On October 2, 2019 Alpine Immune Sciences, Inc. (NASDAQ:ALPN), a leading clinical-stage immunotherapy company focused on developing innovative treatments for cancer, autoimmune/inflammatory, and other diseases, reported planned poster presentations at upcoming scientific meetings highlighting new preclinical data on the Company’s lead programs: ALPN-101, a first-in-class dual CD28/ICOS inhibitor for the treatment of autoimmune diseases, and ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor for the treatment of cancers (Press release, Alpine Immune Sciences, OCT 2, 2019, View Source [SID1234540010]).

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2019 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting – National Harbor, MD

Abstract Title: ALPN-202, a Conditional CD28 Costimulator and Dual Checkpoint Inhibitor, Utilizes Multiple Mechanisms to Elicit Potent Anti-Tumor Immunity Superior to Checkpoint Blockade Alone
Poster #: P793
Date: Friday, November 8, 2019
Time: 7:00 a.m. – 8:00 p.m. ET

Abstract Title: ALPN-202, a Conditional CD28 Costimulator and Dual Checkpoint Inhibitor, Enhances the Activity of Multiple Standard of Care Modalities
Poster #: P467
Date: Friday, November 8, 2019
Time: 7:00 a.m. – 8:00 p.m. ET

American College of Rheumatology 2019 ACR/ARHP Annual Meeting – Atlanta, GA

Abstract Title: ALPN-101, a First-in-Class Dual ICOS/CD28 Antagonist, Suppresses Key Effector Mechanisms Underlying Rheumatoid and Psoriatic Arthritis
Session Title: Spondyloarthritis Including PsA–Clinical Poster II: Treatment of Axial Spondyloarthritis and Psoriatic Arthritis
Date: Monday, November 11, 2019
Time: 9:00 a.m. – 11:00 a.m. ET

Abstract Title: ALPN-101, a First-in-Class Dual ICOS/CD28 Antagonist, Suppresses Key Effector Mechanisms Associated with Sjögren’s Syndrome
Session Title: Sjögrenʼs Syndrome–Basic & Clinical Science Poster I
Date: Tuesday, November 12, 2019
Time: 9:00 a.m. – 11:00 a.m. ET

On September 27, 2019, Rigel Pharmaceuticals, Inc., a Delaware corporation (the "Company") reported that entered into a Credit and Security Agreement, dated as of September 27, 2019 (the "Closing Date") by and among the Company, the lenders party thereto from time to time and MidCap Financial Trust, as administrative agent and collateral agent ("Agent") (the "Term Loan Credit Agreement"), which provides for a $60 million term loan facility (Filing, 8-K, Rigel, OCT 2, 2019, View Source [SID1234540009]). The Term Loan Credit Agreement provides for (i) on the Closing Date, $10.0 million aggregate principal amount of term loans, (ii) at the Company’s option, until December 31, 2020, an additional $10.0 million term loan facility, (iii) at the Company’s option, until March 31, 2021, an additional $20.0 million term loan facility subject to the satisfaction of certain conditions ("Tranche Three") and (iv) at the Company’s option, until March 31, 2022, an additional $20.0 million term loan facility subject to the satisfaction of certain conditions ("Tranche 4") (collectively, the "Term Loans"). The Company used the proceeds of the Term Loans for general corporate purposes

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The obligations under the Term Loan Credit Agreement are secured by a perfected security interest in all of the Company’s assets except for intellectual property and certain other customary excluded property pursuant to the terms of the Term Loan Credit Agreement.

The Term Loans are subject to an origination fee of 0.25% of each funded tranche of Term Loans. The Company will pay the Agent an annual administrative fee of 0.25% of the amount borrowed under the Term Loans, payable annually. The Term Loans may be prepaid in full or in part through September 27, 2020 with payment of a 2.5% prepayment premium, after which they may be prepaid in full or in part through September 27, 2021 with payment of a 1.5% prepayment premium, after which they may be prepaid in full or in part through September 27, 2022 with payment of a 1.0% prepayment premium, after which they may be prepaid in full or in part with no prepayment premium. An additional 2.5% of the amount of Terms Loans advanced by the lenders will be due upon prepayment or repayment of the Term Loans in full.

The interest rate applicable to the Term Loans is LIBOR plus 5.65%, subject to a LIBOR floor of 1.50%. Commencing October 1, 2019, the Company initially will make interest-only payments for 24 months, followed by 36 months of amortization payments. The interest-only period will be extended to 36 months and again to 48 months upon the satisfaction of certain conditions set forth in the Term Loan Credit Agreement. All unpaid principal and accrued interest is due and payable in full no later than September 1, 2024.

The Term Loan Credit Agreement requires that the Company (i) upon both of (x) the draw of Tranche 3 or Tranche 4 and (y) cash falling below 1.25x Term Loans outstanding, maintain U.S. Tavalisse Net Revenue (as defined in the Term Loan Credit Agreement) in amounts set forth in the Term Loan Credit Agreement and (ii) upon the draw of Tranche 3 or Tranche 4, maintain cash and cash equivalents of at least $10.0 million. The Term Loan Credit Agreement also contains customary representations and warranties and customary affirmative and negative covenants, including, among other things, restrictions on indebtedness, liens, investments, mergers, dispositions, prepayment of other indebtedness and dividends and other distributions.

Events of default under the Term Loan Credit Agreement include: (i) failure by the Company to timely make payments due under the Term Loan Credit Agreement; (ii) material misrepresentations or misstatements in any representation or warranty by the Company when made; (iii) failure by the Company or its subsidiaries to comply with the covenants under the Term Loan Credit Agreement and other related agreements; (iv) certain defaults under a specified amount of other indebtedness of the Company or its subsidiaries; (v) insolvency or bankruptcy-related events with respect to the Company or any of its subsidiaries; (vi) certain undischarged judgments against the Company or its subsidiaries; (vii) certain ERISA-related events with respect to the Company or its subsidiaries above a specified amount; (viii) certain security interests or liens under the loan documents ceasing to be, or being asserted by the Company not to be, in full force and effect; (ix) the institution of criminal proceedings against the Company; (x) an event of default under the guarantee of the obligations under the Term Loan Credit Agreement; (xi) the prepayment of any subordinated debt other than as specifically permitted by the terms of such subordination; (xii) the occurrence of a Material Adverse Change (as defined in the Term Loan Credit Agreement); (xiii) certain adverse actions by the FDA or DEA with respect to certain products or which could be reasonably expected to result in a Material Adverse Change (as defined in the Term Loan Credit Agreement); (xiv) a default or material breach under certain specified material contracts and (xv) any loan document ceasing to be, or any challenge or assertion by the Company that such loan document is not, in full force and effect. If one or more events of default occurs and continues beyond any applicable cure period, the Agent may, with the consent of the lenders holding a majority of the loans and commitments under the facilities, or will, at the request of such lenders, terminate the commitments of the lenders to make further loans and declare all of the obligations of the Company under the Term Loan Credit Agreement to be immediately due and payable.

On October 2, 2019 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported that KEYTRUDA, Merck’s anti-PD-1 therapy, has been approved by the National Medical Products Administration (NMPA) in China as monotherapy for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (tumor proportion score [TPS] ≥1%) as determined by a NMPA-approved test, with no EGFR or ALK genomic tumor aberrations (Press release, Merck & Co, OCT 2, 2019, View Source [SID1234540008]). This new indication was granted full approval based on the overall survival (OS) findings from the Phase 3 KEYNOTE-042 trial, including data from an extension of the global study in Chinese patients. KEYTRUDA is now the first anti-PD-1 therapy approved in China as both monotherapy and in combination with chemotherapy for the first-line treatment of appropriate patients with NSCLC.

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"New treatment options that can help improve survival outcomes are desperately needed in China, as lung cancer remains the leading cause of cancer deaths in this country," said Professor Yi-Long Wu, honorary director of the Guangdong Lung Cancer Research Institute, and tenured professor of Guangdong Provincial People’s Hospital. "In KEYNOTE-042, KEYTRUDA monotherapy demonstrated a survival benefit, compared with chemotherapy alone, across histologies in patients with either locally advanced or metastatic non-small cell lung cancer whose tumors expressed PD-L1 in at least 1% of tumor cells."

KEYNOTE-042 is an international, randomized, multi-center, open-label, active-controlled trial in patients with stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC, and whose tumors expressed PD-L1 (TPS ≥1%) and who had not received prior systemic treatment for metastatic NSCLC. In the extension of the global study in Chinese patients, KEYTRUDA monotherapy demonstrated a statistically significant improvement in OS compared with chemotherapy in patients whose tumors expressed PD-L1 with a TPS ≥50% (HR=0.62 [95% CI, 0.38-1.00]), with a TPS ≥20% (HR=0.62 [95% CI, 0.41-0.95]) and in the entire study population with a TPS ≥1% (HR=0.65 [95% CI, 0.45-0.94]). Results from the KEYNOTE-042 China extension study were recently presented for the first time at the IASLC 2019 World Conference on Lung Cancer (WCLC) hosted by the International Association for the Study of Lung Cancer and showed consistent results in Chinese patients.

"KEYTRUDA is now the first anti-PD-1 therapy approved in China as both a monotherapy and in combination with chemotherapy in the first-line setting for appropriate patients with advanced non-small cell lung cancer," said Dr. Jonathan Cheng, vice president, oncology clinical research, Merck Research Laboratories. "For patients for whom combination therapy is not preferred, KEYTRUDA monotherapy represents an important new treatment option that has demonstrated a significant improvement in survival outcomes."

"In China, we launched KEYTRUDA one year ago, and already it has had an impact on patient care in the approved indications," said Joseph Romanelli, president of MSD in China. "Now, with a third indication in China, we look forward to offering an additional effective option in non-small cell lung cancer patients with PD-L1 levels of 1% or greater."

About Lung Cancer in China
Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death in China and worldwide. Each year, more than 787,000 new cases of lung cancer are diagnosed in China and more than 631,000 deaths result from the disease. The two main types of lung cancer are non-small cell and small cell. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for about 85% of all cases. There are several subtypes of NSCLC, including adenocarcinoma (accounting for 40% of lung cancers), squamous cell carcinoma (25 to 30%) and large cell carcinoma (10 to 15%).

About KEYTRUDA (pembrolizumab) Injection, 100 mg
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 1,000 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.

Selected Indications for KEYTRUDA (pembrolizumab) in the U.S.
Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer
KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is 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.

Small Cell Lung Cancer
KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line 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.

Head and Neck Squamous Cell Cancer
KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) ≥1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, 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.

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 3 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.

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 treatment of patients with PMBCL who require urgent cytoreductive therapy.

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 confirmatory trials.

KEYTRUDA is 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.

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.

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 (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.

Esophageal Cancer
KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

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.

Hepatocellular Carcinoma
KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. 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.

Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). 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.

Renal Cell Carcinoma
KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

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 with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grades 3-5 in 1.5% of patients.

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.

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 KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)
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.

Hepatotoxicity in Combination With Axitinib
KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed.

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 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. 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, including classical Hodgkin lymphoma, 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 (26%) developed graft-versus-host disease (GVHD) (1 fatal case) and 2 (9%) 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 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 trials.

Embryofetal Toxicity
Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

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-002, KEYTRUDA was permanently discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). The most common adverse reactions were fatigue (43%), pruritus (28%), rash (24%), constipation (22%), nausea (22%), diarrhea (20%), and decreased appetite (20%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea (28%).

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-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (≥20%) was fatigue (25%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

Adverse reactions occurring in patients with SCLC were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (≥20%) were fatigue (33%), constipation (20%), and rash (20%).

In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (≥20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).

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 who received KEYTRUDA as a monotherapy, 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%).

Adverse reactions occurring in patients with gastric cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

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%).

Adverse reactions occurring in patients with hepatocellular carcinoma (HCC) were generally similar to those in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of ascites (8% Grades 3–4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3–4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).

Among the 50 patients with MCC enrolled in study KEYNOTE-017, adverse reactions occurring in patients with MCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. Laboratory abnormalities (Grades 3–4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).

In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%).

Lactation
Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the final dose.

Pediatric Use
There is limited experience in pediatric patients. In a trial, 40 pediatric patients (16 children aged 2 years to younger than 12 years and 24 adolescents aged 12 years to 18 years) with various cancers, including unapproved usages, 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 2 doses or more. The safety profile in these pediatric patients was similar to that seen in adults; adverse reactions 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%), increased transaminases (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, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology 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 October 2, 2019 Theragnostics, which is developing innovative radiopharmaceuticals to improve cancer diagnosis and treatment, reported the successful completion of a phase two clinical study of novel prostate cancer diagnostic imaging Gallium-68 (68Ga) THP-PSMA PET/CT (Press release, Theragnostics, OCT 2, 2019, View Source [SID1234540007]).

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The PRONOUNCED trial is a prospective open-label study of 50 patients to evaluate the safety and clinical impact of 68Ga THP-PSMA PET/CT imaging (THP-PSMA) on patient management and treatment decisions in men who are newly diagnosed or have biochemically recurrent prostate cancer after initial treatment.

The study met its primary and secondary endpoints. Data demonstrates that post THP-PSMA scan, one third of newly diagnosed prostate cancer patients, and over 50% of patients with biochemically recurrent disease including 75% in a post-radical radiotherapy setting, saw their treatment plan altered to be more appropriate as a result of re-staging their prostate cancer. The safety data showed that THP-PSMA was well tolerated with no serious adverse events reported and was therefore considered safe.

"The PRONOUNCED study was completed with a substantial number of changes to the treatment regime made following the THP-PSMA scan and shows how this exciting technology can influence the management of prostate cancer patients," said Professor Jamshed Bomanji, co-investigator and head of department at the Institute of Nuclear Medicine, UCLH. "The new THP-PSMA PET/CT imaging allows for prospective analysis of the clinical disease status rather than retrospective, allowing for better informed decision making."

Greg Mullen, PhD., CEO of Theragnostics added, "We are very pleased that the PRONOUNCED trial has completed with such a positive result, this combined with a positive meeting with the FDA earlier this year on our route to NDA submission are key milestones in bringing THP-PSMA to patients. We are convinced that a THP-PSMA scan will benefit the treatment of prostate cancer patients by better informed and faster decision making. We look forward to sharing these data with the medical community at upcoming scientific congresses and in peer-reviewed publications."

The trial is jointly funded by Innovate UK and Theragnostics and conducted at University College London Hospitals NHS Foundation Trust (UCLH) with multiple referral sites in the UK including Guys and St. Thomas’ NHS Foundation Trust (GSTT), Barts Health NHS Trust, Royal Free London NHS Foundation Trust. The study was led by Dr Asim Afaq, UCLH Consultant Radiologist at the Institute of Nuclear Medicine, together with UCLH uro-oncology colleagues including Professor Heather Payne, Dr Reena Davda, Mr John Hines and Prof Gary Cook, Professor of Clinical PET imaging at King’s College London and GSTT.

The study was completed with support from the National Institute for Health Research University College London Hospitals Biomedical Research Centre and the Cancer Research UK University College London Experimental Cancer Medicine Centre.

About the PRONOUNCED Trial

The PRONOUNCED trial, "68Ga THP-PSMA PET/CT Imaging in High Risk Primary Prostate Cancer or Biochemical Recurrence of Prostate Cancer (PRONOUNCED)," was an open-label study in the UK designed to assess the clinical utility of THP-PSMA scan in the management of patients with primary prostate cancer or with biochemical recurrence of prostate cancer after initial treatment. The primary endpoint evaluated the clinical impact of PSMA (68Ga) scan on treatment decisions, assessed by comparing records of the patient’s treatment plan after a THP-PSMA scan with the treatment plan prior to the scan. Secondary endpoints included evaluation of the effect of treatment change in patients with positive THP-PSMA scan findings who had a treatment change involving radical salvage therapy; diagnostic performance; PSA threshold; safety assessment and comparison with standard of care imaging (if performed). Follow up of the efficacy and safety of THP-PSMA scan on impacting patient management decisions is ongoing. Theragnostics plans to present results of the PRONOUNCED trial at an upcoming medical congress and subsequently publish full results in a peer-reviewed publication.

About the PSMA (68Ga) kit for PSMA PET/CT

PSMA stands for prostate-specific membrane antigen. Its presence is increased in prostate cancer tissue, especially in metastatic tissue. It has been a marker for adverse pathological characteristics and likelihood of relapse of prostate cancer. The THP-PSMA kit provides a clinical tool for detection and imaging of PMSA in real time in the patient.

The enabling THP-PSMA kit binding technology will widen the access of PSMA PET/CT to prostate cancer patients once approved. The ease of use of this kit as well as the lower regulatory requirements for labelling PSMA with 68Ga allows for more clinics and pharmacies to perform the labelling in-house.

About Prostate / Recurrent Prostate Cancer

Prostate cancer is the second leading cause of cancer death in men in the United States and EU. The THP-PSMA scan will provide additional information in newly diagnosed high risk prostate cancer patients and determine whether the cancer has spread outside of the prostate bed. While most primary prostate cancer can be successfully treated, the disease recurs in approximately one-third of patients. Post radical treatment, in some patients, recurrent disease is detectable only by a rise in prostate specific antigen (PSA) levels, yet the location of the recurrence cannot be located by conventional imaging, potentially impacting subsequent management of these patients.

On October 2, 2019 Deciphera Pharmaceuticals, Inc. (Nasdaq:DCPH), a clinical-stage biopharmaceutical company addressing key mechanisms of tumor drug resistance, reported that it has appointed Matthew L. Sherman, M.D. as Executive Vice President and Chief Medical Officer (Press release, Deciphera Pharmaceuticals, OCT 2, 2019, View Source [SID1234540005]). Dr. Sherman brings over 25 years of experience as a physician-scientist in clinical drug development in oncology and hematology at leading biotechnology and pharmaceutical companies. Dr. Sherman will be responsible for leading the clinical development and medical affairs strategy for the Company’s pipeline of small molecule drug candidates designed using its proprietary kinase switch control inhibitor platform.

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"We are thrilled to welcome Matt to the Deciphera team at this exciting time for our company," said Steve Hoerter, President and Chief Executive Officer of Deciphera. "Matt’s deep expertise in successfully developing oncology therapeutics will be an incredible asset to Deciphera as we prepare the new drug application, or NDA, for ripretinib and advance our pipeline of novel product candidates. I look forward to working with Matt as we continue our mission to develop important new medicines for the treatment of cancer."

"Deciphera’s proprietary kinase switch control inhibitor platform has generated a diverse portfolio of product candidates spanning late-stage to preclinical development that are designed to address unmet needs in the treatment of cancer," said Dr. Sherman. "I am excited to join Deciphera and its impressive leadership team at this pivotal moment for the Company, and I look forward to contributing to its future success."

From 2006 to 2018, Dr. Sherman served as Chief Medical Officer of Acceleron Pharma, Inc., where he led medical research, clinical operations, biostatistics, data management, clinical pharmacology, medical writing, outsourcing and pharmacovigilance. Before joining Acceleron, Dr. Sherman was Senior Vice President and Chief Medical Officer at Synta Pharmaceuticals (now Madrigal Pharmaceuticals). Prior to Synta, Dr. Sherman spent over a decade at Wyeth-Ayerst Research/Genetics Institute, where he led the successful submission, positive Oncologic Drug Advisory Committee recommendation, and FDA approval for the first antibody immune-drug conjugate for acute myeloid leukemia. He has published 260 original papers, book chapters, reviews and abstracts, and is listed as an inventor on 13 patents. He currently serves as a director of Pieris Pharmaceuticals, Pulmatrix, and NewLink Genetics. He also serves on the Geisel School of Medicine at Dartmouth Board of Advisors and Alumni Council. Dr. Sherman received a S.B. in Chemistry from the Massachusetts Institute of Technology and a M.D. from Dartmouth Medical School. He completed his internal medicine residency at Georgetown University Medical Center and fellowship in Medical Oncology at the Dana-Farber Cancer Institute. Dr. Sherman is board certified in Internal Medicine and Medical Oncology and has held various academic and teaching positions at Harvard Medical School with corresponding clinical appointments at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston.