On September 16, 2016 Pfizer Inc. (NYSE:PFE) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending that IBRANCE (palbociclib) be granted marketing authorization in the European Union (EU) for the treatment of women with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) locally advanced or metastatic breast cancer (Press release, Pfizer, SEP 16, 2016, View Source [SID:SID1234515189]). The CHMP’s positive opinion is for IBRANCE to be used in combination with an aromatase inhibitor, as well as in combination with fulvestrant in women who have received prior endocrine therapy. The CHMP’s opinion will now be reviewed by the European Commission (EC).

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If approved, IBRANCE would be the first medicine in a new class of anti-cancer treatments, cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors, to be approved by the EC.

"Today’s opinion by the CHMP to recommend marketing authorization of IBRANCE in the EU is an important step toward expanding treatment options for women in Europe with HR+/HER2- metastatic breast cancer, and a step toward a potential new standard of care for this cancer," said Mace Rothenberg, M.D., chief development officer, Pfizer Oncology. "The opinion is supported by robust data with consistent results observed across three separate randomized trials in which the addition of IBRANCE to standard endocrine therapy resulted in significant prolongation of progression-free survival compared to endocrine therapy alone."

"There have been only modest improvements in the prognosis of patients with metastatic breast cancer in Europe over the past three decades, underscoring the need for new treatment advances," said Andreas Penk, M.D., regional president, International Developed Markets, Pfizer Oncology. "We look forward to working with the EC as they conduct their review, with the goal of bringing this first-in-class medicine to appropriate patients across the EU."

Breast cancer is the most common invasive cancer among women in Europe, with more than 464,200 new cases and 131,260 deaths per year.1 Up to 30 percent of women diagnosed with and treated for early breast cancer will go on to develop metastatic breast cancer,2,3 which occurs when the cancer spreads beyond the breast to other parts of the body.4 There is no cure for metastatic breast cancer,5 and patients are in need of new treatment options that help keep their cancer from worsening, manage symptoms and help them maintain quality of life for as long as possible.2,4

Pfizer announced last year that the EMA validated for review the Marketing Authorization Application (MAA) for IBRANCE, which was submitted based on final results from the Phase 2 PALOMA-1 and Phase 3 PALOMA-3 trials. These studies demonstrated that IBRANCE in combination with an endocrine therapy improved progression-free survival (PFS) compared to the endocrine therapy alone or with placebo in certain patients with HR+/HER2- metastatic breast cancer. Results from a separate Phase 3 trial, PALOMA-2, conducted in the same patient population as the Phase 2 PALOMA-1 trial, also demonstrated an improvement in PFS and were added during the MAA review.

About IBRANCE (palbociclib)

IBRANCE is an oral inhibitor of cyclin dependent kinases (CDKs) 4 and 6,6 which are key regulators of the cell cycle that trigger cellular progression.7,8

In the European Union, IBRANCE is an investigational agent and has not been approved.

IBRANCE is approved by the U.S. Food and Drug Administration (FDA) for the treatment of HR+/HER2- advanced or metastatic breast cancer in combination with letrozole as initial endocrine based therapy in postmenopausal women, or fulvestrant in women with disease progression following endocrine therapy.6 The indication in combination with letrozole is approved in the U.S. under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.6 Outside of the U.S., IBRANCE has received regulatory approval in 19 countries to date.

IMPORTANT IBRANCE (palbociclib) SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION

Neutropenia was the most frequently reported adverse reaction in Study 1 (PALOMA-1) (75%) and Study 2 (PALOMA-3) (83%). In Study 1, Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. In Study 2, Grade 3 (56%) or Grade 4 (11%) decreased neutrophil counts were reported in patients receiving IBRANCE plus fulvestrant. Febrile neutropenia has been reported in about 1% of patients exposed to IBRANCE. One death due to neutropenic sepsis was observed in Study 2. Inform patients to promptly report any fever.

Monitor complete blood count prior to starting IBRANCE, at the beginning of each cycle, on Day 14 of first 2 cycles, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Pulmonary embolism (PE) has been reported at a higher rate in patients treated with IBRANCE plus letrozole in Study 1 (5%) and in patients treated with IBRANCE plus fulvestrant in Study 2 (1%) compared with no cases in patients treated either with letrozole alone or fulvestrant plus placebo. Monitor for signs and symptoms of PE and treat as medically appropriate.

Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females of reproductive potential to use effective contraception during IBRANCE treatment and for at least 3 weeks after the last dose. IBRANCE may impair fertility in males and has the potential to cause genotoxicity. Advise male patients with female partners of reproductive potential to use effective contraception during IBRANCE treatment and for 3 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise women not to breastfeed during IBRANCE treatment and for 3 weeks after the last dose because of the potential for serious adverse reactions in nursing infants.

The most common adverse reactions (≥10%) of any grade reported in Study 1 of IBRANCE plus letrozole vs letrozole alone included neutropenia (75% vs 5%), leukopenia (43% vs 3%), fatigue (41% vs 23%), anemia (35% vs 7%), upper respiratory infection (31% vs 18%), nausea (25% vs 13%), stomatitis (25% vs 7%), alopecia (22% vs 3%), diarrhea (21% vs 10%), thrombocytopenia (17% vs 1%), decreased appetite (16% vs 7%), vomiting (15% vs 4%), asthenia (13% vs 4%), peripheral neuropathy (13% vs 5%), and epistaxis (11% vs 1%).

Grade 3/4 adverse reactions (≥10%) in Study 1 reported at a higher incidence in the IBRANCE plus letrozole group vs the letrozole alone group included neutropenia (54% vs 1%) and leukopenia (19% vs 0%). The most frequently reported serious adverse events in patients receiving IBRANCE plus letrozole were pulmonary embolism (4%) and diarrhea (2%).

Lab abnormalities occurring in Study 1 (all grades, IBRANCE plus letrozole vs letrozole alone) were decreased WBC (95% vs 26%), decreased neutrophils (94% vs 17%), decreased lymphocytes (81% vs 35%), decreased hemoglobin (83% vs 40%), and decreased platelets (61% vs 16%).

The most common adverse reactions (≥10%) of any grade reported in Study 2 of IBRANCE plus fulvestrant vs fulvestrant plus placebo included neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), headache (26% vs 20%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), constipation (20% vs 16%), vomiting (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased appetite (16% vs 8%), and pyrexia (13% vs 5%).

Grade 3/4 adverse reactions (≥10%) in Study 2 reported at a higher incidence in the IBRANCE plus fulvestrant group vs the fulvestrant plus placebo group included neutropenia (66% vs 1%) and leukopenia (31% vs 2%). The most frequently reported serious adverse reactions in patients receiving IBRANCE plus fulvestrant were infections (3%), pyrexia (1%), neutropenia (1%), and pulmonary embolism (1%).

Lab abnormalities occurring in Study 2 (all grades, IBRANCE plus fulvestrant vs fulvestrant plus placebo) were decreased WBC (99% vs 26%), decreased neutrophils (96% vs 14%), anemia (78% vs 40%), and decreased platelets (62% vs 10%).

Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg/day. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided. Avoid concomitant use of strong CYP3A inducers. The dose of sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure.

IBRANCE has not been studied in patients with moderate to severe hepatic impairment or in patients with severe renal impairment (CrCl <30 mL/min).

On September 16, 2016 Eli Lilly and Company (NYSE: LLY) reported that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending the granting of a conditional marketing authorization for olaratumab, in combination with doxorubicin, for the treatment of adults in the European Union (EU) with advanced soft tissue sarcoma (STS) not amenable to curative treatment with radiotherapy or surgery and who have not been previously treated with doxorubicin (Press release, Eli Lilly, SEP 16, 2016, View Source [SID:SID1234515180]). The CHMP reviewed olaratumab under EMA’s accelerated assessment program. If approved, olaratumab will be marketed under the trade name LARTRUVO.

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This is the first regulatory step in the world towards approval for olaratumab. The CHMP positive opinion is now referred for final action to the European Commission, which grants marketing authorization in the EU. The Commission usually makes a decision on marketing authorization within two to three months of the CHMP issuing its recommendation.

"Patients with advanced soft tissue sarcoma have been seeking new treatment options that can potentially extend lives, so they can have more time with their families and loved ones," said Richard Gaynor, M.D., senior vice president of product development and medical affairs for Lilly Oncology. "Advanced soft tissue sarcoma is a rare disease that is difficult to treat, and this milestone brings us one step closer to providing physicians in Europe with a new option that they can offer to their patients."

This will be Lilly’s first conditional approval in the EU. As part of a conditional marketing authorization, Lilly will need to provide results from an ongoing Phase 3 study. This study, ANNOUNCE, is fully enrolled. Until availability of the full data, the CHMP will review the benefits and risks of olaratumab annually to determine whether the conditional marketing authorization can be maintained.

The EMA previously granted olaratumab with Orphan Drug Designation for the treatment of soft tissue sarcoma in the EU.

The EU submission is based on data from Phase 2 JGDG, an open-label, randomized trial that compared olaratumab, in combination with doxorubicin chemotherapy, to doxorubicin alone in patients with advanced STS not amenable to curative treatment with surgery or radiotherapy and who have not been previously treated with doxorubicin. Efficacy endpoints included progression-free survival, overall survival and objective response rate.

Lilly has also submitted the results of this study to the U.S. Food and Drug Administration (FDA) for regulatory review. The FDA recently granted Lilly Priority Review status for olaratumab. Lilly also has received additional designations for olaratumab from the FDA for this indication, including Breakthrough Therapy, Fast Track and Orphan Drug.

Notes to Editor
About Olaratumab
Olaratumab is a PDGFRα blocking antibody that specifically binds PDGFRα and prevents receptor activation. Olaratumab exhibited in vitro and in vivo anti-tumor activity against selected sarcoma cell lines and disrupted the PDGFRα signaling pathway in in vivo tumor implant models. Information about additional clinical trials for olaratumab in sarcoma can be found at ClinicalTrials.gov (in the search box on the home page, type in "olaratumab").

A Phase 3 trial of olaratumab and doxorubicin in advanced STS is fully enrolled (ClinicalTrials.gov Identifier: NCT02451943).

About the JGDG Trial
The open-label, randomized Phase 1b/2 study, JGDG, compared olaratumab in combination with doxorubicin chemotherapy to the control arm of doxorubicin alone in patients with unresectable, advanced STS not amenable to curative treatment with surgery or radiotherapy. After confirmation of safety in the Phase 1b portion of the study, 133 doxorubicin-naïve patients were randomized 1:1 in the Phase 2 portion of the study. A total of 66 patients were treated on the olaratumab-doxorubicin arm, and 67 on the placebo-doxorubicin arm. Efficacy endpoints included progression-free survival, overall survival and objective response rate.

About Sarcomas
Sarcomas are a diverse and relatively rare type of cancer that usually develop in the connective tissue of the body, which include fat, blood vessels, nerves, bones, muscles, deep skin tissues and cartilage. STS is a complex disease with multiple subtypes, making it very hard to diagnose and difficult to treat. For decades, there have been no front-line therapeutic advancements for advanced STS that have improved overall survival. An estimated 23,000 people in the EU will be diagnosed with STS this year.