On November 7, 2018 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported the first presentations of preliminary safety and efficacy data from Phase 1/2 dose finding studies for the company’s investigational anti-LAG-3 therapy (MK-4280) and anti-TIGIT therapy (MK-7684) in patients with advanced solid tumors (Press release, Merck & Co, NOV 7, 2018, View Source [SID1234530855]). LAG-3 and TIGIT are negative immune regulators and play different roles in downregulating the immune response. The preliminary findings from the studies demonstrated acceptable safety profiles with no dose limiting toxicities and early signals of anti-tumor activity for Merck’s anti-LAG-3 therapy (MK-4280) (Abstract #O26) and anti-TIGIT therapy (MK-7684) (Abstract #O25) as monotherapies and in combination with KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy.

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These early data will be presented Nov. 9th in oral sessions at SITC (Free SITC Whitepaper)’s 33rd Annual Meeting. To date, Merck has presented early safety and efficacy data for six investigational therapies from its oncology pipeline of more than 20 immuno-therapeutic candidates targeting different pathways.

"New early data at SITC (Free SITC Whitepaper) highlight the advancement of our broad oncology discovery research program, as well as our strategy to maximize the potential of different novel immune-based therapies in combination with KEYTRUDA," said Dr. Eric H. Rubin, senior vice president, early-stage development, clinical oncology, Merck Research Laboratories. "These early studies are providing valuable early insights into the anti-tumor activity for our investigational anti-LAG-3 and anti-TIGIT therapies in patients with advanced and metastatic cancer."

MK-4280 (Anti-LAG-3 Therapy): Study Design and Early Findings (Abstract #O26)

In this Phase 1/2, open-label, multi-arm, multicenter, dose-finding trial (CT.gov: NCT02720068) MK-4280, Merck’s investigational anti-LAG-3 therapy, was evaluated both as monotherapy (n=18) and in combination with KEYTRUDA (n=15) in 33 patients with metastatic solid tumors who had failed standard treatment options. MK-4280 (dose range: 7, 21, 70, 210, and 700 mg) and KEYTRUDA (200 mg fixed dose) were administered every three weeks for 35 cycles or until progression, intolerable toxicity, or investigator or patient decision. The study objectives included evaluation of safety, tolerability, pharmacodynamics, pharmacokinetics, and overall response rate (ORR) as determined by RECIST v1.1 criteria.

Preliminary data showed MK-4280 as monotherapy and in combination with KEYTRUDA was generally well-tolerated and had a manageable safety profile across all dose levels tested. There were no dose limiting toxicities recorded. Treatment-related adverse events (TRAEs) occurred in 61 percent of patients in the monotherapy arm and 53 percent of patients in the combination arm of which 6 percent and 20 percent were Grade 3-4 toxicities respectively. Six percent of patients in the monotherapy arm and 13 percent of patients in the combination arm discontinued treatment. The most common TRAEs (occurring in ≥10% of patients) were fatigue and arthralgia in the monotherapy arm and fatigue, pyrexia, pruritus, and maculopapular rash in the combination therapy arm. In the monotherapy arm, one partial response was observed (6%) (n=1/18). In the combination arm, partial responses were observed in four patients (27%) (n=4/15). The disease control rates for the monotherapy and combination arms were 17 percent and 40 percent, respectively.

MK-7684 (Anti-TIGIT Therapy): Study Design and Early Findings (Abstract #O25)

In this Phase 1, open-label, multi-arm, multicenter, dose-finding clinical trial (CT.gov: NCT02964013), MK-7684, Merck’s investigational anti-TIGIT therapy, was evaluated as monotherapy (n=34) and in combination with KEYTRUDA (n=34) in 68 patients with advanced solid tumors who had failed standard treatment options. Thirteen patients who progressed on the monotherapy arm crossed over to the combination arm. MK-7684 (dose range: 2.1, 7, 21, 70, 210 and 700 mg) and KEYTRUDA (200 mg fixed dose) were administered every three weeks for up to 35 cycles or until progression, intolerable toxicity, or investigator or patient decision. Primary study objectives included evaluation of safety and tolerability, pharmacokinetics, and ORR as determined by RECIST v1.1 criteria.

Preliminary data showed MK-7684 as monotherapy and in combination with KEYTRUDA was generally well tolerated and had a manageable safety profile across all dose levels tested. There were no dose limiting toxicities recorded. TRAEs occurred in 56 percent of patients in the monotherapy arm and 60 percent in the combination arm of which 6 percent and 11 percent were Grade 3-4 toxicities, respectively. No patients discontinued because of TRAEs. The most common TRAEs (occurring in ≥ 10% of patients), were fatigue and pruritus in the monotherapy arm and pruritus in the combination arm. In the monotherapy and combination arms, one partial response (3%) (n=1/34) and eight partial responses were observed (19%) (n=8/43), and the disease control rates were 35 percent and 47 percent, respectively.

About LAG-3 and MK-4280

Lymphocyte-activation gene 3 or LAG-3 is a cell surface molecule that plays a role in downregulating the immune response. LAG-3 expression on tumor-infiltrating lymphocytes is associated with tumor-mediated immune suppression.

MK-4280 is a humanized, IgG4, anti-LAG-3 monoclonal antibody that prevents LAG-3 from binding to its major ligand, MHC Class II. MK-4280 is being evaluated as monotherapy and in combination with KEYTRUDA in clinical trials for the treatment of solid tumors and hematologic malignancies.

About TIGIT and MK-7684

TIGIT is an immunomodulatory receptor that may play a role in the suppression of T-cell production and activation. TIGIT is also involved in tumor cell immune evasion and the inhibition of antiviral immune responses.

MK-7684, Merck’s anti-TIGIT antibody, is designed to target TIGIT in order to boost the strength of a T-cell-mediated response against cancer cells. MK-7684 is currently being evaluated in a Phase I clinical trial for the treatment of metastatic solid tumors.

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, in combination with carboplatin and either paclitaxel or nab-paclitaxel, 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 metastatic 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 the chemotherapy agents administered in combination with KEYTRUDA 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-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or nab-paclitaxel 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-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%).

Adverse reactions occurring in patients with gastric cancer were similar to those occurring in patients with melanoma or NSCLC.

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%).

On November 7, 2018 Verastem, Inc. (Nasdaq: VSTM) (Verastem Oncology or the Company), focused on developing and commercializing medicines to improve the survival and quality of life of cancer patients, reported a collaboration with The Leukemia & Lymphoma Society (LLS), to accelerate the development of duvelisib for the treatment of patients with peripheral T-cell lymphoma (PTCL), an aggressive type of non-Hodgkin lymphoma (NHL) (Press release, Verastem, NOV 7, 2018, View Source;p=irol-newsArticle&ID=2375824 [SID1234530899]). Verastem Oncology’s duvelisib was selected for the LLS’s Therapy Acceleration Program (TAP) which provides additional resources to support the development of therapies for patients with blood cancers. The Company plans to use the funds to conduct certain translational and clinical activities relating to the development of duvelisib for the treatment of PTCL. LLS and Verastem Oncology will share the cost of the development program, portions of which will be conducted in collaboration with Memorial Sloan Kettering Cancer Center, The Dana-Farber Cancer Institute, The Washington University in St. Louis and Stanford University.

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"The selection of duvelisib for a TAP collaboration with the LLS underscores the potential of this innovative, oral monotherapy for patients with relapsed or refractory PTCL," said Robert Forrester, President and Chief Executive Officer of Verastem Oncology. "This collaboration provides important funding to accelerate the advancement of duvelisib as a potential new treatment for patients battling PTCL, either as a monotherapy or in combination with other anti-cancer agents. We look forward to collaborating with the LLS team on the exciting work ahead in order to advance duvelisib through the clinic and ultimately to the patients and families suffering from this devastating cancer."

Duvelisib is an oral inhibitor of phosphoinositide 3-kinase (PI3K), and the first approved dual inhibitor of PI3K-delta and PI3K-gamma, that has demonstrated clinical activity in a Phase 1 clinical trial in 16 heavily pre-treated patients with relapsed or refractory PTCL (Horwitz, et al. Blood. Feb 2018). Results from the study showed duvelisib demonstrated a 50% overall response rate, including 19% complete responses.

Verastem Oncology is currently conducting an open-label, multicenter, Phase 2 clinical trial (the PRIMO study) evaluating the efficacy and safety of duvelisib monotherapy in adult patients with histologically confirmed relapsed or refractory PTCL. This study is expected to enroll approximately 120 patients.

In addition, funds from the TAP will be used to support the expansion of an investigator-sponsored study being conducted by Steven Horwitz, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center and NYC Health + Hospitals/Bellevue. This study is evaluating the combination of duvelisib with romidepsin, an HDAC inhibitor, with a goal to create deeper and more durable responses for patients with relapsed or refractory PTCL. Initial data on the combination as presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2017 Annual Meeting, demonstrated a 64% overall response rate including 34% complete responses.

"The mission of our TAP program is to identify and fund the most promising investigational therapies that have the potential to change the standard of care for patients with blood cancers, with a particular focus on areas of the highest unmet medical need, such as relapsed or refractory PTCL," Lee Greenberger, PhD, Chief Scientific Officer of LLS, commented. "Our partnership with Verastem Oncology is an excellent fit with our key initiative to accelerate development of new and cutting edge therapies like duvelisib, which specifically inhibits only certain PI3K family members, that have shown promising early clinical results in PTCL."

* Duvelisib’s use in patients suffering from PTCL is solely investigational in nature; its use has not been deemed safe and effective by the U.S. Food and Drug Administration.

About the Therapy Acceleration Program

The Leukemia & Lymphoma Society’s Therapy Acceleration Program (TAP) identifies and funds innovative projects related to therapies, supportive care or diagnostics that have the potential to change the standard of care for patients with blood cancer, especially in areas of high unmet medical need. TAP funding assists both clinical investigators and companies in gaining critical clinical proof of concept data that better enables them to obtain the resources they need or a partner to complete the testing, registration and marketing of new treatments, supportive care and diagnostics for leukemia, lymphoma and myeloma. TAP funding is different from the traditional grant at LLS. The TAP review process is separate from the grant process and each approved project is closely monitored by TAP staff. To learn more about how TAP works, please click here.

About Peripheral T-Cell Lymphoma

Peripheral T-cell lymphoma (PTCL) is a rare, aggressive type of non-Hodgkin lymphoma (NHL) that develops in mature white blood cells called "T cells" and "natural killer (NK) cells"1 which circulate with the lymphatic system.2 PTCL accounts for between 10-15% of all non-Hodgkin lymphomas (NHLs) and generally affects people aged 60 years and older.1 Although there are many different subtypes of peripheral T-cell lymphoma, they often present in a similar way, with widespread, enlarged, painless lymph nodes in the neck, armpit or groin.2 There is currently no established standard of care for patients with relapsed or refractory disease.1

On November 7, 2018 Verastem, Inc. (Nasdaq: VSTM) (Verastem Oncology or the Company), focused on developing and commercializing medicines to improve the survival and quality of life of cancer patients, reported financial results for the third quarter ended September 30, 2018 and provided an overview of certain corporate developments (Press release, Verastem, NOV 7, 2018, View Source;p=irol-newsArticle&ID=2375990 [SID1234530916]).

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"During the third quarter, we achieved a remarkable milestone with our lead product COPIKTRA (duvelisib) receiving its first regulatory approval from the U.S. Food and Drug Administration," said Robert Forrester, President and Chief Executive Officer of Verastem Oncology. "We were also delighted to have signed an exclusive licensing agreement with CSPC Pharmaceutical Group Limited for the development and commercialization of COPIKTRA for all oncology indications in China, further extending the global reach of our product. This is an exciting time at Verastem Oncology, and we believe this is just the beginning for both COPIKTRA and the Company. It is our goal to unlock the potential of PI3K inhibition, initially as a monotherapy, and through novel combinations to potentially expand its use to broader hematologic and solid tumors."

"The COPIKTRA launch is well underway and proceeding on track," said Joseph Lobacki, Executive Vice President and Chief Commercial Officer of Verastem Oncology. "We had the necessary staffing in place and were ready to distribute COPIKTRA on the day of approval. Our commercial field force and medical affairs teams are engaging with physicians, and our contracted specialty pharmacy partners are receiving prescriptions. We are thrilled that within six weeks of the approval date, COPIKTRA has been included in the NCCN guidelines and we’ve secured reimbursement coverage, including the top national plans, for 72% of the U.S. Pharmacy lives. This is an exciting time for Verastem Oncology, and I am proud of the team’s diligent efforts and early progress in the launch."

Third Quarter 2018 and Recent Highlights:

COPIKTRA (duvelisib)

COPIKTRA (duvelisib) Capsules Approved by the FDA – On September 24, 2018, the U.S. Food and Drug Administration (FDA) approved COPIKTRA, an oral inhibitor of phosphoinositide 3-kinase (PI3K), and the first approved dual inhibitor of PI3K-delta and PI3K-gamma. COPIKTRA was approved for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies. COPIKTRA also received accelerated approval for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. The indication in FL is approved under accelerated approval based on overall response rate. Continued approval for this indication is contingent upon verification and description of clinical benefit in confirmatory trials. The commercial launch of COPIKTRA is ongoing.
COPIKTRA Added to NCCN Guidelines for CLL/SLL and FL – In early October 2018, following its approval by the FDA, the National Comprehensive Cancer Network (NCCN) added COPIKTRA to the Clinical Practice Guidelines in Oncology (NCCN Guidelines). Physicians use the NCCN Guidelines as the standard resource for determining the best course of treatment for patients, and the Company believes these updated guidelines will increase awareness for COPIKTRA and help health care providers make informed decisions for patients battling these difficult to treat advanced cancers.
Phase 3 DUO Study Results Published in the Journal BLOOD – In early October 2018, the results of the randomized, multicenter, open-label Phase 3 DUO study (NCT02004522), which evaluated COPIKTRA versus ofatumumab in patients with relapsed or refractory CLL/SLL, were published online in the peer-reviewed journal Blood. The full manuscript titled "The phase 3 DUO trial: duvelisib versus ofatumumab in relapsed and refractory CLL/SLL," is available at www.bloodjournal.org.
Investigator-Sponsored Study Initiated Evaluating COPIKTRA in Combination with Venetoclax – In early September 2018, the first patient was dosed in a multicenter Phase 1/2 clinical trial investigating COPIKTRA in combination with venetoclax, an oral selective inhibitor of BCL-2, in patients with relapsed or refractory CLL/SLL. Preclinical data support this combination, as COPIKTRA has been shown to upregulate BCL-2 transcript and protein expression levels and potentially enhance the ability of venetoclax to induce apoptosis in ex vivo human CLL cells. The primary objectives of the Phase 1 portion of the trial are to determine the maximum tolerated dose and the recommended Phase 2 dose of venetoclax for this combination regimen. The trial is being led by Matthew Davids, M.D., MMSc, Assistant Professor of Medicine, Harvard Medical School, and Associate Director, Center for Chronic Lymphocytic Leukemia, Dana-Farber Cancer Institute.
Eight Abstracts Selected for Presentation at the Upcoming American Society of Hematology (ASH) (Free ASH Whitepaper) 2018 Annual Meeting (ASH 2018) – In November 2018, the Company announced that eight abstracts were selected for presentation, including one oral presentation, at ASH (Free ASH Whitepaper) 2018 which is being held December 1-4, 2018 in San Diego, CA. The oral presentation will highlight data from the Phase 1 study evaluating COPIKTRA in combination with romidepsin in relapsed or refractory peripheral T-cell lymphoma. Additional poster presentations will showcase preclinical and clinical data reinforcing the potential of COPIKTRA.
Corporate and Financial

Signed Exclusive License Agreement with CSPC Pharmaceutical Group Limited (CSPC) for the Development and Commercialization of Duvelisib in China – In September 2018, Verastem Oncology announced its entry into an exclusive license agreement with CSPC to develop and commercialize COPIKTRA in China, Hong Kong, Macau and Taiwan (collectively, the CSPC Territory) for all oncology indications. Under the terms of the agreement, Verastem Oncology is to receive an upfront payment of $15.0 million and is entitled to receive aggregate payments of up to $160.0 million if certain development, regulatory and commercial milestones are successfully achieved, plus double-digit royalties on net sales of products containing duvelisib in the CSPC Territory. CSPC will receive exclusive rights to develop and commercialize COPIKTRA and hold the marketing authorization and product license for COPIKTRA in the CSPC Territory. Additionally, CSPC will have the right to collaborate with Verastem Oncology on certain global development and clinical trial activities and will share pro-rata in the cost of studies that they elect to participate in. CSPC is a leading pharmaceutical group in China. CSPC has been listed on the Main Board of the Hong Kong Stock Exchange since 1994 and is currently a constituent stock of the Hang Seng Index. CSPC is a leading developer and manufacturer of innovative and generic drugs in China.
Collaboration with The Leukemia & Lymphoma Society for Development of Duvelisib in Peripheral T-Cell Lymphoma – Verastem Oncology’s duvelisib was selected for The Leukemia & Lymphoma Society’s (LLS) Therapy Acceleration Program (TAP) which provides additional resources to support the development of therapies for patients with blood cancers. The Company plans to use the TAP funds to conduct certain translational and clinical activities relating to the development of duvelisib for the treatment of Peripheral T-Cell Lymphoma (PTCL). LLS and Verastem Oncology will share the cost of the PTCL development program, portions of which will be conducted in collaboration with Memorial Sloan Kettering Cancer Center, The Dana-Farber Cancer Institute, The Washington University in St. Louis and Stanford University.
Sale of Convertible Senior Notes for Gross Proceeds of $150 Million – In October 2018, the Company completed an offering of 5.00% convertible senior notes due 2048 through a registered direct offering. The Company received net proceeds of $145.1 million, after transaction fees and expenses.
Robert E. Gagnon Appointed Chief Financial Officer – In August 2018, Mr. Gagnon was appointed Chief Financial Officer. He comes to Verastem Oncology from Harvard Bioscience, Inc., where he served as Chief Financial Officer. Prior to Harvard Bioscience, he served as Executive Vice President, Chief Financial Officer and Treasurer at Clean Harbors, Inc., as well as Chief Accounting Officer and Controller at Biogen Idec, Inc. Earlier, he worked in a variety of senior positions at Deloitte & Touche, LLP, and Price Waterhouse Coopers, LLP. Mr. Gagnon holds an M.B.A. from the MIT Sloan School of Management and a Bachelor of Arts degree in accounting from Bentley College. His prior experience heading global finance operations, and his overall business acumen, will be a great asset to the Company as it executes on its growth strategy.
Gina Consylman Appointed to Board of Directors – In October 2018, Ms. Consylman was appointed to the Company’s Board of Directors (the Board) and will serve as Chair of the Board’s Audit Committee. Ms. Consylman replaces Louise Phanstiel who left the Board to pursue other professional opportunities. Ms. Consylman currently serves as Senior Vice President and Chief Financial Officer of Ironwood Pharmaceuticals, Inc., a commercial biotech company, where she oversees the finance, planning, accounting, tax, treasury and insurance functions. Prior to joining Ironwood, she held various senior level accounting and corporate controller positions at Analogic Corporation, Biogen Inc., and Varian Semiconductor Equipment Associates, Inc. Ms. Consylman holds a Bachelor of Science degree in accounting from Johnson & Wales University, a Master of Science degree in taxation from Bentley University and is a Certified Public Accountant.
Hagop Youssoufian, MSc, M.D., Appointed Head of Medical Strategy – In October 2018, the Company announced that Dr. Youssoufian would transition to Head of Medical Strategy from his prior role as Head of Hematology and Oncology Development. Dr. Youssoufian will be taking over responsibilities from Diep Le, M.D., Ph.D., who stepped down as Chief Medical Officer.
Third Quarter 2018 Financial Results

License revenue for the three months ended September 30, 2018 (2018 Quarter) was $15.0 million and was related to an upfront payment pursuant to the license and collaboration agreement executed between Verastem Oncology and CSPC in September 2018. Verastem Oncology had no license revenue during the three months ended September 30, 2017 (2017 Quarter).

Verastem Oncology began commercial sales of COPIKTRA within the United States in September 2018, following receipt of FDA marketing approval on September 24, 2018. For the 2018 Quarter, the Company recorded approximately $508,000 of net product revenue. Verastem Oncology had no product revenue during the 2017 Quarter.

Costs of revenues, excluding amortization of acquired intangible assets (cost of revenues) of approximately $49,000 for the 2018 Quarter, consisted of costs associated with the manufacturing of COPIKTRA, royalties owed to Infinity Pharmaceuticals, Inc. (Infinity) on such sales, and certain period costs. Verastem Oncology expensed the manufacturing costs of COPIKTRA as operating expenses in the periods prior to July 1, 2018. Verastem Oncology had no cost of revenues during the 2017 Quarter.

Research and development expense for the 2018 Quarter was $11.6 million compared to $17.7 million for the 2017 Quarter. The $6.1 million decrease from the 2017 Quarter to the 2018 Quarter was primarily related to a decrease of $6.0 million in license fees related to a one-time milestone payment pursuant to the Infinity license agreement that was recognized in the 2017 Quarter and a decrease of $1.2 million in consulting fees. These decreases were offset by an increase of $1.1 million in personnel related costs, including non-cash stock-based compensation.

Selling, general and administrative expense for the 2018 Quarter was $25.4 million compared to $5.4 million for the 2017 Quarter. The increase of $20.0 million from the 2017 Quarter to the 2018 Quarter primarily resulted from an increase in personnel related costs, including non-cash stock-based compensation, of $9.7 million, primarily related to the hiring and staffing of Verastem Oncology’s sales and commercial teams, an increase in consulting and professional fees of $9.1 million, primarily related to the support of commercial launch preparation activities, and travel and other costs of $1.2 million.

Amortization of acquired intangible assets for the 2018 Quarter of approximately $31,000 was related to the COPIKTRA finite-lived intangible asset which Verastem Oncology recognized and began amortizing in September 2018. There was no amortization of acquired intangible assets in the 2017 Quarter.

Net loss for the 2018 Quarter was $21.7 million, or $0.29 per share, as compared to a net loss of $23.1 million, or $0.61 per share, for 2017 Quarter.

As of September 30, 2018, Verastem Oncology had cash, cash equivalents and investments of $145.6 million compared to $86.7 million of cash, cash equivalents and investments as of December 31, 2017. Cash, cash equivalents and investments for the 2018 Quarter does not include the $145.1 million in net proceeds from the registered direct offering of convertible notes in October 2018.

The number of outstanding common shares as of September 30, 2018 was 73,703,423.

Indications and Usage

Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

COPIKTRA is indicated for the treatment of adult patients with relapsed or refractory CLL or SLL after at least two prior therapies.

Follicular Lymphoma (FL)*

COPIKTRA is indicated for the treatment of adult patients with relapsed or refractory FL after at least two prior systemic therapies.

*This indication is approved under accelerated approval based on overall response rate (ORR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

COPIKTRA Clinical Trials

Efficacy in Relapsed or Refractory CLL/SLL

A randomized, multicenter, open-label trial (DUO; NCT02004522) compared COPIKTRA versus ofatumumab in 319 adult patients with CLL (N = 312) or SLL (N = 7) after at least one prior therapy. The study randomized patients with a 1:1 ratio to receive either COPIKTRA 25mg BID until disease progression or unacceptable toxicity, or ofatumumab for 7 cycles.

The approval of COPIKTRA was based on efficacy and safety analysis of patients with at least 2 prior lines of therapy, where the benefit:risk appeared greater in this more heavily pretreated population compared to the overall trial population.

In this subset (95 randomized to COPIKTRA, 101 to ofatumumab), the median patient age was 69 years (range: 40 to 90 years), 59% were male, and 88% had an ECOG performance status of 0 or 1. Forty-six percent received 2 prior lines of therapy, and 54% received 3 or more prior lines. At baseline, 52% of patients had at least one tumor ≥ 5 cm, and 22% of patients had a documented 17p deletion.

During randomized treatment, the median duration of exposure to COPIKTRA was 13 months (range: 0.2 to 37), with 80% of patients receiving at least 6 months and 52% receiving at least 12 months of COPIKTRA. The median duration of exposure to ofatumumab was 5 months (range: < 0.1 to 6).

Efficacy in Relapsed or Refractory FL

Efficacy of COPIKTRA in patients with previously treated FL is based on a single-arm, multicenter trial (DYNAMO; NCT01882803).

In DYNAMO, COPIKTRA 25 mg BID was administered in patients with FL (N = 83) who were refractory to rituximab and to either chemotherapy or radioimmunotherapy. Refractory disease was defined as less than a partial remission or relapse within 6 months after the last dose. The trial excluded patients with Grade 3b FL, large cell transformation, prior allogeneic transplant, and prior exposure to a PI3K inhibitor or to a Bruton’s tyrosine kinase inhibitor.

The median age was 64 years (range: 30 to 82 years), 68% were male, and 37% had bulky disease assessed at baseline (target lesion ≥ 5 cm). Patients had a median of 3 prior lines of therapy (range: 1 to 10), with 94% being refractory to their last therapy and 81% being refractory to 2 or more prior lines of therapy. Most patients (93%) had an ECOG performance status of 0 or 1.

The median duration of exposure to COPIKTRA was 5 months (range: 0.4 to 24), with 41% of patients receiving at least 6 months and 10% receiving at least 12 months of COPIKTRA.

Important Safety Information

WARNING: FATAL AND SERIOUS TOXICITIES: INFECTIONS, DIARRHEA OR COLITIS, CUTANEOUS REACTIONS, and PNEUMONITIS

See full prescribing information for complete boxed warning

Fatal and/or serious infections occurred in 31% of COPIKTRA-treated patients. Monitor for signs and symptoms of infection. Withhold COPIKTRA if infection is suspected.
Fatal and/or serious diarrhea or colitis occurred in 18% of COPIKTRA-treated patients. Monitor for the development of severe diarrhea or colitis. Withhold COPIKTRA.
Fatal and/or serious cutaneous reactions occurred in 5% of COPIKTRA-treated patients. Withhold COPIKTRA.
Fatal and/or serious pneumonitis occurred in 5% of COPIKTRA-treated patients. Monitor for pulmonary symptoms and interstitial infiltrates. Withhold COPIKTRA.
WARNINGS AND PRECAUTIONS

Infections: Serious, including fatal (18/442; 4%), infections occurred in 31% of patients receiving COPIKTRA 25 mg BID (N=442). The most common serious infections were pneumonia, sepsis, and lower respiratory infections. Median time to onset of any grade infection was 3 months (range: 1 day to 32 months), with 75% of cases occurring within 6 months. Treat infections prior to initiation of COPIKTRA. Advise patients to report new or worsening signs and symptoms of infection. For grade 3 or higher infection, withhold COPIKTRA until infection has resolved. Resume COPIKTRA at the same or reduced dose.

Serious, including fatal, Pneumocystis jirovecii pneumonia (PJP) occurred in 1% of patients taking COPIKTRA. Provide prophylaxis for PJP during treatment with COPIKTRA and following completion of treatment with COPIKTRA until the absolute CD4+ T cell count is greater than 200 cells/μL. Withhold COPIKTRA in patients with suspected PJP of any grade, and permanently discontinue if PJP is confirmed.

Cytomegalovirus (CMV) reactivation/infection occurred in 1% of patients taking COPIKTRA. Consider prophylactic antivirals during COPIKTRA treatment to prevent CMV infection including CMV reactivation. For clinical CMV infection or viremia, withhold COPIKTRA until infection or viremia resolves. If COPIKTRA is resumed, administer the same or reduced dose and monitor patients for CMV reactivation by PCR or antigen test at least monthly.

Diarrhea or Colitis: Serious, including fatal (1/442; <1%), diarrhea or colitis occurred in 18% of patients receiving COPIKTRA 25 mg BID (N=442). Median time to onset of any grade diarrhea or colitis was 4 months (range: 1 day to 33 months), with 75% of cases occurring by 8 months. The median event duration was 0.5 months (range: 1 day to 29 months; 75th percentile: 1 month).

Advise patients to report any new or worsening diarrhea. For patients presenting with mild or moderate diarrhea (Grade 1-2) (i.e., up to 6 stools per day over baseline) or asymptomatic (Grade 1) colitis, initiate supportive care with antidiarrheal agents, continue COPIKTRA at the current dose, and monitor the patient at least weekly until the event resolves. If the diarrhea is unresponsive to antidiarrheal therapy, withhold COPIKTRA and initiate supportive therapy with enteric acting steroids (e.g., budesonide). Monitor the patient at least weekly. Upon resolution of the diarrhea, consider restarting COPIKTRA at a reduced dose.

For patients presenting with abdominal pain, stool with mucus or blood, change in bowel habits, peritoneal signs, or with severe diarrhea (Grade 3) (i.e., > 6 stools per day over baseline), withhold COPIKTRA and initiate supportive therapy with enteric acting steroids (e.g., budesonide) or systemic steroids. A diagnostic work-up to determine etiology, including colonoscopy, should be performed. Monitor at least weekly. Upon resolution of the diarrhea or colitis, restart COPIKTRA at a reduced dose. For recurrent Grade 3 diarrhea or recurrent colitis of any grade, discontinue COPIKTRA. Discontinue COPIKTRA for life-threatening diarrhea or colitis.

Cutaneous Reactions: Serious, including fatal (2/442; <1%), cutaneous reactions occurred in 5% of patients receiving COPIKTRA 25 mg BID (N=442). Fatal cases included drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN). Median time to onset of any grade cutaneous reaction was 3 months (range: 1 day to 29 months, 75th percentile: 6 months) with a median event duration of 1 month (range: 1 day to 37 months, 75th percentile: 2 months).

Presenting features for the serious events were primarily described as pruritic, erythematous, or maculo-papular. Less common presenting features include exanthem, desquamation, erythroderma, skin exfoliation, keratinocyte necrosis, and papular rash. Advise patients to report new or worsening cutaneous reactions. Review all concomitant medications and discontinue any medications potentially contributing to the event. For patients presenting with mild or moderate (Grade 1-2) cutaneous reactions, continue COPIKTRA at the current dose, initiate supportive care with emollients, antihistamines (for pruritus), or topical steroids, and monitor the patient closely. Withhold COPIKTRA for severe (Grade 3) cutaneous reaction until resolution. Initiate supportive care with steroids (topical or systemic) or antihistamines (for pruritus). Monitor at least weekly until resolved. Upon resolution of the event, restart COPIKTRA at a reduced dose. Discontinue COPIKTRA if severe cutaneous reaction does not improve, worsens, or recurs. For life-threatening cutaneous reactions, discontinue COPIKTRA. In patients with SJS, TEN, or DRESS of any grade, discontinue COPIKTRA.

Pneumonitis: Serious, including fatal (1/442; <1%), pneumonitis without an apparent infectious cause occurred in 5% of patients receiving COPIKTRA 25 mg BID (N=442). Median time to onset of any grade pneumonitis was 4 months (range: 9 days to 27 months), with 75% of cases occurring within 9 months. The median event duration was 1 month, with 75% of cases resolving by 2 months.

Withhold COPIKTRA in patients with new or progressive pulmonary signs and symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on a radiologic exam, or a decline by more than 5% in oxygen saturation, and evaluate for etiology. If the pneumonitis is infectious, patients may be restarted on COPIKTRA at the previous dose once the infection, pulmonary signs and symptoms resolve. For moderate non-infectious pneumonitis (Grade 2), treat with systemic corticosteroids and resume COPIKTRA at a reduced dose upon resolution. If non-infectious pneumonitis recurs or does not respond to steroid therapy, discontinue COPIKTRA. For severe or life-threatening non-infectious pneumonitis, discontinue COPIKTRA and treat with systemic steroids.

Hepatotoxicity: Grade 3 and 4 ALT and/or AST elevation developed in 8% and 2%, respectively, of patients receiving COPIKTRA 25 mg BID (N=442). Two percent of patients had both an ALT or AST > 3 X ULN and total bilirubin > 2 X ULN. Median time to onset of any grade transaminase elevation was 2 months (range: 3 days to 26 months), with a median event duration of 1 month (range: 1 day to 16 months).

Monitor hepatic function during treatment with COPIKTRA. For Grade 2 ALT/AST elevation (> 3 to 5 X ULN), maintain COPIKTRA dose and monitor at least weekly until return to < 3 X ULN. For Grade 3 ALT/AST elevation (> 5 to 20 X ULN), withhold COPIKTRA and monitor at least weekly until return to < 3 X ULN. Resume COPIKTRA at the same dose (first occurrence) or at a reduced dose for subsequent occurrences. For grade 4 ALT/AST elevation (> 20 X ULN), discontinue COPIKTRA.

Neutropenia: Grade 3 or 4 neutropenia occurred in 42% of patients receiving COPIKTRA 25 mg BID (N=442), with Grade 4 neutropenia occurring in 24% of all patients. Median time to onset of grade ≥3 neutropenia was 2 months (range: 3 days to 31 months), with 75% of cases occurring within 4 months.

Monitor neutrophil counts at least every 2 weeks for the first 2 months of COPIKTRA therapy, and at least weekly in patients with neutrophil counts < 1.0 Gi/L (Grade 3-4). Withhold COPIKTRA in patients presenting with neutrophil counts < 0.5 Gi/L (Grade 4). Monitor until ANC is > 0.5 Gi/L, then resume COPIKTRA at same dose for the first occurrence or at a reduced dose for subsequent occurrences.

Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, COPIKTRA can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Conduct pregnancy testing before initiating COPIKTRA treatment. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose.

ADVERSE REACTIONS

B-cell Malignancies Summary

Fatal adverse reactions within 30 days of the last dose occurred in 8% (36/442) of patients treated with COPIKTRA 25 mg BID. Serious adverse reactions were reported in 289 patients (65%). The most frequent serious adverse reactions that occurred were infection (31%), diarrhea or colitis (18%), pneumonia (17%), rash (5%), and pneumonitis (5%).

Adverse reactions resulted in treatment discontinuation in 156 patients (35%) most often due to diarrhea or colitis, infection, and rash. COPIKTRA was dose reduced in 104 patients (24%) due to adverse reactions, most often due to diarrhea or colitis and transaminase elevation. The most common adverse reactions (reported in ≥ 20% of patients) were diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain and anemia.

CLL/SLL: Fatal adverse reactions within 30 days of the last dose occurred in 12% (19/158) of patients treated with COPIKTRA and in 4% (7/155) of patients treated with ofatumumab. Serious adverse reactions were reported in 73% (115/158) of patients treated with COPIKTRA and most often involved infection (38%; 60/158) and diarrhea or colitis (23%; 36/158). COPIKTRA was discontinued in 57 patients (36%), most often due to diarrhea or colitis, infection, and rash. COPIKTRA was dose reduced in 46 patients (29%) due to adverse reactions, most often due to diarrhea or colitis and rash. The most common adverse reactions with COPIKTRA (reported in ≥20% of patients) were diarrhea or colitis, neutropenia, pyrexia, upper respiratory tract infection, pneumonia, rash, fatigue, nausea, anemia and cough.

FL: Serious adverse reactions were reported in 58% of patients and most often involved diarrhea or colitis, pneumonia, renal insufficiency, rash, and sepsis. The most common adverse reactions (≥20% of patients) were diarrhea or colitis, nausea, fatigue, musculoskeletal pain, rash, neutropenia, cough, anemia, pyrexia, headache, mucositis, abdominal pain, vomiting, transaminase elevation, and thrombocytopenia. Adverse reactions resulted in COPIKTRA discontinuation in 29% of patients, most often due to diarrhea or colitis and rash. COPIKTRA was dose reduced in 23% due to adverse reactions, most often due to transaminase elevation, diarrhea or colitis, lipase increased and infection.

DRUG INTERACTIONS

CYP3A Inducers: Coadministration with a strong CYP3A inducer may reduce COPIKTRA efficacy. Avoid coadministration with strong CYP3A4 inducers.
CYP3A Inhibitors: Coadministration with a strong CYP3A inhibitor may increase the risk of COPIKTRA toxicities. Reduce COPIKTRA dose to 15 mg BID when coadministered with a strong CYP3A4 inhibitor.
CYP3A Substrates: Coadministration of COPIKTRA with sensitive CYP3A4 substrates may increase the risk of toxicities of these drugs. Consider reducing the dose of the sensitive CYP3A4 substrate and monitor for signs of toxicities of the coadministered sensitive CYP3A substrate.
About Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are cancers that affect lymphocytes and are essentially the same disease, with the only difference being the location where the cancer primarily occurs. When most of the cancer cells are located in the bloodstream and the bone marrow, the disease is referred to as CLL, although the lymph nodes and spleen are often involved. When the cancer cells are located mostly in the lymph nodes, the disease is called SLL. The symptoms of CLL/SLL include a tender, swollen abdomen and feeling full even after eating only a small amount. Other symptoms can include fatigue, shortness of breath, anemia, bruising easily, night sweats, weight loss, and frequent infections. However, many patients with CLL/SLL will live for years without symptoms. There are approximately 200,000 patients in the US affected by CLL/SLL with nearly 20,000 new diagnoses this year alone. While there are therapies currently available, real-world data reveals that a significant number of patients either relapse following treatment, become refractory to current agents, or are unable to tolerate treatment, representing a significant medical need. The potential of additional oral agents, particularly as a monotherapy that can be used in the general community physician’s armamentarium, may hold significant value in the treatment of patients with CLL/SLL.

About Follicular Lymphoma

Follicular lymphoma (FL) is typically a slow-growing or indolent form of non-Hodgkin lymphoma (NHL) that arises from B-lymphocytes, making it a B-cell lymphoma. This lymphoma subtype accounts for 20 to 30 percent of all NHL cases, with more than 140,000 people in the US with FL and more than 13,000 newly diagnosed patients this year. Common symptoms of FL include enlargement of the lymph nodes in the neck, underarms, abdomen, or groin, as well as fatigue, shortness of breath, night sweats, and weight loss. Often, patients with FL have no obvious symptoms of the disease at diagnosis. Follicular lymphoma is usually not considered to be curable, but more of a chronic disease, with patients living for many years with this form of lymphoma. The potential of additional oral agents, particularly as a monotherapy that can be used in the general community physician’s armamentarium, may hold significant value in the treatment of patients with FL.

About COPIKTRA (duvelisib)

COPIKTRA is an oral inhibitor of phosphoinositide 3-kinase (PI3K), and the first approved dual inhibitor of PI3K-delta and PI3K-gamma, two enzymes known to help support the growth and survival of malignant B-cells. PI3K signaling may lead to the proliferation of malignant B-cells and is thought to play a role in the formation and maintenance of the supportive tumor microenvironment.2,3,4 COPIKTRA is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies and relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. COPIKTRA is also being developed by Verastem Oncology for the treatment of peripheral T-cell lymphoma (PTCL), for which it has received Fast Track status, and is being investigated in combination with other agents through investigator-sponsored studies.5 For more information on COPIKTRA, please visit www.COPIKTRA.com. Information about duvelisib clinical trials can be found on www.clinicaltrials.gov.

On November 7, 2018 Jazz Pharmaceuticals plc (Nasdaq: JAZZ) reported that the company will be webcasting its corporate presentations at four upcoming investor conferences (Press release, Jazz Pharmaceuticals, NOV 7, 2018, View Source;p=RssLanding&cat=news&id=2375980 [SID1234530973]).

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Stifel Healthcare Conference in New York, NY on Wednesday, November 14, 2018 at 9:30 a.m. EST / 2:30 p.m. GMT. Bruce Cozadd, chairman and chief executive officer, will provide an overview of the company and a business and financial update.
Jefferies London Healthcare Conference in London on Wednesday, November 14, 2018 at 9:20 a.m. GMT / 4:20 a.m. EST. Iain McGill, senior vice president, Jazz Pharmaceuticals Europe and rest of world, will provide an overview of the company and a business and financial update.
Evercore ISI Healthcare Conference in Boston, MA on Tuesday, November 27, 2018 at 8:00 a.m. EST / 1:00 p.m. GMT. Matt Young, executive vice president and chief financial officer, will provide an overview of the company and a business and financial update.
Piper Jaffray 30th Annual Healthcare Conference in New York, NY on Wednesday, November 28, 2018 at 11:00 a.m. EST / 4:00 p.m. GMT. Matt Young, executive vice president and chief financial officer, will provide an overview of the company and a business and financial update.
A live audio webcast of each presentation may be accessed from the Investors section of the Jazz Pharmaceuticals website at View Source Please connect to the website prior to the start of the presentation to ensure adequate time for any software downloads that may be necessary to listen to the webcast.

An archive of the webcast will be available for at least one week following the presentation on the Investors section of the company’s website at View Source

On November 7, 2018 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a clinical stage targeted oncology company, reported that it will present at the 27th Annual Credit Suisse Healthcare Conference in Scottsdale, Arizona on Wednesday, November 14th at 1:40 p.m. MST/ 12:40 p.m. PST. Charles M. Baum, M.D., Ph.D., President and Chief Executive Officer will present a corporate overview at the conference (Press release, Mirati, NOV 7, 2018, View Source [SID1234530832]).

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The presentation will be webcast and made available through the "Investors" section of www.mirati.com, and replays will be made available for 90 days following the events.