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Merck’s Investigational Anti-PD-1 Antibody, Pembrolizumab, Under Regulatory Review in Europe for the Treatment of Advanced Melanoma

On June 30, 2014 Merck & Co reported that the European Medicines Agency (EMA) has accepted for review a Marketing Authorization Application (MAA) for pembrolizumab (MK-3475), the company’s investigational anti-PD-1 antibody, for the treatment of advanced melanoma. If approved by the European Commission (EC), pembrolizumab has the potential to be the first anti-PD-1 therapy in Europe (Press release Merck & Co, JUN 30, 2014, View Source [SID:1234500606]). Additional regulatory filings in other countries outside of Europe are planned by the end of 2014.

"With the five-year survival rate for patients with advanced melanoma at less than 20 percent, there remains a need to offer patients additional options," said Dr. Roy Baynes, senior vice president, clinical development, Merck Research Laboratories. "We are pleased to have regulatory applications under review in the United States and Europe as we work toward bringing pembrolizumab to patients around the world."

Pembrolizumab (MK-3475) is an investigational, selective, humanized, monoclonal anti-PD-1 antibody designed to reactivate anti-tumor immunity. Pembrolizumab exerts dual ligand blockade of the PD-1 pathway by inhibiting the interaction of PD-1 on T cells with its ligands PD-L1 and PD-L2.

Today, pembrolizumab is being evaluated across more than 30 types of cancers, as monotherapy and in combination. It is anticipated that by the end of 2014, the pembrolizumab development program will grow to more than 24 clinical trials, enrolling an estimated 6,000 patients at nearly 300 clinical trial sites worldwide.

The Biologics License Application (BLA) for pembrolizumab is under priority review with the U.S. Food and Drug Administration (FDA) for the treatment of patients with advanced melanoma previously-treated with ipilimumab; the PDUFA date is October 28, 2014. Pembrolizumab has been granted FDA’s Breakthrough Therapy designation for advanced melanoma. If approved by the FDA, pembrolizumab has the potential to be the first anti-PD-1 therapy approved within the United States.

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GSK and Genmab announce top-line results from a Phase III study of ofatumumab versus physicians’ choice for bulky fludarabine-refractory CLL

On June 27, 2014 GlaxoSmithKline and Genmab reported that the Phase III study of ofatumumab (Arzerra) versus physicians’ choice in patients with bulky fludarabine-refractory chronic lymphocytic leukaemia (CLL) did not meet its primary endpoint of progression free survival (PFS) (Press release Genmab, JUN 27, 2014, View Source [SID:1234500604]). The median PFS, as assessed by the Independent Review Committee, was 5.36 months for ofatumumab and 3.61 months for physicians’ choice (Hazard Ratio 0.79, p=0.267).

The result reported here is headline data; the full analysis of safety and efficacy data is underway and will be completed in the coming months. This study (OMB114242) was conducted to meet the requirements from the EU Commission for the conditional approval of ofatumumab for the treatment of CLL in patients who are refractory to fludarabine and alemtuzumab. The current indications in the EU or US do not include bulky fludarabine-refractory CLL patients.

“It was our priority to share this result with the scientific community as soon it became available. We will now work to further analyse the data and to better understand the totality of the efficacy and safety findings,” said Dr. Rafael Amado, Head of Oncology R&D at GSK. “We are very grateful to the CLL patients who participated in this trial.”

“Although ofatumumab performed broadly in-line with previous data, today’s result is disappointing. Based on this result, we do not anticipate applying for a label expansion for ofatumumab in this specific refractory CLL population,” said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

About the study
This Phase III open-label study randomised 122 patients with bulky fludarabine-refractory CLL to one of two treatment arms. Patients were randomised to either ofatumumab or physicians’ choice (2:1). Patients randomised to ofatumumab received an initial dose of 300 mg, followed 1 week later by 2,000 mg once weekly for 7 weeks, followed 4 weeks later by one infusion of 2,000 mg every 4 weeks for a total treatment duration of 6 to 12 months. Patients in the physicians’ choice arm received a treatment regimen chosen by a physician for up to six months.

The primary endpoint of the study was progression free survival as adjudicated by the Independent Review Committee. Secondary objectives are to evaluate response, overall survival, safety, tolerability and health-related quality of life of subjects treated with ofatumumab versus physicians’ choice of treatment.

CHMP recommends EU approval of Roche's Avastin for platinum-resistant recurrent ovarian cancer

On June 27, 2014 Roche reported that the EU Committee for Medicinal Products for Human Use (CHMP) recommended that the European Commission approve the use of Avastin (bevacizumab) in combination with chemotherapy as a treatment for women with ovarian cancer that is resistant to platinum-containing chemotherapy (Press release Hoffmann-La Roche, JUN 26, 2014, View Source [SID:1234500690]). Ovarian cancer has the highest mortality rate of all gynaecological cancers.1 Of the 230,000 women diagnosed worldwide each year many will have advanced disease that will return after initial treatment.

"Women with platinum-resistant ovarian cancer have limited medicines available for their difficult disease," said Sandra Horning M.D., Chief Medical Officer and Head, Global Product Development. "EU approval of Avastin for platinum-resistant ovarian cancer would be an important step in helping these women live longer without their disease progressing, and we look forward to receiving the final decision from the European Commission in the coming months."

When treating recurrent ovarian cancer, the time between receiving the last dose of platinum-based chemotherapy and disease recurrence is used to help determine the choice of chemotherapy used in the next line of treatment. Patients are said to have ‘platinum-resistant’ disease if their disease worsens between one and six months following completion of their platinum-based chemotherapy, and ‘platinum-sensitive’ disease if it worsens more than six months after. A quarter of those who relapse after initial treatment – nearly 60,000 women a year globally – will have platinum-resistant cancer, the most difficult to treat form of the disease. Median overall survival of patients with platinum-resistant ovarian cancer is approximately 12 months, and novel strategies are needed.

Ovarian cancer is associated with high concentrations of vascular endothelial growth factor (VEGF), a protein linked to tumour growth and spread. Studies have shown a correlation between a high concentration of VEGF and ascites development (excess fluid in the abdominal cavity), disease worsening, and a poorer prognosis in women with ovarian cancer. Avastin is designed to specifically target VEGF and is currently the only targeted therapy approved by the European Medicines Agency (EMA) for ovarian cancer. Avastin is EU approved as a front-line (first line following surgery) treatment of advanced ovarian cancer, and as a treatment for recurrent, platinum-sensitive ovarian cancer.

The new EU filing was based on results of the phase III AURELIA study which involved women with recurrent, platinum-resistant ovarian cancer who received either chemotherapy (weekly paclitaxel, topotecan or pegylated liposomal doxorubicin) or Avastin added to chemotherapy.4 Results showed that at a median follow-up of 13 months for women who had received chemotherapy alone and 13.9 months for those who had received the combination, the addition of Avastin to chemotherapy gave a clinically meaningful benefit, nearly doubling the median PFS from 3.4 months to 6.7 months (HR=0.38, p<0.0001).4,6 AURELIA is the fourth phase III study of Avastin in ovarian cancer (following GOG 0218, ICON7 and OCEANS) to show that adding Avastin to chemotherapy significantly increased the time women with ovarian cancer lived without their disease getting worse.
AURELIA additional study results

Women with recurrent, platinum-resistant ovarian cancer who received Avastin in combination with chemotherapy (weekly paclitaxel, topotecan or pegylated liposomal doxorubicin) had a median overall survival of 16.6 months compared to 13.3 months for women treated with chemotherapy alone (HR=0.87, p=0.27).
In addition, women who received Avastin in combination with chemotherapy had a significantly higher rate of tumour shrinkage (objective response rate, ORR) compared to women who received chemotherapy alone (28.2 percent versus 12.5 percent, p=0.0007).
The results of prespecified Quality of Life (QoL) analyses indicated that the benefits of Avastin in AURELIA extended beyond the prolongation of PFS to include greater improvements in ovarian cancer associated abdominal/gastrointestinal symptoms.
No new safety findings were observed in the AURELIA study and adverse events were consistent with those seen in previous trials of Avastin across tumour types for approved indications.4

About the AURELIA study

AURELIA is a multicentre, randomised, open-label, two-arm phase III study in 361 women with platinum-resistant recurrent epithelial ovarian, primary peritoneal or fallopian tube cancer. Women in AURELIA had received no more than two anticancer regimens prior to enrolment in the trial. The trial was designed to evaluate Avastin (10mg/kg every two weeks or 15mg/kg every three weeks) in combination with standard chemotherapy (either weekly paclitaxel or topotecan or pegylated liposomal doxorubicin) compared to standard chemotherapy alone.

The trial was set up in cooperation with the Group d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO) and was conducted by the international network of the Gynecologic Cancer Intergroup (GCIG) and the pan-European Network of Gynaecological Oncological Trial Groups (ENGOT). The primary endpoint of the study was progression-free survival. The secondary endpoints of the study included overall survival, objective response rate, Quality of Life, safety and tolerability.

FDA Advisory Committee votes on accelerated approval for investigational medicine olaparib

On June 25, 2014 AstraZeneca reported that the US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) voted 11 to 2 that current evidence from clinical studies does not support an accelerated approval for use of olaparib as a maintenance treatment for women with platinum-sensitive relapsed ovarian cancer who have the germline BRCA (gBRCA) mutation, and who are in complete or partial response to platinum-based chemotherapy (Press release AstraZeneca, JUN 25, 2014, View Source;zfda-advisory-committee-votes-on-accelerated-approval [SID:1234500602]).

The ODAC provides the FDA with independent, expert advice and recommendations, however the final decision regarding approval is made by the FDA.

AstraZeneca filed the US regulatory submission for olaparib in February 2014. The FDA granted priority review status for the NDA in April and set a Prescription Drug User Fee Act (PDUFA) action date of 3 October 2014.

Briggs Morrison, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca said: “Patients with germline BRCA-mutated serous ovarian cancer have few options available to treat this disease. We are disappointed with today’s recommendation, and strongly believe that olaparib has the potential to provide patients with relapsed BRCA-mutated ovarian cancer and their doctors with a much-needed treatment option. We look forward to continuing to work with the FDA as it evaluates the Advisory Committee recommendation and completes its review of the application. In the meantime, we are continuing with our Phase III clinical programme to evaluate the benefit of olaparib for this patient population. We aim to have completed this study by the end of 2015.”

The NDA filing was based on a subgroup analysis of Phase II data recently published in Lancet Oncology (Lancet Oncol. 2014 May 29. pii: S1470-2045(14)70228-1. doi: 10.1016/S1470-2045(14)70228-1. View Source). The Phase II study was a randomised, double-blind, placebo-controlled trial which evaluated olaparib versus placebo as maintenance treatment in platinum-sensitive relapsed serous ovarian cancer patients who had received previous treatment with at least two platinum regimens and were in a maintained partial or complete response following their last platinum regimen. The study met its primary endpoint of progression-free survival by Response Evaluation Criteria in Solid Tumours guidelines. A pre-defined subgroup analysis was conducted in patients who have germline BRCA mutations.

In addition, as part of its commitment to bring the potential benefits of olaparib to ovarian cancer patients, AstraZeneca has initiated and is committed to complete the Phase III SOLO programme, designed to evaluate the efficacy and safety of olaparib as a maintenance monotherapy in ovarian cancer patients who have a BRCA mutation who are in complete or partial response following platinum-based chemotherapy in the relapsed setting.

(Press release, Ligand, JUN 24, 2014, View Source [SID:1234502817])