publication date: Mar. 17, 2017

Drugs and Targets

Kisqali gets FDA approval as first-line treatment for HR+/HER2- metastatic breast cancer in combination with any aromatase inhibitor

FDA approved Kisqali (ribociclib, formerly known as LEE011) in combination with an aromatase inhibitor as initial endocrine-based therapy for treatment of postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer.

Kisqali is a CDK4/6 inhibitor approved based on a first-line phase III trial that met its primary endpoint early, demonstrating statistically significant improvement in progression-free survival (PFS) compared to letrozole alone at the first pre-planned interim analysis. Kisqali was reviewed and approved under the FDA Breakthrough Therapy designation and Priority Review programs.

FDA approval is based on the superior efficacy and demonstrated safety of Kisqali plus letrozole versus letrozole alone in the pivotal phase III MONALEESA-2 trial. The trial, which enrolled 668 postmenopausal women with HR+/HER2- advanced or metastatic breast cancer who received no prior systemic therapy for their advanced breast cancer, showed that Kisqali plus an aromatase inhibitor, letrozole, reduced the risk of progression or death by 44 percent over letrozole alone (median PFS not reached (95% CI: 19.3 months-not reached) vs. 14.7 months (95% CI: 13.0-16.5 months); HR=0.556 (95% CI: 0.429-0.720); p<0.0001).

More than half of patients taking Kisqali plus letrozole remained alive and progression free at the time of interim analysis, therefore median PFS could not be determined. At a subsequent analysis with additional 11-month follow-up and progression events, a median PFS of 25.3 months for Kisqali plus letrozole and 16.0 months for letrozole alone was observed. Overall survival data is not yet mature and will be available at a later date.

“In the MONALEESA-2 trial, ribociclib plus letrozole reduced the risk of disease progression or death by 44 percent over letrozole alone, and more than half of patients (53%) with measurable disease taking ribociclib plus letrozole experienced a tumor burden reduction of at least 30 percent. This is a significant result for women with this serious form of breast cancer,” said Gabriel Hortobagyi, professor of medicine, Department of Breast Medical Oncology, MD Anderson Cancer Center, and MONALEESA-2 principal investigator.

“These results affirm that combination therapy with a CDK4/6 inhibitor like ribociclib and an aromatase inhibitor should be a new standard of care for initial treatment of HR+ advanced breast cancer.” Kisqali was developed by the Novartis Institutes for BioMedical Research under a research collaboration with Astex Pharmaceuticals.

Prescribing information for Kisqali is posted at


Keytruda gets accelerated approval for classical Hodgkin lymphoma

FDA granted an accelerated approval to Keytruda (pembrolizumab) for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or those who have relapsed after three or more prior lines of therapy.

Keytruda is sponsored by Merck & Co. Inc. Approval was based on data from 210 adult cHL patients enrolled in a multicenter, non-randomized, open-label clinical trial. Patients had refractory or relapsed disease after autologous stem cell transplantation (ASCT; 129 patients) and/or brentuximab vedotin (175 patients), and received a median of four prior systemic therapies (range: 1, 12). With a median follow-up of 9.4 months (range: 1-15), the overall response rate was 69% (95% CI: 62, 75). This included partial responses in 47% of patients and complete responses in 22%.

The estimated median response duration was 11.1 months (range 0+ to 11.1). Efficacy in pediatric patients was extrapolated from results observed in adults. Safety was evaluated in 210 adults with cHL. In adults, the most common (at least 20%) adverse reactions were fatigue, pyrexia, cough, musculoskeletal pain, diarrhea, rash and hypertransaminasemia. Additional common adverse reactions (at least 10%) included dyspnea, arthralgia, vomiting, nausea, pruritus, hypothyroidism, upper respiratory tract infections, headache, peripheral neuropathy, hyperbilirubinemia and increased creatinine. Other immune-mediated adverse reactions occurring in 0.5%-9% of patients included infusion reactions, hyperthyroidism, pneumonitis, uveitis, myositis, myelitis and myocarditis. Fifteen percent had an adverse reaction requiring systemic corticosteroid therapy.

Pembrolizumab was discontinued due to adverse reactions in 5% of patients, and treatment was interrupted due to adverse reactions in 26%. Safety was also evaluated in 40 children with advanced melanoma, PD-L1 positive solid tumors, or lymphoma. The safety profile in the pediatric patients was similar to that observed in adults. Adverse reactions occurring at a higher rate (difference of 15% or greater) in children than adults included fatigue, vomiting, abdominal pain, hypertransaminasemia and hyponatremia. Pembrolizumab exposure in these pediatric patients at a dose of 2 mg/kg every 3 weeks was comparable to that seen in adults. FDA has required the sponsor to evaluate pembrolizumab’s long-term safety in pre-pubertal patients, and those who have not completed pubertal development.

A new “Warning and Precaution” was added for complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT) after pembrolizumab. Transplant-related deaths have occurred, and health care professionals should follow patients closely for early evidence of transplant-related complications, such as hyperacute graft-versus-host-disease (GVHD), severe (grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions. FDA has required the sponsor to further study the safety of allogeneic HSCT after pembrolizumab therapy. The recommended dose and schedule of pembrolizumab for cHL is 200 mg every 3 weeks for adults and 2 mg/kg (up to 200 mg) every 3 weeks for pediatric patients.

Full prescribing information for pembrolizumab is available at

FDA granted pembrolizumab Orphan Drug Designation for the treatment of HL, and Breakthrough Therapy Designation for the current indication. This application also received priority review status and accelerated approval.


FDA extends Keytruda PDUFA date for microsatellite instability-high cancer

FDA extended the action date for the supplemental Biologics License Application for Keytruda (pembrolizumab) for previously treated patients with advanced microsatellite instability-high cancer.

The drug is sponsored by Merck & Co. Inc. The company recently submitted additional data and analyses to the FDA related to the pending application. The submission of additional data is considered a major amendment to the sBLA under the Prescription Drug User Fee Act (PDUFA), thus extending the target action date by three months.

The new FDA target action date is June 9.


Mylan announces settlement, license deals with Genentech and Roche on Herceptin

Mylan N.V. announced that the company has agreed to the terms of a global settlement with Genentech, Inc. and F. Hoffmann-La Roche Ltd. in relation to patents for Herceptin (trastuzumab), which provides Mylan with global licenses for its trastuzumab product.

The global license will provide a clear pathway for Mylan to commercialize its trastuzumab product in various markets around the world, commencing on the license effective dates, which are confidential. The licenses pertain to all countries except Japan, Brazil and Mexico.

In addition to eliminating any legal uncertainty over the launch of Mylan’s trastuzumab, the settlement eliminates further patent litigation expenses associated with Genentech and Roche. Mylan has agreed to withdraw its pending Inter Partes Review (IPR) challenges against two U.S. Genentech patents (patent numbers 6,407,213 and 6,331,415) as part of the settlement.

Following this settlement and the recent acceptance of Mylan’s application for its proposed biosimilar trastuzumab with the FDA, Mylan anticipates potentially being the first company to launch a biosimilar to Herceptin in the U.S. Mylan’s proposed biosimilar trastuzumab is one of the six biologic products co-developed by Mylan and Biocon for the global marketplace. Mylan has exclusive commercialization rights for the proposed biosimilar trastuzumab in the U.S., Canada, Japan, Australia, New Zealand and in the European Union and European Free Trade Association countries. Biocon has co-exclusive commercialization rights with Mylan for the product in the rest of the world.

In the U.S., Mylan’s Biologics License Application for proposed biosimilar trastuzumab is under review by FDA. The anticipated FDA goal date set under the Biosimilar User Fee Act is Sept. 3.

Mylan markets its trastuzumab products in 14 emerging markets and has submissions pending in the European Union and several additional emerging markets, in addition to the U.S.


Oncoceutics expands DRD2 research collaborations with NIH

Oncoceutics Inc. announced research collaborations with various groups within the NIH to study DRD2 as a novel therapeutic target in oncology.   

DRD2, a member of the dopamine receptor family that is part of the G protein-coupled receptor superfamily, is a well-known drug target but one that has not been explored previously as a target for clinical oncology. As a result of recent work by Oncoceutics with its cancer drug candidate called ONC201 that selectively antagonizes DRD2 and is in phase II clinical trials, Oncoceutics has generated interest by multiple institutions within the NIH to study basic, translational, and clinical research opportunities for both ONC201 and other related drug candidates called imipridones. 

In addition to Oncoceutics’ relationship with NCI, the company has recently expanded its collaborations throughout NIH institutions to include:

  • Preclinical and clinical evaluation of ONC201 in advanced breast and endometrial cancers by a team led by Stanley Lipkowitz, chief of Women’s Malignancies Branch at the NCI;

  • DRD2 receptor pharmacology and signaling studies of imipridones by the laboratory of David Sibley, chief of the Molecular Neuropharmacology Section at the National Institute of Neurological Disorders and Stroke; and

  • Translational evaluation of ONC206 (a related drug candidate also under development by Oncoceutics) as a potent and selective DRD2 antagonist for neuro-oncology by a team of investigators led by Mark Gilbert, at the Neuro-oncology branch that itself is a collaboration between NCI and NINDS.

NCI also continues to support clinical investigation of ONC201 as a single agent in recurrent glioblastoma through a small business innovation research grant, and discussions are underway with the NCI regarding the clinical evaluation of ONC201 in combination with targeted agents.   

“The unique pharmacology and mechanism of action associated with ONC201 and other imipridones that has come to light in the past year opens up an exciting new arena for basic and clinical investigations,” said Joshua Allen, vice president of research and development at Oncoceutics. “We are delighted to work with these expert multi-disciplinary teams to continue to elucidate the elegant and complex basic biology of this receptor, how imipridones uniquely target this receptor, and how we assimilate this information to maximize the clinical benefit offered by imipridones to cancer patients.”   

“True medical breakthroughs in oncology and other diseases are driven by the introduction of novel classes of therapeutic targets,” said Keith Flaherty, director of Developmental Therapeutics at Massachusetts General Hospital.

“We have seen this in recent history with oncogene targeted therapies that have been followed by immune checkpoint inhibitors, and the question is what realm of therapeutic targets will be the next to drive a quantum leap. G protein-coupled receptors are a befitting family of druggable receptors that are dysregulated in cancer and control broadly important signal transduction pathways.”   

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