Pfizer Inc. and Merck & Co. Inc., known as MSD outside the United States and Canada, through a subsidiary, announced today that they have entered into an agreement to explore the therapeutic potential of the combination of Pfizer’s crizotinib (XALKORI®) with Merck’s investigational anti-PD-1 antibody pembrolizumab, in a Phase 1b clinical study evaluating the safety and tolerability of the combination in patients with ALK-positive advanced or metastatic non-small cell lung cancer (NSCLC). The financial terms of the agreement were not disclosed.
“Forward-Looking Information That May Affect Future Results”
“This collaboration between Pfizer and Merck is just one example of the willingness of sponsors to work together in an effort to accelerate progress against some of the most difficult-to-treat cancers,” said Dr. Mace Rothenberg, senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology told NV Observer. “Understanding the effects of combining one drug, XALKORI, which inhibits an abnormally activated enzyme in patients with ALK-positive metastatic lung cancer, with the investigational drug, pembrolizumab, which harnesses the body’s immune system to fight cancer, is vital if we are to continue to advance the care of lung cancer patients.”
This multi-center, open-label clinical study is expected to begin in 2015. Pfizer will conduct the study.
“We are pleased to build upon our ongoing collaboration with Pfizer to evaluate potential combination regimens incorporating Merck’s investigational immunotherapy pembrolizumab,” said Dr. Eric Rubin, vice president, Oncology, Merck Research Laboratories. “Evidence from early studies of pembrolizumab monotherapy together with XALKORI’s proven targeted therapeutic approach provides the scientific rationale for evaluating this combination for the treatment of lung cancer.”
Both companies previously announced plans to evaluate the safety and efficacy of pembrolizumab in combination with Pfizer’s small molecule kinase inhibitor axitinib (INLYTA®) in patients with renal cell carcinoma. Separately, pembrolizumab plus Pfizer’s PF-05082566 (PF-2566), an investigational immuno-oncology agent that targets the human 4-1BB receptor, will be evaluated in multiple cancer types. These studies are expected to begin enrollment later this year.
Pembrolizumab (MK-3475) is an investigational, humanized, monoclonal antibody against PD-1 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.
Pembrolizumab is currently 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. For information about Merck’s oncology clinical studies, please visit http://www.merck.com/clinical-trials/index.html.
XALKORI® (crizotinib) Indication and Important Safety Information
XALKORI is a kinase inhibitor indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.
Hepatotoxicity: Across three main clinical trials fatal hepatotoxicity occurred in 0.2% of patients. Monitor with periodic liver testing. Temporarily suspend, dose reduce, or permanently discontinue XALKORI.
Pneumonitis: Across three main clinical trials interstitial lung disease (ILD)/pneumonitis occurred in 2% of patients. Permanently discontinue in patients with ILD/pneumonitis.
QT Interval Prolongation: Across three main clinical trials QT interval prolongation occurred in 2.7% of patients. Monitor with electrocardiograms and electrolytes in patients who have a history of or predisposition for QTc prolongation, or who are taking medications that prolong QT. Temporarily suspend, dose reduce, or permanently discontinue XALKORI.
Bradycardia: Xalkori can cause bradycardia. Across three main clinical trials 11% of patients experienced a heart rate of less than 50 beats per minute. Monitor heart rate and blood pressure regularly. Temporarily suspend, dose reduce, or permanently discontinue XALKORI.
Embryofetal Toxicity: XALKORI can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving XALKORI.
Adverse Reactions: Across three main clinical trials the most common adverse reactions (≥25%) were vision disorders, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue.
In a phase 3 study in patients with ALK-positive metastatic NSCLC randomized to XALKORI (n=172) or chemotherapy (n=171), serious adverse reactions were reported in 37.2% of patients treated with XALKORI. The most frequent serious adverse reactions reported in patients treated with XALKORI were pneumonia (4.1%), pulmonary embolism (3.5%), dyspnea (2.3%), and ILD (2.9%). Fatal adverse reactions in XALKORI-treated patients occurred in 9 (5%) patients, consisting of: acute respiratory distress syndrome, arrhythmia, dyspnea, ILD, pneumonia, pneumonitis, pulmonary embolism, respiratory failure, and sepsis. Grade 3 or 4 events occurring at a higher incidence with XALKORI than with chemotherapy and at greater than 2%, were syncope (3%), QT prolongation (3%), and pulmonary embolism (5%). Elevation of ALT of any grade occurred in 76% of patients and grade 3 or 4 in 17% of patients. Neutropenia of any grade occurred in 49% of patients and grade 3 or 4 in 12% of patients. Lymphopenia of any grade occurred in 51% of patients and grade 3 or 4 in 9% of patients. Renal cysts occurred in 4% and neuropathy occurred in 19% of patients treated with XALKORI.
Drug Interactions: Exercise caution with concomitant use of moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice which may increase plasma concentrations of crizotinib. Avoid concomitant use of strong CYP3A inducers and inhibitors. Dose reduction may be needed for co-administered drugs that are predominantly metabolized by CYP3A.
Nursing Mothers: Given the potential for serious adverse reactions in nursing infants, consider whether to discontinue nursing or discontinue XALKORI.
Hepatic Impairment: XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Use caution in patients with hepatic impairment.
Renal Impairment: Administer XALKORI at a starting dose of 250 mg taken orally once daily in patients with severe renal impairment (CLcr<30 mL/min) not requiring dialysis. No starting dose adjustment is needed for patients with mild and moderate renal impairment.