On October 22, 2018 Celgene Corporation (NASDAQ:CELG) reported the first results from the IMpassion130 study evaluating ABRAXANE (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) in combination with atezolizumab (Tecentriq) in patients with first-line locally advanced triple negative breast cancer (TNBC) and the IMpower130 study evaluating ABRAXANE/carboplatin in combination with atezolizumab in first-line advanced non-squamous non-small cell lung cancer (Press release, Celgene, OCT 22, 2018, View Source [SID1234530032]). These findings were presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress, taking place from October 19-23 in Munich, Germany. Both studies were sponsored by Roche.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

IMpassion130 Demonstrated a PFS Benefit of ABRAXANE plus Atezolizumab Combination as Initial Treatment in Locally Advanced or Metastatic TNBC

Results from the Phase 3 Impassion study showed that the investigational combination of ABRAXANE plus atezolizumab significantly reduced the risk of disease worsening or death (PFS) in first-line metastatic or unresectable locally advanced TNBC patients compared to ABRAXANE alone (7.2 months vs. 5.5 months [p=0.0025; HR=0.80 (95% CI: 0.69,0.92)]) in all randomized patients and in the PD-L1 positive subgroup population (median PFS=7.5 months vs. 5.0 months; HR=0.62(95% CI: 0.49-0.78, p<0.0001).

At this first interim analysis, statistical significance was not met for overall survival (OS) in the ITT population (median OS=21.3 months in the ABRAXANE plus atezolizumab arm vs. 17.6 months in the ABRAXANE monotherapy arm; HR=0.84, 95% CI 0.69-1.02, p=0.0840). In the PD-L1-positive population (which was not tested due to hierarchal design), the ABRAXANE plus atezolizumab arm demonstrated a 9.5-month OS improvement (median OS=25.0 vs. 15.5 months; HR=0.62, 95% CI 0.45-0.86). Follow-up will continue until the next planned analysis. The safety findings were consistent with the known profiles of the individual regimens investigated.

IMpassion130 is the first phase III study to demonstrate a statistically significant PFS improvement in first-line metastatic or unresectable locally advanced TNBC.

"The findings of the IMpassion130 trial illustrate that the ABRAXANE plus atezolizumab regimen has activity in an aggressive type of breast cancer with few viable treatments," said Jay Backstrom, M.D., Chief Medical Officer and Head of Global Regulatory Affairs for Celgene. "We are particularly excited about these findings because triple negative breast cancer is such a difficult disease to treat and patients are in need of additional treatment options."

The most common Grade 3/4 treatment-emergent adverse events (TEAE) were neutropenia (8% in both treatment arms), decreased neutrophil count (ABRAXANE plus atezolizumab: 5%; ABRAXANE plus placebo: 3%), peripheral neuropathy (ABRAXANE plus atezolizumab: 6%; ABRAXANE plus placebo: 3%), fatigue (ABRAXANE plus atezolizumab: 4%; ABRAXANE plus placebo: 3%) and anemia (3% in both treatment groups). A higher proportion of patients in the ABRAXANE plus atezolizumab arm reported serious AEs (23% vs. 18%).

IMpower130 Demonstrated Significant OS and PFS Benefit of ABRAXANE/Carboplatin plus Atezolizumab in Advanced Non-Squamous NSCLC

Results from the Phase III IMpower130 study showed that first-line treatment with the investigational combination of ABRAXANE/carboplatin plus atezolizumab significantly improved overall survival of patients with previously untreated metastatic non-squamous NSCLC compared to ABRAXANE/carboplatin alone (median OS= 18.6 versus 13.9 months; HR= 0.79; 95 percent CI: 0.64–0.98; p=0.033) in the intention-to-treat wild-type (ITT-WT) population. The ABRAXANE/carboplatin plus atezolizumab combination also significantly reduced the risk of disease worsening or death (PFS) compared to ABRAXANE/carboplatin alone (median PFS=7.0 versus 5.5 months; HR=0.64; 95 percent CI: 0.54–0.77; p<0.0001) in the ITT-WT population.

Safety for the ABRAXANE/carboplatin plus atezolizumab combination appeared consistent with the known safety profile of the individual medicines. Grade 3/4 TEAEs were reported in 73.2 percent of people receiving ABRAXANE/carboplatin plus atezolizumab compared to 60.3 percent of people receiving ABRAXANE/carboplatin alone. The most common Grade 3/4 AEs in people receiving ABRAXANE/carboplatin plus atezolizumab were: an abnormal low count of a certain type of white blood cell (neutropenia, 32.1 percent), a decrease in red blood cells (anemia, 29.2 percent) and a decreased neutrophil count (12.1 percent).

"Data from these studies continue to shape our understanding of the current and future treatment landscapes in areas where historically there have been limited treatment options available to patients," said Nadim Ahmed, President, Hematology and Oncology for Celgene. "We are very encouraged by the findings of these studies as they add to the growing body of research evaluating the potential of ABRAXANE as a backbone therapy in combination with immunotherapy."

ABRAXANE alone or in combination with atezolizumab is not approved for the first-line treatment of triple negative breast cancer, and ABRAXANE/carboplatin in combination with atezolizumab is not approved for the treatment of advanced NSCLC.

Tecentriq (atezolizumab) is a registered trademark of Genentech, a member of the Roche Group.

About the IMpassion130 study

IMpassion130is a Phase III multicenter, randomized, double-blind study evaluating the efficacy, safety, and pharmacokinetics of ABRAXANE and atezolizumabcompared with placebo in combination with ABRAXANE alone in patients with locally advanced or metastatic TNBC who have not received prior systemic therapy for metastatic breast cancer (mBC). The study enrolled 902 people who were randomized equally (1:1). The co-primary endpoints were PFS (RECIST 1.1) in all randomized participants, as well as in those who disease expressed PD-L1, and OS in all randomized participants. Secondary endpoints included overall response rate, duration of response and time to deterioration in Global Health Status/Health-Related Quality of Life.

During the treatment duration, people in:

Arm Areceived atezolizumab at a fixed dose of 840 milligrams via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle and ABRAXANE at a dose of 100 milligrams per square meter via IV infusion on Days 1, 8, and 15 of each 28-day cycle.ABRAXANEwas administered for a target of at least 6 cycles, with no maximum. Participants received both agents until unacceptable toxicity or disease progression.
Arm Breceived ABRAXANE at a dose of 100 milligrams per square meter via IV infusion on Days 1, 8, and 15 of each 28-day cycle. ABRAXANE was administered for a target of at least 6 cycles, with no maximum, and placebo was administered via IV infusion on Days 1 and 15 of each 28-day cycle. Participants assigned to placebo plus ABRAXANE received both agents until unacceptable toxicity or disease progression.
About the IMpower130 study

IMpower130 is a Phase III, multicenter, open-label, randomized study evaluating the efficacy and safety of atezolizumab in combination with carboplatin and ABRAXANE versus chemotherapy (carboplatin and ABRAXANE) alone for chemotherapy-naïve patients with stage IV non-squamous NSCLC. The study enrolled 723 people who were randomized (2:1) to receive:

Atezolizumab (1200 mg via IV every 3 weeks) plus carboplatin (AUC 6 mg/mL/min via IV every 3 weeks) and ABRAXANE (100 mg/m2 via IV every 3 weeks) (Arm A), or
Carboplatin (AUC 6 mg/mL/min via IV every 3 weeks) and ABRAXANE (100 mg/m2 via IV every 3 weeks) (Arm B, control arm)
During the treatment-induction phase, people in Arm A received atezolizumab and carboplatin on day 1 of each 21-day cycle, and ABRAXANE on days 1, 8 and 15 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit, whichever occurs first. People received atezolizumab during the maintenance treatment phase until loss of clinical benefit was observed.

During the treatment-induction phase, people in Arm B received carboplatin on day 1 and ABRAXANE on days 1, 8 and 15 of each 21-day cycle for 4 or 6 cycles or until disease progression, whichever occurred first. People received best supportive care during the maintenance treatment phase. Switch maintenance to pemetrexed was also permitted. People who were consented prior to a protocol revision were given the option to crossover to receive atezolizumab as monotherapy until disease progression.

The co-primary endpoints were:

PFS as determined by the investigator using RECIST v1.1 in the ITT-WT population
OS in the ITT-WT population
About ABRAXANE

ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

Important Safety Information

WARNING – NEUTROPENIA

Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm 3 . In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE
Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS
CONTRAINDICATIONS

Neutrophil Counts

ABRAXANE should not be used in patients who have baseline neutrophil counts of <1500 cells/mm3
Hypersensitivity

Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug
WARNINGS AND PRECAUTIONS

Hematologic Effects

Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC) and 47% of patients with non–small cell lung cancer (NSCLC)
Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 for NSCLC
Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3
In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC
In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1500 cells/mm3 and platelets recover to a level >100,000 cells/mm3
In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle
Nervous System

Sensory neuropathy is dose- and schedule-dependent
The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification
If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC followed by a dose reduction for all subsequent courses of ABRAXANE
Hypersensitivity

Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported
Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug
Cross-hypersensitivity between ABRAXANE and other taxane products has been reported and may include severe reactions such as anaphylaxis. Patients with a previous history of hypersensitivity to other taxanes should be closely monitored during initiation of ABRAXANE therapy
Hepatic Impairment

Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution
Patients with hepatic impairment may be at an increased risk of toxicity, particularly from myelosuppression, and should be monitored for development of profound myelosuppression
For MBC and NSCLC, the starting dose should be reduced for patients with moderate or severe hepatic impairment
Albumin (Human)

ABRAXANE contains albumin (human), a derivative of human blood
Embryo Fetal Toxicity

Based on mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman
Advise females of reproductive potential of the potential risk to a fetus.
Advise females of reproductive potential to use effective contraception and avoid becoming pregnant during treatment with ABRAXANE and for at least six months after the last dose of ABRAXANE
Advise male patients with female partners of reproductive potential to use effective contraception and avoid fathering a child during treatment with ABRAXANE and for at least three months after the last dose of ABRAXANE
ADVERSE REACTIONS

Randomized Metastatic Breast Cancer (MBC) Study

The most common adverse reactions (≥20%) with single-agent use of ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%, 94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%, <1%), nausea (any 30%, 22%; severe 3%, <1%), diarrhea (any 27%, 15%; severe <1%, 1%) and infections (24%, 20%), respectively
Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients
Other adverse reactions of note with the use of ABRAXANE vs paclitaxel injection included vomiting (any 18%, 10%; severe 4%, 1%), fluid retention (any 10%, 8%; severe 0%, <1%), mucositis (any 7%, 6%; severe <1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%, 12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe <1%, <1%), neutropenic sepsis (<1%, <1%), and injection site reactions (<1%, 1%), respectively. Dehydration and pyrexia were also reported
Renal dysfunction (any 11%, severe 1%) was reported in patients treated with ABRAXANE (n=229)
In all ABRAXANE-treated patients (n=366), ocular/visual disturbances were reported (any 13%; severe 1%)
Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension
Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported
Non–Small Cell Lung Cancer (NSCLC) Study

The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue
The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC are anemia (4%) and pneumonia (3%)
The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%)
The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%)
The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%)
The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin–treated and paclitaxel injection plus carboplatin–treated patients: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%); incidence rates are for the ABRAXANE plus carboplatin treatment group
Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%), neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral neuropathy (3%, 12%), respectively
Adverse reactions with a difference of ≥5%, Grades 1-4, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and myalgia (10%, 19%), respectively
Neutropenia (all grades) was reported in 85% of patients who received ABRAXANE and carboplatin vs 83% of patients who received paclitaxel injection and carboplatin
Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations

Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. In postmarketing experience, cross-hypersensitivity between ABRAXANE and other taxanes has been reported
There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs
There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration
DRUG INTERACTIONS

Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4
USE IN SPECIFIC POPULATIONS

Pregnancy

Based on the mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. Advise females of the potential risk to a fetus and to avoid becoming pregnant while receiving ABRAXANE
Lactation

Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Nursing must be discontinued when receiving treatment with ABRAXANE and for two weeks after the last dose
Females and Males of Reproductive Potential

Females of reproductive potential should have a pregnancy test prior to starting treatment with ABRAXANE
Advise females of reproductive potential to use effective contraception and avoid becoming pregnant during treatment with and for at least six months after the last dose of ABRAXANE [see Warnings and Precautions]
Advise males with female partners of reproductive potential to use effective contraception and avoid fathering a child during treatment with ABRAXANE and for at least three months after the last dose of ABRAXANE [see Warnings and Precautions]
Based on findings in animals, ABRAXANE may impair fertility in females and males of reproductive potential
Pediatric

The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated
Geriatric

A higher incidence of epistaxis, diarrhea, dehydration, fatigue, and peripheral edema was found in patients 65 years or older who received ABRAXANE for MBC in a pooled analysis of clinical studies
Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC
Renal Impairment

There are insufficient data to permit dosage recommendations in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance <30 mL/min)
DOSAGE AND ADMINISTRATION

Do not administer ABRAXANE to any patient with total bilirubin greater than 5 x ULN or AST greater than 10 x ULN
For MBC and NSCLC, reduce starting dose in patients with moderate to severe hepatic impairment
Dose reductions or discontinuation may be needed based on severe hematologic or neurologic toxicity
Monitor patients closely

On October 22, 2018 Genomic Health, Inc. (Nasdaq: GHDX) reported results from multiple studies of its Oncotype DX tests highlighting their value in optimizing treatment for patients with various stages of breast and prostate cancer (Press release, Genomic Health, OCT 22, 2018, View Source [SID1234530031]). The findings, presented at the ESMO (Free ESMO Whitepaper) 2018 Congress in Munich, Germany, demonstrated that the Oncotype DX tests identify patients who will or will not benefit from a specific treatment.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Underscoring the growing international impact of the Oncotype DX Breast Recurrence Score test, two European-based studies involving patients from Ireland, France and Italy demonstrated its impact on treatment decisions for women with node-negative and node-positive breast cancer. Additionally, three prostate cancer studies in the United States demonstrated how the Oncotype DX Genomic Prostate Score (GPS) and AR-V7 Nucleus Detect tests refine treatment decisions in men with clinically low-intermediate risk or metastatic prostate cancer based on the aggressiveness of their tumor or their resistance to androgen receptor (AR)-targeted drugs.

"Oncotype DX tests have contributed to precision medicine in breast cancer for nearly 15 years, and there is now a growing body of evidence for their predictive value and clinical utility in guiding treatment selection for men with early-stage, as well as metastatic prostate cancer," said Steven Shak, M.D., chief scientific and medical officer, Genomic Health.

Oncotype DX in Node-negative and Node-positive Breast Cancer
In Ireland, researchers assessed the impact of the Oncotype DX Breast Recurrence Score on treatment decisions in routine clinical practice for early-stage breast cancer patients whose disease had spread to one to three lymph nodes (Poster #208P). Results showed that oncologists believed the test significantly changed their treatment recommendations 64 percent of the time, and that use of the Oncotype DX test led to a 27 percent reduction in recommendations for chemotherapy.

Additionally, results from a real-life, decision-impact study of breast cancer patients in France and Italy, including those with node-negative and node-positive disease, showed that treatment recommendations changed in 35 percent of patients based on their Oncotype DX test results (Poster #194P). This resulted in a 43 percent reduction in chemotherapy recommendations.

Importantly, in each country, the Oncotype DX Breast Recurrence Score result, when high, also identified the minority of patients for whom chemotherapy is potentially life-saving, highlighting the distinctive predictive value that only the Oncotype DX test delivers.

"These new results strengthen published findings from our PlanB study and show the unique value of adding genomic information provided by the Oncotype DX test to better target chemotherapy. Oncotype DX identifies patients who can safely be spared chemotherapy toxicity and side effects. Furthermore, we have to be concerned about a relevant proportion of patients who seem to be undertreated if the risk of recurrence is evaluated using only traditional clinical parameters," said Prof. Ulrike Nitz, head of the breast cancer/senology unit at the Bethesda Hospital, Moenchengladbach, Germany. "The use of the Oncotype DX test allows us to tailor treatment plans more accurately to suit the needs of individuals, and to use resources more effectively."

Oncotype DX Optimizes Treatment in Early-stage and Metastatic Prostate Cancer
Based on results from a published study, the Center for Prostatic Disease Research (CPDR) of the Uniformed Services University of the Health Sciences conducted additional analysis of the Oncotype DX Genomic Prostate Score test results in 395 men with clinically low, and intermediate-risk prostate cancer (Poster #837P). Results demonstrated that the GPS test was a significant, independent predictor of increased risk of biopsy upgrade in these patients. These data add to a separate recent independent study published by the University of California, San Francisco (UCSF) and underscore the value of the GPS test in identifying patients with more aggressive tumor biology who should be more aggressively treated at diagnosis.

The Oncotype DX GPS test is the only genomic assay designed for men at the time of diagnosis with clinically low-risk or favorable intermediate-risk cancer to help make treatment decisions based on their likelihood of adverse pathology. Developed by Genomic Health, based on results from multiple studies led by Cleveland Clinic and UCSF, the GPS test optimizes treatment by providing physicians with an assessment of both the current status (adverse pathology) and future risk (metastasis and mortality) of a patient’s cancer in making confident treatment decisions regarding active surveillance versus immediate aggressive treatment.

In metastatic prostate cancer, presentations included two studies of the Oncotype DX AR-V7 Nucleus Detect, a CTC-based, liquid biopsy test that helps determine which patients with metastatic castration-resistant prostate cancer (mCRPC) are resistant, or not, to AR-targeted therapies, such as enzalutamide and abiraterone, and which patients may benefit from chemotherapy. The Oncotype DX AR-V7 Nucleus Detect test is commercially available in the United States through Epic Science’s collaboration with Genomic Health.

A new analysis, combining data from two published studies, confirmed that the Oncotype DX AR-V7 Nucleus Detect test for AR-V7 protein is a predictive biomarker for identifying patients who will not respond to additional AR-targeted therapy (Poster #848P). These data further support that detection of nuclear-localized AR-V7-positive circulating tumor cells (CTCs) by the Oncotype DX test indicates that the patient will not benefit from additional treatment with commonly-prescribed AR-targeted therapy and should consider switching to an alternative therapy to increase survival.

Separately, an independent study of the Oncotype DX AR-V7 Nucleus Detect test conducted by Epic Sciences in collaboration with its academic partners confirmed that the use of AR-V7 optimizes therapy guidance over risk assessment alone (Poster #836P).

About Oncotype DX
The Oncotype DX portfolio of breast, colon and prostate cancer tests applies advanced genomic science to reveal the unique biology of a tumor in order to optimize cancer treatment decisions. The company’s flagship product, the Oncotype DX Breast Recurrence Score test, is the only test that has been shown to predict the likelihood of chemotherapy benefit as well as recurrence in invasive breast cancer. Additionally, the Oncotype DX Breast DCIS Score test predicts the likelihood of recurrence in a pre-invasive form of breast cancer called DCIS. In prostate cancer, the Oncotype DX Genomic Prostate Score test predicts disease aggressiveness and further clarifies the current and future risk of the cancer prior to treatment intervention and the Oncotype DX AR-V7 Nucleus Detect test helps determine which patients with metastatic castration-resistant prostate cancer (mCRPC) are resistant to AR-targeted therapies. The Oncotype DX AR-V7 Nucleus Detect test is performed by Epic Sciences at its centralized, CLIA-certified laboratory in San Diego and offered exclusively by Genomic Health. With more than 900,000 patients tested in more than 90 countries, the Oncotype DX tests have redefined personalized medicine by making genomics a critical part of cancer diagnosis and treatment. To learn more about Oncotype DX tests, visit www.OncotypeIQ.com, www.MyBreastCancerTreatment.org or www.MyProstateCancerTreatement.org.

On October 22, 2018 Halozyme Therapeutics, Inc. (NASDAQ: HALO) reported the presentation of data from two clinical trials for PEGPH20 (pegvorhyaluronidase alfa) in patients with advanced pancreas and metastatic breast cancer (Press release, Halozyme, OCT 22, 2018, View Source [SID1234530030]). The presentations were made at the annual European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress, taking place October 19-23 in Munich. PEGPH20 is Halozyme’s proprietary PEGylated recombinant human hyaluronidase enzyme that degrades hyaluronan (HA), a glycosaminoglycan or naturally occurring sugar in the body. HA accumulates in many solid tumors, potentially impeding the immune response and the access of anti-cancer therapies. PEGPH20 is being developed as an investigational new drug for the treatment of advanced pancreas cancer, specifically in patients with tumors that accumulate HA, referred to as HA-high.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"These data reinforce the potential for PEGPH20 in combination with chemotherapy in these well-defined patient populations. It adds to the supportive evidence that suggests PEGPH20 could play a critical role in degrading tumor HA, allowing greater penetration of chemotherapy and improved access of the immune system into the tumor," said Dr. Helen Torley, president and chief executive officer of Halozyme. "PEGPH20 may provide a unique targeted approach for patients with late-stage cancers where new treatment options are needed."

Poster Presentations of PEGPH20 Clinical Studies at ESMO (Free ESMO Whitepaper) 2018

Abstract 5965/730P – A pilot study of gemcitabine, nab-paclitaxel, PEGPH20 and rivaroxaban for advanced pancreatic adenocarcinoma: interim safety and efficacy analysis
K. Yu, Memorial Sloan-Kettering Cancer Center, et al.

This investigator sponsored study has enrolled 60 patients with advanced pancreatic adenocarcinoma (PDAC), 42 patients without prior thromboembolic events (TE) in cohort 1 and 18 patients with prior TE in cohort 2. Patients received PEGPH20 (3 ug/kg, the same dose as is being evaluated in HALO-301), plus the standard dose and schedule for nab-paclitaxel (125 mg/m2), and gemcitabine (1000 mg/m2), plus rivaroxaban (15 mg PO BID for 21 days induction, then 20 mg PO QD), an oral anticoagulant that has been shown to reduce TE in patients receiving chemotherapy. The primary objective was the rate of symptomatic TE events, and the secondary objectives included PFS, OS and major bleeding rate.

All 60 patients are evaluable for safety and efficacy. Two (3%) grade 3/4 TE events occurred (one in each cohort), and two grade 3 GI hemorrhages; these AEs resolved with supportive treatment. There were three (5%) complete responses, 28 (47%) partial responses, 20 (33%) stable disease responses, and 9 (15%) progressive disease/non-evaluable responses. Median PFS is 7.0 months across both cohorts, and median overall survival has not been reached. Efficacy and safety are similar for patients with and without prior TE. Tissue biopsies have been collected to evaluate response by HA level but the analysis is not yet completed.

Abstract 5999/311P – Early results from an Open-label Phase 1b/2 study of eribulin mesylate (EM) + pegvorhyaluronidase alpha (PEGPH20) combination for the treatment of patients with HER2-negative, high-hyaluronan (HA) metastatic breast cancer (MBC)
M. Shum, The Oncology Institute Whittier, et al.

The Phase 1b portion of the study enrolled 14 patients with HER2 negative metastatic breast cancer without regard for HA status. Patients were treated with IV PEGPH20 plus eribulin mesylate (HALAVEN), a microtubule inhibitor approved for the treatment of metastatic breast cancer in patients previously treated with up to two lines of systemic anticancer therapy. Two different dose-levels of PEGPH20 (3ug/kg and 1.6ug/kg) were tested in combination with 1.4 mg/m2 EM. The data cut-off date for this analysis was February 2018. The median number of 21-day treatment cycles in this trial was six. No complete responses were reported, four (28.6%) patients had a partial response and three (21%) had stable disease. Drug related treatment emergent adverse events (TEAEs) occurred in 86% of patients, with 79% of patients experiencing grade 3 or higher TEAEs. There were three serious adverse events, and the overall safety profile for PEGPH20 + eribulin mesylate was in line with previous observations, with no new safety signals identified. As a result of dose limiting toxicities at the higher dose,1.6ug/kg was determined to be the appropriate dose for this combination. An additional response was confirmed following the data cutoff, increasing the overall response rate to 36%. The overall response rate is encouraging and the PEGPH20 + eribulin mesylate combination warrants further investigation.

About PEGPH20

PEGPH20 is an investigational PEGylated form of Halozyme’s proprietary recombinant human hyaluronidase enzyme under clinical development for the potential systemic treatment of tumors that accumulate hyaluronan (HA). PEGPH20 targets and degrades hyaluronan, a glycosaminoglycan or naturally occurring sugar in the body. HA accumulates in many solid tumors, potentially constricting blood vessels, impeding the immune response and the access of anti-cancer therapies. PEGPH20 is being studied in a Phase 3 trial in patients with late stage HA-high pancreas tumors.

On October 22, 2018 Aeglea BioTherapeutics, Inc. (NASDAQ: AGLE), a clinical-stage biotechnology company that designs and develops innovative human enzyme therapeutics for patients with rare genetic diseases and cancer, reported that it presented positive clinical data for pegzilarginase in melanoma patients at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress in Munich, Germany (Press release, Aeglea BioTherapeutics, OCT 22, 2018, View Source [SID1234530029]). The poster, titled "Initial cohort expansion results of sustained arginine depletion with Pegzilarginase in melanoma patients in a phase 1 advanced solid tumor trial," was presented on October 21. Clinical data from the Company’s ongoing Phase 1 clinical trial investigating pegzilarginase as a single agent includes expansion cohorts for cutaneous melanoma and uveal melanoma.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"This ongoing clinical study of pegzilarginase demonstrated single agent anti-tumor activity in what is a difficult-to-treat population of heavily pre-treated melanoma patients," said James Wooldridge, M.D., chief medical officer of Aeglea. "These findings are in line with expectations from our single agent preclinical studies. Given the significant synergies we observed in preclinical studies with immune checkpoint inhibitors, we look forward to data readouts from the Phase 1/2 combination clinical trial."

Data highlights from ESMO (Free ESMO Whitepaper) 2018:

Pegzilarginase demonstrated single agent anti-tumor activity in patients with advanced melanoma

–Of the 28 patients included in the two cohorts, there was one confirmed partial response (PR) and eight patients with stable disease (SD). Six patients remained on treatment at the time of the data cutoff.
–Anti-tumor activity appeared greater in patients with tumors that lack ASS1 (argininosuccinate synthetase 1) expression, which is consistent with preclinical studies that suggest tumors lacking ASS1 expression are dependent on extracellular arginine for survival.

Pegzilarginase rapidly and sustainably depleted plasma arginine with a manageable safety profile, treatment related adverse events were grade three or lower
About Pegzilarginase in Cancer
Pegzilarginase is an enhanced human arginase that enzymatically degrades the amino acid arginine. In some cancers, tumor cells stop producing specific amino acids and must acquire them from the blood, making the tumor cells susceptible to starvation through depletion of those amino acids. Aeglea is developing pegzilarginase to exploit vulnerabilities in some cancers that lead to an increased dependency on extracellular arginine. Pegzilarginase targets these arginine dependent cancers by depleting blood arginine levels to below the normal range. Preclinical data demonstrated that the resulting arginine starvation inhibits proliferation, induces cell death, increases turnover of cell components and promotes anti-tumor immune responses. The Company’s Phase 1 data in advanced solid tumors demonstrated that pegzilarginase was well tolerated at doses that produced marked and sustained reductions in blood arginine levels below the normal range.

On October 22, 2018 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported the first presentation of interim data from the pivotal Phase 3 KEYNOTE-048 trial investigating KEYTRUDA, Merck’s anti-PD-1 therapy, as both monotherapy and in combination with chemotherapy, for the first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) (Press release, Merck & Co, OCT 22, 2018, View Source [SID1234530028]). These interim results are being presented today during the Presidential Symposium at the ESMO (Free ESMO Whitepaper) 2018 Congress (Abstract # LBA8_PR) and are included in the official Press Program.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Interim data from KEYNOTE-048 showed KEYTRUDA monotherapy improved overall survival (OS), a primary endpoint of the study, by 39 percent (HR 0.61 [95% CI, 0.45-0.83]; p=0.0007) in patients whose tumors expressed PD-L1 with Combined Positive Score (CPS) ≥20, and by 22 percent (HR 0.78 [95% CI, 0.64-0.96]; p=0.0086) in patients with CPS≥1, compared to the EXTREME regimen (cetuximab with carboplatin or cisplatin plus 5-fluorouracil (5-FU), the current standard of care. In addition, KEYTRUDA in combination with chemotherapy (carboplatin or cisplatin plus 5-FU) (KEYTRUDA combination) demonstrated improved OS compared to the EXTREME regimen by 23 percent (HR 0.77 [95% CI, 0.63-0.93]; p=0.0034), regardless of PD-L1 expression. At the final analysis, superiority for OS will be evaluated for KEYTRUDA monotherapy in the total population and KEYTRUDA combination in patients whose tumors express PD-L1 at CPS≥20 and CPS≥1; at this interim analysis, based upon the prespecified testing algorithm, non-inferiority for KEYTRUDA monotherapy in the total population was demonstrated and statistical significance was not achieved for the KEYTRUDA combination in the subset of patients whose tumors expressed PD-L1 at CPS ≥20 or ≥1. Additionally, at this time point there was no difference in progression-free-survival (PFS), a dual primary endpoint of the study, in any of the groups studied. There were no new safety concerns identified with the use of KEYTRUDA in KEYNOTE-048.

"In this study, KEYTRUDA showed the potential to significantly prolong survival when used as first-line therapy for patients whose head and neck cancer had recurred or spread," said Dr. Barbara Burtness, lead investigator for KEYNOTE-048, professor of medicine at Yale School of Medicine and co-director, Development Therapeutics Research Program, Yale Cancer Center. "This is a devastating cancer when it recurs, and there has not been any advance in first-line treatment for over a decade. It is thrilling to see these new data, which have the potential to alter the standard of care in the first-line treatment of head and neck cancer."

"KEYTRUDA is the first anti-PD-1 therapy to show superior overall survival as first-line treatment compared to the EXTREME regimen, the current standard of care in patients with recurrent or metastatic head and neck cancer," said Dr. Roy Baynes, senior vice president and head of Global Clinical Development, chief medical officer, Merck Research Laboratories. "Recurrent or metastatic head and neck cancer is a very challenging disease. Merck would like to thank the patients and investigators for participating in this important study, which is helping to advance our understanding of the potential for KEYTRUDA and PD-1 inhibition in the first-line setting."

KEYTRUDA is currently approved in 61 countries for the treatment of second-line recurrent or metastatic HNSCC, including the U.S. and Europe. Merck plans to file a supplemental Biologics License Application (sBLA) with the U.S. Food and Drug Administration (FDA) for a first-line indication based on KEYNOTE-048 data and will include data from the Phase 3 KEYNOTE-040 trial as supportive data. Based on these results, Merck has withdrawn the sBLA for KEYNOTE-040 for KEYTRUDA as a second-line treatment in patients with recurrent or metastatic HNSCC, which was previously assigned a Prescription Drug User Fee Act (PDUFA) or target action date of Dec. 28, 2018. The results from KEYNOTE-048 will also be submitted to regulatory authorities worldwide.

Study Design and Additional Data from KEYNOTE-048 (Abstract # LBA8_PR)

KEYNOTE-048, a randomized, open-label Phase 3 trial (ClinicalTrials.gov, NCT02358031), evaluated KEYTRUDA monotherapy or KEYTRUDA combination, compared with the EXTREME regimen, as first-line treatment in 882 patients with recurrent or metastatic HSNCC. The dual primary endpoints were OS and PFS. The secondary endpoints were PFS (at 6 months and 12 months), objective response rate (ORR) and time to deterioration in Quality of Life Global Health Status/Quality of Life Scales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire and Safety. Duration of response (DOR) was evaluated as part of a pre-specified exploratory analysis. The primary and secondary endpoints, as well as exploratory DOR analysis, were evaluated in patients whose tumors expressed PD-L1 with CPS ≥20 and CPS ≥1, and in the total population, regardless of PD-L1 expression, based on a fixed sequential testing strategy. At the time of the analysis, the median follow-up was 11.7 months for KEYTRUDA monotherapy, 13.0 months for KEYTRUDA combination and 10.7 months for the EXTREME regimen, respectively.

In the first comparison group, OS in the CPS ≥20 population was significantly longer with KEYTRUDA monotherapy (14.9 months) (n=133) compared to the EXTREME regimen (10.7 months) (n=122) (HR 0.61 [95% CI, 0.45-0.83]; p=0.0007). There was no difference in PFS between the study arms (HR 0.99 [95% CI, 0.75-1.29]; p=0.5). ORR was 23.3 percent for KEYTRUDA monotherapy and 36.1 percent for the EXTREME regimen, respectively. The median DOR was substantially longer with KEYTRUDA monotherapy (20.9 months) compared to the EXTREME regimen (4.2 months).

Similarly, OS in the CPS ≥1 population was significantly longer with KEYTRUDA monotherapy (12.3 months) (n=257) compared to the EXTREME regimen (10.3 months) (n=255) (HR 0.78 [95% CI, 0.64-0.96]; p=0.0086). There was no difference in PFS between the study arms (HR 1.16 [95% CI, 0.96-1.39]). ORR was 19.1 percent for KEYTRUDA monotherapy and 34.9 percent for the EXTREME regimen, respectively. The median DOR was substantially longer with KEYTRUDA (20.9 months) compared to the EXTREME regimen (4.5 months).

In the second comparison group, OS in the total population was significantly longer with the KEYTRUDA combination (13.0 months) (n=281) compared to the EXTREME regimen (10.7 months) (n=278) (HR 0.77 [95% CI, 0.63-0.93]; p=0.0034). There was no difference in PFS between the study arms (HR 0.92; 95% CI, 0.77-1.10). ORR was 35.6 percent for the KEYTRUDA combination and 36.3 percent for the EXTREME regimen, respectively. The median DOR was longer with KEYTRUDA combination (6.7 months) compared to the EXTREME regimen (4.3 months).

There were no new safety concerns identified with the use of KEYTRUDA in KEYNOTE-048. Grade 3-5 treatment-related adverse events (TRAEs) occurred in 16.7 percent, 71.0 percent and 69.0 percent (n=198/287) of patients in the KEYTRUDA monotherapy, KEYTRUDA combination and the EXTREME regimen arms, respectively. TRAEs resulting in discontinuation occurred in 4.7 percent, 22.8 percent and 19.9 percent of patients in the KEYTRUDA monotherapy, KEYTRUDA combination and the EXTREME regimen arms, respectively. There were no TRAEs observed with an incidence of ≥15% in the KEYTRUDA monotherapy arm. The most common TRAEs (occurring in ≥15% of patients) in the KEYTRUDA combination arm included anemia (48.2%), nausea (44.9%), neutropenia (33.0%), fatigue (30.4%), mucosal inflammation (27.9%), thrombocytopenia (27.2%), vomiting (27.2%), stomatitis (24.3%), decreased appetite (22.5%), platelet count decreased (18.5%), diarrhea (17.8%) and neutrophil count decreased (16.7%).

Immune-mediated adverse events in patients receiving KEYTRUDA monotherapy or combination therapy were hypothyroidism (18.0% and 15.2%, respectively), pneumonitis (6.0% and 5.4%, respectively), hyperthyroidism (2.7% and 4.7%, respectively), severe skin reactions (2.7% and 0.7%, respectively), infusion reactions (1.3% and 2.2%, respectively), colitis (1.0% and 2.5%, respectively), nephritis (0.7% in both arms), pancreatitis (0.7% and 0.4%, respectively), hypophysitis (0.3% and 0.4%, respectively); hepatitis (0.7% monotherapy only); myocarditis and thyroiditis (0.4% each, combination only); and adrenal insufficiency, encephalitis and uveitis (0.3% each, monotherapy only). Treatment-related deaths occurred in 3 patients in the KEYTRUDA monotherapy arm [auto-inflammatory disease, disseminated intravascular coagulation, and pneumonitis (n=1 each)]; 10 patients in the KEYTRUDA combination arm [septic shock (n=5), cerebral ischemia, hemorrhage, interstitial lung disease, sepsis, and tumor hemorrhage (n=1 each)]; and 8 patients in the EXTREME regimen arm [pneumonia (n=3), sepsis (n=2), and hypoxia, osteomyelitis, and pulmonary artery thrombosis (n=1 each)].

Additional Information About KEYNOTE-048

KEYNOTE-048 enrolled 882 patients with recurrent or metastatic HSNCC who were randomized to one of three regimens as first-line therapy, as follows:

KEYTRUDA monotherapy (200 mg fixed dosed every three weeks [Q3W]) for up to 24 months (n=301); or
KEYTRUDA (200 mg fixed dose Q3W) in combination with cisplatin (100 mg/m2 IV Q3W) or carboplatin (AUC 5 IV Q3W) plus 5-FU (1000 mg/m2/day IV continuous from Day 1-4 Q3W (maximum six cycles), followed by additional KEYTRUDA monotherapy maintenance therapy until progression of disease, toxicity or until the patient had received a maximum of 24 months total treatment (n=281); or
EXTREME regimen including cetuximab at a loading dose (400 mg/m2 IV) followed by weekly doses (250 mg/m2 IV) in combination with cisplatin (100 mg/m2 IV Q3W) or carboplatin (AUC 5 IV Q3W) plus 5-FU (1000 mg/m2/day IV) continuous from Day 1-4 Q3W (maximum six cycles), followed by additional cetuximab monotherapy maintenance therapy until progression of disease or toxicity (n=300).
About Head and Neck Cancer

Head and neck cancer describes a number of different tumors that develop in or around the throat, larynx, nose, sinuses and mouth. Most head and neck cancers are squamous cell carcinomas that begin in the flat, squamous cells that make up the thin surface layer of the structures in the head and neck. The leading modifiable risk factors for head and neck cancer include tobacco and heavy alcohol use. Other risk factors include infection with certain types of HPV, also called human papillomaviruses. Worldwide, an estimated 835,000 new head and neck cancer cases will be diagnosed in 2018, and an estimated 431,000 people will die from the disease this year. In the U.S., there were an estimated 63,000 new cases diagnosed in 2017.

About KEYTRUDA (pembrolizumab) Injection 100mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 850 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

KEYTRUDA (pembrolizumab) Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALKgenomic tumor aberrations.

KEYTRUDA, as a single agent, is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for pemetrexed and carboplatin or cisplatin, as appropriate.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for the treatment of patients with PMBCL who require urgent cytoreductive therapy.

In adults with PMBCL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with PMBCL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is also indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of 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, or
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In children with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity or up to 24 months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%), and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue for Grade 4 colitis.

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in patients with HNSCC occurring in 15% (28/192) of patients. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency), thyroid function (prior to and periodically during treatment), and hyperglycemia. For hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or 4 hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 developed graft-versus-host disease (GVHD) (1 fatal case) and 2 developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

Increased Mortality in Patients with Multiple Myeloma

In clinical trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled clinical trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ≥1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (≥20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

Lactation

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

Pediatric Use

There is limited experience in pediatric patients. In a study in 40 pediatric patients with advanced melanoma, lymphoma, or PD-L1–positive advanced, relapsed, or refractory solid tumors, the safety profile was similar to that seen in adults treated with KEYTRUDA. Toxicities that occurred at a higher rate (≥15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia (18%).

Merck’s Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.