Author: RR

FDA Approves KEYTRUDA® for Advanced Small Cell Lung Cancer

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SUMMARY: The FDA on June 17, 2019 granted accelerated approval to KEYTRUDA® (Pembrolizumab) for patients with metastatic Small Cell Lung Cancer (SCLC) with disease progression on or after Platinum-based chemotherapy, and at least one other prior line of therapy. The American Cancer Society estimates that for 2019 about 228,150 new cases of lung cancer will be diagnosed and about 142,670 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Small cell lung cancer (SCLC) accounts for approximately 13-15% of all lung cancers, and is aggressive. Patients with SCLC are often treated with platinum based chemotherapy as first-line treatment, and the tumor response rates are as high as 60-80%. However, only 20% of patients with Limited Stage SCLC are cured, and majority of the patients relapse within months of completing initial therapy. Patients often receive HYCAMTIN® (Topotecan) for recurrent or progressive SCLC (second-line treatment) and after failure on second-line therapy, treatment options are limited. The 5 year survival rate for Extensive Stage SCLC is less than 5%, with a median survival of 9-10 months from the time of diagnosis.

KEYTRUDA® is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells.

The present FDA approval was based on pooled data from two Basket studies, KEYNOTE-158 (cohort G) and KEYNOTE-028 (cohort C1), which are two multicenter, multi-cohort, non-randomized, open-label trials, evaluating KEYTRUDA® in patients with SCLC, who had disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy. In Basket trials, patients with different tumor histologies receive a single treatment and have a single biomarker. Among the 83 patients evaluated in both these studies for efficacy, 64% received two prior lines of therapy and 36% received three or more lines of therapy; 60% received prior thoracic radiation therapy; 51% received prior radiation therapy to the brain. Patients in the KEYNOTE-028 were required to have tumors expressing PD-L1, whereas PD-L1 positivity was not required for KEYNOTE-158. Patients in the KEYNOTE-028 study received KEYTRUDA® 10 mg/kg IV every 2 weeks (N=19), whereas those in KEYNOTE-158 received KEYTRUDA® 200 mg IV every 3 weeks (N=64). Treatment was continued until documented disease progression, unacceptable toxicity, or a maximum of 24 months. The major efficacy outcome measures included Objective Response Rate (ORR) and Duration of Response (DOR).

Treatment with KEYTRUDA® resulted in an Overall Response Rate of 19%, with a Complete Response Rate of 2% and a Partial Response Rate of 17%. Of the responding patients, 94% had a Duration of Response (DOR) of 6 months or longer, 63% had a DOR of 12 months or longer, and 56% had a DOR of 18 months or longer. Responses ranged from 4.1 to over 35.8 months. Adverse Events were similar to those occurring in patients with other solid tumors who received KEYTRUDA® as a single agent and the common adverse reactions included fatigue, decreased appetite, cough, nausea and constipation.

It was concluded that this new indication marks the first FDA approval for KEYTRUDA® in Small Cell Lung Cancer, and provides an additional treatment option for patients with advanced stage disease, based on clinical response rates. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-metastatic-small-cell-lung-cancer

Prognostic Value of Progesterone Receptor in Estrogen Receptor-Positive, HER-2 Negative Breast Cancer

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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 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. About 70% of breast tumors express Estrogen Receptors (ER) and/or Progesterone Receptors (PR) and these patients are often treated with anti-estrogen therapy.

It has been well established that the detection of Estrogen, Progesterone and HER-2 neu receptors on the tumor cell expressed either alone or together, is a significant prognostic factor, and is associated with the conditional gene expression in the tumor cell itself. The St. Gallen International Expert Consensus in 2011 classified breast cancer into five molecular subtypes with prognostic significance, based on these genetically determined expressions in the tumor cell. The five molecular subtypes of breast cancer include 1) Luminal A (ER+ and/or PR+, HER-2 negative, Ki-67 less than 14%) constituting about 26% of patients 2) Luminal B with HER-2 negative (ER+ and/or PR+, HER-2 negative, Ki-67 14% or more) constituting about 32% 3) Luminal B with HER-2 positive (ER+ and/or PR+, HER-2+, any Ki-67) constituting about 25% 4) HER-2 enriched (ER-, PR-, HER-2+) accounting for about 8% of patients 5) Basal-like (triple negative) (ER-, PR-, HER-2 negative, CK5/6+ and/or EGFR+) constituting about 9% of all breast cancer patients. According to the 2015 St. Gallen guidelines, adjuvant chemotherapy can avoided in Luminal A patients, whereas patients with ER+ HER-2 negative tumors with low or no PR expression or with high Ki-67 expression are considered to have a high risk of relapse and adjuvant chemotherapy is often recommended. It should be noted however that low PR expression in Luminal A patients can carry a poor prognosis as well.

The Progesterone Receptor (PR) is a member of the nuclear receptor family and is regulated by the Estrogen Receptor. It is expressed in over two-thirds of ER-positive breast cancers and is more highly expressed in the Luminal A breast cancer subtype. Several studies have demonstrated improved prognosis among PR-positive breast cancer patients. Further, in ER+, HER-2 negative breast cancers, the Progesterone Receptor is an independent prognostic marker. However, the prognostic value of PR by tumor grade has been unclear.

The authors hypothesized that patient with high-grade tumors might do well if PR is positive. The objective of this study therefore was to study the prognostic value of PR in tumors with high tumor proliferative index, using tumor grade as a surrogate for the proliferative activity of ER+, HER-2 negative breast cancer. This retrospective study included women with primary operable, invasive, ER+ HER-2 negative breast cancer, diagnosed between 2000 and 2012, treated at University Hospitals Leuven. The association of PR status and subtype (Grade 1-2 versus Grade 3) was assessed with Distant Recurrence Free Interval (DRFI) and Breast Cancer specific survival. The data set from BIG 1-98 trial was used for validation. A total of 4,228 patients from Leuven and 5,419 from BIG 1-98 were analyzed. The median patient age was 58 years, 73% had Luminal A-like subtype, 27% had Luminal B-like subtype, lymph node status was predominantly negative (62%) and PR was positive in 89% of patients. Median tumor size was 2.1 cm and most of the patients received adjuvant endocrine therapy (96%) and/or radiotherapy (87%). Adjuvant chemotherapy was administered to 29% of the patients. The median follow up period was 8.6 years.

It was noted in this study that PR positive tumors were more strongly associated with better prognosis in Luminal B-like than in Luminal A-like breast cancer, suggesting that PR is more prognostic in Luminal B-like versus Luminal A-like tumors. Among the Luminal B-like tumors, the 5-year cumulative incidences of distant recurrence were 18.7% in PR negative and 9.2% in PR positive tumors. 

It was concluded PR positivity may be more protective against metastatic relapse in Luminal B-like versus Luminal A-like breast cancer. An absent PR is a clinically more important negative prognostic factor in tumors with a high proliferative index than in low proliferative ER+ HER-2 negative breast tumors. Prognostic Value of the Progesterone Receptor by Subtype in Patients with Estrogen Receptor-Positive, HER-2 Negative Breast Cancer. Van Astena K, Slembroucka L, Olbrecht S, et al. The Oncologist 2019;24:165-171

XPOVIO® (Selinexor)

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The FDA on July 3, 2019 granted accelerated approval to XPOVIO® in combination with Dexamethasone for adult patients with Relapsed or Refractory Multiple Myeloma (RRMM) who have received at least four prior therapies, and whose disease is refractory to at least two Proteasome Inhibitors, at least two Immunomodulatory agents, and an anti-CD38 monoclonal antibody. XPOVIO® is a product of Karyopharm Therapeutics.

DARZALEX® (Daratumumab)

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The FDA on June 27, 2019 approved DARZALEX® in combination with REVLIMID® (Lenalidomide) and Dexamethasone for patients with newly diagnosed Multiple Myeloma who are ineligible for Autologous Stem Cell Transplant. DARZALEX® is a product of Janssen Biotech, Inc.

KEYTRUDA® (Pembrolizumab)

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The FDA on June 17, 2019 granted accelerated approval to KEYTRUDA® for patients with metastatic Small Cell Lung Cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy. KEYTRUDA® is a product of Merck.

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

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 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

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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 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

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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

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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

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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