On June 19, 2017 Amgen (NASDAQ: AMGN) reported that the U.S. Food and Drug Administration (FDA) has accepted the XGEVA (denosumab) supplemental Biologics License Application (sBLA) that seeks to expand the currently approved indication for the prevention of fractures and other skeletal-related events in patients with bone metastases from solid tumors to include patients with multiple myeloma (Press release, Amgen, JUN 19, 2017, View Source [SID1234519610]). The FDA has set a Prescription Drug User Fee Act (PDUFA) action date of Feb. 3, 2018.

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"Multiple myeloma patients with fractures and other bone complications have a very poor prognosis. Bisphosphonates are the only approved class of agents for the prevention of skeletal-related events in this patient population. However, these agents have several limitations, including kidney toxicity and acute phase reactions," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "Based on the data we have submitted to the FDA, we look forward to potentially making XGEVA available as a novel option for patients with multiple myeloma."

XGEVA is the first fully human monoclonal antibody that binds to and neutralizes RANK ligand (RANKL) – a protein essential for the formation, function and survival of osteoclasts, which break down bone – thereby inhibiting osteoclast-mediated bone destruction. XGEVA is not cleared by the kidneys. XGEVA is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors and is the number one prescribed agent by oncologists for this indication in the U.S. In the U.S., XGEVA currently has a limitation of use noting that it is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

The sBLA, submitted on April 3, 2017, is based on the efficacy and safety data from the pivotal Phase 3 ‘482 study, the largest international multiple myeloma trial ever conducted, which successfully demonstrated that XGEVA is non-inferior to zoledronic acid in delaying the time to first on-study skeletal-related event in patients with multiple myeloma. The secondary endpoints of superiority in delaying time to first on-study skeletal-related event and delaying time to first-and-subsequent skeletal-related event were not met in this study. Progression-free survival was an exploratory endpoint. The hazard ratio of XGEVA versus zoledronic acid for progression-free survival was 0.82 (95 percent CI: 0.68, 0.99; descriptive p=0.036) and the median difference in progression-free survival between arms was 10.7 months in favor of XGEVA. Data from the ‘482 study are also the basis of an application for a variation to the marketing authorization submitted to the European Medicines Agency (EMA).

About ‘482 Study (NCT01345019)
The ‘482 study was an international, Phase 3, randomized, double-blind, multicenter trial of XGEVA compared with zoledronic acid in the prevention of skeletal-related events in adult patients with newly diagnosed multiple myeloma. In the study, a total of 1,718 patients (859 on each arm) were randomized to receive either subcutaneous XGEVA 120 mg and intravenous placebo every four weeks, or intravenous zoledronic acid 4 mg (adjusted for renal function) and subcutaneous placebo every four weeks.

The primary endpoint of the study was non-inferiority of XGEVA versus zoledronic acid with respect to time to first on-study skeletal-related event (pathologic fracture, radiation to bone, surgery to bone or spinal cord compression). Secondary endpoints included superiority of XGEVA over zoledronic acid with respect to time to first on-study and first-and-subsequent on-study skeletal-related event and evaluation of overall survival. The hazard ratio of overall survival was 0.90 for XGEVA as compared to zoledronic acid (95 percent CI: 0.70, 1.16). The hazard ratio of XGEVA versus zoledronic acid for progression-free survival, an exploratory endpoint, was 0.82 (95 percent CI: 0.68, 0.99; descriptive p=0.036). The median difference in progression-free survival between arms was 10.7 months in favor of XGEVA. The safety and tolerability of XGEVA were also compared with zoledronic acid in the study. The most common adverse events (greater than or equal to 25 percent) in both arms were diarrhea and nausea.

About Multiple Myeloma and Bone Complications (Skeletal-Related Events)
Multiple myeloma is the second most common hematologic cancer, and it develops in plasma cells located in the bone marrow microenvironment.1,2 It is typically characterized by osteolytic bone lesions and renal impairment, which are both part of diagnosis (CRAB criteria).3,4 Each year an estimated 114,000 new cases of multiple myeloma are diagnosed worldwide, resulting in more than 80,000 deaths per year.1

More than 90 percent of patients develop osteolytic lesions during the course of the disease.3 Current treatment options for bone complications are limited to bisphosphonates, including zoledronic acid; these are cleared by the kidneys and are associated with renal toxicity which is a common complication among multiple myeloma patients.5 The majority (approximately six out of 10) of all multiple myeloma patients have or will develop renal impairment over the course of the disease.6 Preventing bone complications is a critical aspect of caring for patients with multiple myeloma, because these events can cause significant morbidity.7

About XGEVA (denosumab)
XGEVA targets the RANKL pathway to prevent the formation, function and survival of osteoclasts, which break down bone. As a monoclonal antibody, XGEVA is not cleared by the kidneys. XGEVA is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. In the U.S., XGEVA currently has a limitation of use noting that it is not indicated for the prevention of skeletal-related events in patients with multiple myeloma. XGEVA is also indicated for the treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. XGEVA is also indicated in the U.S. for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

U.S. Important Safety Information

Hypocalcemia
Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA. XGEVA can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Monitor calcium levels, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake.

Hypersensitivity
XGEVA is contraindicated in patients with known clinically significant hypersensitivity to XGEVA, including anaphylaxis that has been reported with use of XGEVA. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue XGEVA therapy permanently.

Drug Products with Same Active Ingredient
Patients receiving XGEVA should not take Prolia (denosumab).

Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) has been reported in patients receiving XGEVA, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure.

Patients with a history of tooth extraction, poor oral hygiene, or use of a dental appliance are at a greater risk to develop ONJ. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, and gingival infections.

Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA and periodically during XGEVA therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA. Consider temporarily interrupting XGEVA therapy if an invasive dental procedure must be performed.

Patients who are suspected of having or who develop ONJ while on XGEVA should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture
Atypical femoral fracture has been reported with XGEVA. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.

Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During XGEVA treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of XGEVA therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Hypercalcemia Following Treatment Discontinuation in Patients with Growing Skeletons
Clinically significant hypercalcemia has been reported in XGEVA treated patients with growing skeletons, weeks to months following treatment discontinuation. Monitor patients for signs and symptoms of hypercalcemia and treat appropriately.

Embryo-Fetal Toxicity
XGEVA can cause fetal harm when administered to a pregnant woman. Based on findings in animals, XGEVA is expected to result in adverse reproductive effects.

Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of XGEVA. Apprise the patient of the potential hazard to a fetus if XGEVA is used during pregnancy or if the patient becomes pregnant while patients are exposed to XGEVA.

Adverse Reactions
The most common adverse reactions in patients receiving XGEVA with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia.

The most common adverse reactions in patients receiving XGEVA for giant cell tumor of bone were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. The most common serious adverse reactions were osteonecrosis of the jaw and osteomyelitis. The most common adverse reactions resulting in discontinuation of XGEVA were osteonecrosis of the jaw and tooth abscess or tooth infection.

The most common adverse reactions in patients receiving XGEVA for hypercalcemia of malignancy were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.

Denosumab is also marketed as Prolia in other indications.

Please visit www.amgen.com or www.xgeva.com for Full U.S. Prescribing Information.

On June 19, 2017 Merrimack Pharmaceuticals, Inc. (NASDAQ: MACK) reported that it has enrolled the last patient in the ongoing CARRIE study, a Phase 2, double-blind, placebo-controlled, randomized trial, evaluating MM-141 (istiratumab) in combination with standard of care in previously untreated patients with metastatic pancreatic cancer (Press release, Merrimack, JUN 19, 2017, View Source [SID1234519606]). MM-141 is a bispecific antibody targeting both the Insulin Like Growth Factor 1 Receptor (IGF-1R) and the HER3 receptor, and is a potent inhibitor of the PI3K/AKT/mTOR signaling pathway.

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"Today, as we recognize the 10th anniversary of the National Pancreatic Cancer Advocacy Day, we are marking a significant milestone with the CARRIE study, which reflects both the significant need for new therapies in metastatic pancreatic cancer and the potential of MM-141 to play a critical role in addressing that need," said Richard Peters, M.D., Ph.D., President and Chief Executive Officer of Merrimack. "We are moving with great urgency in this study and in each of our clinical-stage development programs to investigate a biomarker-driven treatment strategy and efficiently establish the role of our therapies for well-defined patient groups. With enrollment now complete, we look forward to reporting results from this trial in the first half of 2018."

The CARRIE study is evaluating MM-141 in patients with high levels of the IGF-1 protein, which is known to play a role in tumor proliferation and metastasis. Patients with metastatic pancreatic cancer and high levels of free IGF-1 were randomized 1:1 to receive either MM-141 plus nab-paclitaxel/gemcitabine chemotherapy or placebo plus chemotherapy. The primary endpoint is progression-free survival, with objective response rate, disease control rate, duration of response and overall survival as secondary measures.

"On behalf of our entire team at Merrimack, I would like to thank our investigators and their staff for their dedication in ensuring the rapid execution of this study, as well as patients and their families for their commitment to advance pancreatic cancer care through participation in this trial," said Vasileios Askoxylakis, M.D., Ph.D., Medical Director and Project Leader for MM-141.

On June 19, 2017 Exelixis, Inc. (NASDAQ:EXEL) reported that the analysis of the review by a blinded independent radiology review committee (IRC) has confirmed the primary efficacy endpoint results of investigator-assessed progression-free survival (PFS) from the CABOSUN randomized phase 2 trial of cabozantinib as compared with sunitinib in patients with previously untreated advanced renal cell carcinoma (RCC) with intermediate- or poor-risk disease per the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) (Press release, Exelixis, JUN 19, 2017, View Source [SID1234519605]). Per the IRC analysis, cabozantinib demonstrated a clinically meaningful and statistically significant reduction in the rate of disease progression or death as measured by PFS. Exelixis remains on target to complete a supplemental New Drug Application (sNDA) for cabozantinib as a treatment of first-line advanced renal cell carcinoma in the third quarter of 2017.

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CABOSUN was conducted by The Alliance for Clinical Trials in Oncology as part of Exelixis’ agreement with the National Cancer Institute’s Cancer Therapy Evaluation Program (NCI-CTEP). Exelixis and the Alliance cooperative group plan to submit these results for presentation at an upcoming international medical meeting.

"We are very pleased that CABOSUN’s primary endpoint of a statistically significant improvement of progression-free survival has been confirmed by the independent radiology review committee," said Michael M. Morrissey, Ph.D., President and Chief Executive Officer of Exelixis. "We continue in our focused efforts to complete the regulatory filing of cabozantinib for the treatment of patients with previously untreated advanced renal cell carcinoma and are on track to submit a supplemental New Drug Application in the third quarter of this year. Patients in the first-line setting with either intermediate- or poor-risk disease progress rapidly with sunitinib, a current standard of care, highlighting a clear need for new options that provide improved clinical benefit in this difficult to treat patient population."

About the CABOSUN Study

On May 23, 2016, Exelixis announced that CABOSUN met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in PFS compared with sunitinib in patients with advanced intermediate- or poor-risk RCC as determined by investigator assessment. CABOSUN was conducted by The Alliance for Clinical Trials in Oncology as part of Exelixis’ collaboration with the NCI-CTEP. These results were first presented by Dr. Toni Choueiri at the meeting of the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016, and published in the Journal of Clinical Oncology (Choueiri, JCO, 2016).1

CABOSUN was a randomized, open-label, active-controlled phase 2 trial that enrolled 157 patients with advanced RCC determined to be intermediate- or poor-risk by the IMDC criteria. Patients were randomized 1:1 to receive cabozantinib (60 mg once daily) or sunitinib (50 mg once daily, four weeks on followed by two weeks off). The primary endpoint was PFS. Secondary endpoints included overall survival and objective response rate. Eligible patients were required to have locally advanced or metastatic clear-cell RCC, ECOG performance status 0-2, and had to be intermediate or poor risk per the IMDC criteria (Heng, JCO, 2009).2 Prior systemic treatment for RCC was not permitted.

Please see Important Safety Information below and full U.S. prescribing information at View Source

About Advanced Renal Cell Carcinoma

The American Cancer Society’s 2017 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.3 Clear cell RCC is the most common type of kidney cancer in adults.4 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 12 percent, with no identified cure for the disease.5 Approximately 30,000 patients in the U.S. and 68,000 globally require treatment.6

The majority of clear cell RCC tumors have lower than normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL and VEGF.7,8 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.9-12 MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors.8,9

About CABOMETYX (cabozantinib)

CABOMETYX is the tablet formulation of cabozantinib. Its targets include MET, AXL and VEGFR-1, -2 and -3. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis and drug resistance.

CABOMETYX is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily.

On April 25, 2016, the FDA approved CABOMETYX tablets for the treatment of patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy. On September 9, 2016, the European Commission approved CABOMETYX tablets for the treatment of advanced renal cell carcinoma in adults who have received prior vascular endothelial growth factor (VEGF)-targeted therapy in the European Union, Norway and Iceland.

U.S. Important Safety Information

Hemorrhage: Severe hemorrhage occurred with CABOMETYX. The incidence of Grade ≥3 hemorrhagic events was 2.1% in CABOMETYX-treated patients and 1.6% in everolimus-treated patients. Fatal hemorrhages also occurred in the cabozantinib clinical program. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.

Gastrointestinal (GI) Perforations and Fistulas: Fistulas were reported in 1.2% (including 0.6% anal fistula) of CABOMETYX-treated patients and 0% of everolimus-treated patients. GI perforations were reported in 0.9% of CABOMETYX-treated patients and 0.6% of everolimus-treated patients. Fatal perforations occurred in the cabozantinib clinical program. Monitor patients for symptoms of fistulas and perforations. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed or a GI perforation.

Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. Venous thromboembolism was reported in 7.3% of CABOMETYX-treated patients and 2.5% of everolimus-treated patients. Pulmonary embolism occurred in 3.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Events of arterial thromboembolism were reported in 0.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Fatal thrombotic events occurred in the cabozantinib clinical program. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or any other arterial thromboembolic complication.

Hypertension and Hypertensive Crisis: CABOMETYX treatment results in an increased incidence of treatment-emergent hypertension. Hypertension was reported in 37% (15% Grade ≥3) of CABOMETYX-treated patients and 7.1% (3.1% Grade ≥3) of everolimus-treated patients. Monitor blood pressure prior to initiation and regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy. Discontinue CABOMETYX if there is evidence of hypertensive crisis or severe hypertension despite optimal medical management.

Diarrhea: Diarrhea occurred in 74% of patients treated with CABOMETYX and in 28% of patients treated with everolimus. Grade 3 diarrhea occurred in 11% of CABOMETYX-treated patients and in 2% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to diarrhea occurred in 26% of patients.

Palmar-Plantar Erythrodysesthesia Syndrome (PPES): Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 42% of patients treated with CABOMETYX and in 6% of patients treated with everolimus. Grade 3 PPES occurred in 8.2% of CABOMETYX-treated patients and in <1% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPES or Grade 3 PPES until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to PPES occurred in 16% of patients.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in the cabozantinib clinical program. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Embryo-fetal Toxicity: CABOMETYX can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose.

Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, PPES, hypertension, vomiting, weight decreased, and constipation.

Drug Interactions: Strong CYP3A4 inhibitors and inducers: Reduce the dosage of CABOMETYX if concomitant use with strong CYP3A4 inhibitors cannot be avoided. Increase the dosage of CABOMETYX if concomitant use with strong CYP3A4 inducers cannot be avoided.

Lactation: Advise a lactating woman not to breastfeed during treatment with CABOMETYX and for 4 months after the final dose.

Reproductive Potential: Contraception―Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the final dose. Infertility ―CABOMETYX may impair fertility in females and males of reproductive potential.

Hepatic Impairment: Reduce the CABOMETYX dose in patients with mild (Child-Pugh score [C-P] A) or moderate (C-P B) hepatic impairment. CABOMETYX is not recommended for use in patients with severe hepatic impairment.

Please see full Prescribing Information at View Source

On June 19, 2017 Clovis Oncology, Inc. (NASDAQ: CLVS) reported topline data from the confirmatory phase 3 ARIEL3 trial of rucaparib, which successfully achieved the primary endpoint of improved progression-free survival (PFS) by investigator review in each of the three populations studied (Press release, Clovis Oncology, JUN 19, 2017, View Source [SID1234519604]). PFS was also improved in the rucaparib group compared with placebo by blinded independent central review (BICR), a key secondary endpoint. Based on these findings, the Company plans to submit a supplemental New Drug Application (sNDA) within the next four months for a second-line and later maintenance treatment indication for all women with platinum-sensitive ovarian cancer who have responded to their most recent platinum therapy.

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"We are very pleased with these positive ARIEL3 topline results that strongly demonstrate the potential of rucaparib to help women with platinum-sensitive, advanced ovarian cancer," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "These results reinforce the potentially foundational role of rucaparib in the management of advanced ovarian cancer, as demonstrated by both investigator review and the blinded independent central review. Most importantly, we are grateful to the patients, caregivers and investigators who participated in this study. We look forward to sharing these data in greater detail at a medical meeting later this year and submitting our sNDA as rapidly as possible, with the ultimate goal of making rucaparib available to more women battling ovarian cancer."

"Based on these encouraging data, it is clear that rucaparib demonstrates a clinically meaningful impact in delaying disease recurrence in women in this trial with advanced ovarian cancer," said Robert L. Coleman, M.D., professor and vice chair, clinical research, in the Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center in Houston and the U.S. Principal Investigator for the ARIEL3 study. "The PFS and safety results achieved in this study are particularly promising, because they suggest women are able to stay on rucaparib for a prolonged period of time while gaining benefit. It is also clinically significant that rucaparib not only sustained the most recent response to platinum, but in some patients also enhanced that response, including the elimination of residual tumor."

"I first dosed a patient with rucaparib over five years ago, and these robust and exciting data are consistent with my experience," said Professor Jonathan Ledermann, Professor of Medical Oncology, Director, Cancer Research UK and UCL Cancer Trials Centre, UCL Cancer Institute, and European and ROW Principal Investigator for the ARIEL3 study. "These results show that rucaparib has the potential to provide an enduring and important clinical benefit in women with advanced ovarian cancer, irrespective of their tumor genetics. This is a very important step forward for women with advanced ovarian cancer."

ARIEL3 is a double-blind, placebo-controlled, phase 3 trial of rucaparib that enrolled 564 women with platinum-sensitive, high-grade ovarian, fallopian tube, or primary peritoneal cancer. The primary efficacy analysis evaluated three prospectively defined molecular sub-groups in a step-down manner: 1) tumor BRCA mutant (tBRCAmut) patients, inclusive of germline and somatic mutations of BRCA; 2) HRD-positive patients, including BRCA-mutant patients and BRCA wild-type with high loss of heterozygosity, or LOH-high patients; and, finally, 3) the intent-to-treat population, or all patients treated in ARIEL3.

Following is a table and a summary of the primary efficacy analyses and selected exploratory PFS endpoints per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by each of investigator review, which was the primary analysis of ARIEL3, and independent review (BICR), a key secondary endpoint of the study.

Summary of Primary Efficacy Analyses and Selected Exploratory Endpoints for ARIEL3

ARIEL3
Analysis Population

PFS by Investigator Review
(Primary Endpoint)

PFS by Blinded Independent Central Review
(Key Secondary Endpoint)
Primary Analyses
Hazard Ratio
Median PFS (months)
Rucaparib vs. Placebo
Hazard Ratio
Median PFS (months)
Rucaparib vs. Placebo
tBRCAmut
(n=196)
0.23; p<0.0001 16.6 vs. 5.4 0.20; p<0.0001 26.8 vs. 5.4
HRD-positive
(n=354)
0.32; p<0.0001 13.6 vs. 5.4 0.34; p<0.0001 22.9 vs. 5.5
Intent-to-Treat
(n=564)
0.36; p<0.0001 10.8 vs. 5.4 0.35; p<0.0001 13.7 vs. 5.4
Exploratory Analyses
BRCAwt / HRD-positive
(n=158)
0.44; p<0.0001 9.7 vs. 5.4 0.55; p=0.0135 11.1 vs. 5.6
BRCAwt / HRD-negative (n=161) 0.58; p=0.0049 6.7 vs. 5.4
0.47; p=0.0003
8.2 vs. 5.3
PFS: progression-free survival; tBRCAmut: tumor BRCA mutant; HRD: homologous recombination deficiency; BRCAwt: BRCA wild type

"Ovarian cancer is the deadliest gynecologic cancer and until very recently, there were limited treatment options for advanced disease," said David Barley, Chief Executive Officer of the National Ovarian Cancer Coalition. "The potential for targeted therapies that can meaningfully delay recurrence for a large percentage of women with this disease is significant, and we are encouraged by these results from ARIEL3."

Significant Improvement in PFS in the tBRCAmut Patient Population

The most robust clinical outcomes were observed among ARIEL3 patients with a germline or somatic BRCA mutation (n=196). By investigator review, the rucaparib arm successfully achieved statistical significance over the placebo arm for the primary endpoint of PFS with a hazard ratio of 0.23 (p<0.0001). The median PFS for the tBRCAmut patients treated with rucaparib was 16.6 months vs. 5.4 months among those who received placebo.

By independent review (BICR), the rucaparib arm improved PFS over the placebo arm with a hazard ratio of 0.20 (p<0.0001). The median PFS for the tBRCAmut patients treated with rucaparib was 26.8 months vs. 5.4 months among those who received placebo.

Results were consistent for the germline BRCA (n=130) and somatic BRCA (n=56) populations.

Significant Improvement in PFS in the HRD-positive Patient Population

This population included patients with a germline or somatic mutation of BRCA, as well as those whose tumors were BRCA wild type (BRCAwt) but determined to be HRD positive as defined by a Foundation Medicine assay (n=354). By investigator review, the rucaparib arm successfully achieved statistical significance over the placebo arm for the primary endpoint of PFS with a hazard ratio of 0.32 (p<0.0001). The median PFS for the HRD-positive patients treated with rucaparib was 13.6 months vs. 5.4 months among those who received placebo.

By independent review (BICR), the rucaparib arm improved PFS over the placebo arm with a hazard ratio of 0.34 (p<0.0001). The median PFS for the HRD-positive patients treated with rucaparib was 22.9 months vs. 5.5 months among those who received placebo.

Significant Improvement in PFS in All Patients Studied

Rucaparib also showed statistical significance in all 564 patients enrolled in the study. By investigator review, the rucaparib arm successfully achieved statistical significance over the placebo arm for the primary endpoint of PFS with a hazard ratio of 0.36 (p<0.0001). The median PFS for all patients treated with rucaparib was 10.8 months vs. 5.4 months for those who received placebo.

By independent review (BICR), the rucaparib arm improved PFS over the placebo arm with a hazard ratio of 0.35 (p<0.0001). The median PFS for all patients enrolled in ARIEL3 and treated with rucaparib was 13.7 months vs. 5.4 months for those who received placebo.

Exploratory PFS Endpoint Achieved in BRCAwt/HRD-positive Subgroup

The exploratory PFS endpoint was achieved in the 158 patients identified as BRCAwt HRD positive. By investigator review, the rucaparib arm successfully achieved its endpoint over the placebo arm for the primary endpoint of PFS with a hazard ratio of 0.44 (p<0.0001). The median PFS for these patients treated with rucaparib was 9.7 months vs. 5.4 months for those who received placebo.

By independent review (BICR), the rucaparib arm improved PFS over the placebo arm with a hazard ratio of 0.55 (p=0.014). The median PFS for these patients treated with rucaparib was 11.1 months vs. 5.6 months for those who received placebo.

Exploratory PFS Endpoint Achieved in BRCAwt/HRD-negative Subgroup

The exploratory PFS endpoint was achieved in the 161 patients identified as BRCAwt and HRD negative. By investigator review, the rucaparib arm successfully achieved its endpoint over the placebo arm for the primary endpoint of PFS with a hazard ratio of 0.58 (p=0.0049). The median PFS for these patients treated with rucaparib was 6.7 months vs. 5.4 months for those who received placebo.

By independent review (BICR), the rucaparib arm improved PFS over the placebo arm with a hazard ratio of 0.47 (p=.0003). The median PFS for these patients treated with rucaparib was 8.2 months vs. 5.3 months for those who received placebo.

Exploratory Endpoint of Response Rate

Enrollment in ARIEL3 included one-third of patients who had achieved a complete response to their prior platinum-based therapy, and two-thirds of patients who had achieved a partial response to their prior platinum-based therapy. Of those with a partial response, 37% had measurable disease at the time of enrollment and were therefore evaluable for response. The confirmed overall response rate by investigator-assessed RECISTv1.1 in the tBRCAmut group treated with rucaparib was 38% (15/40), of these, 18% (7/40) were complete responses. This compared with 9% (2/23) in the placebo group (p=0.0055). No complete responses were seen in the tBRCAmut placebo group. RECIST responses were also observed in BRCA wild-type HRD-positive and BRCA wild-type HRD-negative subgroups.

RECIST responses were not assessed by independent blinded review.

Summary of ARIEL3 Safety

The most common (≥5%) treatment-emergent grade 3/4 adverse events (TEAEs) among all patients treated with rucaparib in the ARIEL3 study were anemia/decreased hemoglobin (19%), ALT/AST increase (11%), asthenia/fatigue (7%), neutropenia (7%), and thrombocytopenia (5%).The discontinuation rate for TEAEs was 14% for rucaparib-treated patients and 2.6% for the placebo arm. The rate of treatment-emergent myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) in the rucaparib arm was <1% (3/372), and no patients on the placebo arm experienced treatment-emergent MDS/AML.

Clovis Oncology plans to provide an expanded description of the ARIEL3 results in a scientific session at a medical meeting later this year.

Rucaparib and Rubraca Regulatory Status

In December 2016, Rubraca (rucaparib) tablets became the first poly ADP-ribose polymerase (PARP) inhibitor approved by the U.S. Food and Drug Administration (FDA) as monotherapy for treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more prior chemotherapies. The Company intends to submit a sNDA for a second line or later maintenance treatment indication in ovarian cancer based on the ARIEL3 data within the next four months, and the Company also plans to file a Marketing Authorization Application (MAA) in Europe for the maintenance indication.

About the ARIEL3 Clinical Trial

The ARIEL3 pivotal study of rucaparib is a confirmatory randomized, double-blind study comparing the effects of rucaparib against placebo to evaluate whether rucaparib given as a maintenance treatment to platinum-sensitive ovarian cancer patients can extend the period of time for which the disease is controlled after a complete or partial response to platinum-based chemotherapy. The study enrolled 564 patients with high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer. To be eligible for the study, participants had to have received at least two prior platinum-based treatment regimens, been sensitive to the penultimate platinum regimen, and achieved a complete or partial response to their most recent platinum-based regimen. There were no genomic selection criteria for this study. Trial participants were randomized 2:1 to receive 600 milligrams of rucaparib twice daily (BID) or placebo.

About Rucaparib

Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in ovarian cancer as well as several additional solid tumor indications. The MAA submission in Europe for an ovarian cancer treatment indication was submitted and accepted for review during the fourth quarter of 2016. The company plans to submit data from the completed ARIEL3 trial to the FDA for an sNDA for a second line and later maintenance treatment indication. Rucaparib is also being developed in patients with mutant BRCA tumors and other DNA repair deficiencies beyond BRCA – commonly referred to as homologous recombination deficiencies, or HRD. Clovis holds worldwide rights for rucaparib.

About Ovarian Cancer

According to the American Cancer Society, more than 22,400 women will be diagnosed with ovarian cancer in the U.S. in 2017. 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.