FDA Approves DOPTELET® for Thrombocytopenia in Chronic Liver Disease

SUMMARY: The FDA on May 21, 2018, approved DOPTELET® (Avatrombopag) for thrombocytopenia in adults with Chronic Liver Disease (CLD) scheduled to undergo a procedure. Thrombocytopenia is the most common hematological abnormality encountered in patients with Chronic Liver Disease (CLD), occurring in 65-85% of patients. Thrombocytopenia is an indicator of advanced disease and is associated with a poorer prognosis, and can impact routine care of patients with CLD, interfering with diagnostic and therapeutic interventions. Therefore treatment options that can safely and effectively raise platelet levels could have a significant impact on care of these patients.

The cause of thrombocytopenia in CLD is multifactorial and can be due to decreased production, splenic sequestration, and increased destruction. Thrombopoietin (TPO) regulates platelet production and maturation, and CLD is associated with depressed Thrombopoietin levels . Bone marrow suppression can be also be caused by alcohol, viruses, medications and iron overload. Hypersplenism causes splenic platelet sequestration. Increased platelet destruction in cirrhosis can be due to increased shear stress, increased fibrinolysis, increased platelet aggregation related to infections, or immune mediated platelet destruction secondary to antiplatelet antibodies.

DOPTELET® (Avatrombopag), a second generation orally administered Thrombopoietin Receptor Agonist (TPO-RA), designed to mimic the effects of TPO, the primary regulator of normal platelet production. DOPTELET® stimulates the proliferation and differentiation of megakaryocytes from bone marrow progenitor cells and results in increased production of platelets.

The approval of DOPTELET® by the FDA was based on two identically designed, international, randomized, double-blind, placebo-controlled phase III trials, ADAPT-1 (N=231) and ADAPT-2 (N=204). In these two studies totaling 430 patients with Chronic Liver Disease and thrombocytopenia (N=430), patients were randomized 2:1 to DOPTELET® (N=274) or placebo (N=156) daily for 5 days prior to a scheduled procedure, and had at least 1 post-dose safety assessment. Patients randomized to DOPTELET® received differential dosing based on mean platelet count at entry. Patients with a baseline platelet count less than 40,000/uL (low baseline platelet cohort) received DOPTELET® 60 mg orally once daily for 5 consecutive days. Those with a baseline platelet count of 40,000 to less than 50,000/uL (high baseline platelet cohort) received DOPTELET® 40 mg orally once daily for 5 consecutive days. Eligible patients were scheduled to undergo their procedure 5 to 8 days after the last dose of study drug. Patients were stratified according to HepatoCellular Cancer status and bleeding risk associated with the elective procedure (low, moderate, or high). The Primary efficacy endpoint was the proportion of patients, or responders, who did not require a platelet transfusion or any rescue procedure for bleeding after randomization, and for up to 7 days following an elective procedure.

In both trials, DOPTELET® exhibited superiority compared to placebo, in increasing the proportion of patients not requiring platelet transfusions or rescue procedures for bleeding up to 7 days, following a scheduled procedure. In the low baseline platelet cohort, 66% and 69% of patients treated with DOPTELET® responded in the ADAPT-1 and ADAPT-2 trials, respectively. For those receiving placebo, 23% (treatment difference 43%, P<0.0001) and 35% (treatment difference 34%, P=0.0006) responded in the ADAPT-1 and ADAPT-2 trials, respectively. In the high baseline platelet cohort, 88% of DOPTELET®-treated patients in both trials responded compared to 38% and 33% of placebo-treated patients. Treatment difference was 50% (P<0.0001) in the ADAPT-1 trial and 55% (P<0.0001) in the ADAPT-2 trial. Additionally, DOPTELET® was statistically superior to placebo at the two Secondary efficacy endpoints in each trial which included proportion of patients with platelet count of 50,000/uL or more by procedure day, and mean change in the platelet count from baseline to procedure day. The most common adverse reactions reported in at least 3% of patients were pyrexia, abdominal pain, nausea, headache, fatigue, and peripheral edema.

It was concluded that DOPTELET® is the first orally administered treatment option approved by the FDA for patients with Chronic Liver Disease who routinely undergo multiple, invasive procedures. The availability of this new oral agent can lead to a measured increase in platelets and minimize the risk of bleeding and need for platelet transfusions. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm608323.htm

KISQALI® plus FASLODEX® Improve Progression Free Survival in Advanced Breast Cancer

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 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients.

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

KISQALI® (Ribociclib) is an orally bioavailable, selective, small-molecule inhibitor of CDK4/6 that blocks the phosphorylation of RetinoBlastoma protein, thereby preventing cell-cycle progression and inducing G1 phase arrest. KISQALI® in combination with an Aromatase Inhibitor has been approved by the FDA for pre and perimenopausal women with HR (Hormone Receptor)-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine-based therapy. The efficacy of KISQALI® was evaluated in two prior randomized phase III studies. In the MONALEESA-2 trial which evaluated KISQALI® in combination with FEMARA® (Letrozole) compared to FEMARA® alone, in postmenopausal women with HR-positive, HER2-negative advanced breast cancer who received no prior therapy for their advanced breast cancer, the addition of KISQALI® to FEMARA® significantly prolonged Progression Free Survival (PFS) compared to FEMARA® alone. In the MONALEESA-7 study, KISQALI® in combination with Tamoxifen or a Non-Steroidal Aromatase Inhibitor plus ZOLADEX® (Goserelin) was compared with Tamoxifen or an Aromatase Inhibitor plus ZOLADEX®, in premenopausal or perimenopausal women with HR-positive, HER2- negative advanced breast cancer, who had not previously received endocrine therapy for advanced disease. In this study of premenopausal women, KISQALI® plus endocrine therapy significantly improved PFS compared with placebo plus endocrine therapy

MONALEESA-3 is a randomized, double-blind, placebo-controlled Phase III study which compared the efficacy of KISQALI® in combination with FASLODEX® with FASLODEX® alone, among postmenopausal women with HR-positive, HER2-negative advanced breast cancer who received no prior or only one line of prior endocrine therapy for advanced disease. In this trial, 726 women were randomized, of whom 367 were treatment-naïve and 345 patients had received up to one line of prior endocrine therapy for advanced disease. . Patients were randomized 2:1 to receive KISQALI® plus FASLODEX® (N=484) or placebo plus FASLODEX® (N=242). Treatment consisted of KISQALI® 600 mg orally daily 3 weeks on and 1 week off and FASLODEX® 500 mg IM on day 1 of each 28-day cycle, with an additional dose given on day 15 of cycle 1. Patients were stratified by the presence or absence of lung or liver metastases and prior endocrine therapy (first-line versus second-line). The median age in both groups was 63 years. The Primary endpoint was Progression Free Survival. Secondary end points included Overall Survival, Overall Response Rate, and Safety. The median time from randomization to data cutoff was 20.4 months.

Among all randomized patients, the median PFS in the KISQALI® plus FASLODEX® group was 20.5 months compared to 12.8 months in the FASLODEX® plus placebo group (HR= 0.59; P<0.001). This represented a 41% reduction in the risk of disease progression. The PFS benefit was consistent among the 367 patients who were treatment-naïve (HR=0.57) and 345 patients had received up to one line of prior endocrine therapy for advanced disease (HR=0.56). In the subgroup of patients taking KISQALI® plus FASLODEX® as first-line treatment, the median PFS was not reached and 70% were estimated to remain Progression Free at median follow up of 16.5 months. Among those patients with measurable disease at baseline, the Overall Response Rate was 40.9% for the KISQALI® plus FASLODEX® arm versus 28.7% for FASLODEX® plus placebo group (P=0.003). At first interim analysis, the Overall Survival data were immature. The most common grade 3/4 Adverse Events in patients receiving KISQALI® plus FASLODEX® compared to FASLODEX® alone were neutropenia (53.4% versus 0%) and leukopenia (14.1% versus 0%).

It was concluded that KISQALI® plus FASLODEX® might represent a new, first or second-line treatment option for patients with Hormone Receptor-positive, Human Epidermal growth factor Receptor 2-negative advanced breast cancer. MONALEESA-3 is the only randomized Phase III trial to study a CDK4/6 inhibitor plus FASLODEX® in the first-line setting, with demonstrable efficacy in patients with de novo advanced breast cancer and those who had not received adjuvant therapy in more than a year. Ribociclib (RIB) + fulvestrant (FUL) in postmenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2 –) advanced breast cancer (ABC): Results from MONALEESA-3. Slamon DJ, Neven P, Chia SKL, et al. J Clin Oncol. 2018: 36, (suppl; abstr 1000).

FDA Approves LENVIMA® for Unresectable Hepatocellular Carcinoma

SUMMARY: The FDA on August 16, 2018, approved LENVIMA® (Lenvatinib) for first-line treatment of patients with unresectable HepatoCellular Carcinoma (HCC). The American Cancer Society estimates that for 2018, about 42,220 new cases of primary liver cancer will be diagnosed in the US and 30,200 patients will die of their disease. Liver cancer is seen more often in men than in women and the incidence has more than tripled since 1980. This increase has been attributed to the higher rate of Hepatitis C virus (HCV) infection among baby boomers (born between 1945 through 1965). Obesity and type II diabetes have also likely contributed to the trend. Other risk factors include alcohol, which increases liver cancer risk by about 10% per drink per day, and tobacco use which increases liver cancer risk by approximately 50%. HepatoCellular Carcinoma (HCC) is the second most common cause of cancer-related deaths worldwide.

NEXAVAR® (Sorafenib) was approved by the FDA in 2007 for the treatment of unresectable HepatoCellular Carcinoma (HCC) and is the only approved agent for the first line treatment of unresectable HCC. LENVIMA® is an oral multitargeted TKI which targets Vascular Endothelial Growth Factor Receptor (VEGFR) 1-3, Fibroblast Growth Factor Receptor (FGFR) 1-4, Rearranged during Transfection tyrosine kinase receptor (RET), c-KIT, and Platelet Derived Growth Factor Receptor (PDGFR). LENVIMA® differs from other TKIs with antiangiogenesis properties by its ability to inhibit FGFR-1, thereby blocking the mechanisms of resistance to VEGF/VEGFR inhibitors. In addition, it controls tumor cell growth by inhibiting RET, c-KIT, and PDGFR beta and influences tumor microenvironment by inhibiting FGFR and PDGFR beta. Based on the activity of LENVIMA® in unresectable HCC in a phase II trial, the efficacy of LENVIMA® was evaluated comparing this agent with NEXAVAR® in treatment naïve patients with unresectable HCC.Multikinase-Inhibition-by-Lenvatinib

This present approval by the FDA was based on an international, multicenter, randomized, open-label, noninferiority trial (REFLECT study) in which 954 patients with previously untreated, metastatic or unresectable HCC were randomized in a 1:1 ratio to receive LENVIMA® 12 mg orally once daily for patients with a baseline body weight of 60 kg or more and 8 mg orally once daily for patients with a baseline body weight of less than 60 kg (N=478) or NEXAVAR® 400 mg orally twice daily (N=476). Treatment was continued until radiological disease progression or unacceptable toxicity. Patients had one or more measurable target lesions, Barcelona Clinic Liver Cancer (BCLC) Stage B or C, Child-Pugh Class A, ECOG PS of 1 or less, and no prior systemic therapy. Baseline characteristics were similar in both treatment groups. The median age was 62 years, the most common Child-Pugh class was A (99%) and 79% of patients had BCLC stage C disease. Twenty percent (20%) of patients had 3 or more sites of disease involvement, and 50% of patients had underlying Hepatitis B infection. The median baseline AFP level was 133 ng/mL in the LENVIMA® group and 71 ng/mL in the NEXAVAR® group. The Primary endpoint of this study was noninferiority for Overall Survival (OS). Secondary efficacy endpoints included Progression Free Survival (PFS), Time to Progression (TTP) and Objective Response Rate (ORR).

In this study, LENVIMA® was noninferior, but not statistically superior to NEXAVAR® for Overall Survival (HR=0.92). The median OS in the LENVIMA® arm was 13.6 months and 12.3 months in the NEXAVAR® arm. There was however a statistically significant improvement in Progression Free Survival with LENVIMA® when compared to NEXAVAR®, with a median PFS of 7.3 months in the LENVIMA® group 3.6 months in the NEXAVAR® arm (HR=0.64; P<0.0001). The Objective Response Rate was higher for the LENVIMA® group as compared to NEXAVAR® group – 40.6% versus 12.4% per modified RECIST assessment (P<0.0001). The median TTP in this review was 8.9 months with LENVIMA® versus 3.7 months for NEXAVAR® (HR=0.60; P<0.0001). More patients in the LENVIMA® group experienced hypertension, decreased weight, proteinuria and decreased platelet count, whereas Palmar Plantar Erythrodysesthesia and diarrhea were more common in the NEXAVAR® group.

It was concluded that LENVIMA® is noninferior to NEXAVAR® in OS, and achieves statistically significant and clinically meaningful improvements in PFS, TTP, and ORR as first line therapy, for patients with HepatoCellular Carcinoma. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Kudo M, Finn RS, Qin S, et al. The Lancet 2018;391:1163-1173

FDA Approves OPDIVO® for Metastatic Small Cell Lung Cancer

SUMMARY: The FDA on August 16, 2018, granted accelerated approval to OPDIVO® (Nivolumab), for patients with metastatic Small Cell Lung Cancer (SCLC) with progression after platinum-based chemotherapy and at least one other line of therapy. 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 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 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. The only FDA-approved agent for recurrent or progressive SCLC (second-line treatment) is HYCAMTIN® (Topotecan) and there is presently no standard therapy, after failure on second-line therapy. The 5 year survival rate for Extensive Stage SCLC is less than 5%, with a median survival of 9 to 10 months from the time of diagnosis.Unleashing-T-Cell-Function-with-PD-1-and-PD-L1-Antibodies

OPDIVO® is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor (Checkpoint proteins) and blocks its interaction with PD-L1 and PD-L2. Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response.

The present FDA approval for OPDIVO® was based on the results of phase I/II CheckMate-032 trial, which is a multicenter, open-label, ongoing study. This study included 245 patients with SCLC who experienced disease progression after platinum-based chemotherapy. Efficacy data was submitted by the investigators to the FDA from 109 patients who received OPDIVO® after disease progression on platinum-based chemotherapy and at least one other prior line of therapy, to support this present indication. Patients received OPDIVO® 3 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity. The first tumor assessments were conducted 6 weeks after the first dose and were continued every 6 weeks for the first 24 weeks and every 12 weeks thereafter. The Primary endpoint of the study was Objective Response Rate (ORR). Secondary outcome measures included Overall Survival (OS), Progression Free Survival (PFS), Duration of Response (DOR), and the occurrence of treatment-related Adverse Events (AEs) leading to treatment discontinuation.

The results from a blinded, independent central review showed that the ORR was 12% and among the responders, the median Duration of Response was 17.9 months. The responses were durable for 6 months or longer in 77%, 12 months or longer in 62%, and 18 months or longer in 39% of the responding patients. These treatment responses were noted regardless of PD-L1 expression. OPDIVO® was granted accelerated approval for this indication on the basis of Overall Response Rate and Duration of Response, and further proof of benefit in confirmatory trials may be required for full approval.

It was concluded that OPDIVO® is the first new agent approved in nearly 20 years for Small Cell Lung Cancer, and is the first checkpoint inhibitor approved for this patient group. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm617370.htm

American Cancer Society Updates Colorectal Cancer Screening Guideline for Average Risk Adults

SUMMARY: The American Cancer Society estimates that approximately 140,250 new cases of ColoRectal Cancer 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%). ColoRectal cancer (CRC) is the fourth most common cancer diagnosed among adults in the US and the second leading cause of death from cancer.

The ACS recently updated Colorectal Cancer Screening Guideline using prevailing evidence as well as microsimulation modeling analyses, and included a new evaluation of the age, to begin screening by race and sex and additional modeling that incorporates changes in United States CRC incidence. The ACS Guideline Development Group applied the Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria in developing and rating the recommendations. The new guideline does not prioritize among screening test options. This is because test preferences vary among individuals and the guidelines development committee emphasized that screening rates could be improved by endorsing the full range of tests without preference.

Even though the incidence of Colorectal cancer (CRC) in the United States has been rapidly declining overall in people 55 and over primarily driven by screening, among adults younger than 55 years there was a 51% increase in the incidence of colorectal cancer (CRC) from 1994 to 2014 and a 11% increase in deaths from 2005 to 2015. Adults born around 1990 have twice the risk of colon cancer and four times the risk of rectal cancer compared with adults born around 1950, who have the lowest risk. Studies suggest that the younger individuals will continue to be at a higher risk as they age. The increase in the incidence of CRC in young adults has been attributed to western life style including high carbohydrate, high fat, low fiber diet which can initiate inflammation and proliferation in the colonic mucosa within two weeks. Other lifestyle factors associated with CRC include obesity, high consumption of processed meat and alcohol, low levels of physical activity and cigarette smoking. Further, young patients are 58% more likely than older patients to be diagnosed with advanced versus localized stage CRC, due to delayed follow up of symptoms, sometimes for years, and these young adults are less likely to be screened for colon cancer, despite their symptoms.

The current ACS recommendations are as follows:

1) Adults aged 45 and older with an average risk of colorectal cancer should undergo regular screening with either a high-sensitivity stool-based test or a structural (visual) exam, depending on patient preference and test availability.

2) As a part of the screening process, all positive results on non-colonoscopy screening tests should be followed up with timely colonoscopy.

3) The recommendation to begin screening at age 45 years is a “qualified recommendation”. The change in starting age is designated as a “qualified recommendation” because there is less direct evidence of the balance of benefits and harms, or patients’ values and preferences, related to colorectal cancer screening in adults aged 45 to 49, since most studies have only included adults aged 50 and older.

4) The recommendation for regular screening in adults aged 50 years and older is designated as a “strong recommendation,” on the basis of the greater strength of the evidence and the judgment of the overall benefit.

5) Average-risk adults in good health with a life expectancy of greater than 10 years should continue colorectal cancer screening through age 75 years.

6) Clinicians should individualize colorectal cancer screening decisions for individuals aged 76 through 85 years, based on patient preferences, life expectancy, health status, and prior screening history.

7) Clinicians should discourage individuals over age 85 years from continuing colorectal cancer screening.

Test options for CRC screening include the following:

Stool-based tests

1) Highly sensitive Fecal Immunochemical Test (FIT) annually

2) Highly sensitive guaiac-based Fecal Occult Blood Test (gFOBT) annually

3) Multi-targeted stool DNA test every 3 years

Visual exams

1) Colonoscopy every 10 years

2) CT colonography (virtual colonoscopy) every 5 years

3) Flexible sigmoidoscopy every 5 years

Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. Wolf AM, Fontham ET, Church TR, et al. CA Cancer J Clin 2018;68:250-281.

Tumor Mutation Burden is a Predictive Biomarker for Response to Immune Checkpoint Inhibitors

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 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Patients with advanced NSCLC (Non-Small Cell Lung Cancer) often receive either platinum-doublet chemotherapy combination as first line therapy or KEYTRUDA® (Pembrolizumab) if the tumor PD-L1 expression is 50% or more. About 20-25% of patients benefit from immunotherapy. Other biomarkers besides PD-L1 are needed, to select appropriate patients for immunotherapy.

Tumor Mutational Burden (TMB) has recently emerged as a potential biomarker for immunotherapy with anti PD-1 antibodies. TMB can be measured using Next-Generation Sequencing (NGS) and is defined as the number of somatic, coding base substitutions and short insertions and deletions (indels) per megabase of genome examined. In a previously published trial (CheckMate 568), patients most likely to have a response to a combination of OPDIVO® (Nivolumab) plus YERVOY® (Ipilimumab), irrespective of tumor PD-L1 expression level in NSCLC, had a TMB of at least 10 mutations per megabase. This was the basis for CheckMate 227, which evaluated the efficacy of OPDIVO® and OPDIVO®-based regimens, as first line treatment in biomarker-selected groups of patients with advanced NSCLC.Unleashing-T-Cell-Function-with-Combination-Immunotherapy

OPDIVO® is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, whereas YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4(Cytotoxic T-Lymphocyte Antigen 4, also known as CD152). Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. The complementary mechanisms of action of OPDIVO® and YERVOY® combination resulted in greater efficacy in phase I trials, compared with OPDIVO® monotherapy.

CheckMate 227 is a three part, open-label, randomized, phase III trial, designed to compare different OPDIVO® -based regimens with chemotherapy in distinct patient populations. This study enrolled 1,739 patients with previously untreated Stage IV or recurrent NSCLC with no known sensitizing EGFR or ALK mutations and patients were randomized in a 1:1:1 ratio and the comparison was between either OPDIVO®, OPDIVO® plus YERVOY® or OPDIVO® plus platinum-doublet chemotherapy and platinum-doublet chemotherapy alone. Patients were stratified according to tumor histology and PD-L1 expression of 1% or more (positive) or less than 1% (negative). The study incorporated Tumor Mutational Burden (TMB) as a biomarker. This was determined by the FoundationOne CDx assay, an FDA approved test for molecular profiling, using the validated cutoff of TMB of 10 or more mutations/megabase as High, and less than 10 mutations/megabase as Low.

The authors in this publication reported data from part 1 of this study, which was a comparison between OPDIVO® plus YERVOY® versus chemotherapy, in patients with previously untreated Stage IV or recurrent NSCLC. In this comparison, 139 TMB-High patients were treated with OPDIVO® 3 mg/kg IV every 2 weeks plus YERVOY® 1 mg/kg IV every 6 weeks, whereas 160 TMB-High patients received chemotherapy, based on tumor histology. All treatments were continued until disease progression or unacceptable toxicity. Part 1 of the study had two Coprimary end points. One Coprimary end point was Progression Free Survival (PFS) with OPDIVO® plus YERVOY® versus chemotherapy in a patient population selected on the basis of TMB. The other Coprimary end point was Overall Survival (OS) with OPDIVO® plus YERVOY® versus chemotherapy in a patient population selected on the basis of the PD-L1 expression level.

It was noted that the PFS among patients with High TMB was significantly longer with OPDIVO® plus YERVOY®, compared with chemotherapy. The median PFS with the immunotherapy combination was 7.2 months compared to 5.5 months with chemotherapy (HR=0.58; P<0.001). This represented a 42% reduction in the risk of disease progression or death. The 1 year PFS more than tripled with combination immunotherapy at 42.6% versus 13.2% with chemotherapy. The Objective Response Rate (ORR) was 45.3% with immunotherapy combination and 26.9% with chemotherapy. The improved outcomes with OPDIVO® plus YERVOY® over chemotherapy was broadly consistent within all subgroups and was independent of tumor histology and PD-L1 expression. There was a clear trend toward improved survival with the immunotherapy combination although this data is immature. Grade 3 or 4 treatment related adverse events were 31.2% with immunotherapy combination and 36.1% with chemotherapy.

The authors concluded that this is the first phase III study to evaluate Tumor Mutational Burden as a predictive biomarker for immunotherapy as a coprimary endpoint. They added that these results highlight that Tumor Mutational Burden and PD-L1 are independent biomarkers and TMB is predictive of benefit with OPDIVO® plus YERVOY® irrespective of PD-L1 expression. TMB-High therefore is a new biomarker and represents a distinct subgroup of NSCLC. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. N Engl J Med 2018; 378:2093-2104

POMALYST® Combination Significantly Improves Progression Free Survival in Relapsed/Refractory 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, 30,770 new cases will be diagnosed in 2018 and 12,770 patients are expected to die of the disease. Multiple Myeloma in 2018 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). POMALYST® (Pomalidomide) is a novel, oral, immunomodulatory drug which is far more potent than THALOMID® (Thalidomide) and REVLIMID® (Lenalidomide), and has been shown to be active in REVLIMID® and VELCADE® (Bortezomib) refractory patients. POMALYST® is approved by the FDA for use in combination with Dexamethasone for the treatment of patients with Multiple Myeloma who have received at least 2 prior therapies including REVLIMID® and a Proteasome Inhibitor, and have had disease progression on or within 60 days of completing their last therapy.

POMALYST® has demonstrated synergistic anti-myeloma activity with Dexamethasone and Proteasome Inhibitors. It has been shown to inhibit proliferation of REVLIMID® resistant cells in preclinical studies. With the increasing use of REVLIMID® as first line treatment for patients with Multiple Myeloma, there is a clinically relevant unmet medical need for patients who have progressed on REVLIMID®. The authors herein report the outcomes of a first phase III trial, comparing a combination of POMALYST®, VELCADE® and low dose Dexamethasone (PVd) with VELCADE® and Dexamethasone (Vd), in an entirely post-REVLIMID® treated population.

OPTIMISMM is an international, open label phase III study in which 559 patients with Relapsed/Refractory Multiple Myeloma were randomized in a 1:1 ratio to receive POMALYST® in combination with VELCADE® and low dose Dexamethasone (PVd – N=281) or VELCADE® and Dexamethasone (Vd – N=278). Patients in both treatment groups received VELCADE® 1.3 mg/m² SC, on days 1, 4, 8, and 11 of cycles 1 thru 8, and on days 1 and 8 of cycle 9 and beyond, of each 21 day cycle. Dexamethasone was given to all patients at 20 mg orally daily (10 mg/day if more than 75 years of age) on the days of and after VELCADE® treatment. In the experimental arm, patients received POMALYST® 4 mg orally daily on days 1 thru 14, of each 21 day cycle. The median age was 67.5 years and both treatment groups were well balanced. All patients had prior treatment with REVLIMID® and 70% were refractory to this agent, whereas 72% of the patients had prior treatment with VELCADE® and 68% were refractory to the last treatment. The median number of prior treatment lines was 2 and approximately 40% of the patients in both treatment groups had one prior line of therapy. The percentage of patients with high-risk cytogenetics such as del(17p), t(4;14), and or t(14;16]), was similar in both treatment groups. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Duration of Response, and Safety.

At a median follow up of 16 months, the median PFS was 11.2 months with PVd compared with 7.1 months with Vd alone (HR=0.61; P<0.0001). This meant a 39% reduction in the risk of progression or death with POMALYST®, VELCADE® and low dose Dexamethasone combination, compared with VELCADE® and low dose Dexamethasone alone. This PFS benefit was noted regardless of age, performance status, high-risk cytogenetics, number of prior therapies, and types of prior therapy. The OS data are not mature. The most common side effects of the drug combinations were neutropenia, infections, and thrombocytopenia, which were manageable.

It was concluded that in the treatment of Multiple Myeloma, there remains an unmet medical need for those patients who have received REVLIMID® based therapies and are in early relapse. OPTIMISMM is the only phase III study to date in early Relapsed/Refractory Multiple Myeloma, that has demonstrated a significant and clinically meaningful PFS improvement in patients who have previously received REVLIMID® and especially those who are refractory to REVLIMID®, suggesting that the combination of POMALYST®, VELCADE® and low dose Dexamethasone may be a new standard of care in patients with Relapsed/Refractory Multiple Myeloma, with prior exposure to REVLIMID®. Pomalidomide (POM), bortezomib, and low‐dose dexamethasone (PVd) vs bortezomib and low-dose dexamethasone (Vd) in lenalidomide (LEN)-exposed patients (pts) with relapsed or refractory multiple myeloma (RRMM): Phase 3 OPTIMISMM trial. Richardson PG, Rocafiguera AO, Beksac M, et al. J Clin Oncol 36, 2018 (suppl; abstr 8001)

Late Breaking Abstract – ASCO 2018 Broad Range of MSI-H tumors Linked with Lynch Syndrome

SUMMARY: The FDA in 2017 granted accelerated approval to KEYTRUDA® (Pembrolizumab), a PD-1 blocking antibody, for adult and pediatric patients with unresectable or metastatic, MicroSatellite Instability-High (MSI-H) or MisMatch Repair Deficient (dMMR) solid tumors that have progressed following prior treatment, and who have no satisfactory alternative treatment options. This has led to routine MSI-H/dMMR testing in advanced solid tumors. 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 is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system and occurs in 15% of all colorectal cancers.Testing-for-MicroSatellite-Instability-and-MisMatch-Repair-Deficiency

Defective MisMatchRepair can be a sporadic or heritable event. Defective MisMatchRepair can manifest as a germline mutation occurring in MisMatchRepair genes including MLH1, MSH2, MSH6, PMS2 and EPCAM. This produces Lynch Syndrome often called Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC, an Autosomal Dominant disorder, that is often associated with a high risk for Colorectal and Endometrial carcinoma, as well as several other malignancies including Ovary, Stomach, Small bowel, Hepatobiliary tract, Brain and Skin. MSI is a hallmark of Lynch Syndrome-associated 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 blockade with immune checkpoint inhibitors. MSI 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). NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer. Unlike Colorectal and Endometrial cancer, where MSI-H/dMMR testing is routinely undertaken, the characterization of Lynch Syndrome across heterogeneous MSI-H/dMMR tumors is unknown.

The aim of the study was to determine the prevalence of germline mutations in the DNA mismatch repair genes diagnostic of Lynch Syndrome, across MSI-H tumors. The researchers in this study analyzed 15,045 tumor samples collected from patients with more than 50 different types of cancer using a comprehensive genomic test called MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), a next-generation sequencing platform. The MSK-IMPACT assay is a qualitative in-vitro diagnostic test that uses targeted next-generation sequencing of Formalin Fixed Paraffin-Embedded (FFPE) tumor tissue matched with normal specimens, from patients with solid tumors, to detect tumor gene alterations in a broad multigene panel. It is the first multiplex tumor profiling test to receive FDA authorization. The MSK-IMPACT test can look for gene mutations and other errors in all solid tumors, regardless of their origin.

Scores of less than 3, 3-9 and 10 or more were designated MSS, MSI-Indeterminate (MSI-I) or MSI-H status, respectively. Germline mutations were assessed in MLH1, MSH2, MSH6, PMS2, EPCAM. ImmunoHistoChemical staining (IHC) for dMMR, and tumor signatures in Lynch Syndrome patients were assessed.

Of the tumor samples analyzed, 93.2% were MSS, 4.6% were MSI-I, and 2.2% were MSI-H. Germline mutations indicative of Lynch Syndrome were identified in 0.3% of microsatellite-stable tumors, 1.9% of MSI-I tumors, and 16.3% of MSI-H tumors (P<0.001). The authors noted that nearly 50% of patients with MSI-H/MSI-I tumors identified as having Lynch Syndrome, had cancers other than colorectal or endometrial carcinoma – the two malignancies that are typically seen with Lynch Syndrome. The cancer types identified that were previously not linked to or rarely, linked to the Lynch Syndrome, included Mesothelioma, Sarcoma, Adrenocortical cancer, Melanoma, Prostate and Ovarian germ cell cancer. Nearly 40% of these patients did not meet the genetic testing criteria for Lynch Syndrome. MMR-deficiency was found in 98.3% of MSI-I/MSI-H tumor samples.

It was concluded that MSI-H/dMMR tumors, regardless of cancer type and irrespective of the family history, should prompt germline testing for the evaluation of Lynch Syndrome. This will increase the ability to recognize Lynch Syndrome, not only in the patients tested, but also in at-risk family members, thus enabling the implementation of enhanced surveillance and risk reduction measures. Pan-cancer microsatellite instability to predict for presence of Lynch syndrome. Schwark AL, Srinivasan P, Kemel Y, et al. J Clin Oncol 36, 2018 (suppl; abstr LBA1509)

AR-V7 in Circulating Tumor Cells (Liquid Biopsy) Can Guide Treatment in Castrate Resistant 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 164,690 new cases of prostate cancer will be diagnosed in 2018 and 29,430 men will die of the disease. Prostate cancer is driven by Androgen Receptor (AR) and its signaling pathways. Initial treatment strategies for patients with metastatic prostate cancer include lowering the levels of circulating androgens with medical or surgical castration or blocking the binding of androgens to the androgen receptor. Upon progression, {described as Castrate Resistant Prostate Cancer (CRPC), as these tumors are not androgen independent and continue to rely on Androgen Receptor signaling}, Androgen Receptor Signaling (ARS) inhibitors, such as ZYTIGA ® (Abiraterone acetate) and XTANDI® (Enzalutamide), and Taxanes such as TAXOTERE® (Docetaxel) and JEVTANA® (Cabazitaxel) are the most widely used drug classes in the United States. ZYTIGA® inhibits CYP17A1 enzyme and depletes adrenal and intratumoral androgens, thereby impairing AR signaling. XTANDI® competes with Testosterone and Dihydrotestosterone and avidly binds to the Androgen Receptor, thereby inhibiting AR signaling, and in addition inhibits translocation of the AR into the nucleus and thus inhibits the transcriptional activities of the AR. About 20-40% of the patients do not respond to these newer agents (ARS inhibitors), and even those who respond will invariably develop resistance to these drugs.Androgen-Receptor-Variant-7-and-Drug-Resistance

ARS inhibitors are often the preferred choice for the first-line treatment of metastatic CRPC (mCRPC). In clinical practice, the majority of patients with mCRPC who progress on first-line ARS inhibitor receive a second ARS inhibitor, as there are no formal guidelines on how best to sequence these agents after progression on first-line ARS inhibition. Resistance to ARS inhibitors has been attributed to persistent AR signaling by variant forms of Androgen Receptor, generated through somatic mutation or aberrant RNA splicing. Androgen Receptor splice Variant 7 (AR-V7) is the most widely studied and can be detected in the CTCs (Circulating Tumor Cells). AR-V7 does not have the domain to bind androgens and may be associated with resistance to XTANDI®. Further AR-V7 is constitutively active and can independently activate transcription factors and therefore is not effected by androgen depleting agents including ZYTIGA®.

A critical unmet need is a test that can provide guidance on selecting appropriate therapy in the second and later lines, for this patient group. Accurately detecting a splice variant of the Androgen Receptor protein (AR-V7) in the nucleus of Circulating Tumor Cells (CTCs) using peripheral blood (liquid biopsy), would enable treating physicians to confidently decide whether patients treated with an ARS inhibitor, upon progression, would benefit from a second ARS inhibitor or should be switched to chemotherapy. This study focused on the patients receiving second-line treatment, to determine if an assay for the nuclear-localized AR-V7 protein in CTCs can be used to determine treatment for mCRPC.

The authors conducted this independent, multicenter cohort study to determine whether a validated assay for the nuclear-localized Androgen Receptor splice Variant 7 (AR-V7) protein in Circulating Tumor Cells (CTCs) can be used as a treatment-selection marker for metastatic CRPC, and whether it can determine Overall Survival difference among patients with mCRPC treated with Taxanes versus ARS inhibitors. This blinded correlative study included 142 patients with histologically confirmed mCRPC. Blood samples were obtained prior to administration of ARS inhibitors (N=70) or Taxanes (N=72), as a second-line therapy or later, for progressing mCRPC . Mean age was 69.5 years. Seventy (N=70) patients were designated as high risk by conventional prognostic factors. The Primary outcome measure was Overall Survival after treatment with an ARS inhibitor or Taxane, in relation to pretreatment AR-V7 status.

It was noted that the presence of AR-V7 protein in CTCs was associated with a greater benefit from Taxane treatment whereas outcomes in AR-V7 negative patients were better with ARS inhibitor treatment. The median survival of patients with AR-V7 negative CTCs was 19.8 months for those treated with an ARS inhibitor and 12.8 months for those treated with a Taxane (P=0.05). In contrast, among patients with AR-V7 positive CTCs, those receiving Taxanes had longer observed median survival times compared to those treated with ARS inhibitors (14.3 vs 7.3 months; HR=0.62; P=0.25). The observed difference was not statistically significant and may have been attributable to the small sample size.

The authors concluded that this study suggests that nuclear-localized AR-V7 protein in Circulating Tumor Cells (liquid biopsy test) can identify patients who may live longer with Taxane chemotherapy versus ARS inhibitor treatment. This tailored treatment approach addresses a critical unmet need by predicting and enabling selection of therapy that can improve median survival. Assessment of the Validity of Nuclear-Localized Androgen Receptor Splice Variant 7 in Circulating Tumor Cells as a Predictive Biomarker for Castration-Resistant Prostate Cancer. Scher HI, Graf RP, Schreiber NA, et al. JAMA Oncol. Published online June 28, 2018. doi:10.1001/jamaoncol.2018.1621

Late Breaking Abstract – ASCO 2018 Chemoprevention of Esophageal Cancer with NEXIUM® and Aspirin

SUMMARY: The American Cancer Society estimates that in 2018, about 17,290 new cases of esophageal cancer will be diagnosed in the US and about 15,850 individuals will die of the disease. It is the sixth most common cause of global cancer death. Squamous Cell Carcinoma is the most common type of cancer of the esophagus among African Americans, while Adenocarcinoma is more common in caucasians. In those with esophageal adenocarcinoma detected through symptoms, 5-year survival is less than 10%.

Barrett esophagus, defined as intestinal metaplasia in the distal esophagus, is a complication of GastroEsophageal Reflux Disease (GERD) and affects 2% of the adult population in western countries. In patients with Barrett’s esophagus, a portion of the esophagus that is usually lined with squamous epithelium undergoes metaplastic change to become columnar mucosa. Barrett esophagus predisposes patients to esophageal adenocarcinoma through a series of pathological events which include esophagitis, metaplasia, dysplasia and subsequently adenocarcinoma. Patients with Barrett’s esophagus are often screened for early malignancy with endoscopic evaluation with modest benefit. This is unlike screening for colorectal cancer that has proved successful in reducing colorectal cancer deaths.

It has been shown in observational studies that powerful acid suppression with Proton Pump Inhibitors (PPIs) could reduce risk of neoplastic progression in patients with Barrett’s esophagus, by downregulating cylcogoxygenase-2 expression. Esomeprazole (NEXIUM®) is the most commonly used PPI in the USA, and allows the healing of esophagitis without promoting clonal expansion of Barrett’s esophagus. Aspirin use in observational studies has been associated with reduced risk of esophageal adenocarcinoma. Based on these findings, the authors evaluated the efficacy and safety of these two drugs in the Aspirin and Esomeprazole Chemoprevention in Barrett’s metaplasia Trial (AspECT).

AspECT is a prospective, factorial design, multicenter, randomized, phase III study of chemoprevention by Aspirin and NEXIUM®, in patients with Barrett’s esophagus. Patients with Barrett’s esophagus of 1 cm or more (N=2557) were randomised 1:1:1:1 to Low-dose NEXIUM® (20 mg qd) and no Aspirin (N=705), High-dose NEXIUM® (40 mg bid) and no Aspirin (N=704), Low-dose NEXIUM® with Aspirin 300 mg qd (N=571) and High-dose NEXIUM® with Aspirin (N=577). The median follow up and treatment duration was 8.9 years. The Primary composite endpoint was time to all-cause mortality, esophageal adenocarcinoma, or high-grade dysplasia. The co-primary end points were the efficacy of High-dose PPI versus Low-dose PPI, and the efficacy of Aspirin versus no Aspirin.

It was noted that High-dose PPI was superior to Low-dose PPI (P=0.038). Aspirin was not significantly better than no Aspirin (P=0.068). However, if patients using Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) were censored at the time of first use, Aspirin was significantly better than no Aspirin (P=0.043). The most benefit was noted when High-dose PPI was combined with Aspirin compared with Low-dose PPI without Aspirin (P=0.0068). It appeared that the use of Aspirin and NEXIUM® (Proton Pump Inhibitor) would improve outcomes in Barrett’s esophagus, if given for at least 9 years. Serious adverse events were reported in only 1% of the participants.

It was concluded that in this largest randomized, controlled, chemoprevention trial in patients with Barrett’s esophagus, High dose NEXIUM® (given twice daily) along with Aspirin significantly reduces rates of death, esophageal adenocarcinoma, or high-grade dysplasia, with twice-daily NEXIUM® producing more effective suppression of acid reflux than once-daily dosing. Chemoprevention of esophageal cancer with esomeprazole and aspirin therapy: Efficacy and safety in the phase III randomized factorial ASPECT trial. Jankowski J, de Caestecker J, Love S, et al. J Clin Oncol 36, 2018 (suppl; abstr LBA4008)