had Gastric Adenocarcinoma cancer and 30% had GEJ Adenocarcinoma. Patients were randomized 1:1:1 to receive KEYTRUDA® 200 mg IV every 3 weeks for up to 2 years (N=256), KEYTRUDA® plus Cisplatin 80 mg/m2 IV every three weeks along with either 5-Fluorouracil 800 mg/m2 daily on Days 1-5 every three weeks or XELODA® (Capecitabine) 1000 mg/m2 twice a day on Days 1-14 every three weeks (N=257 ) or placebo plus Cisplatin and either 5-FU or XELODA® given at a similar dose and schedule as the second group (N=250). The median patient age was 62 years and PD-L1 expression was assessed by Combined Positive Score (CPS). The Primary endpoints were Overall Survival (OS) in patients whose tumors expressed PD-L1 CPS 1 or more and CPS 10 or more in the KEYTRUDA® monotherapy group and in combination with chemotherapy group, as well as Progression Free Survival (PFS) in patients whose tumors expressed PD-L1 CPS 1 or more in the combination arm. Secondary endpoints included Overall Response Rate (ORR) and Duration of Response (DOR) in patients whose tumors express PD-L1 CPS 1 or more. In the current trial, all patients had a PD-L1 CPS of at least 1, and 281 patients (37%) had a PD-L1 CPS score of 10 or more. The median follow-up was 11.3 months.

The trial met its Primary endpoint and among patients with a PD-L1 CPS of 1 or more, Overall Survival was noninferior to chemotherapy. The median Overall Survival was 10.6 months in the KEYTRUDA® monotherapy group compared with 11.1 months in the chemotherapy group (HR=0.91). Among patients with a PD-L1 CPS 10 or more, Overall Survival with KEYTRUDA® was superior to chemotherapy. The median Overall Survival was 17.4 months for those receiving KEYTRUDA® compared with 10.8 months for those receiving chemotherapy. After 2 years, 39% of people taking KEYTRUDA® were alive compared with 22% of those taking chemotherapy (HR=0.69). The OS and PFS rates for the combination of KEYTRUDA® and chemotherapy were comparable with those of chemotherapy alone, regardless of PD-L1 CPS. The efficacy outcomes were not influenced by age, tumor size or location, histological subtype, number of metastatic sites and prior gastrectomy status.

It was concluded that KEYTRUDA® monotherapy is noninferior to chemotherapy for OS among patients with PD-L1 CPS 1 or more. There was however a clinically meaningful improvement in OS among patients with PD-L1 CPS 10 or more. Further, there was a more favorable safety profile for KEYTRUDA® over chemotherapy, making this a more desirable treatment option for elderly patients, for whom platinum based chemotherapy may not be appropriate. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: The phase III KEYNOTE-062 study. Tabernero J, Van Cutsem E, Bang Y-J, et al. J Clin Oncol 37, 2019 (suppl; abstr LBA4007)

FDA Approves Antibody-Drug Conjugate POLIVY® for Diffuse Large B-Cell Lymphoma

SUMMARY: The FDA on June 10, 2019, granted accelerated approval to POLIVY® (Polatuzumab vedotin-piiq), a CD79b-directed Antibody-Drug Conjugate, indicated in combination with Bendamustine and a Rituximab product, for adult patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL), Not Otherwise Specified, after at least two prior therapies.

The American Cancer Society estimates that in 2019, about 74,200 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,970 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphoma’s in the United States, and the incidence has steadily increased 3-4% each year. More than half of patients are 65 or older at the time of diagnosis and the incidence is likely to increase with the aging of the American population. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), UltraViolet radiation, pesticides, hair dyes, and diet. DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using gene expression profiling: Germinal Center B-cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher five year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless, R-CHOP regimen (RITUXAN®-Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL, regardless of molecular subtype. Approximately 30-40% of patients experience disease progression or relapse, during the first 2 years and attempts to improve on R-CHOP regimen have not been successful. Maintenance treatment strategy following R-CHOP, to better control the disease, delay disease progression and improve long term survival, have included Autologous Stem Cell Transplantation, maintenance treatment with agents such as oral protein kinase inhibitor Enzastaurin and Everolimus. Outcomes for transplant-ineligible patients with Relapsed/Refractory DLBCL patients remain poor.

CD79b is a B-cell specific surface protein, which is a component of the B-cell receptor. POLIVY® is a CD79b-directed Antibody-Drug Conjugate (ADC) with activity against dividing B cells. It consists of three components: 1) the humanized ImmunoGlobulin G1 (IgG1) monoclonal antibody specific for human CD79b; 2) the small molecule anti-mitotic agent MMAE (monomethyl auristatin E) and 3) a protease-cleavable linker that covalently attaches MMAE to the Polatuzumab antibody. Upon binding to CD79b, POLIVY® is internalized, and the linker is cleaved by lysosomal proteases thus enabling intracellular delivery of MMAE. MMAE then binds to microtubules and kills dividing cells by inhibiting cell division and inducing apoptosis.

The present FDA approval was based on an open-label, randomized, multicenter, Phase II clinical trial (Study GO29365) which included a cohort of 80 transplant-ineligible patients with Relapsed or Refractory DLBCL. Patients who had received at least one prior regimen were randomized (1:1) to receive either POLIVY® in combination with Bendamustine and RITUXAN® (Rituximab) or GAZYVA® (Obinutuzumab) – (P+BR) or BR alone, every 21 days for up to 6 cycles. RITUXAN® or GAZYVA® were administered on day 1 of each cycle at 375 mg/m2 intravenously IV or 1000 mg IV respectively, POLIVY® 1.8 mg/kg IV, was given on day 2 of cycle 1 and on day 1 of subsequent cycles and Bendamustine 90 mg/m2 IV was administered on days 2 and 3 of cycle 1 and on days 1 and 2 of subsequent cycles. The median age was 68 years.

The Primary aim of this study was to assess the efficacy of P+BR versus BR at end of treatment, by an Independent Review Committee (IRC). Responses were assessed using the modified Lugano Classification, and Complete Response (CR) required Positron Emission Tomography (PET) negativity and negative bone marrow biopsy, if positive or unknown at the time of screening. Other end points included Duration of Response (DoR), Progression Free Survival (PFS) and Overall Survival (OS). Efficacy was also evaluated based on Cell of Origin – Activated B-cell-like (ABC), Germinal B-cell-like (GCB), as well as MYC/BCL2 double expression. The median follow up for this cohort of patients was 22.3 months.

The combination of POLIVY® plus BR (P+BR) showed significantly higher PET-CR rates vs BR alone (40% vs 18%; P=0.026). The Objective Response Rate (ORR) was 45% vs 18% with a significantly longer DoR of 10.3 months vs 4.1 months (HR=0.44; P=0.032), favoring P+BR regimen. Among those who achieved Partial or Complete Response to P+BR, 64% had response durations of at least six months and 48% had response durations of at least 12 months. The PFS was 7.6 months vs 2 months (HR=0.34; P<0.0001) and OS was 12.4 months vs 4.7 months (HR=0.42; P=0.0023), all favoring P+BR over BR. For ABC patients the median PFS with P+BR was 10.5 months vs 2.5 months for BR and the median OS was 13.9 vs 4.3 months, respectively. For GCB patients, median PFS with P+BR was 4.7 vs 1.5 months for BR and the median OS was 9.3 vs 3.2 months, respectively. Among those with MYC/BCL2 Double Expression, the median PFS was 7.0 months vs 0.7 months with P+BR, and median OS was 12.9 vs 3.8 months compared to BR. For non-Double Expression group of patients, the median PFS was 6.3 months vs 2.5 months and median OS was 10.5 vs 3.8 months with P+BR vs BR, respectively.

It was concluded that a combination of POLIVY® given along with Bendamustine and RITUXAN® or GAZYVA® provides a promising treatment option for Relapsed/Refractory DLBCL patients who are transplant ineligible, with durables responses in some patients of over 20 months and median OS surpassing 12 months. Polatuzumab vedotin (Pola) plus bendamustine (B) with rituximab (R) or obinutuzumab (G) in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): updated results of a phase (Ph) Ib/II study. Sehn LH, Herrera AF, Matasar MJ, et al. Blood. 2018;132:1683.

Five-Year Outcomes with TAFINLAR® plus MEKINIST® in Metastatic Melanoma

SUMMARY: It is estimated that in the US, approximately 96,480 new cases of Melanoma will be diagnosed in 2019 and about 7,230 patients are expected to die of the disease. The incidence of Melanoma has been on the rise for the past three decades. Surgical resection with a curative intent is the standard of care for patients with early stage Melanoma, with a 5-year survival rate of 98% for stage I disease and 90% for stage II disease. Patients with locally advanced or metastatic Melanoma historically have had poor outcomes. With the development and availability of immune checkpoint inhibitors and BRAF and MEK inhibitors, this patient group now has significantly improved outcomes. In treatment naïve patients receiving anti-PD-1 therapies such as KEYTRUDA® (Pembrolizumab) or OPDIVO® (Nivolumab) in phase 3 trials, the Progression Free Survival (PFS) rates have ranged from 27-31%, with an Overall Survival (OS) rate of 46% at 4 years. The 5-year OS among patients receiving KEYTRUDA® was 43%, and in those treated with a combination of OPDIVO® plus YERVOY® (Ipilimumab), 4-year PFS and OS rates were 37% and 53%, respectively.BRAF-and-MEK-Inhibition-in-MAPK-Pathway

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been detected in 6-8% of all malignancies. The most common BRAF mutation in Melanoma is at the V600E/K site and is detected in approximately 50% of Melanomas, and result in constitutive activation of the MAPK pathway.

TAFINLAR® (Dabrafenib), is a selective oral BRAF inhibitor and MEKINIST® (Trametinib) is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway. It has been well established that patients who have unresectable or metastatic Melanoma with a BRAFV600E or V600K mutation have prolonged PFS and OS when treated with a combination of BRAF and MEK inhibitors. However, long-term 4 and 5-year clinical outcomes in these patient’s have not been reported.

Two randomized Phase III trials helped address this issue. COMBI-d involved 423 patients randomized to TAFINLAR® plus MEKINIST® (N=211) or to TAFINLAR® plus placebo (N=212). In COMBO-v, 704 patients were randomized to TAFINLAR® plus MEKINIST® (N=352) or to single-agent ZELBORAF® (Vemurafenib; N=352). In a previously published pooled analysis of patients treated in the COMBI-d and COMBI-v trials, 3-year PFS and OS were 23% and 44% respectively. Further, there was a significant association between several baseline factors such as performance status, age, sex, number of organ sites with metastasis, serum LDH level and both PFS as well as OS.

In this review, the researchers analyzed pooled long term survival data from two randomized Phase III COMBI-d and COMBI-v trials, which involved previously untreated, unresectable or metastatic Melanoma patients, with BRAFV600E or V600K mutation, who had received BRAF inhibitor TAFINLAR® 150 mg orally twice daily along with a MEK inhibitor MEKINIST® 2 mg orally once daily. These two trials evaluated the efficacy and safety of TAFINLAR® plus MEKINIST®, as compared with BRAF inhibitor monotherapy. The long term, 5-year survival data from these two trials was reported, along with clinical characteristics of the patients who derived long-term benefit from this treatment. The Primary end points in the COMBI-d and COMBI-v trials were PFS and OS, respectively. The median patient age in these trials was 55 years, 3% of patients had nonmetastatic disease and two-thirds had M1c metastatic disease.

A total of 563 patients (211 in the COMBI-d trial and 352 in the COMBI-v trial) were randomly assigned to receive TAFINLAR® plus MEKINIST®. The PFS rates were 21% at 4 years and 19% at 5 years. The OS rates were 37% at 4 years and 34% at 5 years. The 5-year OS rate was 71% among patients who had a Complete Response and 55% among those who had a normal Lactate Dehydrogenase level plus fewer than three metastatic organ sites at baseline.

It was concluded that first-line treatment with TAFINLAR® plus MEKINIST® led to long-term benefit in approximately one third of the patients who had unresectable or metastatic Melanoma with a BRAF V600E or V600K mutation. The authors added that this is the largest data set and longest follow-up in this patient population treated with BRAF and MEK inhibitors. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. Robert C, Grob JJ, Stroyakovskiy D, et al. June 4, 2019. DOI: 10.1056/NEJMoa1904059

Late Breaking Abstract – ASCO 2019 XTANDI® Improves Overall Survival in Metastatic Hormone-Sensitive Prostate Cancer

SUMMARY: 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 174,650 new cases of Prostate cancer will be diagnosed in 2019 and 31,620 men will die of the disease. The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer and is the first treatment intervention.

The first-generation NonSteroidal Anti-Androgen (NSAA) agents such as EULEXIN® (Flutamide), CASODEX® (Bicalutamide) and NILANDRON® (Nilutamide) act by binding to the Androgen Receptor (AR) and prevent the activation of the AR and subsequent up-regulation of androgen responsive genes. They may also accelerate the degradation of the AR. These agents have a range of pharmacologic activity from being pure anti-androgens to androgen agonists. CASODEX® is a nonsteroidal oral anti-androgen, that is often prescribed along with GnRH (Gonadotropin-Releasing Hormone) agonists for metastatic disease, or as a single agent second line hormonal therapy for those who had progressed on LHRH agonists. XTANDI® (Enzalutamide) is an orally administered, second-generation, anti-androgen, with no reported agonistic effects. It competitively inhibits androgens and AR binding to androgens as well as AR nuclear translocation and interaction with DNA. It thus inhibits several steps in the AR signaling pathway and was designed to overcome acquired resistance to first-generation nonsteroidal anti-androgens. Previously published studies have shown that XTANDI® improved Overall Survival in Castration-Resistant Prostate Cancer, regardless of whether it was used before or after Docetaxel chemotherapy. The benefits of adding Docetaxel or ZYTIGA® (Abiraterone) to testosterone suppression in men with metastatic, hormone-sensitive Prostate cancer have been established in randomized clinical trials.XTANDI - Mechanism-of-Action

ENZAMET (Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer) is an open-label, international, randomized, Phase III trial, conducted to evaluate the benefits of adding XTANDI® to initial standard treatment of Androgen Deprivation Therapy (ADT) with or without early Docetaxel, among patients with metastatic hormone-sensitive Prostate cancer.

A total of 1125 men with metastatic hormone-sensitive Prostate cancer were randomly assigned 1:1 to receive either ADT plus XTANDI® or NonSteroidal Anti-Androgens (NSAA). ADT consisted of parenteral injection of a testosterone-suppressing agent (such as Goserelin, Leuprolide, or Degarelix) with either a 160 mg dose of XTANDI® daily or one of the standard NSAA’s such as CASODEX®, EULEXIN® or NILANDRON®. Of the 1,125 men enrolled in the trial, 503 men received early doses of Docetaxel, and 602 did not. The decision to initiate early treatment with Docetaxel was at the treating physician’s discretion and was administered at 75 mg/m2 IV without prednisone every 3 weeks for a maximum of six cycles. Randomized patients were stratified according to the volume of disease (High Risk- defined as the presence of visceral metastases or at least four bone lesions with at least one lesion located beyond the vertebral bodies and pelvis or low), planned use of early Docetaxel, planned use of bone antiresorptive therapy, and score on ACE-27 (Adult Comorbidity Evaluation 27), with no coexisting conditions rated as 0, mild rated as 1, moderate rated as 2, and severe or multiple conditions rated as 3. The mean age was 68 years, 45% of patients received early Docetaxel as planned treatment and over 50% of the patients had high volume disease. The Primary end point was Overall Survival (OS) and Secondary end points included Progression Free Survival (PFS) as determined by the PSA level, clinical PFS, and adverse events. The median follow up was 34 months.

At the time of the first interim analysis, there was a 33% reduction in the risk of death in the XTANDI® group compared to the standard treatment group ((HR=0.67; P<0.002) and the estimated Overall Survival at 3 years were 80% in the XTANDI® group and 72% in the standard-of-care group. The addition of XTANDI® also improved PSA Progression Free Survival with a 61% reduction in the risk of PSA progression (HR=0.39; P<0.001) and 60% improvement in clinical PFS (HR=0.40; P<0.001). The effects of XTANDI® on clinical PFS were noted in all predefined subgroups, including those with early Docetaxel treatment. Among the patient group who also received early Docetaxel treatment, there was however no significant improvement in Overall Survival. Adding XTANDI® to standard ADT was associated with a higher frequency of toxic effects, especially peripheral neuropathy, associated with the concomitant use of Docetaxel, fatigue and slightly higher risk of seizures compared to standard therapy, and more patients discontinued treatment due to adverse events in the XTANDI® group.

It was concluded that XTANDI® was associated with significantly longer Progression Free Survival and Overall Survival than standard intervention, in men with metastatic, hormone-sensitive Prostate cancer receiving Androgen Deprivation Therapy. Patients who received early Docetaxel treatment, however did not have significant survival benefit. The authors added that ENZAMET is the first metastatic hormone-sensitive Prostate cancer trial to report Overall Survival data of an androgen receptor inhibitor (XTANDI®), and outcomes among a set of patients who also concurrently received Docetaxel. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. Davis ID, Martin AJ, Stockler MR, et al. for the ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. June 2, 2019. DOI: 10.1056/NEJMoa1903835

KEYTRUDA® (Pembrolizumab)

The FDA on June 10, 2019 approved KEYTRUDA® for the first-line treatment of patients with metastatic or unresectable recurrent Head and Neck Squamous Cell Carcinoma (HNSCC). KEYTRUDA® is a product of Merck.

POLIVY® (Polatuzumab vedotin-piiq)

The FDA on June 10, 2019 granted accelerated approval to POLIVY®, a CD79b-directed Antibody-Drug Conjugate indicated in combination with Bendamustine and a Rituximab product for adult patients with relapsed or refractory Diffuse Large B-Cell Lymphoma (DLBCL), Not Otherwise Specified, after at least two prior therapies. POLIVY® is a product of Genentech, Inc.

XOSPATA® (Gilteritinib)

The FDA on May 29, 2019 approved the addition of overall survival data in labeling for XOSPATA®, indicated for adult patients who have relapsed or refractory Acute Myeloid Leukemia (AML) with a FLT3 mutation, as detected by an FDA-approved test. XOSPATA® is a product of Astellas Pharma US, Inc.

Late Breaking Abstract – ASCO 2019 Five-Year Survival Data for KEYTRUDA® 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 and 27% of all cancer deaths. The American Cancer Society estimates that for 2019 about 228,150 new cases of lung cancer will be diagnosed and 142,670 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. High level of Programmed Death-Ligand 1 (PD-L1) expression is defined as membranous PD-L1 expression on at least 50% of the tumor cells, regardless of the staining intensity. It is estimated that based on observations from previous studies, approximately 25% of the patients with advanced 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-PD-1-and-PDL1-Antibodies

The FDA approved KEYTRUDA® for the first-line treatment of patients with Stage III Non-Small Cell Lung Cancer (NSCLC) who are not candidates for surgical resection or definitive chemoradiation, as well as those with metastatic NSCLC whose tumors express PD-L1 (Tumor Proportion Score-TPS of 1% or more), as determined by an FDA-approved test. KEYTRUDA® is also approved for the first-line treatment of advanced NSCLC with high PD-L1 expression (Tumor Proportion Score of 50% or more), based on KEYNOTE-024 trial, as well as in combination with Pemetrexed and Carboplatin, as first-line treatment of patients with metastatic non-squamous NSCLC, based on KEYNOTE-021 study. It is also indicated for previously treated advanced NSCLC with a much lower level of PD-L1 expression such as PD-L1 Tumor Proportion Score of 1% or higher, based on KEYNOTE-010 trial.

The authors in this publication presented the 5-year Overall Survival (OS) for patients enrolled in the Phase 1b KEYNOTE-001 study, which was the first trial evaluating KEYTRUDA® in advanced NSCLC. In this trial, 550 patients were enrolled of whom 101 patients were treatment-naïve (N=101) and 449 patients were previously treated (N=449). Patients received KEYTRUDA® 2 mg/kg IV every 3 weeks or KEYTRUDA® 10 mg/kg IV every 2 or 3 weeks. The protocol in the recent years was changed to a straight dose of KEYTRUDA® 200 mg IV every 3 weeks, which is the typical regimen used in clinical practice. The Primary endpoint was Objective Response Rate (ORR). Secondary endpoints included Progression Free Survival (PFS), Overall Survival (OS) and Duration of Response (DOR). The median follow up was 60.6 months and 18% of participants (N=100) were still alive at that point.

The 5-year OS in the treatment-naïve patients (N=101) was 23.2% and 15.5% in previously treated patients (N=449). In treatment-naive patients, the 5-year OS rate among patients whose tumors expressed PD-L1 expression of 50% or more was 29.6%, compared with 15.7% with PD-L1 expression levels below 50%. In patients who had received previous treatment, the 5-year OS rate among patients whose tumors expressed PD-L1 expression of 50% or more was 25% compared with 12.6% with PD-L1 expression levels between 1% and 49%. Only 3.5% of people with PD-L1 expression levels below 1% were alive after 5 years. The investigator-reported ORR was 41.6% in treatment-naïve patients and 22.9% in previously treated patients. Median Duration of Response was 16.8 months and 38.9 months respectively. Immune-mediated adverse events were reported in 17% of patients at 5 years. Hypothyroidism was the most commonly reported immune-mediated adverse event, followed by pneumonitis, hyperthyroidism and skin toxicities.

It was concluded that the 5-year data from the KEYNOTE-001 trial showed that treatment with KEYTRUDA® was safe and effective and substantially increased Overall Survival in patients with advanced NSCLC. These data provide the longest efficacy and safety follow-up for NSCLC patients treated with KEYTRUDA®. Five-year long-term overall survival for patients with advanced NSCLC treated with pembrolizumab: Results from KEYNOTE-001. Garon EB, Hellmann MD, Costa EC, et al. J Clin Oncol. 2019;37(suppl; abstract LBA9015).