On October 20, 2018 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported the first presentation of preliminary data from a Phase 1 clinical trial evaluating MK-1454, an investigational STING (stimulator of interferon genes) agonist, as monotherapy and in combination with KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy, in patients with advanced solid tumors or lymphomas (Press release, Merck & Co, OCT 20, 2018, View Source [SID1234530007]). MK-1454 is one of more than 20 novel investigational immuno-therapeutic candidates Merck is evaluating as part of its broad oncology pipeline. The findings for MK-1454 were accepted as a late-breaking abstract and are being presented today in a poster discussion session at the ESMO (Free ESMO Whitepaper) 2018 Congress (Abstract #LBA15).

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"Merck is advancing a broad pipeline focused on the development of novel therapies with potential to provide meaningful clinical benefit to people with advanced cancers," said Dr. Eric H. Rubin, senior vice president, early-stage development, clinical oncology, Merck Research Laboratories. "We are encouraged by these early findings with our STING agonist, most notably the observations of several robust anti-tumor responses in patients receiving MK-1454 in combination with KEYTRUDA. Further studies are ongoing."

Study Design and Findings for MK-1454 (Abstract #LBA15)

In this Phase 1, open-label, multi-arm, multicenter, dose-escalation clinical trial (NCT03010176), MK-1454 was administered to patients with advanced solid tumors or lymphomas by intratumoral injection every week for nine weeks for three cycles then every three weeks thereafter. Dose escalations for MK-1454 were 10-3,000 µg (MK-1454 monotherapy arm) and 90-2,000 µg (MK-1454 in combination with KEYTRUDA arm) using accelerated titration followed by modified toxicity probability interval design. KEYTRUDA was administered as an intravenous (IV) injection at a dose of 200 mg every three weeks. Patients receiving MK-1454 as monotherapy who progressed while on therapy were eligible for crossover to the MK-1454-KEYTRUDA combination arm. Study objectives included evaluation of safety, tolerability, pharmacodynamics, pharmacokinetics and tumor responses evaluated using RECIST v1.1 criteria.

Interim data presented at ESMO (Free ESMO Whitepaper) were based on findings from 26 patients enrolled in the MK-1454 monotherapy arm and 25 patients enrolled in the combination arm with KEYTRUDA, plus 9 patients who crossed over from monotherapy to receive the combination regimen. In the monotherapy arm, no complete or partial responses were observed (n=0/20). In the combination arm, partial responses were observed in 24 percent of patients (n=6/25) (three head and neck squamous cell carcinoma, one triple-negative breast cancer, and two anaplastic thyroid carcinoma), with median reductions of 83 percent in the size of both target-injected and non-injected tumors. At the time of analysis, all of the partial responses were ongoing and had lasted six months or longer. None of the responders had previously received a PD-1/PD-L1 inhibitor therapy. The disease control rates were 20 percent and 48 percent for the monotherapy and combination arms, respectively.

Treatment-related adverse events (TRAEs) occurred in 82.6 percent (n=19/23) and 82.1 percent (n=23/28) of patients in monotherapy and combination arms, respectively. TRAEs resulting in trial discontinuation occurred in 7.1 percent of patients (n=2/28) in the combination arm. No TRAE discontinuations were recorded in patients in the monotherapy arm. The most common TRAEs (occurring in ≥10% of patients) in both study arms included: pyrexia, injection site pain, chills, and fatigue. In the monotherapy arm, additional TRAEs occurring in ≥10% of patients included: nausea, myalgia, headache, and tumor pain. In the combination arm, additional TRAEs occurring in ≥10% of patients included: pruritus, diarrhea, rash, and tachycardia.

About STING and MK-1454

STING is a signaling molecule that plays an important role in the body’s first line of defense against pathogens, such as bacteria and viruses (innate immune system). When activated, STING triggers the production of inflammatory proteins that can stimulate the immune system leading to the deployment of T cells, which are important in generating an effective immune mediated response to cancer cells.

Merck is exploring the role of the STING pathway across a variety of tumors as monotherapy and in combination with the company’s anti-PD-1 therapy, KEYTRUDA. MK-1454 is an investigational small molecule STING agonist administered as an intratumoral injection that is currently being evaluated in a Phase 1 clinical trial for the treatment of solid tumors and lymphomas (ClinicalTrials.gov, NCT03010176).

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. There are currently more than 850 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, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC, with no EGFR or ALK genomic tumor aberrations.

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.

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 or cisplatin, as appropriate.

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.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 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 confirmatory trials. KEYTRUDA is not recommended for the treatment of patients with PMBCL who require urgent cytoreductive therapy.

In adults with PMBCL, 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 PMBCL, 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 (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. 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 (mUC) 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 a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. 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 a fixed dose of 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

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%), 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 for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). 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 for Grade 4 colitis.

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). 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.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in patients with HNSCC occurring in 15% (28/192) of patients. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency), thyroid function (prior to and periodically during treatment), and hyperglycemia. For hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or 4 hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

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.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. 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, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

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

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 developed graft-versus-host disease (GVHD) (1 fatal case) and 2 developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). 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. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

Increased Mortality in Patients with Multiple Myeloma

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.

Embryofetal Toxicity

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.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent 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%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

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%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

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 (≥20%) 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 and new or worsening hypothyroidism.

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ≥1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (≥20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

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%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

Lactation

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.

Pediatric Use

There is limited experience in pediatric patients. In a study in 40 pediatric patients with advanced melanoma, lymphoma, or PD-L1–positive advanced, relapsed, or refractory solid tumors, the safety profile 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%).

About Merck’s Oncology Pipeline

As an immuno-oncology research leader, Merck is committed to advancing a broad oncology pipeline targeting multiple aspects of cancer cell biology and immune-based pathways. Specifically, Merck is discovering and developing novel targets in four distinct research areas: immune agonists, negative immune regulators, cancer vaccines and immune modulators of the tumor microenvironment including oncolytic viruses. Today, Merck’s pipeline includes more than 20 investigational immuno-therapeutic candidates – including novel combinations with the company’s approved medicines – in both clinical and pre-clinical development.

On October 20, 2018 ImmunoGen, Inc., (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported initial safety and preliminary anti-tumor activity from the FORWARD II expansion cohort assessing mirvetuximab soravtansine in combination with Merck’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab) (Press release, ImmunoGen, OCT 20, 2018, View Source [SID1234530012]). The data are being presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress, which is being held October 19-23, in Munich, Germany.

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"A high unmet need exists in patients with platinum-resistant ovarian cancer, particularly for heavily pretreated patients, and the goal of this study is to assess whether the addition of a checkpoint inhibitor prolongs the clinical benefit of mirvetuximab soravtansine in later-line patients through concomitant activation of the immune system," said Ursula Matulonis, M.D., Chief, Division of Gynecologic Oncology, Dana-Farber Cancer Institute. "Preliminary activity seen with the mirvetuximab soravtansine and pembrolizumab combination is encouraging, especially when considering other combinations involving pembrolizumab used in this patient population, where recent clinical trials have reported overall response rates below 20 percent."

The data presented at ESMO (Free ESMO Whitepaper) were for 56 patients with platinum-resistant ovarian cancer, of whom 40 have medium or high folate receptor alpha (FRα) expression. Patients had received a median of 3 prior therapies (range 2-7).

The combination of mirvetuximab soravtansine (6 mg/kg adjusted ideal body weight) and pembrolizumab (200 mg, supplied by Merck) demonstrates favorable tolerability and encouraging activity. Adverse events were predominantly mild to moderate (≤ Grade 2), consistent with the known safety profiles of each agent.

Preliminary findings related to activity include:

83% of patients (45/54 with at least one post-baseline scan) experienced tumor shrinkage of target lesions in response to treatment with mirvetuximab soravtansine and pembrolizumab, with more robust reductions observed in patients with tumors expressing FRα at medium or high levels.
Confirmed partial responses (PRs) were observed in 16 patients, with another 9 patients having unconfirmed PRs at the time of data analysis.
In the subset of patients with medium or high FRα expression levels, the confirmed overall response rate (ORR) was 31 percent (95% CI, 17, 48), with a median progression-free survival (PFS) of 5.5 months (95% CI 2.8, 6.3) and a median duration (DOR) of 8.1 months (95% CI 4.2, upper bound not yet reached).
At the time of analysis, the data were immature with 16 patients still on study (all with medium or high FRα expression) and a median follow-up of 8.3 months.
For all patients evaluable for activity, the confirmed ORR was 30 percent (95% CI 18, 44), with a median PFS of 4.2 months (95% CI 2.8, 5.9). The median DOR data of 6.9 months (95% CI 4.2, 8.3) suggest a trend towards improvement over mirvetuximab soravtansine monotherapy.
"The combination of mirvetuximab soravtansine with pembrolizumab continues to demonstrate a favorable tolerability profile in women with platinum-resistant ovarian cancer, with preliminary activity consistent with mirvetuximab monotherapy in heavily pretreated patients," said Anna Berkenblit, M.D., Vice President and Chief Medical Officer of ImmunoGen. "The early duration of response data from the expansion cohort suggest a trend towards improvement over mirvetuximab monotherapy. As the data from this cohort continue to mature, we will use it to guide the further development of this novel combination, as part of our broader strategy to establish mirvetuximab soravtansine as the preferred combination therapy in ovarian cancer."

POSTER PRESENTATION DETAILS

Title: "Mirvetuximab soravtansine, a folate receptor alpha (FRα-targeting antibody-drug conjugate (ADC), with pembrolizumab in platinum-resistant ovarian cancer (PROC): Initial results of an expansion cohort from FORWARD II, a Phase Ib study" (abstract #949P)
Date: October 20, 2018
Time: 12:30 CEST
Lead author: Ursula Matulonis, M.D., Chief, Division of Gynecologic Oncology, Dana-Farber Cancer Institute, Boston, MA
Additional information can be found at www.esmo.org.

About FORWARD II
FORWARD II is a Phase 1b/2 study of mirvetuximab soravtansine in combination with AVASTIN (bevacizumab), or KEYTRUDA (pembrolizumab) in patients with FRα-positive platinum-resistant ovarian cancer, primary peritoneal, or fallopian tube tumors, as well as a combination with carboplatin and a triplet combination of mirvetuximab plus carboplatin and AVASTIN in patients with platinum-sensitive ovarian cancer.

ABOUT MIRVETUXIMAB SORAVTANSINE
Mirvetuximab soravtansine (IMGN853) is the first folate receptor alpha (FRα)-targeting ADC. It uses a humanized FRα-binding antibody to target the ADC specifically to FRα-expressing cancer cells and a potent anti-tumor agent, DM4, to kill the targeted cancer cells.

On October 20, 2018 Euronext (Paris: FR0010331421 – IPH), reported updated data from the Phase II trial evaluating the safety and efficacy of the combination of monalizumab and cetuximab (anti-EGFR) in previously treated patients with recurrent and/or metastatic squamous cell carcinoma of the head & neck (R/M SCCHN) (Press release, Innate Pharma, OCT 20, 2018, View Source [SID1234530305]). The data will be discussed today at the ESMO (Free ESMO Whitepaper) 2018 Congress in Munich, Germany, by Professor Jérôme Fayette, Medical Oncologist at the Centre Léon Bérard Lyon, France. Monalizumab is a first-in-class checkpoint inhibitor targeting NKG2A inhibitory receptors expressed on tumor-infiltrating cytotoxic CD8 T lymphocytes and NK cells.

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"These results confirm the emerging clinical activity reported earlier this year at AACR (Free AACR Whitepaper)." commented Pierre Dodion, Chief Medical Officer of Innate Pharma. "This successfully executed study provides the rationale to advance our clinical program and to further investigate the potential benefits of this innovative and differentiated combination in patients who received both prior platinum-based chemotherapy and PD-1/L1 blockers. These patients represent a population with a high unmet medical need."

As of August 31, 2018, a total of 40 patients with R/M SCCHN were evaluable for safety and efficacy. The highest dose tested for monalizumab in the dose-escalation part of the study (10 mg/kg every 2 weeks) was given in combination with the approved dose and schedule of cetuximab in the Phase II cohort expansion. All patients enrolled had been previously treated with platinum-containing regimens.

In the study evaluating the combination of monalizumab and cetuximab the overall response rate was 27.5% (by RECIST) including 1 confirmed complete response (2.5%) and 10 partial responses (25%). Disease control rate at 24 weeks (DCR) was 35%. Median progression-free survival (PFS) and overall survival (OS) reached 5.0 and 10.3 months, respectively. In addition, there were 3 (18%) responders among the 17 patients who had been previously treated with PD-1/L1 antibodies.

"These data show a response rate and durability of response that are of high interest across the totality of patients. The clinical results are supported by a strong preclinical dataset that demonstrated the synergy between the two components of this non-PD-1/L1 combination therapy," commented Professor Jérôme Fayette, Investigator of the study. "Currently approved PD-1/L1 therapies have shown overall response rates of 13-16% in patients with head and neck cancer in the second-line setting. Almost half of the patients in the study were previously treated with immunotherapy, and achieving responses in this subpopulation with no treatment option is exciting. In today’s treatment landscape, there is much potential to explore other treatment paradigms that provide alternatives especially to non-responding PD-1/L1 patients."

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Among the 40 patients enrolled in the cohort expansion, the safety findings were consistent with previously presented data at AACR (Free AACR Whitepaper) 2017 and 2018, with no additional safety concerns compared to monalizumab or cetuximab given alone. The majority of adverse events (AE) were of Grade 1-2 severity, rapidly reversible and easily manageable. No infusion-related reactions or treatment-related deaths occurred. The most frequent AEs (skin disorders) described with cetuximab were not potentiated by the combination with monalizumab.

The poster is available in the monalizumab section on Innate Pharma’s website.

A KOL call with Dr Cohen, Prof. of Medicine at the Hospital of the University of Pennsylvania, Associate Director of Clinical Research, Abramson Cancer Center Philadelphia and the lead investigator of the study, will be held

Monday, October 22, at 4pm CEST (10am ET)

Dial in numbers:

France and International: +33 (0)1 72 72 74 03 US only: +1 646 722 4916

PIN code: 69616804#

On October 20, 2018 TESARO, Inc. (NASDAQ: TSRO), an oncology-focused biopharmaceutical company, today summarized updated Phase 1 GARNET data of TSR-042 (anti-PD-1 antibody) in patients with recurrent or advanced microsatellite instability high (MSI-H) endometrial cancer presented during the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (Press release, TESARO, OCT 20, 2018, View Source [SID1234529996]). Blinded, pooled interim safety data from the Phase 3 PRIMA trial of niraparib in patients with first-line ovarian cancer regardless of biomarker status were also presented in a poster discussion session and additional data from the QUADRA trial of niraparib for treatment of late-line ovarian cancer beyond BRCAmut were presented in a poster display.

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"The updated results from GARNET presented at ESMO (Free ESMO Whitepaper) demonstrate robust clinical activity of TSR-042 in patients with MSI-H endometrial tumors," said Mary Lynne Hedley, Ph.D., President and COO of TESARO. "In addition, blinded, pooled interim safety data from the ongoing PRIMA study of niraparib as maintenance therapy in first line ovarian cancer demonstrated a favorable tolerability profile for niraparib when dosed according to a patient’s weight and platelet count compared to a fixed starting dose. These prospective data confirmed that adverse events are reduced for patients starting niraparib at an individualized dose, including a reduction in symptomatic events that are particularly meaningful to patients. We look forward to announcing top-line results for the PRIMA study in late 2019."

TSR-042 (anti-PD-1 antibody)

GARNET: Efficacy data indicates robust activity of TSR-042 in patients with MSI-high endometrial cancer
GARNET is a multicenter, open-label, Phase 1 dose-escalation study designed to assess the safety, pharmacokinetics, pharmacodynamics, and clinical activity of TSR-042 in patients with advanced solid tumors. The weight-based dose escalation and fixed-dose safety portions of the GARNET study have been completed. The ongoing cohort expansion portion of GARNET is evaluating TSR-042 at a dose of 500 milligrams every 3 weeks (Q3W) for the first 4 cycles, and 1000 milligrams every 6 weeks (Q6W) thereafter in four cohorts: MSI-H endometrial cancer, MSI-H non-endometrial cancer, MSS endometrial cancer and non-small cell lung cancer (NSCLC). Data presented at ESMO (Free ESMO Whitepaper) included safety and efficacy data from the cohort of patients with MSI-H endometrial cancer.

At the time of data cutoff, 35 patients with MSI-H endometrial cancer had received treatment with TSR-042. Among the 25 patients with MSI-H endometrial cancer who had at least one post-baseline tumor assessment, one had a complete response and 12 had partial responses (including 1 unconfirmed response) by immune related RECIST (irRECIST) criteria (ORR 52%). Twelve of the 13 responses are ongoing (92%), including three patients with partial responses who have thus far received over 60 weeks of treatment with TSR-042. Three additional patients (12%) had stable disease. Median duration of response was not reached.

Preliminary safety findings among the 35 MSI-H endometrial patients indicate TSR-042 is generally well-tolerated. Grade ≥3 treatment-related treatment-emergent adverse events (TEAEs) were reported in 4 out of 35 patients (11.4%).

The data support the unique and convenient dose of TSR-042 of 500 mg Q3W for the first 4 doses, then 1000 mg Q6W thereafter. At this dose, TSR-042 maintained serum concentrations required to retain maximum receptor occupancy throughout the dosing cycle.

The GARNET study is intended to support a Biologics License Application (BLA) submission to the U.S. Food and Drug Administration (FDA) in 2019.

ZEJULA (niraparib)

PRIMA: Prospective validation of individualized niraparib dose regimen based on patient baseline body weight & platelet counts; Rates of adverse events in blinded, pooled patient groups decreased with individualized starting dose compared to fixed starting dose
PRIMA is a double-blind, randomized Phase 3 study designed to evaluate niraparib versus placebo as maintenance therapy in first-line ovarian cancer patients. Platinum responsive patients were initially randomized 2:1 to start niraparib at 300 mg once-daily or placebo and the protocol was subsequently amended to require an individualized starting dose of 200 mg once-daily in patients with baseline weight <77kg or platelet count <150K/μL and 300 mg in all other patients. The trial remains blinded for efficacy and safety.

Among the 727 patients dosed on the study, 480 patients were treated with a fixed 300 mg starting dose of niraparib or placebo and 247 patients were treated with an individualized dose of 300 mg or 200 mg of niraparib based on weight and platelet count or placebo. The findings presented were from evaluable patients with ≥30 days of safety data from blinded pooled niraparib and placebo and indicate improved tolerability with niraparib at the individualized starting dose. TEAEs grade ≥ 3 were lower (36%) in the individualized dosing group (pooled niraparib and placebo) as compared with the group that received a fixed starting dose of 300 mg of niraparib or placebo (52.7%). There were fewer dose reductions and dose discontinuations in patients treated with the individualized starting dose compared with the fixed starting dose. TEAEs leading to treatment discontinuation remained low for both groups at 7.9% for the fixed starting dose and 5.3% for the individualized starting dose group.

The rates of hematologic toxicities of all grades, including grade ≥ 3, were lower with introduction of an individualized starting dose. Grade ≥3 non-hematologic toxicities (nausea, vomiting, fatigue, hypertension, and insomnia) decreased with an individualized starting dose.

QUADRA: Clinical benefit of niraparib treatment demonstrated in late-line ovarian cancer setting, including patients with platinum resistant and refractory disease
Late line ovarian cancer represents a high unmet medical need and efficacy of cytotoxic chemotherapy is limited in patients with heavily-pretreated ovarian cancer. Previous studies have shown meaningful activity of other PARP inhibitors in the late-line treatment of ovarian cancer only in populations with BRCA mutations. QUADRA, a single arm study, was conducted to assess the activity of ZEJULA monotherapy in the fourth-line or later treatment of patients with ovarian cancer, regardless of platinum sensitivity or biomarker status.

Niraparib treatment demonstrated durable clinical activity in late-line (≥ 4th line) patients with BRCAmut tumors, with an ORR of approximately 30%, including patients with platinum-sensitive, -resistant, and -refractory disease, and a median duration of response of 9.2 months. The clinical benefit rate (CBR; CR+PR+SD) at 16 weeks and 24 weeks were 56% and 38%, respectively. A gradient of clinical activity based on platinum sensitivity was demonstrated in the BRCAmut patient population, with greatest activity demonstrated in patients with platinum-sensitive disease (ORR 39%), mOS was not reached (95% CI 19, NE). However, even patients with platinum-resistant and platinum-refractory disease experienced benefit from niraparib treatment with ORR of 33% and 19%, and mOS of 26.0 and 23.3 months, respectively.

Clinical benefit of niraparib extended beyond patients with BRCA mutations in this late-line setting. Patients with non-BRCAmut/HRDpos platinum-sensitive disease had an ORR of 20%. In total, the biomarker-driven population (BRCAmut regardless of platinum status and non-BRCAmut HRDpos platinum-sensitive patients) included 98 patients with ORR of 26%, mDOR of 8.3 months, and a mOS of 23.3 months.

The safety profile in the QUADRA treatment study was consistent with the safety profile observed in the NOVA maintenance population.

Details of TESARO’s poster presentations are as follows (all times local):

ZEJULA (niraparib)

Saturday, October 20, 2018, 9:15 AM – 10:45 AM; Lecture time: 9:59 AM

A prospective evaluation of tolerability of niraparib dosing based upon baseline body weight (wt) and platelet (plt) count: Blinded pooled interim safety data from the PRIMA Study

Poster Discussion, Abstract: 941PD, Location: ICM – Room 13, Poster Displayed: Hall B4

Saturday, October 20, 2018, 12:30 PM – 1:30 PM

QUADRA: A phase 2, open-label, single-arm study to evaluate niraparib in patients with relapsed ovarian cancer in 4th or later line of therapy: results from the BRCAmut subset

Poster Session, Abstract: 944P, Location: Hall A3

Saturday, October 20, 2018, 12:30 PM – 1:30 PM

OVARIO: A single-arm, open-label phase 2 study of maintenance therapy with niraparib + bevacizumab in patients with advanced ovarian cancer after response to frontline platinum-based chemotherapy

Poster Session, Abstract: 999TiP, Location: Hall A3

Saturday, October 20, 2018, 12:30 PM – 1:30 PM

Real world occurrence of top three clinical-trial reported adverse events of PARP inhibitor niraparib maintenance therapy in platinum-sensitive recurrent ovarian cancer, a national retrospective observational study of a 200 mg/day starting-dose cohort

Poster Session, Abstract: 986P, Location: Hall A3

Saturday, October 20, 2018, 12:30 PM – 1:30 PM

Brain metastases in primary ovarian cancer: real-world data

Poster Session, Abstract: 946P, Location: Hall A3

TSR-042 (anti-PD-1)

Saturday, October 20, 2018, 9:15 AM – 10:45 AM; Lecture time: 9:15 AM

Preliminary safety, efficacy, and PK/PD characterization from GARNET, a phase 1 clinical trial of the anti–PD-1 monoclonal antibody, TSR-042, in patients with recurrent or advanced MSI-H endometrial cancer

Poster Discussion, Abstract: 935PD, Location: ICM – Room 13, Poster displayed: Hall B4

Niraparib is marketed in the United States and Europe under trade name ZEJULA.

About ZEJULA (Niraparib)
ZEJULA (niraparib) is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated in the United States and in the EU for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. In preclinical studies, ZEJULA concentrates in the tumor relative to plasma, delivering greater than 90% durable inhibition of PARP 1/2 and a persistent antitumor effect. Important Safety Information Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML), including some fatal cases, was reported in 1.4% of patients receiving ZEJULA vs 1.1% of patients receiving placebo in Trial 1 (NOVA), and 0.9% of patients treated with ZEJULA in all clinical studies. The duration of ZEJULA treatment in patients prior to developing MDS/AML varied from <1 month to 2 years. All patients had received prior chemotherapy with platinum and some had also received other DNA damaging agents and radiotherapy. Discontinue ZEJULA if MDS/AML is confirmed.

Hematologic adverse reactions (thrombocytopenia, anemia and neutropenia) have been reported in patients receiving ZEJULA. Grade ≥3 thrombocytopenia, anemia and neutropenia were reported in 29%, 25%, and 20% of patients receiving ZEJULA, respectively. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred, in 3%, 1%, and 2% of patients, respectively. Do not start ZEJULA until patients have recovered from hematological toxicity caused by prior chemotherapy (≤ Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically thereafter. If hematological toxicities do not resolve within 28 days following interruption, discontinue ZEJULA, and refer the patient to a hematologist for further investigations.

Hypertension and hypertensive crisis have been reported in patients receiving ZEJULA. Grade 3-4 hypertension occurred in 9% of patients receiving ZEJULA vs 2% of patients receiving placebo in Trial 1, with discontinuation occurring in <1% of patients.
ZEJULA can cause fetal harm and females of reproductive potential should use effective contraception.

In clinical studies, the most common adverse reactions (Grades 1-4) in ≥10% of patients included: thrombocytopenia (61%), anemia (50%), neutropenia (30%), leukopenia (17%), palpitations (10%), nausea (74%), constipation (40%), vomiting (34%), abdominal pain/distention (33%), mucositis/stomatitis (20%), diarrhea (20%), dyspepsia (18%), dry mouth (10%), fatigue/asthenia (57%), decreased appetite (25%), urinary tract infection (13%), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation (10%), myalgia (19%), back pain (18%), arthralgia (13%), headache (26%), dizziness (18%), dysgeusia (10%), insomnia (27%), anxiety (11%), nasopharyngitis (23%), dyspnea (20%), cough (16%), rash (21%) and hypertension (20%).

Common lab abnormalities (Grades 1-4) in ≥25% of patients included: decrease in hemoglobin (85%), decrease in platelet count (72%), decrease in white blood cell count (66%), decrease in absolute neutrophil count (53%), increase in AST (36%) and increase in ALT (28%). Please see full U.S. prescribing information, including additional important safety information, available at www.zejula.com.

About GARNET
The ongoing Phase I GARNET trial is evaluating TSR-042 as monotherapy in patients with advanced solid tumors. GARNET included a weight-based dose escalation study (Part 1) and a fixed-dose safety study (Part 2A), both of which have been completed. Results of these studies were used to determine the recommended Phase 2 dose (RP2D; 500 mg Q3W for the first 4 cycles then 1000 mg Q6W). The study is now enrolling patients with MSI-H endometrial cancer, MSI-H non-endometrial cancer, MSS endometrial cancer, and NSCLC into four large expansion cohorts.

About TSR-042

TSR-042 is an investigational humanized anti-programmed death (PD)-1 monoclonal antibody that binds with high affinity to the PD-1 receptor and effectively blocks its interaction with the ligands PD-L1 and PD-L2. TSR-042 is the only anti-PD-1 therapy administered as monotherapy every 3 weeks for 4 doses then every 6 weeks thereafter. TSR-042 was developed as part of the collaboration between TESARO and AnaptysBio, Inc. This collaboration was initiated in March of 2014, and is focused on the development of monospecific antibody drugs targeting PD-1, TIM-3 (TSR-022), and LAG-3 (TSR-033), in addition to a bi-specific antibody drug candidate targeting PD-1/LAG-3 (TSR-075).

On October 20, 2018 Pfizer Inc.(NYSE:PFE) reported detailed overall survival (OS) data from the PALOMA-3 trial, which evaluated IBRANCE (palbociclib) in combination with fulvestrant compared to placebo plus fulvestrant in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer whose disease progressed on or after prior endocrine therapy (Press release, Pfizer, OCT 20, 2018, View Source [SID1234530013]). In the study, there was a numerical improvement in OS of nearly seven months with IBRANCE plus fulvestrant compared to placebo plus fulvestrant, although this difference did not reach the prespecified threshold for statistical significance (median OS: 34.9 months [95% CI: 28.8, 40.0] versus 28.0 months [95% CI: 23.6, 34.6]; HR=0.81 [95% CI: 0.64, 1.03], 1-sided p=0.0429). These data will be presented as a late-breaking oral abstract during the Presidential Symposium at the ESMO (Free ESMO Whitepaper) 2018 Congress (European Society for Medical Oncology) in Munich, Germany, and simultaneously published in The New England Journal of Medicine.

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The difference in median OS demonstrated in this analysis (6.9 months) is consistent with the improvement previously demonstrated for the primary endpoint of median progression-free survival (mPFS). In the updated PFS analysis for this study (non-prespecified), the combination of IBRANCE plus fulvestrant showed a statistically significant and clinically meaningful 6.6-month mPFS improvement compared to placebo plus fulvestrant (11.2 vs. 4.6 months; HR=0.50 [95% CI: 0.40-0.62], p<0.000001).1 Overall survival is a secondary endpoint of PALOMA-3, and the trial design was not optimized to detect a statistically significant difference in OS.

"It’s noteworthy that the magnitude of progression-free survival benefit observed in PALOMA-3 has translated to a similar difference of nearly seven months in overall survival, which is clinically meaningful. This is particularly significant given the challenges of demonstrating overall survival in this disease setting, where post-progression therapy is often substantially longer than time on study," said Massimo Cristofanilli, M.D., associate director for Translational Research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, as well as senior investigator of the PALOMA-3 trial. "The overall survival data, coupled with the previously demonstrated progression-free survival benefit, are encouraging for patients."

At the time of this analysis, follow-up was 44.8 months and approximately 60 percent (n=310) of events had occurred in the 521 patients enrolled. Patients on both arms received up to 10 lines (range 1-10) of post-progression treatment.

The trend toward OS favoring the IBRANCE plus fulvestrant arm was observed across most subgroups, with hazard ratios consistent with the overall population. In addition, for the overall population, the difference in OS was associated with prolonged time from randomization to first use of chemotherapy post-progression, an exploratory endpoint (HR=0.58 [95% CI: 0.47, 0.73], 1-sided p<0.000001). Median time to chemotherapy was 17.6 months (95% CI: 15.2, 19.7) for patients who received IBRANCE plus fulvestrant, twice that observed in patients who received placebo plus fulvestrant (8.8 months [95% CI: 7.3, 12.7]).

"Delaying the need for chemotherapy is a central goal of treatment for women with this disease. These new data from PALOMA-3 show that adding IBRANCE to fulvestrant led to a substantial improvement in this important area," said Nicholas Turner, M.D., Ph.D., professor of molecular oncology at The Institute of Cancer Research, London, and consultant medical oncologist at The Royal Marsden NHS Foundation Trust, as well as principal investigator of the PALOMA-3 trial. "The difference in overall survival and prolonged time to chemotherapy demonstrated in PALOMA-3 further support the role of IBRANCE in combination with endocrine therapy as a standard of care in HR+, HER2- metastatic breast cancer."

"Looking at the data from the PALOMA-3 trial and across the PALOMA program, IBRANCE has transformed the treatment landscape for this disease," said Mace Rothenberg, M.D., chief development officer, Oncology, Pfizer Global Product Development. "We are proud of the compelling body of evidence supporting the use of IBRANCE in this setting, and the difference this medicine continues to make in the lives of patients."

The most common adverse reactions in PALOMA-3 included neutropenia, leukopenia, infections, fatigue and nausea. No new safety signals observed with longer follow-up were identified as part of this final OS analysis.

About IBRANCE (palbociclib) 125 mg capsules

IBRANCE is an oral inhibitor of CDKs 4 and 6,2 which are key regulators of the cell cycle that trigger cellular progression.3,4 In the U.S., IBRANCE is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women, or fulvestrant in women with disease progression following endocrine therapy.

IBRANCE currently is approved in more than 85 countries and has been prescribed to more than 160,000 patients globally.

The full prescribing information for IBRANCE can be found at www.pfizer.com.

IMPORTANT IBRANCE (palbociclib) SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION

Neutropenia was the most frequently reported adverse reaction in PALOMA-2 (80%) and PALOMA-3 (83%). In PALOMA-2, Grade 3 (56%) or 4 (10%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. In PALOMA-3, Grade 3 (55%) or Grade 4 (11%) decreased neutrophil counts were reported in patients receiving IBRANCE plus fulvestrant. Febrile neutropenia has been reported in 1.8% of patients exposed to IBRANCE across PALOMA-2 and PALOMA-3. One death due to neutropenic sepsis was observed in PALOMA-3. Inform patients to promptly report any fever.

Monitor complete blood count prior to starting IBRANCE, at the beginning of each cycle, on Day 15 of first 2 cycles and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females of reproductive potential to use effective contraception during IBRANCE treatment and for at least 3 weeks after the last dose. IBRANCE may impair fertility in males and has the potential to cause genotoxicity. Advise male patients with female partners of reproductive potential to use effective contraception during IBRANCE treatment and for 3 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise women not to breastfeed during IBRANCE treatment and for 3 weeks after the last dose because of the potential for serious adverse reactions in nursing infants.

The most common adverse reactions (≥10%) of any grade reported in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were neutropenia (80% vs 6%), infections (60% vs 42%), leukopenia (39% vs 2%), fatigue (37% vs 28%), nausea (35% vs 26%), alopecia (33% vs 16%), stomatitis (30% vs 14%), diarrhea (26% vs 19%), anemia (24% vs 9%), rash (18% vs 12%), asthenia (17% vs 12%), thrombocytopenia (16% vs 1%), vomiting (16% vs 17%), decreased appetite (15% vs 9%), dry skin (12% vs 6%), pyrexia (12% vs 9%), and dysgeusia (10% vs 5%).

The most frequently reported Grade ≥3 adverse reactions (≥5%) in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were neutropenia (66% vs 2%), leukopenia (25% vs 0%), infections (7% vs 3%), and anemia (5% vs 2%).

Lab abnormalities of any grade occurring in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were decreased WBC (97% vs 25%), decreased neutrophils (95% vs 20%), anemia (78% vs 42%), decreased platelets (63% vs 14%), increased aspartate aminotransferase (52% vs 34%), and increased alanine aminotransferase (43% vs 30%).

The most common adverse reactions (≥10%) of any grade reported in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), vomiting (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased appetite (16% vs 8%), and pyrexia (13% vs 5%).

The most frequently reported Grade ≥3 adverse reactions (≥5%) in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were neutropenia (66% vs 1%) and leukopenia (31% vs 2%).

Lab abnormalities of any grade occurring in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were decreased WBC (99% vs 26%), decreased neutrophils (96% vs 14%), anemia (78% vs 40%), decreased platelets (62% vs 10%), increased aspartate aminotransferase (43% vs 48%), and increased alanine aminotransferase (36% vs 34%).

Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided. Avoid concomitant use of strong CYP3A inducers. The dose of sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure.

For patients with severe hepatic impairment (Child-Pugh class C), the recommended dose of IBRANCE is 75 mg. The pharmacokinetics of IBRANCE have not been studied in patients requiring hemodialysis.