On April 16, 2019 Phoenix Molecular Designs (PhoenixMD), a privately-held biotechnology company designing precise cancer therapeutics by targeting essential kinases, reported that it has entered into a collaboration with STA Pharmaceutical Co., Ltd (STA), a WuXi AppTec group company, to manufacture the PMD-026 needed for IND-enabling toxicology studies and a Phase I study in women (Press release, Phoenix Molecular Designs, APR 16, 2018, View Source [SID1234536961]).

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Under the terms of the collaboration agreement, STA will become a new manufacturing partner for PhoenixMD for their platform of kinase inhibitor drug candidates to treat a wide range of unmet medical needs, with an initial focus on triple negative breast cancer (TNBC). STA will be responsible for the early manufacturing work through their GMP-certified site in San Diego, CA. Through these collaborative efforts, PhoenixMD expects to file an Investigational New Drug Application (IND) with the U.S. Food and Drug Administration (FDA) for PMD-026.

Dr. Minzhang Chen, CEO of STA, commented, "We are excited to manufacture PMD-026 and enable Phoenix MD to advance this novel RSK inhibitor to shrink tumors in Phase 1 studies in women."

"We’re thrilled to collaborate with STA, a global leader in drug development and manufacturing, who has helped us achieve an important milestone in the efficient and scalable manufacturing of PMD-026," said Sandra E. Dunn, CEO PhoenixMD. "Through this work, we have demonstrated that PMD-026 has the potential to be disease-modifying with its ability to block the RSK pathway signaling and initiating significant tumor shrinkage of up to 70% in TNBC xenograft models. Looking ahead, we expect to build upon this progress and file an IND for PMD-026, with the ultimate goal of confirming these revolutionary results in women suffering from TNBC."

Gerrit Los, CSO of PhoenixMD added, "It is critical to have a manufacturing partner at this stage of development for PMD-026. This collaboration will allow us to move PMD-026 into IND enabling toxicology studies and to get ready for a successful IND filing. Importantly, it provides us the security to have access to GMP quality API when we are ready to start our Phase I study."

About Triple Negative Breast Cancer (TNBC) and RSK Kinases

Approximately 400,000 cases of TNBC are diagnosed every year worldwide and it is one of the most difficult breast cancer subtypes to treat due to lack of effective, targeted therapies. TNBC also claims the lives of young women more than any other type of breast cancer due to a lack of understanding around the therapeutic bullseye. It is also a very heterogeneous disease, therefore a common denominator across TNBC types was necessary to identify the bullseye. Through genome-wide screens, RSK was identified as the prime target for TNBC by scientists at PhoenixMD. Currently, there are still no targeted therapies available for TNBC.

There are four types of RSK involved in cancer, known as RSK1-4, and each type has a unique role in the development of the disease. RSK1 is responsible for cancer cell invasion and is an important driver in the spread of cancer. RSK2 controls cancer cell growth, and RSK3 and RSK4 are associated with drug resistance.

RSK1 and RSK2 have been proven critical to the survival of patients with TNBC. Over 90% of primary TNBC express high levels of RSK1 and RSK2. Inhibiting RSK2 eliminates TNBC cells completely, including cancer stem cells, which give rise to cancer recurrence. PhoenixMD, with its novel, targeted approach, is focused on creating patented cancer RSK inhibitors and companion diagnostics for cancer indications – initially in breast cancer – with the potential to treat blood, brain, ovarian, lung, skin, prostate, colon, head and neck cancers.

Currently, there are no approved targeted therapies for TNBC, although several drugs are subject to research studies and clinical trials. PhoenixMD is addressing this unmet medical need through a novel, targeted approach by inhibiting critical kinases, such as RSK1-4, a group of highly conserved Ser/Thr kinases that promote cell proliferation, growth, motility and survival. For this target, PhoenixMD developed PMD-026, a first-in-class, specific RSK inhibitor that blocks downstream signaling of RSK and induces apoptosis.

On April 15, 2018 Merck (NYSE:MRK), known as MSD outside the United States and Canada, and the European Organisation for Research and Treatment of Cancer (EORTC), reported findings from the Phase 3 EORTC1325/KEYNOTE-054 trial investigating KEYTRUDA, Merck’s anti-PD-1 therapy, as adjuvant therapy in resected, high-risk stage III melanoma (Press release, Merck & Co, APR 15, 2018, View Source [SID1234525462]). Study results showed KEYTRUDA significantly prolonged recurrence-free survival (RFS), reducing the risk of disease recurrence or death by 43 percent compared to placebo in the overall study population (HR=0.57 [98.4% CI, 0.43-0.74]; p<0.0001). For the primary endpoint of RFS in the overall study population, the one-year RFS rate was 75.4 percent (95% CI, 71.3-78.9) for KEYTRUDA compared to 61.0 percent (95% CI, 56.5-65.1) for placebo. For the co-primary endpoint of RFS in patients whose tumors were considered PD-L1 positive, KEYTRUDA demonstrated significantly prolonged RFS compared to placebo (HR=0.54; 95% CI, 0.42-0.69; p<0.0001). The safety profile of KEYTRUDA was consistent with what has been seen in previous trials among patients with advanced melanoma. These results are being presented today for the first time in the opening plenary session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 (Abstract #10526), with simultaneous publication in The New England Journal of Medicine.

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"The EORTC is very pleased to have collaborated with Merck on this important study which showed a significant recurrence-free survival benefit across all stage III melanoma," said Alexander Eggermont, study chair, director general at the Gustave Roussy Cancer Institute, professor of oncology, University of Paris-Saclay.

"These data demonstrate compelling evidence that adjuvant treatment with KEYTRUDA provides significant recurrence-free survival benefit after surgery in patients with high-risk Stage III melanoma," said Roy Baynes, M.D., Ph.D., senior vice president and head of Global Clinical Development, chief medical officer, Merck Research Laboratories. "These are the first data for KEYTRUDA in the adjuvant setting and mark an important advancement for the treatment of resected stage III melanoma. We are pleased to be sharing these data with global regulatory authorities."

KEYTRUDA is the first anti-PD-1 therapy to show RFS benefit across stage IIIA (> 1 mm lymph node metastasis), IIIB and IIIC melanoma. The RFS benefit was also seen regardless of BRAF mutation status (HR=0.64 [99% CI, 0.42-0.96] for patients with wild-type BRAF status; HR=0.57 [99% CI, 0.37-0.89] for patients with mutant BRAF status). As previously announced, Merck is working to submit data from EORTC1325/KEYNOTE-054 to regulatory agencies in the U.S. and around the world.

"As an organization dedicated to eliminating melanoma suffering and death, we are thrilled to see these important new data on KEYTRUDA," said Louise M. Perkins, Ph.D., chief science officer, Melanoma Research Alliance. "The ability to significantly prevent melanoma from coming back after surgery, along with a demonstrated safety profile, makes this a welcome development in the fight against melanoma."

Merck has a broad clinical development program in melanoma with KEYTRUDA as monotherapy and in combination with other novel mechanisms. The program, which is comprised of more than 4,500 patients across 10 clinical studies, is evaluating KEYTRUDA across all settings and stages of the disease.

Additional Data and Safety Information from EORTC1325/KEYNOTE-054 (Abstract #10526)

EORTC 1325/KEYNOTE-054 is a randomized, double-blind, Phase 3 study (ClinicalTrials.gov, NCT02362594) sponsored by Merck and conducted in collaboration with the EORTC. The study is evaluating adjuvant therapy with KEYTRUDA compared to placebo in patients with resected high-risk melanoma (stage IIIA [> 1 mm lymph node metastasis], IIIB and IIIC). In total, the study enrolled 1,019 patients who were randomly assigned to receive either an intravenous infusion of KEYTRUDA 200 mg (n=514) or placebo (n=505) every three weeks for up to 1 year (a total of 18 doses). Upon documented recurrence, patients were eligible for cross-over/re-challenge with KEYTRUDA. Co-primary endpoints were RFS for all patients and RFS in patients whose tumors express PD-L1; secondary endpoints include distant metastases-free survival and overall survival (OS) in all patients and in patients whose tumors express PD-L1. RFS was defined as the time from randomization until the date of first recurrence (local, regional or distant metastasis) or death from any cause. In accordance with the trial protocol, the study is continuing in order to evaluate secondary endpoints including OS.

With an overall median follow-up of 15.1 months, in the overall intent-to-treat population the 12-month RFS rate was 75.4 percent (95% CI, 71.3-78.9) in the KEYTRUDA group and 61.0 percent (95% CI, 56.5-65.1) in the placebo group. RFS was significantly prolonged, resulting in reduced risk of recurrence or death of 43 percent with KEYTRUDA (HR=0.57; 98.4% CI, 0.43-0.74; p<0.0001) compared to placebo. At 18 months, the RFS rates were 71.4 percent (95% CI, 66.8-75.4) and 53.2 percent (95% CI, 47.9-58.2), respectively.

In patients with PD-L1 positive tumors (n=853), the 12-month RFS rate was 77.1 percent (95% CI, 72.7-80.9) in the KEYTRUDA group and 62.6 percent (95% CI, 57.7-67.0) in the placebo group. In these patients, RFS was significantly longer, resulting in reduced risk of recurrence or death of 46 percent with KEYTRUDA (HR=0.54; 95% CI, 0.42-0.69; p<0.0001) compared to placebo. RFS benefit demonstrated with KEYTRUDA was consistent in patients with PD-L1-negative tumors and in those with an undetermined tumor PD-L1 expression.

In addition, RFS benefit seen with KEYTRUDA was similar across other subgroups including stage of disease and nodal involvement; BRAF-status, sex and baseline body mass index did not significantly influence the treatment difference.

The safety profile of KEYTRUDA was consistent with what has been seen in previously reported studies among patients with advanced melanoma. Drug-related grade 3 to 5 adverse events were reported in 14.7 percent of patients in the KEYTRUDA group and 3.4 percent in patients in the placebo group. The most common treatment-related adverse events (TRAEs) for KEYTRUDA were fatigue or asthenia (37.1%), skin reactions (28.3%), diarrhea (19.1%), arthralgia (12.0%), and nausea (11.4%). The highest incidence of immune-related adverse events (irAEs), mostly grade 1 to 2, were endocrine disorders (most commonly hypothyroidism [14.3%], hyperthyroidism [10.2%], and thyroiditis [3.1%]). The incidence of grade 3-5 irAEs was 7.1 percent and included colitis (2.0%), pneumonitis (0.8%), and hepatitis (1.4%); all others had incidences ≤ 1 percent. There was one death due to myositis in the KEYTRUDA group.

About EORTC

The European Organisation for Research and Treatment of Cancer (EORTC) unites cancer clinical research experts to define better treatments for cancer patients to prolong survival and improve quality of life. Both international and multidisciplinary, EORTC’s Network comprises over 4600 collaborators involved in cancer treatment and research in more than 800 hospitals across 35 countries. Through translational and clinical research, EORTC offers an integrated approach to therapeutic strategies, drug evaluation programs, survivorship issues, and quality of life. EORTC Headquarters, a unique international clinical research infrastructure, is based in Brussels, Belgium, from where its various activities are coordinated and run.

About Melanoma

Melanoma, the most serious form of skin cancer, is characterized by the uncontrolled growth of pigment-producing cells. The incidence of melanoma has been increasing over the past four decades – approximately 232,000 new cases were diagnosed worldwide in 2012. In the U.S., melanoma is one of the most common types of cancer diagnosed and is responsible for the vast majority of skin cancer deaths. In 2018, an estimated 91,270 people are expected to be diagnosed and an estimated 9,320 people are expected to die of the disease in the U.S. alone.

Merck Investor Webcast

Merck will hold a live investor audio webcast in conjunction with the 2018 AACR (Free AACR Whitepaper) Annual Meeting on Monday, April 16 at 6:45 p.m. CDT (7:45 p.m. EDT). Those interested in participating can register and join here.

About KEYTRUDA (pembrolizumab) Injection 100mg

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.

Merck has the industry’s largest immuno-oncology clinical research program, which currently involves more than 700 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

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 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 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 children 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.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted 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. The recommended dose of KEYTRUDA is 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in patients with HNSCC, occurring in 28 (15%) of 192 patients with HNSCC, including Grade 3 (0.5%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

KEYTRUDA can cause other clinically important immune-mediated adverse reactions. These immune-mediated reactions may occur in any organ system. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Solid organ transplant rejection has been reported in postmarketing use of KEYTRUDA. Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with KEYTRUDA vs the risk of possible organ rejection in these patients.

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for signs and symptoms of infusion-related reactions, including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after being treated with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after treatment with KEYTRUDA on any trial, 6 patients (26%) developed graft-versus-host disease (GVHD), one of which was fatal, and 2 patients (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning, one of which was fatal. Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation.

These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT. Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

In clinical trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled clinical trials.

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). The most common adverse reactions with KEYTRUDA vs ipilimumab were fatigue (28% vs 28%), diarrhea (26% with KEYTRUDA), rash (24% vs 23%), and nausea (21% with KEYTRUDA). Corresponding incidence rates are listed for ipilimumab only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most common adverse reactions (occurring in at least 20% of patients and at a higher incidence than with docetaxel) were decreased appetite (25% vs 23%), dyspnea (23% vs 20%), and nausea (20% vs 18%).

In KEYNOTE-021(G1), when KEYTRUDA was administered in combination with carboplatin and pemetrexed (carbo/pem) in advanced nonsquamous NSCLC, KEYTRUDA was discontinued in 10% of 59 patients. The most common adverse reaction resulting in discontinuation of KEYTRUDA (≥2%) was acute kidney injury (3.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 39% of patients; the most common (≥2%) were fatigue (8%), neutrophil count decreased (8%), anemia (5%), dyspnea (3.4%), and pneumonitis (3.4%). The most common adverse reactions (≥20%) with KEYTRUDA compared to carbo/pem alone were fatigue (71% vs 50%), nausea (68% vs 56%), constipation (51% vs 37%), rash (42% vs 21%), vomiting (39% vs 27%), dyspnea (39% vs 21%), diarrhea (37% vs 23%), decreased appetite (31% vs 23%), headache (31% vs 16%), cough (24% vs 18%), dizziness (24% vs 16%), insomnia (24% vs 15%), pruritus (24% vs 4.8%), peripheral edema (22% vs 18%), dysgeusia (20% vs 11%), alopecia (20% vs 3.2%), upper respiratory tract infection (20% vs 3.2%), and arthralgia (15% vs 24%). This study was not designed to demonstrate a statistically significant difference in adverse reaction rates for KEYTRUDA as compared to carbo/pem alone for any specified adverse reaction.

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (reported in at least 20% of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3 or 4) and new or worsening hypothyroidism.

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL, and treatment was interrupted due to adverse reactions in 26% of patients. Fifteen percent (15%) of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 16% of patients. The most frequent serious adverse reactions (≥1%) included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock. The most common adverse reactions (occurring in ≥20% of patients) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reactions (in ≥20% of patients) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%). Eighteen patients (5%) died from causes other than disease progression. Five patients (1.4%) who were treated with KEYTRUDA experienced sepsis which led to death, and 3 patients (0.8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (≥1%) were liver enzyme increase, diarrhea, urinary tract infection, acute kidney injury, fatigue, joint pain, and pneumonia. Serious adverse reactions occurred in 42% of patients, the most frequent (≥2%) of which were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis.

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Adverse reactions leading to interruption of KEYTRUDA occurred in 20% of patients; the most common (≥1%) were urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%). The most common adverse reactions (≥20%) in patients who received KEYTRUDA vs those who received chemotherapy were fatigue (38% vs 56%), musculoskeletal pain (32% vs 27%), pruritus (23% vs 6%), decreased appetite (21% vs 21%), nausea (21% vs 29%), and rash (20% vs 13%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients, the most frequent (≥2%) of which were urinary tract infection, pneumonia, anemia, and pneumonitis.

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

There is limited experience in pediatric patients. In a study, 40 pediatric patients (16 children aged 2 years to younger than 12 years and 24 adolescents aged 12 years to 18 years) with advanced melanoma, lymphoma, or PD-L1–positive advanced, relapsed, or refractory solid tumors were administered KEYTRUDA 2 mg/kg every 3 weeks. Patients received KEYTRUDA for a median of 3 doses (range 1–17 doses), with 34 patients (85%) receiving KEYTRUDA for 2 doses or more. The safety profile in these pediatric patients was similar to that seen in adults treated with KEYTRUDA. Toxicities that occurred at a higher rate (≥15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia (18%).

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 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

On April 15, 2018 Blueprint Medicines Corporation (NASDAQ:BPMC), a leader in discovering and developing targeted kinase medicines for patients with genomically defined diseases, reported proof-of-concept data from the ongoing Phase 1 ARROW clinical trial of BLU-667 in patients with RET-altered solid tumors (Press release, Blueprint Medicines, APR 15, 2018, View Source;p=RssLanding&cat=news&id=2342578 [SID1234525309]). Designed and developed by Blueprint Medicines, BLU-667 is a potent and highly selective inhibitor targeting oncogenic RET fusions and mutations, which are key drivers across multiple cancers, including subsets of patients with non-small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC). The data will be presented today in a clinical trials plenary session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Chicago, Illinois.

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The data from the dose escalation portion of the ARROW trial showed broad and robust clinical activity for once-daily (QD) dosing of BLU-667 across multiple tumor types and RET genotypes, including in patients whose disease had progressed on prior multi-kinase inhibitor therapy. As of the data cutoff date of April 6, 2018, the data showed radiographic tumor reductions in 84 percent of patients with RET-altered solid tumors with measurable target lesions. In patients evaluable for response, preliminary overall response rates (ORR) were 50 percent in patients with NSCLC and 40 percent in patients with MTC. As of the data cutoff date, QD dosing of BLU-667 was well-tolerated, and most adverse events (AEs) reported by investigators were Grade 1 or 2.
"The data announced today reveal the broad clinical potential of BLU-667, a potent and highly selective RET inhibitor, and further demonstrate the power and reproducibility of Blueprint Medicines’ proprietary drug discovery platform," said Andy Boral, M.D., Ph.D., Chief Medical Officer at Blueprint Medicines. "We believe the safety, clinical activity and pharmacodynamic results from the dose escalation portion of the Phase 1 ARROW trial demonstrate compelling proof-of-concept for BLU-667. We are particularly encouraged by the consistency of these early BLU-667 data across multiple tumor types, RET alterations and prior lines of therapy. Based on these data, we are excited to rapidly advance the global expansion portion of the trial, which will further evaluate an optimized dose of BLU-667 across a broad patient population with a focus on durability of activity."
Data from the Ongoing Phase 1 ARROW Clinical Trial
As of the data cutoff date of April 6, 2018, 53 patients had been treated with BLU-667 in the dose escalation portion of the Phase 1 ARROW clinical trial across multiple dose levels ranging from 30 mg to 600 mg QD, including 19 patients with NSCLC, 29 patients with MTC and five patients with other solid tumors. Of these 53 patients, 27 patients (51 percent) had been previously treated with a multi-kinase inhibitor and 18 patients (34 percent) had been previously treated with an immunotherapy.
Pharmacokinetic (PK) data across all QD dose levels demonstrated rapid absorption of BLU-667 and a mean half-life greater than 12 hours, supporting a QD dosing regimen.
Preliminary Safety Data:
As of the data cutoff date, QD dosing of BLU-667 was observed to be well-tolerated. The maximum tolerated dose (MTD) for BLU-667 was determined to be 400 mg QD using a Bayesian optimal interval design. At QD dose levels up to and including the MTD, the majority of AEs reported by investigators were Grade 1 or 2. AEs reported by investigators (≥20 percent) most commonly included constipation (24 percent), increased alanine aminotransferase (ALT) (22 percent) and increased aspartate aminotransferase (20 percent). Investigators reported treatment-related Grade 3 AEs in eight patients (16 percent). Treatment-related Grade 3 AEs occurring in two or more patients included hypertension and neutropenia. There were no treatment-related Grade 4 or 5 AEs.
Across all QD dose levels up to 600 mg QD, seven patients experienced dose-limiting toxicities. Only one patient discontinued treatment with BLU-667 due to a dose-limiting toxicity (Grade 3 ALT increase). An additional 11 patients discontinued treatment, including eight patients due to progressive disease, one patient due to an AE unrelated to BLU-667 and one patient due to non-compliance. One patient passed away, and the death was deemed unrelated to BLU-667. Among all 53 enrolled patients, 41 patients (77 percent) remained on BLU-667 as of the data cutoff date. Duration of treatment ranged from 0.3 to 11.5 months.
Preliminary Clinical Activity Data:
As of the data cutoff date, 40 patients with RET-altered tumors were evaluable for response assessment, including 14 patients with NSCLC, 25 patients with MTC and one patient with papillary thyroid cancer (PTC). CT and MRI imaging was used to measure clinical activity by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Of the remaining 13 enrolled patients who were not evaluable for response assessment, two patients did not have RET-altered tumors, one patient died due to an AE unrelated to BLU-667 prior to any response assessment and 10 recently enrolled patients had not been evaluated for response by the data cutoff date.
Across all evaluable patients, the preliminary ORR was 45 percent. Responses were observed in patients previously treated with multi-kinase therapy, immunotherapy and chemotherapy.
RET-altered NSCLC
85% of NSCLC patients with measurable target lesions had radiographic tumor reductions.
Seven patients achieved a partial response (PR) (five confirmed, two pending confirmation), representing a preliminary ORR of 50 percent.
Responses were observed in patients with the most common RET alterations in NSCLC, including RET-KIF5B and RET-CCDC6 fusions.
Preliminary evidence of anti-tumor activity in the brain was observed in metastatic NSCLC.
RET-altered MTC
83% of MTC patients with measurable target lesions had radiographic tumor reductions.
One patient achieved a confirmed complete response, nine patients achieved a PR (five confirmed, four pending confirmation), representing a preliminary ORR of 40 percent.
Responses were observed in patients with the most common activating RET mutations in MTC, including the RET-M918T mutation.
Other RET-altered solid tumors
One patient with RET-altered PTC achieved a PR (pending confirmation).
Based on the favorable tolerability and encouraging clinical activity observed for BLU-667 to date, Blueprint Medicines initiated and is actively enrolling patients in the global expansion portion of the ARROW trial.
Investor Event and Webcast Information
Blueprint Medicines will host an investor event on Sunday, April 15, 2018 beginning at 7:00 p.m. CT (8:00 p.m. ET) in Chicago to review the preliminary clinical data presented at AACR (Free AACR Whitepaper) for BLU-667. Formal presentations and the live webcast will begin at 7:30 p.m. CT (8:30 p.m. ET). The event can be accessed by dialing 1-855-728-4793 (domestic) or 1-503-343-6666 (international) and providing the passcode 6080608. A live webcast will also be available under "Events & Presentations" in the Investors section of Blueprint Medicines’ website at View Source The archived webcast will be available on Blueprint Medicines’ website approximately two hours after the event concludes and will be available for 30 days following the event.
About the Phase 1 ARROW Clinical Trial of BLU-667
ARROW is a Phase 1 clinical trial of BLU-667 designed to evaluate the safety and tolerability of BLU-667 in multiple ascending doses in adults with RET-altered NSCLC, MTC and other advanced solid tumors. The trial consists of two parts: a dose escalation portion and an expansion portion. Enrollment in the dose escalation portion is complete, and the expansion portion has been initiated and is actively enrolling patients in four defined cohorts at the MTD of 400mg QD: (1) RET-altered NSCLC patients previously treated with a tyrosine kinase inhibitor (TKI), (2) RET-altered NSCLC patients who have not previously received any TKI treatment, (3) patients with medullary thyroid cancer, and (4) patients with other RET-altered solid tumors. Trial objectives include assessing response, pharmacokinetics, pharmacodynamics and safety.
Patients and physicians interested in the ARROW trial can contact the Blueprint Medicines study team at [email protected] or 1-617-714-6707. More information about the ARROW trial is also available at www.arrowtrial.com or www.clinicaltrials.gov (Identifier: NCT03037385).
About RET-Altered NSCLC, MTC and Other Solid Tumors
RET activating fusions and mutations are a key disease driver in multiple cancers, including NSCLC and MTC. RET fusions are implicated in approximately 1-2% of patients with NSCLC, while RET mutations are implicated in approximately 60% of patients with MTC. In addition, genomic analyses published by scientists at Blueprint Medicines have identified RET fusions at low frequencies in colon and breast cancer. Currently, there are no approved therapies that selectively target RET-driven cancers, though there are several approved multi-kinase inhibitors with RET activity being evaluated in clinical trials. Thus far, clinical activity attributable to RET inhibition has been uncertain for these inhibitors, likely due to insufficient inhibition of RET and off-target toxicities.
About BLU-667
BLU-667 is an orally available, potent and highly selective inhibitor designed to target RET fusions, mutations and predicted resistance mutations. Blueprint Medicines is developing BLU-667, an investigational medicine, for the treatment of patients with RET-altered NSCLC, MTC and other solid tumors. BLU-667 was discovered by Blueprint Medicine’s research team leveraging its proprietary compound library, and Blueprint Medicines retains worldwide development and commercialization rights for BLU-667.

On April 15, 2018 Five Prime Therapeutics, Inc. (Nasdaq:FPRX), a clinical-stage biotechnology company focused on discovering and developing innovative immuno-oncology protein therapeutics, reported that an oral presentation featuring FPA150, Five Prime’s first-in-class B7-H4 antibody, was given today at the 2018 AACR (Free AACR Whitepaper) Annual Meeting in Chicago (Press release, Five Prime Therapeutics, APR 15, 2018, View Source [SID1234525310]). The presentation titled "FPA150: A Recombinant, Afucosylated, Fully Human IgG1 Monoclonal Antibody for the Treatment of Malignancies that Express High Levels of B7-H4" by Charles Kaplan is available at View Source

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FPA150 is a novel B7-H4 antibody that possesses both T cell immune checkpoint blockade and antibody-dependent cellular cytotoxicity (ADCC) activities. FPA150 demonstrates dose-dependent anti-tumor activity in vivo as a monotherapy and elicits complete tumor regressions in preclinical tumor models when given in combination with PD-1 blockade. Five Prime is currently studying FPA150 in a Phase 1 monotherapy trial in patients with solid tumors that overexpress B7-H4.
"Our monoclonal B7-H4 antibody, FPA150, appears to possess both T cell checkpoint blockade activity and enhanced ADCC," said Bryan Irving, Ph.D., Senior Vice President of Research, at Five Prime. "We are studying FPA150 in patients whose tumors overexpress B7-H4 and in which there is high unmet need for immuno-oncology treatments, such as in breast, ovarian and endometrial cancer. Based on the therapeutic properties of FPA150, we believe that this agent has the potential to be an effective therapeutic by improving anti-tumor immune responses in cancer patients."

B7-H4 is a member of the B7-family of T cell immune checkpoint ligands and shares significant homology with other family members, including PD-L1 and PD-L2. B7-H4 is expressed in several human tumors such as carcinomas of the bladder, breast, ovary and endometrium, and its expression tends to correlate with poor prognosis. B7-H4 is also a documented T cell immune checkpoint inhibitory ligand capable of directly suppressing T cell responses.

In Investigational New Drug (IND)-enabling pharmacokinetics (PK) and toxicity studies, FPA150 demonstrated a suitable PK profile and was generally well tolerated. A B7-H4 immunohistochemistry (IHC) assay is in development for clinical use as a companion diagnostic to help identify the patients who might benefit most from this treatment.
Five Prime is studying FPA150 in a Phase 1 monotherapy trial with a dose-escalation phase in patients with solid tumors, followed by dose expansion in pre-specified cohorts in tumor types based on B7-H4 expression levels. The initial targeted tumors are advanced or metastatic breast, ovarian, endometrial and bladder cancers.

About FPA150
FPA150 is a novel, fully human, afucosylated monoclonal antibody targeting B7-H4. B7-H4 expression is observed in multiple solid tumors, including breast, bladder, ovarian and endometrial cancers, and has been documented to correlate with poor prognosis. FPA150 is designed with a dual mechanism of action: blocking the T cell checkpoint activity of B7-H4 as well as delivering potent ADCC against tumor cells expressing B7-H4. FPA150 is currently being studied in a Phase 1 clinical trial in advanced or metastatic breast, ovarian, endometrial and bladder cancers.

On April 15, 2018 AstraZeneca and Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that presented data from the Phase 3 OlympiAD trial showing the final overall survival (OS) results for LYNPARZA in metastatic breast cancer at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Chicago from April 14-18 (Press release, Merck & Co, APR 15, 2018, View Source [SID1234525311]).

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The trial compared LYNPARZA with chemotherapy (physician’s choice of capecitabine, eribulin or vinorelbine) for patients with germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer and met its primary endpoint of progression-free survival (PFS).

Results at AACR (Free AACR Whitepaper) include updated findings from the secondary endpoint of overall survival (OS). While the trial was not powered to demonstrate a statistically significant difference, the median OS was 19.3 months in patients treated with LYNPARZA and 17.1 months for patients treated with chemotherapy (HR 0.90, 95% CI 0.66-1.23; p=0.513). At the final OS data cutoff (64% maturity), 13 percent of patients remained on LYNPARZA and no patients remained on chemotherapy.

Sean Bohen, executive vice president, global medicines development and chief medical officer at AstraZeneca, said, "OlympiAD is the first Phase 3 trial to demonstrate disease control with a PARP inhibitor in gBRCA-mutated, HER2-negative metastatic breast cancer. While the trial was not powered to show overall survival compared to chemotherapy, the results are another encouraging factor in the use of LYNPARZA for this patient population."
Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said, "For patients and physicians, these results are meaningful in that they support the progression-free survival endpoint – which showed that patients treated with LYNPARZA gained seven months chemotherapy-free time – and reinforce the importance of identifying BRCA status to optimize metastatic breast cancer management."
When analyzing the predefined subgroups, the results were consistent with the overall analysis, which did not show a statistically significant difference between arms. The greatest difference was seen in patients who had not received chemotherapy in the metastatic setting with a median difference in OS of 7.9 months with LYNPARZA (HR 0.51, 95% CI 0.29-0.90; nominal p=0.02; median 22.6 vs 14.7 months).

The safety profile of LYNPARZA remained consistent with the primary analysis. Serious adverse events (AEs) (Grade ≥3) were reported in 38 percent of patients who received LYNPARZA vs 49.5% of patients in the chemotherapy arm. AEs leading to drug discontinuation were 4.9 percent for LYNPARZA vs 7.7 percent for chemotherapy. AEs leading to dose reductions were 25.4 percent for LYNPARZA vs 30.8 percent for chemotherapy. AEs leading to dose interruptions were 36.1 percent for LYNPARZA vs 28.6 percent for chemotherapy. Please see Important Safety Information below.

These results build on previously reported primary and secondary endpoints, which demonstrated LYNPARZA significantly improved PFS (HR 0.58, 95% CI 0.43-0.80; p=0.0009 median 7.0 vs 4.2 months) and showed data beyond initial disease progression, prolonging time to second progression or death (PFS2) by 3.9 months (HR 0.57, 95% CI 0.40-0.83; P=0.003 median 13.2 months vs 9.3 months). Previously reported findings also showed LYNPARZA doubled objective response rates (52% [95% CI 44-60] vs 23% [95% CI 13-35]). The data from the OlympiAD trial can be found in the August 10 2017 issue of the New England Journal of Medicine.
In January 2018, LYNPARZA was approved by the U.S. Food and Drug Administration (FDA) for use in the treatment of g BRCA-mutated metastatic breast cancer based on the OlympiAD data. A Type 2 Variation application was recently validated by the European Medicines Agency for LYNPARZA in BRCA-mutated, HER2-negative metastatic breast cancer.

A Phase 3 trial (n=1800), OlympiA, is evaluating LYNPARZA as an adjuvant treatment in patients with gBRCA, HER2-negative breast cancer with results expected in 2020. The trial is powered to assess potential benefit in OS.
LYNPARZA is approved in around 60 countries for advanced ovarian cancer and has treated more than 20,000 patients globally. It has the broadest clinical development program of any PARP inhibitor, and AstraZeneca and Merck are working together to bring LYNPARZA to more patients across multiple cancers.
Important Safety Information for LYNPARZA (olaparib)
Contraindications

There are no contraindications for LYNPARZA.

Warnings and Precautions

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in <1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy, and some also had a history of more than one primary malignancy or of bone marrow dysplasia.

Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery.

If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA (olaparib) if MDS/AML is confirmed.

Pneumonitis: Occurred in <1% of patients exposed to LYNPARZA, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. A pregnancy test is recommended for females of reproductive potential prior to initiating treatment.
Females

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose.

Males
Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time.
Adverse Reactions—Maintenance Setting
Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA in the maintenance setting for SOLO-2: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%). Study 19: nausea (71%), fatigue (including asthenia) (63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract infection (22%), constipation (22%), headache (21%), and decreased appetite (21%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the maintenance setting (SOLO-2/Study 19) were: increase in mean corpuscular volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute neutrophil count (51%/47%), increase in serum creatinine (44%/45%), and decrease in platelets (42%/36%).

Adverse Reactions—Advanced gBRCAm Ovarian Cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA (olaparib) for advanced gBRCAm ovarian cancer after 3 or more lines of chemotherapy (pooled from 6 studies) were: fatigue (including asthenia) (66%), nausea (64%), vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia (22%), decreased appetite (22%), and arthralgia/musculoskeletal pain (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer (pooled from 6 studies) were: decrease in hemoglobin (90%), increase in mean corpuscular volume (57%), decrease in lymphocytes (56%), increase in serum creatinine (30%), decrease in platelets (30%), and decrease in absolute neutrophil count (25%).

Adverse Reactions—gBRCAm, HER2-Negative Breast Cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients in OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%).

Drug Interactions
Anticancer Agents: Clinical studies of LYNPARZA in combination with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.
CYP3A Inhibitors: Avoid concomitant use of strong or moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor must be co-administered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment.

CYP3A Inducers: Avoid concomitant use of strong or moderate CYP3A inducers when using LYNPARZA (olaparib). If a moderate inducer cannot be avoided, there is a potential for decreased efficacy of LYNPARZA.
Use In Specific Populations

Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose.
Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients.

Hepatic Impairment: No adjustment to the starting dose is required in patients with mild hepatic impairment (Child-Pugh classification A). There are no data in patients with moderate or severe hepatic impairment.

Renal Impairment: No adjustment to the starting dose is necessary in patients with mild renal impairment (CLcr=51-80 mL/min). In patients with moderate renal impairment (CLcr=31-50 mL/min), reduce the dose to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).
Dosing and Administration

To avoid substitution errors and overdose, do not substitute LYNPARZA tablets with LYNPARZA capsules on a milligram-to-milligram basis due to differences in the dosing and bioavailability of each formulation. Recommended tablet dose is 300 mg, taken orally twice daily, with or without food. Continue treatment until disease progression or unacceptable toxicity. For adverse reactions, consider dose interruption or dose reduction.
Indications for LYNPARZA (olaparib) in the U.S.

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:
For the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.

For the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

In patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine treatment. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Please see complete Prescribing Information for LYNPARZA (olaparib), including Patient Information (Medication Guide)
NOTES TO EDITORS
About OlympiAD
OlympiAD is a global, randomized, open-label, multi-center Phase 3 trial of 302 patients, assessing the efficacy and safety of LYNPARZA tablets (300 mg twice daily) compared to chemotherapy (physician’s choice of capecitabine, eribulin or vinorelbine). 205 patients were randomized to receive LYNPARZA and 97 patients were randomized to receive chemotherapy.

Patients in the OlympiAD trial had germline BRCA-mutated, HER2-negative breast cancer and received LYNPARZA for treatment in the metastatic setting. Prior to enrollment, 71 percent of patients had received no more than two previous chemotherapy treatments for metastasized breast cancer and 28 percent of patients had received prior platinum-based chemotherapy. Also enrolled were patients with hormone receptor (HR)-positive breast cancer who had received at least one endocrine therapy (adjuvant therapy or therapy for metastatic disease) and had disease progression during therapy unless they had disease for which the endocrine therapy was considered inappropriate.
The primary endpoint was PFS. Secondary endpoints included OS, time to second progression or death, overall response rate, health-related quality of life, and safety and tolerability.

About Metastatic Breast Cancer
Progesterone receptors (PR), estrogen receptors (ER) and HER2 receptors may be expressed on breast cancer cells. A patient’s breast cancer will test either negative or positive for these three receptors. If a tumor tests positive for PR and/or ER, it is considered HR-positive. If a tumor tests negative for all three receptors, it is considered triple negative. These receptors indicate which hormones or other proteins may be promoting growth of the cancer.
Metastatic breast cancer (MBC) is the most advanced stage of breast cancer (Stage 4), and occurs when cancer cells have spread beyond the initial tumor site to other parts of the body, outside of the breast and nearby lymph nodes.
Despite the increase in treatment options during the past three decades, there is currently no cure for patients diagnosed with MBC and only 26.9 percent of patients survive for five years after diagnosis. Thus, the primary aim of treatment is to slow progression of the disease for as long as possible, improving, or at least maintaining, a patient’s quality of life.

Breast cancer is the most common cancer in women, with an estimated 1.67 million new cases diagnosed worldwide in 2012 alone – one in four of all cancer cases. Approximately 30 percent of women who are diagnosed with early breast cancer will go on to develop advanced disease.
About BRCA Mutations

BRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA and play an important role maintaining the genetic stability of cells. When either of these genes is mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly and cells become unstable. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.

About LYNPARZA (olaparib)
LYNPARZA was the first in class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Specifically, in vitro studies have shown that LYNPARZA-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.
LYNPARZA, which has the broadest clinical development program of any PARP inhibitor, is being investigated in a range of DDR-deficient tumor types