Early Trial of New Drug Shows Promise for Patients with Triple-Negative Breast Cancer

The gist: A drug called pembrolizumab (aka Keytruda or MK-3475) has shown promise for people with metastatic triple-negative breast cancer (TNBC) whose tumors have high levels of a protein called PD-L1.  It was recently tested in patients in a clinical trialPembrolizumab is already approved by the U.S. Food and Drug Administration (FDA) for treating melanoma. It is an immunotherapy, meaning that it boosts a patient’s own immune system to fight cancer. More research will determine just how well pembrolizumab might work for TNBC.

“In patients with metastatic triple-negative breast cancer—a disease with no approved targeted therapies—infusion of pembrolizumab produced durable responses in almost one out of five patients enrolled in a phase-Ib clinical trial, according to data presented Dec. 10, at the 2014 San Antonio Breast Cancer Symposium.

“The multi-center, non-randomized trial was designed to evaluate the safety, tolerability and antitumor activity of bi-weekly infusions of pembrolizumab (MK-3475, marketed as Keytruda®). The researchers enrolled 27 patients, aged 29 to 72 years, who had metastatic triple-negative breast cancer that either relapsed after treatment for early stage disease or progressed on therapy for advanced disease.

” ‘For this group of patients our treatment options are limited to chemotherapy,’ said study director Rita Nanda, MD, assistant professor of medicine and associate director of the breast medical oncology program at the University of Chicago.

“All patients in the study had triple-negative tumors with high levels of a protein called programmed death-ligand 1 (PD-L1). This protein can suppress the immune system’s efforts to eliminate cancer cells. Pembrolizumab is a monoclonal antibody designed to help reactivate a person’s own immune system to help fight the tumor.”

UCLA Scientists Discover Why Certain Patients Respond to a Life-Saving Melanoma Drug

“UCLA researchers have pioneered a new methodology to predict why some patients battling advanced melanoma respond well or not at all to the new breakthrough drug pembrolizumab (Keytruda).

“The study, led by UCLA Jonsson Comprehensive Cancer Center members Drs. Paul Tumeh and Antoni Ribas, primary investigator of pembrolizumab, is the first of its kind since the FDA approved the use of Keytruda in September and could lead the way for more effective use of the drug in patients with melanoma and other cancers.

“A protein known as PD-1 puts the immune system’s brakes on, preventing T cells from attacking cancer cells. Pembrolizumab removes the brake lines, freeing up the immune system to kill cancer cells.”

UC San Francisco and OncoSec Medical Collaborate to Evaluate Investigational Combination of ImmunoPulse and Anti-PD-1 Treatment

The gist: Two drug companies are teaming up to see wether two melanoma treatments can work better together than either on its own. The treatments are Keytruda (aka pembrolizumab) and ImmunoPulse. Both drugs use a patient’s own immune system to fight cancer.

“OncoSec Medical Inc. (OTCQB: ONCS), a company developing DNA-based intratumoral cancer immunotherapies, has entered a clinical collaboration with the University of California, San Francisco (UCSF), to evaluate the safety, tolerability and efficacy of the combination of KEYTRUDA® (pembrolizumab), Merck’s anti-PD-1 therapy, and OncoSec’s ImmunoPulse (intratumoral IL-12) in metastatic melanoma.

“Recent data suggest that patients who are PD-L1 positive and have increased tumor-infiltrating lymphocytes (TILs) are more likely to respond to anti-PD-1/PD-L1 mAbs compared to patients who are PD-L1 negative. Therefore, therapies that promote TIL generation and PD-L1 positivity may play an important role in augmenting the clinical efficacy of these agents.

“Interleukin-12 (IL-12) is an inflammatory cytokine believed to be a master regulator of the immune system, promoting up-regulation of both the innate and adaptive immune responses. More specifically, IL-12 stimulates the production of another cytokine, interferon gamma (IFN-), which results in the stimulation of antigen processing and presentation machinery, leading to increased TILs and anti-tumor cytotoxic T-cell (CTL) activity.”

KEYTRUDA Demonstrated Superiority to Chemotherapy for Primary Endpoint of Progression-Free Survival

The gist: The drug KEYTRUDA (pembrolizumab) might be better than chemotherapy for people with melanoma that is metastatic or can’t be surgically removed, and who tried treatment with the drug ipilimumab without success. That was the conclusion of a recent clinical trial with volunteer patients. KEYTRUDA is an immunotherapy drug, meaning that it boosts the immune system to fight cancer.

“Merck (NYSE:MRK), known as MSD outside the United States and Canada, announced today that a pre-specified analysis of investigational data from a pivotal Phase 2 study (KEYNOTE-002) showed KEYTRUDA® (pembrolizumab), the company’s anti-PD-1 therapy, substantially improved the primary endpoint of progression-free survival (PFS, as assessed by RECIST 1.1, independent central review) (HR 0.57 and 0.50 for 2 mg/kg and 10 mg/kg every three week doses, respectively), compared to chemotherapy (P<0.0001 for both comparisons) in patients with ipilimumab-refractory advanced melanoma (n=540). At six months, the PFS rates for KEYTRUDA were 34 percent at the 2 mg/kg dose (95% CI, 27-41) (n=180) and 38 percent at the 10 mg/kg dose (95% CI, 31-45) (n=181), compared to 16 percent for chemotherapy (95% CI, 10-22) (n=179). The median duration of follow-up at the interim analysis was 10 months.

“These findings, including pre-specified analyses of overall response rate (ORR), duration of response, safety and health-related quality of life (HRQoL), were presented today in an oral session by Dr. Antoni Ribas, professor, Hematology/Oncology and Surgery, and director of the Tumor Immunology Program at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles at the Society of Melanoma Research (SMR) 2014 International Congress in Zurich, Switzerland.”

Merck Receives FDA Breakthrough Therapy Designation for KEYTRUDA® (pembrolizumab) in Advanced Non-Small Cell Lung Cancer

The gist: The U.S. Food and Drug Administration (FDA) has granted “breakthrough therapy designation” to the drug Keytruda (aka pembrolizumab) for treating certain lung cancer patients. This designation means that review and approval will be accelerated so that the drug can more quickly reach patients in the U.S., outside of clinical trials. Keytruda is an immunotherapy drug, meaning that it boosts a patient’s own immune system to fight cancer. The breakthrough therapy designation specifically applies to patients with advanced non-small cell lung cancer (NSCLC) whose tumors have tested negative for EGFR mutation and ALK rearrangement, and whose disease worsened despite treatment with platinum-based chemotherapy.

“Merck (NYSE:MRK), known as MSD outside the United States and Canada, announced today that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to KEYTRUDA® (pembrolizumab), the company’s anti-PD-1 therapy, for the treatment of patients with Epidermal Growth Factor Receptor (EGFR) mutation-negative, and Anaplastic Lymphoma Kinase (ALK) rearrangement-negative non-small cell lung cancer (NSCLC) whose disease has progressed on or following platinum-based chemotherapy. This is the second Breakthrough Therapy Designation granted for KEYTRUDA.

“ ‘The FDA’s Breakthrough Therapy Designation of KEYTRUDA underscores that new treatment approaches for advanced non-small cell lung cancer continue to be needed,’ said Dr. Roger Perlmutter, president, Merck Research Laboratories. ‘Our data investigating the use of KEYTRUDA in this difficult-to-treat malignancy are very encouraging, and we look forward to working closely with the FDA to expedite our clinical program.’ ”

Immune System-Activating Drugs in Combination Treatments May Be Next Big Thing for Melanoma

Among solid tumors, the curative potential of immunotherapies has been explored most in melanoma. One reason for this is that melanoma tumors often contain so-called immune infiltrates—patches of T cells, the killer cells of the immune system. It seems that these fighter cells arrive at the ‘battlefield’ to target tumor cells for killing, but instead become ‘frozen,’ unable to attack.  How to activate the tumor-killing potential of T cells has been an area of intense and fruitful research, leading to the development of several immunotherapy drugs. Continue reading…

Anti–PD-1 Antibody Pembrolizumab Is Active in Ipilimumab-Refractory Advanced Melanoma

The gist: A drug called pembrolizumab (brand name Keytruda) is effective for treating people with melanoma that does not respond to treatment with the drug ipilimumab (Yervoy). That is the conclusion of a recent clinical trial—a research study with volunteer patients. Based on the study, the U.S. Food and Drug Administration (FDA) has already approved Keytruda for treating melanoma that is advanced or unresectable (can’t be removed by a surgeon) and is not responding well to other drugs.

“As reported in The Lancet by Robert et al, the anti–programmed-death receptor-1 (PD-1) antibody pembrolizumab (Keytruda) produced durable responses in a phase I trial in patients with ipilimumab (Yervoy)-refractory melanoma. The study provided the basis for the recent accelerated approval of pembrolizumab for treatment of patients with unresectable or metastatic melanoma with disease progression following treatment with ipilimumab and, in BRAF V600 mutation–positive patients, treatment with a BRAF inhibitor. Pembrolizumab is the first PD-1 inhibitor to be approved for use in the United States…

“In this open-label, international, multicenter expansion cohort of a phase I trial, 173 patients aged ≥ 18 years with advanced melanoma progressing after at least two ipilimumab doses were randomly assigned to receive pembrolizumab intravenously at 2 mg/kg (n = 89) or 10 mg/kg (n = 84) every 3 weeks until disease progression, intolerable toxicity, or consent withdrawal. The primary endpoint was overall response rate. Overall, 97% of patients were white, 17% had BRAF V600 mutant disease, and 73% had received at least two prior therapies for advanced or metastatic disease.”

Immune System-Boosting Drugs, New and Old, Are Explored in Combination Treatments for Lung Cancer

Readers of this blog will already know a thing or two about immunotherapy (immune system-activating drugs) and targeted therapy in lung cancer. Both approaches have benefited many patients in recent years. Now, research is being done to combine immunotherapies with other types of drugs. Of particular interest are immunotherapies that target PD-1, PD-L1, and CTLA4. These drugs, also known as immune checkpoint antibodies, are being tested in combination with other drugs in patients participating in the clinical trials below. Continue reading…

ESMO 2014: Pembrolizumab Shows Promise in Several Solid Tumours

The gist: A new drug called pembrolizumab has shown promise for treating several cancer types, including melanoma and non-small cell lung cancer (NSCLC). Pembrolizumab is an immunotherapy, meaning that it boosts a patient’s own immune system to fight cancer. It has been tested in several clinical trials—research studies with volunteer patients. In one trial, pembrolizumab showed benefits for advanced NSCLC patients. It might be particularly effective for patients whose tumors have high expression of the protein PD-L1. There are ongoing pembrolizumab clinical trials that NSCLC patients can enroll in. Another clinical trial compared different pembrolizumab dosing schedules for melanoma patients. In fact, pembrolizumab, also known as Keytruda, has already been approved by the U.S. Food and Drug Administration (FDA) for certain kinds of melanoma patients.

“Results from the studies of pembrolizumab in advanced non-small-cell lung cancer (NSCLC), melanoma, gastric cancer, urothelial cancer and head and neck carcinoma, presented during the ESMO 2014 Congress (Madrid, Spain), show promising activity and tolerability from this novel monoclonal antibody.

“PD-1 is a negative co-stimulatory receptor expressed primarily on activated T cells. Binding of PD-1 to its ligands inhibits effector T-cell function. Expression of PD-L1 on tumour cells and macrophages can suppress immune surveillance and permit neoplastic growth.

“Pembrolizumab is able to achieve a dual blockade (PD-L1 and PD-L2). It shows no cytotoxic (ADCC/CDC) activity. Pharmacokinetics support dosing every 2 weeks (Q2W) or every 3 weeks (Q3W). Pembrolizumab demonstrated a clinical activity in multiple tumour types…

“The anti-PD-1 antibody pembrolizumab has shown durable antitumour activity and acceptable toxicity in treatment-naïve and previously treated advanced NSCLC patients. Correlation between tumour PD-L1 expression and improved pembrolizumab antitumour activity has been observed. Prof. Edward Garon of the David Geffen School of Medicine at UCLA, Santa Monica, USA presented analysis in 282 patients with treatment-naïve or previously treated advanced NSCLC enrolled in randomised and non-randomised cohorts of the phase I KEYNOTE-001. The results were presented during the Proffered Paper session in metastatic NSCLC.”