Clovis Oncology Presents Efficacy and Safety Data from New Drug Application (NDA) Population for Rucaparib in the Treatment of Advanced Mutant BRCA Ovarian Cancer at 2016 ESMO Congress

On October 7, 2016 Clovis Oncology (NASDAQ:CLVS) reported the oral presentation of the primary efficacy and safety data from its NDA dataset for rucaparib at the 2016 ESMO (Free ESMO Whitepaper) Congress in Copenhagen (Press release, Clovis Oncology, OCT 7, 2016, View Source;p=RssLanding&cat=news&id=2210141 [SID:SID1234515646]). Rucaparib is currently under priority review with FDA for the monotherapy treatment of advanced ovarian cancer in patients with BRCA-mutated tumors inclusive of both germline and somatic BRCA mutations who have been treated with two or more chemotherapies, and the submission has a PDUFA date of February 23, 2017.

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Rucaparib is the Company’s oral, small molecule inhibitor of PARP1, PARP2 and PARP3 currently being developed for the treatment of ovarian cancer, specifically in patients with tumors with BRCA mutations and other DNA repair deficiencies beyond BRCA, including those with high genomic loss of heterozygosity (LOH) also known as "BRCA-like." The current NDA submission seeks approval in patients with tumor BRCA mutations, which includes both germline and somatic mutations.

"These results demonstrate that rucaparib may represent an important option for women with multiply relapsed BRCA-mutated ovarian cancer based on its encouraging efficacy and tolerability," said Rebecca S. Kristeleit, MD, PhD, The University College London, Cancer Institute, London, UK. "In my opinion, rucaparib has the hallmarks of an important new therapeutic option for ovarian cancer patients."

"We are pleased to present the primary efficacy and safety dataset that has been submitted to the FDA as the basis of our NDA for rucaparib in the treatment of advanced ovarian cancer. If approved, rucaparib would be the first PARP inhibitor in the U.S. indicated to treat ovarian cancer patients with germline or somatic BRCA mutations who have received two prior chemotherapies. Women with BRCA mutations represent about 25% of patients in the US living with ovarian cancer," said Patrick J. Mahaffy, CEO and President of Clovis Oncology. "Our NDA review is ongoing with FDA, and in addition we are actively preparing for a European submission during the fourth quarter of 2016."

Data from subgroups of two multicenter, single-arm open-label phase 2 studies, Study 10 (NCT01482715) and ARIEL2 (NCT01891344) were combined for an integrated efficacy and safety analysis which further characterized the clinical benefit of rucaparib at the recommended starting dose of 600 mg BID in women with advanced ovarian cancer. In the two studies, 377 patients met the criteria for inclusion in the safety population (diagnosis of ovarian cancer and having received one or more doses of the recommended dose of 600 mg of rucaparib), and 106 patients met the criteria for inclusion in the efficacy population (received 2 or more prior chemotherapies, including 2 or more platinum-based regimens, had a mutation of BRCA (germline or somatic), and received one or more doses of the recommended dose of 600 mg of rucaparib.

The major efficacy outcome measure for this analysis was objective response rate (ORR) and duration of response (DOR) as assessed by the investigator according to RECIST. All responses were confirmed.

For the efficacy population (n=106), the median number of prior chemotherapies was three, with 39% having received two prior therapies and 61% of patients having received three or more prior therapies. The median number of prior platinum-based therapies was two, with 57% having received two prior platinum-based therapies, and 43% having received three or more prior platinum-based therapies. Seventy-five percent of patients in the efficacy population were platinum-sensitive (as defined by recurrence after progression free interval (PFI) of ≥6 months), 19% were platinum resistant (recurrence after PFI <6 months) and 7% were platinum refractory (progression on platinum, PFI <2 months).

Summary of Efficacy Data

The RECIST ORR (objective response rate as assessed by the investigator, which includes complete and partial responses) in the efficacy population was 57/106, or 54% (95% CI: 43.8-63.5). This includes nine (9%) complete responders (CR) and 48 (45%) partial responders (PR). Thirty-six patients (34%) had stable disease (SD) as the best response, while nine patients (9%) had progressive disease (PD) as the best response and four (4%) were not evaluable (NE). Seventy-five of 106 patients, or 71% (95% CI: 61.1-79.2) had a RECIST or CA-125 response.

For the 42 patients from Study 10 included in the efficacy population, the RECIST ORR was 25/42, or 60% (95% CI: 43.3-74.4). This included four CRs (10%) and 21 PRs (50%). In addition, 12 patients (29%) had SD, two patients (5%) had PD and three (7%) were NE. For the 64 patients from ARIEL2 included in the efficacy population, the RECIST ORR was 32/64, or 50% (95% CI: 37.2-62.8). This included five CRs (8%) and 27 PRs (42%). In addition, 24 patients (38%) had SD, seven (11%) had PD and one (2%) was NE. Study 10 was limited to platinum sensitive patients; ARIEL2 included platinum sensitive, platinum resistant and platinum refractory patients.

In addition, ORR was assessed by subgroups including BRCA mutation type, number of prior chemotherapies and prior platinum regimens, PFI and platinum status. Patients with a BRCA1 (n=67) or BRCA2 (n=39) mutation both showed an ORR of 54% (95% CI: 41.1-66.0, 37.2-69.9, respectively) in line with the overall population. The ORR for patients with germline BRCA mutations (n=88) and somatic BRCA mutations (n=13) was 53% (95% CI: 42.5-64.1) and 46% (95% CI: 19.2-74.9), respectively; in addition, five patients with a BRCA mutation but unknown germline or somatic status had an ORR of 80% (95% CI: 28.4-99.5). Patients who received two prior chemotherapies (n=41) achieved an ORR of 68% (95% CI: 51.9-81.9). Patients who received two prior platinum regimens (n=60) demonstrated an ORR of 65% (95% CI: 51.6-76.9). Response by length of PFI differed for patients with PFI<6 months (n=27), 6-12 months (n=56) and greater than 12 months (n=23), reporting 19% (95% CI: 6.3-38.1), 63% (95% CI: 48.6-75.1) and 74% (95% CI: 51.6-89.8), respectively. Response by platinum status was reported as 0% (95% CI: 0.0-41.0) for platinum-refractory patients (n=7), 25% (95% CI: 8.7-49.1) for platinum-resistant patients (n=20), and 66% (95% CI: 54.3-76.1) for platinum-sensitive patients (n=79).

Duration of response by investigator assessment in the efficacy population was 9.2 months (95% CI: 6.6-11.7 months), and the censoring rate among responders was 47%. As of the cutoff dates, 20 patients with a RECIST response had an ongoing response.

Additionally, analyses not contained within the NDA submission showed median progression-free survival by investigator assessment in the efficacy population to be 10.0 months. Of 106 patients, 50 patients did not have an event of disease progression or death at the data cut-off dates. Of these 50 patients, 32 patients were still on treatment, and 18 patients discontinued treatment for reasons other than disease progression or death at the data cut-off dates. Of note, 79% of patients remained progression-free at six months, and 41% remained progression-free at 12 months.

For the efficacy dataset, the cut off dates were November 30, 2015 and February 29, 2016, for Study 10 and ARIEL2, respectively.

Summary of Safety Data

Of the 377 ovarian cancer patients treated with a starting dose of rucaparib 600 mg, 377 (100%) experienced a treatment-emergent adverse event (AE) of any grade, and 229 (61%) experienced a treatment-emergent AE grade 3 or higher. A total of 360 patients (96%) experienced a treatment-related AE of any grade, and 177 (47%) experienced a treatment-related AE that was grade 3 or higher. AEs leading to dose interruption occurred in 221 patients (59%). Treatment-related AEs leading to dose reduction occurred in 167 patients (44%), and treatment discontinuation in 30 patients (8%). The primary reasons for dose reduction were anemia/decreased hemoglobin (17%), asthenia/fatigue (14%) and nausea (11%). The primary reasons for treatment discontinuation were asthenia/fatigue (2%), small intestinal obstruction (2%) and nausea (1%). Nine patients (2%) had AEs that led to death; eight were due to disease progression, and one death was due to sepsis, which was assessed by the investigator to be unrelated to treatment.

The most common treatment-emergent AEs (all grades) reported in ≥20 percent of patients included nausea (77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%), increased ALT/AST (41%) and constipation (40%). The most common Grade 3/4 treatment-emergent AEs reported in ≥10 percent of patients were anemia (25%), asthenia/fatigue (11%) and ALT/AST elevations (11%).

The increases in aspartate (AST) and alanine (ALT) aminotransferase levels that were observed were asymptomatic, reversible and were rarely associated with increases in bilirubin. The elevations normalized over time with continued rucaparib treatment.

Mild to moderate creatinine elevations were observed within the first few weeks of treatment for most patients, for whom 79 (21%) experienced an AE, of whom two (0.5%) experienced a grade 3/4 event. These elevations in creatinine likely result from inhibition of the renal transporters MATE1 and MATE2-K, which can lead to an increase in serum creatinine in the absence of renal injury.

Myelodysplastic syndrome/acute myeloid leukemia was reported in less than one percent of patients.

The cut-off dates for the safety dataset were March 31, 2016 for Study 10 and April 29, 2016 for ARIEL2.

Presentation Details

The oral presentation, titled "Clinical activity of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib in patients (pts) with high grade ovarian carcinoma (HGOC) and a BRCA mutation (BRCAmut): Analysis of pooled data from Study 10 (parts 1, 2a, and 3) and ARIEL2 (parts 1 and 2)" was presented today by Rebecca S. Kristeleit, PhD, The University College London, Cancer Institute, London, United Kingdom during the Session titled "Gynecological Cancers", from 2:00pm-3:30pm CEST (Abstract 856O: 2:45pm-3:00pm CEST).

The Trials-in-Progress poster presentation, titled "Window study of the PARP inhibitor rucaparib in patients with primary triple negative or BRCA1/2 related breast cancer (RIO)" is being presented Monday by Christy Toms, PhD, The Institute of Cancer Research, Sutton, United Kingdom during the Poster Session titled "Breast Cancer, Early Stage" from 1:00pm-2:00pm CEST (Abstract 219TiP, Poster Board #219).

The presentations will be available online at View Source at the time of their scheduled presentation at the Congress.

About Rucaparib

Rucaparib is an oral, small molecule inhibitor of PARP-1, PARP-2 and PARP-3 being developed for advanced ovarian cancer.

Specifically, rucaparib is being developed as monotherapy treatment of advanced ovarian cancer in patients with deleterious BRCA-mutated tumors inclusive of both germline and somatic BRCA mutations (as detected by an FDA-approved test) who have been treated with two or more chemotherapies. Rucaparib was granted Breakthrough Therapy designation for this proposed indication by the U.S. FDA in April 2015; and in late June 2016, Clovis completed its New Drug Application (NDA) submission to the FDA. The filing for treatment was accepted and has an action date of February 23, 2017. Rucaparib’s Marketing Authorization Application (MAA) to the European Medicines Agency for the proposed treatment indication is planned for Q4 2016.

Foundation Medicine, Clovis’ companion diagnostic partner, has submitted a Premarket Approval (PMA) application for its FoundationFocus CDxBRCA to the FDA in June 2016. The test is designed to identify tumor BRCA mutations. The timing of the submission is expected to allow for regulatory approval of the companion diagnostic in a similar timeframe.

Additionally, rucaparib is being developed as maintenance therapy in the ARIEL3 trial (NCT01968213) for patients with tumors with BRCA mutations and other DNA repair deficiencies beyond BRCA (commonly referred to as homologous recombination deficiencies, or HRD). Data from ARIEL3 are expected in Q4 2017, which is expected to be followed by the submission of a supplemental NDA for second-line maintenance therapy.

Clovis is also exploring rucaparib in other solid tumor types with BRCA mutations or molecular evidence of the HRD signature, including prostate, breast and gastroesophageal cancers.

Clovis holds worldwide rights for rucaparib.

About Ovarian Cancer

According to the American Cancer Society, more than 22,000 women will be diagnosed with ovarian cancer in the U.S. during 2016. There are often no clearly identifiable initial symptoms, and in an estimated 80 to 85% of ovarian cancer cases, the cancer has spread to other parts of the body before a person is diagnosed and can be treated. Ovarian cancer ranks fifth in cancer deaths and causes more deaths than any other cancer of the female reproductive system. One in four women with ovarian cancer have a germline or somatic BRCA mutation, and new treatment options are needed to treat unique patient populations.

Data Presented at ESMO 2016 Adds to Understanding of Abraxane® as a Therapy for Patients with Historically Challenging Solid Tumors

On October 7, 2016 Celgene Corporation (NASDAQ:CELG) reported results from multiple sponsored and independent studies will be presented during the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Annual Meeting evaluating the use of ABRAXANE (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) as a foundational treatment, either alone or in combination with novel agents and novel regimens, for patients with traditionally challenging cancers, including metastatic pancreatic cancer (mPAC), metastatic breast cancer (MBC) and advanced non-small cell lung cancer (NSCLC) (Press release, Celgene, OCT 7, 2016, View Source [SID:SID1234515645]).

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"Celgene continues to evaluate the safety and efficacy of ABRAXANE in patients with particularly challenging advanced diseases or with co-morbidities that limit their treatment options," said Michael Pehl, President, Hematology and Oncology for Celgene. "These data continue to shape our understanding of these difficult to treat diseases which will help evolve the current and future treatment landscapes in areas where there have been historically limited treatment options available to patients."

Investigational Research Evaluates ABRAXANE as a Foundational Treatment in mPAC, NSCLC, and MBC

The cancer treatment landscape has rapidly evolved over the last several years, with the introduction of targeted therapies and immunotherapy. While these advances have generated a lot of excitement, there are patients who may not benefit from these therapies. Celgene remains committed to continuing to explore treatments for these patients and at ESMO (Free ESMO Whitepaper) 2016, several studies evaluating treatment with ABRAXANE as a foundation therapy in these patients are being presented.

New data being presented from the ABOUND trials demonstrate the continued benefit of ABRAXANE/carboplatin doublet therapy in NSCLC. 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. The ABOUND trials included patients 70 years and older, as well as those with poorer performance status or squamous disease.1,2,3

An interim analysis of the ABOUND.70+ study (Poster 1280P) will be presented that evaluated the quality of life impact of elderly patients (aged 70+) with advanced NSCLC and an ECOG status of 0 or 1 treated with an ABRAXANE + carboplatin regimen through 4 cycles of treatment.1

The ABOUND.PS2 study (Poster 1278P) evaluated radiological response following treatment with ABRAXANE + carboplatin in 31 patients with advanced NSCLC and an Eastern Cooperative Oncology Group (ECOG) performance status 2.2
Similarly, interim quality of life results from the ABOUND.sqm study (Poster 1279P) will be presented that evaluated the quality of life in squamous NSCLC patients treated with ABRAXANE + carboplatin.3
Real-world outcomes data will also be presented for patients with metastatic breast cancer (MBC) including in the HR+/Her2- and TNBC subsets treated with ABRAXANE. 4,5

A study of 176 MBC patients (Poster 1030P) reports on time to treatment discontinuation (TTD) and time to next treatment (TTNT) with ABRAXANE compared with eribulin.4

Another retrospective analysis (Poster 1029P) will be presented that evaluated TTD in 411 MBC patients in the second line setting with ABRAXANE vs paclitaxel.5
The use of ABRAXANE in first line mPAC is further investigated by multiple independent studies being reported at ESMO (Free ESMO Whitepaper).

Safety and efficacy results from novel Abraxane regimens like GABRINOX (Abraxane-gemcitabine followed by FOLFIRINOX), and PAXG (Abraxane, cisplatin, capecitabine and gemcitabine) are being reported at ESMO (Free ESMO Whitepaper) 2016 (Posters 679P and 681P).6,7
Safety and efficacy data for Abraxane in patients with elevated bilirubin (posters 684P and 683P) will also be reported.8,9
Investigating ABRAXANE as a Chemotherapy Foundation with Novel Agents

In addition, there is also emerging data that further evaluates ABRAXANE’s use in challenging oncological diseases which illustrates the medical interest in ABRAXANE as a chemotherapy foundation in research with novel agents.

Currently, there are 180 clinical studies evaluating ABRAXANE combinations, including novel agents.10 At this year’s ESMO (Free ESMO Whitepaper), 15 independent studies are presented which evaluate ABRAXANE as a combination therapy with other agents across several tumor types including: TNBC – durvalumab (Poster 221TIP), mPAC – cisplatin, capecitabine, gemcitabine, FOLFIRINOX, ipafricept, vantictumab, PEGPH20, nivolumab (Posters 681P – Reni, 367PD – Weekes, 677P – Messersmith, 682P – Giommoni, and 715 TiP – Van Cutsem), and NSCLC – nivolumab, necitumumab (Posters 1059P – George and 1298 TiP – Socinski).

In addition, Celgene is presenting preliminary tolerability data evaluating the investigational combination use of ABRAXANE with the immunotherapy agent nivolumab (Poster 1059P) in NSCLC and mPAC. The study has been expanded and patients are currently enrolling in part 2. Additional data on the safety and efficacy of this combination in multiple tumor types will be presented at a future medical meeting.11

Update of ESMO (Free ESMO Whitepaper) Clinical Practice Guidelines

The latest edition of ESMO (Free ESMO Whitepaper) lung cancer guidelines have been updated to recommend use of ABRAXANE + carboplatin in patients with stage IV NSCLC. The recommendation is based on the pivotal trial that was conducted for ABRAXANE.12

About ABRAXANE (nab-paclitaxel)

ABRAXANE is a nanotechnology agent that is currently the only albumin-based nanotechnology therapy approved for the treatment of metastatic breast cancer, non-small cell lung cancer and pancreatic cancer in the United States, Europe and other markets around the world. It contains albumin-bound paclitaxel nanoparticles and is manufactured using patented nab technology. ABRAXANE is formulated with albumin, a human protein, and is free of solvents.

ABRAXANE was first approved in January 2005 by the U.S. Food and Drug Administration (FDA) 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. In Europe, ABRAXANE was approved in January 2008 as monotherapy for the treatment of metastatic breast cancer in adult patients who have failed first-line treatment for metastatic disease and for whom standard, anthracycline containing therapy is not indicated. ABRAXANE is now approved in more than 50 countries for the treatment of metastatic breast cancer.

In October 2012, ABRAXANE was approved by the FDA for the first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. ABRAXANE is also approved for the treatment of NSCLC in Argentina, Australia, Chile, Ecuador, Guatemala, Hong Kong, Japan, New Zealand and Singapore.

In September 2013, the FDA approved ABRAXANE as first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine. In December 2013, ABRAXANE in combination with gemcitabine was approved for first-line treatment of adult patients with metastatic adenocarcinoma of the pancreas in Europe. ABRAXANE is also approved for the treatment of metastatic pancreatic cancer in more than 40 countries.

Important Safety Information

WARNING – NEUTROPENIA

Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. 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), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer
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 and for pancreatic cancer)
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
In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended
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 and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE
Sepsis

Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine
Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis
If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics
For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels
Pneumonitis

Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine
Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis
Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis
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
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
For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate to severe hepatic impairment (total bilirubin > 1.5 x ULN and AST ≤10 x ULN)
Albumin (Human)

ABRAXANE contains albumin (human), a derivative of human blood
Use in Pregnancy: Pregnancy Category D

ABRAXANE can cause fetal harm when administered to a pregnant woman
If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus
Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE
Use in Men

Men should be advised not to father a child while receiving 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
Pancreatic Adenocarcinoma Study

Among the most common (≥20%) adverse reactions in the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)
Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%)
Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group
The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%)
The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%)
The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%)
The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%)
Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%), arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%)
Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%)
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
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

Nursing Mothers

It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother
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
Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas
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
For adenocarcinoma of the pancreas, do not administer ABRAXANE to patients who have moderate to severe hepatic impairment
Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity
Monitor patients closely
Please see full Prescribing Information, including Boxed WARNING.

Please refer to the Summary of Product Characteristics for full European prescribing information.

U.S. FDA Grants Priority Review for Daratumumab in Relapsed Multiple Myeloma

On October 7, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported that the U.S. Food and Drug Administration (FDA) has granted Priority Review to the supplemental Biologics License Application (sBLA) for the use of daratumumab (DARZALEX) in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy (Press release, Genmab, OCT 7, 2016, View Source [SID:SID1234515656]). The sBLA was submitted by Genmab’s licensing partner, Janssen Biotech, Inc. in August 2016. Priority Review is an FDA designation for drugs that treat a serious condition and may provide a significant improvement in safety or efficacy. The FDA has assigned a Prescription Drug User Fee Act (PDUFA) target date of February 17, 2017 to take a decision on daratumumab in this indication. In addition, the FDA has granted a Standard Review period for the use of daratumumab in combination with pomalidomide and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received at least two prior therapies, with a proteasome inhibitor and an immunomodulatory agent.

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The PDUFA date for the combination of daratumumab with pomalidomide/dexamethasone is June 17, 2017.
The FDA granted a Breakthrough Therapy Designation for daratumumab in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy in July 2016.

"People suffering from multiple myeloma always ultimately relapse after receiving treatment with the therapies available today. The application for daratumumab in combination with current backbone therapies for patients who have already received at least one type of treatment is a key step towards trying to bring new treatment options to patients with multiple myeloma," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

The sBLA submission included data from two Phase III studies: the CASTOR study of daratumumab in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone alone in patients with relapsed or refractory multiple myeloma, and the POLLUX study of daratumumab in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with relapsed or refractory multiple myeloma. The submission also included data from the Phase I study of daratumumab in combination with pomalidomide and dexamethasone in relapsed or refractory multiple myeloma.

About multiple myeloma
Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excess proliferation of plasma cells.1 Multiple myeloma is the third most common blood cancer in the U.S., after leukemia and lymphoma.2 Approximately 30,330 new patients are expected to be diagnosed with multiple myeloma and approximately 12,650 people are expected to die from the disease in the U.S. in 2016.3 Globally, it was estimated that 124,225 people would be diagnosed and 87,084 would die from the disease in 2015.4 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.5 Patients who relapse after treatment with standard therapies, including proteasome inhibitors or immunomodulatory agents, have poor prognoses and few treatment options.6

About DARZALEX (daratumumab)
DARZALEX (daratumumab) injection for intravenous infusion is indicated in the United States for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.7 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. DARZALEX is indicated in Europe for use as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a PI and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. For more information, visit www.DARZALEX.com.

Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through programmed cell death, or apoptosis,7,8 and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity,7,8 antibody-dependent cellular phagocytosis9,10 and antibody-dependent cellular cytotoxicity.7,8 In addition, daratumumab therapy results in a reduction of immune-suppressive myeloid derived suppressor cells (MDSCs) and subsets of regulatory T cells (Tregs) and B cells (Bregs), all of which express CD38. These reductions in MDSCs, Tregs and Bregs were accompanied by increases in CD4+ and CD8+ T cell numbers in both the peripheral blood and bone marrow.7,11

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. Five Phase III clinical studies with daratumumab in relapsed and frontline settings are currently ongoing, and additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma, non-Hodgkin’s lymphoma and a solid tumor.

Seattle Genetics and Agensys, an Affiliate of Astellas, Highlight Promising Enfortumab Vedotin (ASG-22ME) and ASG-15ME Phase 1 Data in Metastatic Urothelial Cancer at 2016 ESMO Congress

On October 7, 2016 Seattle Genetics, Inc. (NASDAQ: SGEN) and Agensys, an affiliate of Astellas, reported updated clinical data for enfortumab vedotin (ASG-22ME) and ASG-15ME at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress being held October 7-11, 2016 in Copenhagen, Denmark (Press release, Seattle Genetics, OCT 7, 2016, View Source [SID:SID1234515651]). Enfortumab vedotin and ASG-15ME are investigational antibody-drug conjugates (ADCs) that target the cell surface proteins Nectin-4 and SLITRK6, respectively. The clinical data for both agents continue to demonstrate overall response rates in patients with previously treated metastatic urothelial cancer, including those with prior checkpoint inhibitors. Safety and recommended phase II doses were also presented for both programs. While both phase I studies will continue to enroll patients, the companies plan to advance enfortumab vedotin and discuss next steps with regulatory agencies. Evaluation of next developmental steps for ASG-15ME is ongoing.

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"We are pleased to advance the enfortumab vedotin development program for patients with metastatic urothelial cancer. These patients are in dire need of new treatment options as their prognosis is grim, with a five-year survival rate of about 15 percent," said Jonathan Drachman, M.D., chief medical officer and executive vice president, Research and Development at Seattle Genetics. "The antitumor activity and safety profile of enfortumab vedotin in heavily pretreated metastatic patients is encouraging, particularly in those patients who have failed both platinum-based chemotherapy and checkpoint inhibitors. We look forward to discussions with regulatory agencies."

"Both enfortumab vedotin and ASG-15ME hold potential promise for metastatic urothelial cancer patients," said Steven Benner, M.D., senior vice president, therapeutic area head for oncology development, Astellas. "As we consider our next steps in these two development programs, we also pause to thank the patients, caregivers and clinical investigators who participate in these clinical trials for the important role they play in advancing the science of cancer care."

Interim data from two phase I dose-escalation studies of enfortumab vedotin and ASG-15ME monotherapy in patients with metastatic urothelial cancer will be presented at the ESMO (Free ESMO Whitepaper) Congress during poster sessions on Sunday, October 9, 2016. The respective clinical trial data showed that each agent had antitumor activity in patients previously treated with platinum-based chemotherapy, checkpoint inhibitors, taxanes and those with liver metastases. Enfortumab vedotin and ASG-15ME were generally well-tolerated, and phase 1 enrollment is ongoing with both agents, with an increased focus on checkpoint-inhibitor treated patients to further understand safety and activity in this population. Detailed findings are summarized below:

Interim Analysis of a Phase 1 Dose Escalation Trial of ASG-22CE (ASG-22ME; enfortumab vedotin), an Antibody-Drug Conjugate (ADC) in Patients (Pts) with Metastatic Urothelial Cancer (mUC) (Abstract #788P, poster presentation on Sunday, October 9, 2016)

Data were reported from 58 patients with metastatic urothelial cancer having a median age of 67 years. Of these patients, 56 patients (97 percent) had undergone treatment with a platinum-based chemotherapy regimen and 20 patients (35 percent) had progressed on or after treatment with checkpoint inhibitors. Thirty-six patients (62 percent) had received two or more prior systemic therapies. The primary endpoints of the ongoing clinical trial are to evaluate pharmacokinetics and safety of enfortumab vedotin as a monotherapy at escalating doses of 0.5 to 1.25 milligrams per kilogram (mg/kg) weekly for three of every four week cycles. In addition, the trial is evaluating antitumor activity, objective response rate and disease control rate. Key findings include:

Of the 49 patients evaluable for response, 18 patients (37 percent) had an objective response, including one patient (two percent) who achieved a complete response and 17 patients (35 percent) who achieved a partial response. The preliminary estimate of median progression-free survival is 16.6 weeks.
The recommended phase 2 dose is 1.25 mg/kg. In 17 patients treated at the 1.25 mg/kg dose level, 10 patients (59 percent) had a partial response. Disease control was achieved for 14 patients (82 percent), defined as achieving complete response, partial response or stable disease.
In the 16 patients across dose levels who had previously been treated with checkpoint inhibitors, six patients (38 percent) achieved a partial response. At the recommended phase 2 dose, four out of seven patients (57 percent) previously treated with checkpoint inhibitors achieved a partial response.
In the 12 patients whose cancer had metastasized to the liver, which typically has a poor prognosis, five patients (42 percent) achieved an objective response. Of 20 patients previously treated with taxanes, eight (40 percent) achieved an objective response.
The most common treatment related adverse events of any grade occurring in 20 percent or more of patients were pruritis (31 percent), fatigue (30 percent), diarrhea (29 percent), nausea (28 percent), rash (26 percent) and alopecia (21 percent).
Eight of 19 patients (42 percent) experienced a rash at the recommended phase 2 dose and none of these patients required dose modification or discontinued therapy as a result.
Enrollment is ongoing at 1.25 mg/kg and the study has been amended to include a checkpoint inhibitor-treated cohort to further understand safety and activity in this population.
Interim Analysis of a Phase 1 Dose Escalation Trial of the Antibody-Drug Conjugate (ADC) AGS15E (ASG-15ME) in Patients (Pts) with Metastatic Urothelial Cancer (mUC) (Abstract #780PD, poster presentation with discussion on Sunday, October 9, 2016)

Data were reported from 54 patients with metastatic urothelial cancer having a median age of 64 years. Of these patients, 52 patients (96 percent) had previously undergone treatment with a platinum-based chemotherapy regimen and 17 patients (32 percent) had progressed on or after treatment with checkpoint inhibitors. Thirty patients (56 percent) had received two or more prior systemic therapies. The primary endpoints of the ongoing clinical trial are to evaluate the pharmacokinetics and safety of ASG-15ME as a monotherapy at escalating doses of 0.1 to 1.25 mg/kg weekly for three of every four week cycles. In addition, the trial is evaluating antitumor activity, objective response rate and disease control rate. Key findings include:

Of the 48 patients evaluable for response, 18 patients (38 percent) had an objective response, including one patient (two percent) who achieved a complete response and 17 patients (35 percent) who achieved a partial response. The preliminary estimate of median progression-free survival is 16.1 weeks.
The recommended phase 2 dose is 1.0 mg/kg. In 20 patients treated at the 1.0 mg/kg dose level, 10 patients (50 percent) had an objective response, including one patient (five percent) who achieved a complete response and nine patients (45 percent) who achieved a partial response. Disease control was achieved for 14 patients (70 percent), defined as achieving complete response, partial response or stable disease.
Of the 14 patients across dose levels who had previously been treated with checkpoint inhibitors, six patients (43 percent) achieved a partial response. At the recommended phase 2 dose, three out of seven patients (43 percent) previously treated with checkpoint inhibitors achieved a partial response.
In the 13 patients whose cancer had metastasized to the liver, which typically has a poor prognosis, six patients (46 percent) achieved an objective response. Of 22 patients previously treated with taxanes, nine (41 percent) achieved an objective response.
The most common treatment related adverse events of any grade occurring in 20 percent or more of patients were fatigue (44 percent), nausea (22 percent) and decreased appetite (20 percent).
Fourteen patients (26 percent) experienced ocular adverse events and six patients (11 percent) developed ocular symptoms with corneal abnormalities at the recommended phase 2 dose. All events resolved with appropriate management.
Enrollment is ongoing at 1.0 mg/kg and the study has been amended to include a checkpoint inhibitor-treated cohort to further understand safety and activity in this population.
More information about these clinical trials, including enrolling centers, is available by visiting www.clinicaltrials.gov.

About Urothelial Cancer

Urothelial cancers include carcinomas of the bladder, ureter, and renal pelvis, which occur at a ratio of 50:3:1, respectively. Most bladder cancers start in the innermost lining of the bladder, which is called the urothelium or transitional epithelium. Urothelial cancer begins when urothelial cells in the urinary bladder, ureter, or renal pelvis start to grow uncontrollably.

While patients with early stage urothelial cancer are treated with curative intent, outcomes are poor for patients diagnosed with locally advanced or metastatic disease. For the approximately 10 percent of patients with urothelial cancer whose initial diagnoses occur when they have metastatic disease, the average five-year survival is approximately 15 percent. According to the American Cancer Society, in 2016 approximately 77,000 people will be diagnosed and more than 16,000 will die from urothelial bladder cancer.

About Enfortumab Vedotin and ASG-15ME

Enfortumab vedotin is an investigational ADC composed of an anti-Nectin-4 monoclonal antibody attached to a microtubule-disrupting agent, MMAE, using Seattle Genetics proprietary, industry-leading linker technology. Enfortumab vedotin is the first and only agent to target Nectin-4, a cell adhesion molecule identified as an ADC target by Agensys (now Astellas), which is expressed on many solid tumors. Preclinical data demonstrate that enfortumab vedotin effectively binds to target cells, internalizes and induces cell-killing activity.

ASG-15ME is an investigational antibody-drug conjugate (ADC) composed of an anti-SLITRK6 monoclonal antibody attached to a microtubule-disrupting agent, monomethyl auristatin E (MMAE), using Seattle Genetics proprietary, industry-leading linker technology. ASG-15ME is the first and only agent to target SLITRK6, a transmembrane protein identified as an ADC target by Agensys, which is expressed on many solid tumors. Preclinical data demonstrate that ASG-15ME effectively binds to target cells, internalizes and induces cell-killing activity.

Nectin-4 and SLITRK6 are highly expressed in urothelial cancers, particularly bladder cancer. Enfortumab vedotin and ASG-15ME consist of monoclonal antibodies which selectively target and kill tumor cells with microtubule-disrupting agents. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing antitumor activity.

Additional Phase 1 Data from ECHO-202 Reinforce Durability of Response in Patients with Treatment-naive Advanced or Metastatic Melanoma Treated with Epacadostat in Combination with Keytruda® (pembrolizumab)

On October 7, 2016 Incyte Corporation (Nasdaq:INCY) reported that updated data from the Phase I portion of the ECHO-202 trial evaluating the safety and efficacy of epacadostat, Incyte’s selective IDO1 enzyme inhibitor, in combination with pembrolizumab (Keytruda)*, Merck’s anti-PD-1 therapy, have been published as a poster at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Congress 2016 in Copenhagen, Denmark (Press release, Incyte, OCT 7, 2016, View Source [SID:SID1234515643]).

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Further to the previously published abstract, today’s updated data show that among patients with treatment-naïve advanced melanoma (n=19), the combination of epacadostat plus pembrolizumab resulted in progression-free survival (PFS) rates of 74 percent and 57 percent at 6 months and 12 months, respectively. Median PFS has not been reached. The updated data also show an increase in the complete response (CR) rate to 26 percent. The objective response rate (ORR) and disease control rate (DCR) remained consistent with the previously published abstract data, at 58 percent and 74 percent, respectively. All responses are confirmed and ongoing (median follow-up among responders 56 plus [range of 46 to 90 plus] weeks).

"We are excited to share further data with additional follow-up from the Phase 1 portion of the ECHO-202 study," said Steven Stein, M.D., Incyte’s Chief Medical Officer. "The durable responses seen in patients with treatment-naïve advanced or metastatic melanoma reaffirm the activity of this immunotherapy combination, and we look forward to the read-out of ECHO-301, the ongoing, pivotal Phase 3 trial."

Epacadostat in combination with pembrolizumab was well tolerated in the Phase 1 population (n=62). The most common (≥15%) all grade treatment-related AEs (TRAEs) were fatigue, rash, pruritus, arthralgia, diarrhea and nausea. Grade ≥3 TRAEs were observed in 19 percent of patients; the most common were rash (8%) and increased lipase (5%). Five patients (8%) discontinued treatment due to TRAEs.

The ECHO-202 poster was made available to attendees at the ESMO (Free ESMO Whitepaper) Congress today, Friday, 7 October, and will be made available via the Events and Presentations tab of the Investor section of www.incyte.com. Incyte will host an investor conference call and webcast at 14:00 CET (8:00 a.m. ET) today, 7 October 2016, which can also be accessed via the Events and Presentations tab of the Investor section of www.incyte.com

About ECHO-202 (KEYNOTE-037)
The ECHO-202 study (NCT02178722) is evaluating the safety and efficacy of epacadostat, Incyte’s selective IDO1 inhibitor, in combination with pembrolizumab. Patients previously treated with anti-PD-1 or anti-CTLA-4 therapies were excluded from this trial. Enrollment is complete for the Phase 1 dose escalation (epacadostat 25, 50, 100 mg BID + pembrolizumab 2 mg/kg IV Q3W and epacadostat 300 mg BID + pembrolizumab 200 mg IV Q3W) and Phase 1 dose expansion (epacadostat 50, 100, and 300 mg BID + pembrolizumab 200 mg IV Q3W) portions of the trial. Enrollment in Phase 2, tumor-specific, cohorts is ongoing.

About ECHO
The ECHO clinical trial program was established to investigate the efficacy and safety of epacadostat as a core component of combination therapy in oncology. Ongoing Phase 1 and Phase 2 studies evaluating epacadostat in combination with PD-1 and PD-L1 inhibitors collectively plan to enroll over 900 patients in a broad range of solid tumor types as well as hematological malignancies. ECHO-301 (NCT02752074), a Phase 3 randomized, double-blind, placebo-controlled study evaluating pembrolizumab in combination with epacadostat or placebo for the first-line treatment of patients with advanced or metastatic melanoma, is also underway. ECHO-301 was initiated in June 2016 and initial data from this study are expected to be available in 2018.

About Epacadostat (INCB024360)
Indoleamine 2,3-dioxygenase 1 (IDO1) is a key immunosuppressive enzyme that modulates the anti-tumor immune response by promoting regulatory T cell generation and blocking effector T cell activation, thereby facilitating tumor growth by allowing cancer cells to avoid immune surveillance. Epacadostat is a first-in-class, highly potent and selective oral inhibitor of the IDO1 enzyme that reverses tumor-associated immune suppression and restores effective anti-tumor immune responses. In single-arm studies, the combination of epacadostat and immune checkpoint inhibitors has shown proof-of-concept in patients with unresectable or metastatic melanoma. In these studies, epacadostat combined with the CTLA-4 inhibitor ipilimumab or the PD-1 inhibitor pembrolizumab improved response rates compared with studies of the immune checkpoint inhibitors alone.