Data to Be Presented at 2017 ASCO Annual Meeting Include Findings in Patients with Locally Advanced Triple-Negative (TNBC) and Hormone Receptor-Positive/HER2-Negative (HR+/HER2-) Breast Cancers
KENILWORTH, NJ & SAN FRANCISCO, CA, USA I June 5, 2017 I Merck (NYSE:MRK), known as MSD outside the United States and Canada, and QuantumLeap Healthcare Collaborative, today announced results from the Phase 2 I-SPY 2 TRIAL investigating KEYTRUDA® (pembrolizumab), Merck’s anti-PD-1 therapy, in combination with standard therapy [paclitaxel followed by doxorubicin and cyclophosphamide (AC)] as a neoadjuvant (pre-operative) treatment for patients with locally advanced triple-negative breast cancer (TNBC) or hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer. Findings showed that the addition of KEYTRUDA increased the estimated pathologic complete response (pCR) rate nearly threefold in patients with TNBC (60% vs 20%) and in patients with HR+/HER2- breast cancer (34% vs 13%) compared to standard therapy. Overall, based on Bayesian predictive probability of success in a confirmatory Phase 3 trial, KEYTRUDA has graduated from the I-SPY 2 TRIAL for all signatures in which it was tested (TNBC, all HER2-, and HR+/HER2-). Data will be presented today by Dr. Rita Nanda, The University of Chicago, during an oral session at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago (Abstract #506) and will also be presented in subsequent “Best of ASCO” events scheduled throughout the year.
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“KEYTRUDA in combination with standard therapy tripled the rate of pathologic complete responses in HER2- patients in the I-SPY 2 Trial,” said Laura J. Esserman, M.D., MBA, professor of surgery and radiology and director of the Carol Franc Buck Breast Care Center at UCSF Helen Diller Family Comprehensive Cancer Center, and the overall principal investigator for the I-SPY TRIALS. “The regimen indicates a new and important treatment pathway and gives us well-grounded hope for new options for patients with these aggressive breast cancers – and that’s potentially very good news.”
“We recognize that there is a critical unmet need for patients with certain breast cancer subtypes and believe that combination regimens will be important to advancing patient care,” said Dr. Eric Rubin, vice president of early-stage development, clinical oncology, Merck Research Laboratories. “The results presented at ASCO, which add to the growing body of evidence for KEYTRUDA in various types of breast cancer, are exciting and demonstrate the potential benefit of KEYTRUDA in these patients.”
The I-SPY 2 TRIAL (NCT01042379), sponsored by QuantumLeap Healthcare Collaborative, is a standing Phase 2 randomized, controlled, multi-center trial for women with newly diagnosed, locally advanced breast cancer (Stage II/III), and is designed to screen promising new treatments and identify which therapies are most effective in specific patient subgroups based on molecular characteristics (biomarker signatures). The trial is an adaptive study design assessing the combination of biologically targeted investigational drugs with standard chemotherapy in the neoadjuvant setting, compared to standard chemotherapy alone. The primary endpoint is to determine whether the combination of certain therapies increases the probability of pCR in the breast and the lymph nodes at the time of surgery. The data presented at ASCO from the I-SPY 2 TRIAL were based on results observed in patients at high risk of relapse using up-front tumor profiling (including HR status, HER2 status, and the MammaPrint 70-gene signature test). Patients were treated with weekly standard chemotherapy (paclitaxel) for 12 weeks, with or without KEYTRUDA (pembrolizumab), followed by doxorubicin and cyclophosphamide (AC) every 3 weeks for four cycles. Sixty-nine patients were adaptively randomized to receive KEYTRUDA in the trial from December 2015 until it graduated in November 2016. In total, 46 patients have undergone surgery; the other 23 have on-therapy MRI assessments.
In patients with TNBC, an absolute increase in the estimated pCR rate of 40 percent was observed in the KEYTRUDA arm (based on the estimated pCR rate of 60% with KEYTRUDA plus standard therapy compared to 20% with standard therapy alone). In patients with HER2- breast cancer, an absolute increase in the estimated pCR rate of 30 percent was observed in the KEYTRUDA arm (based on the estimated pCR rate of 46% with KEYTRUDA plus standard therapy compared to 16% with standard therapy alone). In patients with HR+/HER2- breast cancer, an absolute increase in the estimated pCR rate of 21 percent was observed in the KEYTRUDA (pembrolizumab) arm (based on the estimated pCR rate of 34% with KEYTRUDA plus standard therapy compared to 13% with standard therapy alone). The Bayesian model estimated pCR rates appropriately adjust to characteristics of the I-SPY 2 population, including MammaPrint status.
| Signature |
Estimated pCR Rate (95% Probability Interval) |
Probability KEYTRUDA Is Superior to Control |
Predictive Probability of Success in Phase 3 |
|||||||||||||
| KEYTRUDA Plus Standard Therapy |
Standard Therapy Alone |
|||||||||||||||
| TNBC |
0.60 (0.43 – 0.78) |
0.20 (0.06 – 0.33) |
>99% | >99% | ||||||||||||
| All HER2- |
0.46 (0.34 – 0.58) |
0.16 (0.06 – 0.27) |
>99% | 99% | ||||||||||||
| HR+/HER2- |
0.34 (0.19 – 0.48) |
0.13 (0.03 – 0.24) |
>99% | 88% | ||||||||||||
The safety profile of KEYTRUDA was consistent with that observed in previously reported studies across tumors. In the KEYTRUDA arm, Grade 3-5 treatment-related adverse events include diarrhea (n=5), febrile neutropenia (n=5), fatigue (n=4), anemia (n=3), nausea (n=3), neutropenia without fever (n=1), peripheral motor neuropathy (n=1), peripheral sensory neuropathy (n=1) and vomiting (n=1). Immune-mediated adverse events of Grade 3-5 include adrenal insufficiency (n=5), hepatitis (n=2), colitis (n=1) and hypothyroidism (n=1). Five of six patients presented with adrenal insufficiency after completion of AC (21-24 weeks after starting KEYTRUDA), and one presented during KEYTRUDA treatment (5 weeks after starting KEYTRUDA).
“Not all breast cancers are the same – and there has continued to be a significant gap in the treatment options available for patients with certain subtypes, particularly TNBC,” said Dr. Rita Nanda, medical oncologist at The University of Chicago. “The results observed in this trial are not only encouraging, but demonstrate the potential for treatment combinations that can make a difference in patient outcomes.”
About I-SPY and the I-SPY 2 TRIAL
The I-SPY (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis) TRIAL is conducted by a consortium that brings together the U.S. Food and Drug Administration (FDA), leading academic medical centers, and patient advocates, as well as Merck and other pharmaceutical and biotech companies.
The I-SPY 2 TRIAL is a collaborative effort among academic investigators from 20 major cancer research centers across the U.S. and QuantumLeap Healthcare Collaborative, the FDA, and the Foundation for the National Institutes of Health (FNIH) Cancer Biomarkers Consortium. Major supporters include The Safeway Foundation and the Bill Bowes Foundation.
The I-SPY 2 TRIAL’s adaptive statistical design was developed by the pioneering principal investigators for the I-SPY trial, Laura J. Esserman, M.D., MBA, and Donald A. Berry, Ph.D., professor of biostatistics at The University of Texas MD Anderson Cancer Center and founder of Berry Consultants in collaboration with the FDA, industry, and many leading academic collaborators including the Agents working group chair (Doug Yee, M.D. from the University of Minnesota) and the Trial Operations working group chair (Angie DeMichele, M.D. from the University of Pennsylvania). The trial is a unique collaborative effort where over 50 clinicians are actively engaged in the conduct of the trial.
The I-SPY 2 TRIAL adaptive-trial design is based on Bayesian predictive probability that a biological regimen will be shown to be statistically superior to standard therapy in an equally randomized 300-patient confirmatory trial. Regimens that have a high Bayesian predictive probability of showing superiority in at least one of 10 predefined signatures graduate from the trial. Regimens are dropped for futility if they show a low predictive probability of showing superiority over standard therapy in all 10 signatures. A maximum total of 120 patients can be assigned to each experimental regimen. A regimen can graduate early and at any time after having 60 patients assigned to it.
About KEYTRUDA® (pembrolizumab) Injection
KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
Studies of KEYTRUDA – from the largest immuno-oncology program in the industry with more than 500 trials – include a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand factors that predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including the exploration of several different biomarkers across a broad range of tumors.
KEYTRUDA (pembrolizumab) is administered as an intravenous infusion over 30 minutes every three weeks for the approved indications. KEYTRUDA for injection is supplied in a 100 mg single-dose vial.
KEYTRUDA (pembrolizumab) Indications and Dosing
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.
Lung Cancer
KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.
KEYTRUDA, as a single agent, is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.
KEYTRUDA, in combination with pemetrexed and carboplatin, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC. This indication is approved under accelerated approval based on tumor response rate and progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for pemetrexed and carboplatin.
Head and Neck Cancer
KEYTRUDA (pembrolizumab) is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Urothelial Carcinoma
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
KEYTRUDA is also indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Microsatellite Instability-High (MSI-H) Cancer
KEYTRUDA (pembrolizumab) is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)
- solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
- colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.
In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Merck’s Focus on Cancer
Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer.
As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program that includes more than 500 clinical trials evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.
For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.
About Merck
For more than a century, Merck, a leading global biopharmaceutical company known as MSD outside of the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the world’s most challenging diseases. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to advance the prevention and treatment of diseases that threaten people and communities around the world – including cancer, cardio-metabolic diseases, emerging animal diseases, Alzheimer’s disease and infectious diseases including HIV and Ebola. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.
SOURCE: Merck
