On September 10, 2017 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported updated results from the phase 3 KEYNOTE-045 trial evaluating KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in patients with locally advanced or metastatic urothelial carcinoma (a type of bladder cancer) with disease progression on or after platinum-containing chemotherapy (post-platinum failure) (Press release, Merck & Co, SEP 10, 2017, View Source [SID1234520454]). Updated data show that with median follow-up of 22.5 months, KEYTRUDA continues to demonstrate an overall survival (OS) benefit over investigator’s choice of paclitaxel, docetaxel or vinflunine as a second-line therapy, post-platinum failure, regardless of PD-L1 expression (HR, 0.70 [95% CI, 0.57-0.86], p=0.0003). Findings are being presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress in Madrid, Spain, on Sunday, Sept. 10 (poster from 2:45 – 4:15 p.m. CEST; discussion: 3:15 – 3:45 p.m. CEST) (Location: Cordoba Auditorium) (Abstract #LBA37_PR).

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"These data at ESMO (Free ESMO Whitepaper) provide further insights and greater understanding in using KEYTRUDA in select second-line advanced urothelial carcinoma treatment settings, and importantly, demonstrate an overall survival advantage with KEYTRUDA compared to standard chemotherapy agents vinflunine, docetaxel and paclitaxel, which are common in clinical practice for the treatment of this disease," said professor Ronald de Wit, M.D., Ph.D., group leader experimental systemic therapy of urogenital cancers, Erasmus MC Cancer Institute. "For previously treated patients, post-platinum failure, these findings are also encouraging as they show an overall survival benefit regardless of PD-L1 status or choice of commonly used chemotherapy."

"With nearly two years follow-up, these updated phase 3 data continue to show an overall survival benefit with KEYTRUDA in patients with advanced urothelial carcinoma whose cancer has progressed after receiving previous treatment for their disease," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "We are pleased that, with the approval in the U.S. and recent approval of KEYTRUDA in the EU, more patients now have an important treatment option available to them."

Currently, Merck also has the largest immuno-oncology clinical development program in bladder cancer, with 29 trials underway involving KEYTRUDA (pembrolizumab) as monotherapy and in combination, including four registration-enabling studies.

Data in Second-Line Post-Platinum Failure Patients, KEYNOTE-045

KEYNOTE-045 is an open-label, randomized phase 3 trial of KEYTRUDA compared to investigator’s choice of chemotherapy (paclitaxel, docetaxel or vinflunine) in patients with locally advanced or metastatic urothelial cancer with disease progression on or after platinum-containing chemotherapy. The trial was prematurely stopped after a pre-planned interim analysis demonstrated significantly longer OS with KEYTRUDA compared to chemotherapy (median follow-up, 14.1 months). Efficacy was assessed in the overall study population (n=542), as well as in patients with PD-L1 expression – defined as a combined positive score of 10 or more (CPS ≥10) (KEYTRUDA arm: n=74/270; chemotherapy arm; n=90/272) (additional details on the trial design are provided below).

Data presented at ESMO (Free ESMO Whitepaper) (Abstract #LBA37_PR) include four months of additional follow-up (data cut-off, May 19, 2017; median follow up, 22.5 months) and continue to show a superior OS advantage with KEYTRUDA compared to chemotherapy in the second-line setting, regardless of PD-L1 expression. In the overall study population, data show a 30 percent reduction in the risk of death with KEYTRUDA (HR, 0.70 [95% CI, 0.57-0.86], p=0.0003), the median OS was 10.3 months with KEYTRUDA (95% CI, 8.0-12.3) and 7.4 months with chemotherapy (95% CI, 6.3-8.3), and the 18-month OS rate was 33.2 percent with KEYTRUDA compared to 19.7 percent with chemotherapy. Analysis of OS based on PD-L1 expression show a 42 percent reduction in the risk of death with KEYTRUDA (HR, 0.58 [95% CI, 0.39-0.86], p=0.0029) in patients whose tumors expressed PD-L1 (CPS ≥10), the median OS was 8.0 months with KEYTRUDA (95% CI, 5.0-12.3) and 5.2 months with chemotherapy (95% CI, 4.2-7.5), and the 18-month OS rate was 30.0 percent with KEYTRUDA compared to 16.9 percent with chemotherapy.

As previously reported, there was no significant difference in progression-free-survival (PFS) between treatment arms in the overall study population (HR, 0.96 [95% CI, 0.79-1.16], p=0.32). The median PFS was 2.1 months with KEYTRUDA (95% CI, 2.0-2.2) and 3.3 months with chemotherapy (95% CI, 2.4-3.5); the 18-month PFS rate was 15.3 percent with KEYTRUDA (pembrolizumab) compared to 4.8 percent with chemotherapy. In patients whose tumors expressed PD-L1 (CPS ≥10), the median PFS was 2.1 months with KEYTRUDA (95% CI, 1.9-2.1) and 3.2 months with chemotherapy (95% CI, 2.2-3.5); the 18-month PFS rate was 16.3 percent with KEYTRUDA compared to 5.3 percent with chemotherapy (HR, 0.93 [95% CI, 0.65-1.33], p=0.32).

Analyses of the secondary endpoints showed nearly double the overall response rate (ORR) with KEYTRUDA compared to chemotherapy in the overall study population, with an ORR of 21.1 percent in the KEYTRUDA arm (complete response rate (CR) of 7.8 percent and a partial response rate (PR) of 13.3 percent) and 11.0 percent in the chemotherapy arm (CR of 2.9 percent and a PR of 8.1 percent). The median time to response was 2.1 months in both treatment arms; 57.9 percent of responses in the KEYTRUDA arm were ongoing at the time of analysis compared to 20.0 percent in the chemotherapy arm. Median duration of response in patients with partial or complete responses had not yet been reached in the KEYTRUDA arm at the time of analysis (range: 1.6+ to 24.6+) with 67.0 percent of responses ongoing at 12 months (calculated per Kaplan-Meier curve); in the chemotherapy arm, the median duration of response was 4.4 months (range: 1.4+ to 24.0+) with 35.0 percent of responses ongoing at 12 months (calculated per Kaplan-Meier curve).

In patients whose tumors expressed PD-L1, the ORR was 20.3 percent in the KEYTRUDA arm (CR of 6.8 percent and a PR of 13.5 percent) and 6.7 percent in the chemotherapy arm (CR of 2.2 percent and a PR of 4.4 percent). The median time to response was 2.0 months in the KEYTRUDA arm and 2.1 months in the chemotherapy arm; 73.3 percent of responses in the KEYTRUDA arm were ongoing at the time of analysis compared to 33.3 percent in the chemotherapy arm. The median duration of response in patients with partial or complete responses had not yet been reached in the KEYTRUDA arm at the time of analysis (range: 1.6+ to 23.5+) with 77.0 percent of responses ongoing at 12 months (calculated per Kaplan-Meier curve); in the chemotherapy arm, the median duration of response was 4.4 months (range: 1.5+ to 20.8+) with 40.0 percent of responses ongoing at 12 months (calculated per Kaplan-Meier curve).

A second abstract including a subgroup analysis from KEYNOTE-045 (Abstract #851PD) was also accepted as a poster at ESMO (Free ESMO Whitepaper) and provides greater insight into the OS advantage with KEYTRUDA compared to the individual chemotherapy agents. The retrospective analysis showed a 27 percent reduction in the risk of death versus paclitaxel (HR, 0.73 [95% CI, 0.55-0.96]), a 21 percent reduction in the risk of death versus docetaxel (HR, 0.79 [95% CI, 0.59-1.07]), and a 35 percent reduction in the risk of death versus vinflunine (HR, 0.65 [95% CI, 0.49-0.87]). No statistically significant difference in PFS was seen between KEYTRUDA and each chemotherapy agent. Analyses of the secondary endpoints showed an ORR of 11.9 percent, 6.0 percent, and 17.2 percent with paclitaxel, docetaxel, and vinflunine, respectively, compared to 21.1 percent in the KEYTRUDA (pembrolizumab) arm.

The safety profile of KEYTRUDA was consistent with that observed in previously reported studies. Treatment-related adverse events (TRAEs) of any grade occurred in 62.0 percent in the KEYTRUDA arm and 90.6 percent in the chemotherapy arm. Grade 3 or higher TRAEs occurred in 16.5 percent and 50.2 percent of KEYTRUDA and chemotherapy patients, respectively. Immune-mediated adverse events occurred in 19.5 percent of patients in the KEYTRUDA arm and 7.5 percent in the chemotherapy arm. The discontinuation rate due to treatment-related adverse events was 7.1 percent of patients in the KEYTRUDA arm and 12.5 percent of patients in the chemotherapy arm. Deaths due to treatment-related adverse events occurred in four patients treated with KEYTRUDA, one patient treated with paclitaxel, and three patients treated with vinflunine.

About KEYNOTE-045

In KEYNOTE-045, patients were randomized to receive either KEYTRUDA 200 mg every three weeks (n=270) or investigator’s choice of any of the following chemotherapy regimens, all given intravenously, every three weeks (n=272): paclitaxel 175 mg/m2, docetaxel 75 mg/m2, or vinflunine 320 mg/m2. The dual primary endpoints were OS and PFS, as assessed by blinded independent central review (BICR) per RECIST (Response Evaluation Criteria in Solid Tumors) v1.1; key secondary endpoints included ORR, as assessed by BICR per RECIST 1.1, duration of response and safety. Efficacy was assessed in all patients, as well as in patients with PD-L1 expression.

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.

Studies of KEYTRUDA – from the largest immuno-oncology program in the industry with more than 550 trials – include a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand factors that predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including the exploration of several different biomarkers across a broad range of tumors.

KEYTRUDA (pembrolizumab) Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, as a single agent, is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

KEYTRUDA, in combination with pemetrexed and carboplatin, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC. This indication is approved under accelerated approval based on tumor response rate and progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for pemetrexed and carboplatin.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Classical Hodgkin Lymphoma

KEYTRUDA (pembrolizumab) is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is also indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA (pembrolizumab) in pediatric patients with MSI-H central nervous system cancers have not been established.

In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

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

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

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

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

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

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

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

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

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

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

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

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

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after being treated with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after treatment with KEYTRUDA on any trial, 6 patients (26%) developed graft-versus-host-disease (GVHD), one of which was fatal, and 2 patients (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning, one of which was fatal. Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT. Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

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

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

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

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

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

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

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

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

There is limited experience in pediatric patients. Efficacy for pediatric patients was extrapolated from the results in the adult cHL population. In a study of 40 pediatric patients with advanced melanoma, PD-L1–positive advanced, relapsed, or refractory solid tumors or lymphoma, patients were treated with KEYTRUDA (pembrolizumab) for a median of 43 days (range 1-414 days), with 24 patients (60%) receiving treatment for 42 days or more. The safety profile in pediatric patients was similar to that seen in adults treated with KEYTRUDA. Toxicities that occurred at a higher rate (≥15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia (18%).

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.

On September 10, 2017 Idera Pharmaceuticals, Inc. (NASDAQ: IDRA), a clinical-stage biopharmaceutical company developing toll-like receptor and RNA therapeutics for patients with rare cancers and rare diseases, reported final results from the dose-selection phase of an ongoing Phase 1/2 trial investigating IMO-2125, Idera’s intratumorally-delivered Toll-like Receptor (TLR) 9 agonist, in combination with ipilimumab (Yervoy), manufactured by Bristol-Myers Squibb (Press release, Idera Pharmaceuticals, SEP 10, 2017, View Source [SID1234520451]). These data were presented at the 2017 European Society for Medical Oncology Congress (ESMO) (Free ESMO Whitepaper) in Madrid, Spain.

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The IMO-2125-ipilimumab dose-selection phase included 18 patients, all but one of whom had progressed on nivolumab or pembrolizumab. Patients were treated with up to 6 doses of intratumoral IMO-2125 at doses ranging from 4 to 32 mg, along with standard dosing of ipilimumab. No dose-limiting toxicities were seen and the maximum tolerated dose (MTD) was not reached. No previously unreported immune-related toxicities were observed. The 8 mg IMO-2125 dose was selected for further development in combination with ipilimumab based upon acceptable safety, clinical activity, and evidence for target engagement on serial biopsies of the injected tumor and a distant (non-injected) metastasis.

Key Findings

Nine patients were treated at the Recommended Phase 2 Dose (RP2D) of 8 mg IMO-2125 (in combination with ipilimumab)
Confirmed RECIST v1.1 responses (including 1 Complete Response (CR) ≥ 1 year) were observed in 4 of these 9 subjects (44%);
Overall 6 patients out of 9 treated at the RP2D (67%) experienced disease control (CR, PR, or durable SD);
A RECIST v1.1 PR of > 1 year duration is ongoing in a patient treated with IMO-2125 4 mg (in combination with ipilimumab);
IMO-2125 in combination with ipilimumab is tolerable at all dose levels studied
IMO-2125 was safely administered via deep injection (using interventional radiology guidance) in patients lacking superficially accessible disease for injection
Dose escalation with IMO-2125 and pembrolizumab is ongoing; one patient has an ongoing PR by RECIST (v1.1), and;
An abstract highlighting translational findings from the trial has been accepted as an oral presentation for the upcoming Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) meeting in November.
"The majority of patients with solid tumors do not respond to anti-PD-1 therapy and the published response rate to ipilimumab alone in anti-PD-1 refractory melanoma is only10-13%; to be seeing 6 out of 9 patients experiencing clear disease control is extremely exciting," stated Adi Diab, M.D., Lead Trial Investigator, Assistant Professor, Department of Melanoma Medical Oncology, Division of Cancer Medicine, University of Texas, MD Anderson Cancer Center.

"Based on these positive and encouraging response data in anti-PD-1 refractory melanoma, where the greatest need exists, we have expanded the target number of patients in the ongoing Phase 2 expansion, including broadening eligibility to patients who have received prior ipilimumab, including the ipilimumab/PD-1 inhibitor combination," stated Joanna Horobin, M.B., Ch.B., Idera’s Chief Medical Officer. "We plan to start a Phase 3 trial in patients with PD-1 refractory melanoma in the first quarter of 2018. Preparations are well-underway for this global initiative which is addressing a major unmet need in melanoma. We are very encouraged by the enthusiasm of investigators to participate in the Phase 3 study."

A copy of the poster presentation is currently available on Idera’s corporate website at View Source." target="_blank" title="View Source." rel="nofollow">View Source

About the Phase 1/2 trial of IMO-2125 in combination with ipilimumab (NCT02644967)
Study 2125-204 is a Phase 1/2 open-label study of intratumoral IMO-2125 given in combination with either ipilimumab or pembrolizumab to patients with PD-(L)1 refractory melanoma with a planned enrollment of approximately 90 patients. IMO-2125 is given in escalating dosages from 4 to 32 mg combined with either ipilimumab (3 mg/kg i.v. every 3 weeks for 4 doses) or pembrolizumab (2 mg/kg i.v. every 3 weeks). Study endpoints are safety, tumor response, pharmacodynamics, and pharmacokinetics. Serial biopsies of both the injected and a distant tumor are being performed for translational immunologic studies. Preliminary data, presented at SITC (Free SITC Whitepaper) 2016, ASCO (Free ASCO Whitepaper)-SITC 2017, AACR (Free AACR Whitepaper) 2017, and CRI-CIMT-EATI-AACR 2017 are available on Idera’s website (View Source).

About IMO-2125
IMO-2125 is a toll-like receptor (TLR) 9 agonist that received orphan drug designation from the US Food and Drug Administration (FDA) in 2017 for the treatment of melanoma Stages IIb to IV. It signals the immune system to create and activate cancer-fighting cells (T-cells) to target solid tumors in refractory melanoma patients. Currently approved immuno-oncology treatments for patients with metastatic melanoma, specifically check-point inhibitors, work for some but not all, as many patients’ immune response is missing or weak and thus they do not benefit from the checkpoint therapy making them so-called "refractory". The combination of ipilimumab and IMO-2125 appears to activate an immune response in these patients who have exhausted all options. Intratumoral injections with IMO-2125 are designed to selectively enable the T-cells to recognize and attack cancers that remained elusive and unrecognized by the immune system exposed to checkpoint inhibitors alone, while limiting toxicity or impact on healthy cells in the body.

About Metastatic Melanoma
Melanoma is a type of skin cancer that begins in a type of skin cell called melanocytes. As is the case in many forms of cancer, melanoma becomes more difficult to treat once the disease has spread beyond the skin to other parts of the body such as the lymphatic system (metastatic disease). Because melanoma occurs in younger individuals, the years of life lost to melanoma are also disproportionately high when compared with other cancers. Although melanoma is a rare form of skin cancer, it comprises over 75% of skin cancer deaths. The American Cancer Society estimates that there were approximately 76,000 new invasive melanoma cases and 10,000 deaths from the disease in the USA in 2016. Additionally, according to the World Health Organization, about 132,000 new cases of melanoma are diagnosed around the world every year.

On September 10, 2017 MacroGenics, Inc. (NASDAQ:MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, as well as autoimmune disorders and infectious diseases, reported the presentation of clinical data from its Phase 1 study of flotetuzumab in an oral session at the European Society for Medical Oncology Annual Congress, ESMO (Free ESMO Whitepaper) 2017, in Madrid, Spain. Norbert Vey, M.D., Team Leader Translational Medicine — Hematology at Institut Paoli-Calmettes, Marseille, France, presented "Interim Results from a Phase 1 First-in-Human study of flotetuzumab, a CD123 x CD3 bispecific DART molecule, in AML/MDS (Press release, MacroGenics, SEP 10, 2017, View Source [SID1234520448])."

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The ongoing Phase 1, first-in-human, dose-escalation study was designed to determine safety, tolerability, maximum tolerated dose and initial anti-leukemic activity of flotetuzumab in patients with relapsed or refractory acute myeloid leukemia (AML) or intermediate-2/high risk myelodysplastic syndrome (MDS).

Flotetuzumab demonstrated acceptable tolerability in the dose escalation portion of the study. Infusion-related reaction and cytokine release syndrome (CRS) were the most common adverse events observed, with Grade 3 CRS occurring in 6 of 47 patients (12.8%). A two-step, lead-in dose as well as early intervention with anti-cytokine therapy was implemented to limit the severity and incidence of CRS.

Encouraging initial anti-leukemic activity has been observed in patients treated at the threshold flotetuzumab dose of 500ng/kg/day or greater. As of the data cut-off date, of the 14 response-evaluable patients treated at this dose, eight (57%) patients had anti-leukemic activity, with six (43%) of these patients experiencing an objective response. This included four (28%) patients who experienced CR/CRi, with one patient who experienced a molecular CR. In the majority of patients who responded, anti-leukemic activity was observed after a single cycle of therapy.

"MacroGenics is pleased with the encouraging data from this ongoing Phase 1 study of flotetuzumab, our first clinical DART molecule focused on T-cell redirected killing," said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics. "Enrollment of the AML and MDS dose-expansion cohorts at the selected dose and schedule are well under way and we expect to present updated clinical data at an additional scientific conference later this year."

The presentation at ESMO (Free ESMO Whitepaper) Congress 2017 is available for download from the Events & Presentations page on MacroGenics’ website at View Source

About Flotetuzumab

Flotetuzumab (also known as MGD006 and S80880) is a clinical-stage molecule that recognizes both CD123 and CD3. CD123, the Interleukin-3 receptor alpha chain, has been reported to be over-expressed on cancer cells in a wide range of hematological malignancies, including AML and MDS. The primary mechanism of action of flotetuzumab is believed to be its ability to redirect T lymphocytes to kill CD123-expressing cells. To achieve this, the DART molecule combines a portion of an antibody recognizing CD3, an activating molecule expressed by T cells, with an arm that recognizes CD123 on the target cancer cells.

Flotetuzumab is currently being evaluated in the U.S. and Europe in a Phase 1 dose-escalation study designed to assess the safety, tolerability, and initial anti-leukemic activity of the molecule in patients with relapsed/refractory AML or intermediate-2/high risk MDS. MacroGenics retains full development and commercialization rights to flotetuzumab in the U.S., Canada, Mexico, Japan, South Korea and India. Servier participates in the development of flotetuzumab and has rights to this molecule in all other countries. The U.S. Food and Drug Administration has granted orphan drug designation to flotetuzumab for the treatment of AML.

On September 10, 2017 Eli Lilly and Company (NYSE: LLY) reported Phase 3 RANGE data from in the Presidential Symposium (abstract#: LBA4_PR) at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress today (Press release, Eli Lilly, SEP 10, 2017, View Source [SID1234520445]). These are the first detailed results from the global, randomized, double-blinded, placebo-controlled RANGE study of CYRAMZA (ramucirumab), in combination with docetaxel, in patients with advanced or metastatic urothelial carcinoma whose disease progressed on or after platinum-based chemotherapy. The data showed a statistically significant improvement in progression-free survival (PFS) in patients treated with ramucirumab plus docetaxel when compared to those who received placebo plus docetaxel, with a 46 percent prolongation in median PFS. These RANGE data will be published online in The Lancet on Tuesday, September 12, 2017 at 6:30 p.m. EDT.

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RANGE is the first and only Phase 3 study of any therapy to show superior PFS over chemotherapy in a post-platinum setting in urothelial cancer. Also, ramucirumab is the first anti-angiogenic agent to extend PFS in a Phase 3 trial in urothelial cancer. Patients previously treated with a checkpoint inhibitor were allowed to enroll in the RANGE study. PFS is the trial’s primary endpoint, and secondary endpoints include overall survival (OS), objective response rate (ORR), disease control rate (DCR) and patient-reported outcomes (PRO).

"It’s been an exciting and eventful time in urothelial carcinoma medicine research and development over the last several years, going from very few approved therapies to many new treatment options now available this year. However, many patients treated with these new therapies have progressive disease as best response–meaning that their cancer is still growing, spreading or getting worse. This is what is driving the clinical community to continue to investigate additional targets for treatments that can help quickly control disease progression," said Daniel Petrylak, M.D., professor of medical oncology and urology at Yale Cancer Center and principal investigator of the RANGE study. "We are looking at ramucirumab in this way, as RANGE is the first Phase 3 study to show the benefit of targeting angiogenesis in urothelial cancer and the first therapy to show superior progression-free survival over chemotherapy in a post-platinum setting. This benefit also confirms the efficacy seen in the Phase 2 study."

Patients treated on the ramucirumab-plus-docetaxel arm (n=263) achieved a median PFS of 4.1 months compared to 2.8 months for patients on the placebo-plus-docetaxel arm (n=267). The PFS hazard ratio (HR) was 0.757 (95% CI, 0.607-0.943, p=0.0118), which corresponds to a 24 percent reduction in the rate of disease progression or death. These investigator-assessed PFS results were confirmed by a blinded central radiographic review (HR, 0.672; 95% CI, 0.536-0.842; p=0.0005). In addition, PFS results were consistent across pre-specified subgroups.

Importantly, the PFS HR was consistent across three subgroups defined by poor prognostic factors (HR, 0.694-0.764)–patients with ECOG 1 performance status, liver metastases or a short interval of < 3 months since prior therapy. The majority of patients (415 of 530) had at least one risk factor–44 percent had two or more.

An analysis of the PFS data in the first 437 patients of the intent-to-treat (ITT) population showed that the ramucirumab-plus-docetaxel arm had an ORR of 24.5 percent (95% CI, 18.8-30.3) compared to 14.0 percent in the placebo-plus-docetaxel arm (95% CI, 9.4-18.6). Given the gated statistical design of the protocol, statistical analysis for significance of ORR will be assessed following the OS endpoint (at the time of the primary PFS analysis, OS data were immature). Although the number of enrolled patients that had received a prior immune checkpoint inhibitor was relatively small–as this trial was initiated in 2015 when several other such trials were ongoing and no approved agents were available–the ORR at this PFS readout in those patients was consistent with the ITT population. Disease control in the ITT population occurred in 63.4 percent (95% CI, 57.0-69.8) of patients in the ramucirumab-plus-docetaxel arm and 56.1 percent (95% CI, 49.6-62.7) in the placebo-plus-docetaxel arm.

The PFS and ORR demonstrated at this RANGE data readout confirm previously reported results from a Phase 2 study evaluating the combination of ramucirumab and docetaxel in the same patient population.1

The safety profile observed in the RANGE study at this data readout was consistent with what has previously been observed for ramucirumab. Grade ≥3 adverse events were reported at a similar frequency in both arms. The grade ≥3 adverse events occurring at a rate of five percent or greater, and that were higher on the ramucirumab-plus-docetaxel arm compared to the placebo-plus-docetaxel arm, were neutropenia (15.1% vs. 13.6%), febrile neutropenia (9.7% vs. 6.4%), and hypertension (5.8% vs. 1.9%). Grade ≥3 cardiovascular events, including arterial or venous thromboembolism and congestive heart failure, were rare in both arms, affecting ≤ 2% of patients.

"We are encouraged by these results from the RANGE study, as patients with this aggressive type of cancer who experience disease progression urgently need additional treatment options that can help stop or slow the cancer from growing and spreading," said Levi Garraway, M.D., Ph.D., senior vice president, global development and medical affairs, Lilly Oncology. "These RANGE data provide additional evidence in favor of combining CYRAMZA with other therapeutic backbones, which has now demonstrated an efficacy improvement in treating several types of aggressive metastatic cancers."

RANGE OS data are immature and final OS results are currently expected in mid-2018. Investigators, patients and Lilly study personnel involved in patient-level decision-making will remain blinded to patient-treatment assignments until that time.

Overall, RANGE is the sixth positive Phase 3 trial of ramucirumab to date. Previously completed Phase 3 studies of ramucirumab have demonstrated benefit in advanced forms of gastric, non-small cell lung and colorectal cancer–three of the world’s leading causes of cancer-related deaths.

Notes to Editor

About the RANGE Study
The RANGE trial, which enrolled 530 patients globally, is a randomized, double-blind study designed to evaluate the safety and efficacy of ramucirumab and docetaxel versus placebo and docetaxel in patients with locally advanced or unresectable or metastatic urothelial carcinoma whose disease progressed on or after platinum-based chemotherapy. The trial includes: 1) patients who progressed following adjuvant and/or neoadjuvant therapy; 2) patients who progressed following first-line metastatic therapy; and 3) patients who had received prior platinum-based and immune checkpoint inhibitor regimens. The trial’s primary endpoint is progression-free survival, and other secondary endpoints include overall survival, objective response rate, disease control rate and patient-reported outcomes.

About Urothelial Cancer
Urothelial cancer includes carcinomas that arise in the urothelial or transitional cells that line the urinary collecting system, including the bladder, which is the most common site for this type of tumor. Other potential primary sites of this cancer include the renal pelvis, ureter and urethra. Bladder cancer accounts for the majority of all urothelial carcinoma.

Worldwide, bladder cancer ranks ninth in the topmost common cancers overall,2 and the ninth leading cause of cancer-related deaths, afflicting approximately 430,000 people per year and resulting in more than 165,000 deaths.3 The global incidence of bladder cancer increased 11 percent from 2008 to 2012. In the U.S., bladder cancer is the sixth most common and deadly cancer,4 with an estimated 79,000 new cases and nearly 17,000 deaths expected in 2017.5

Generally, this is an aggressive disease and, unfortunately, despite recently approved therapies, the majority of patients who have disease progression will eventually succumb to their cancer.

About CYRAMZA (ramucirumab)
In the U.S., CYRAMZA (ramucirumab) is approved for use as a single agent or in combination with paclitaxel as a treatment for people with advanced or metastatic gastric (stomach) or gastroesophageal junction (GEJ) adenocarcinoma whose cancer has progressed on or after prior fluoropyrimidine- or platinum-containing chemotherapy. It is also approved in combination with docetaxel as a treatment for people with metastatic non-small cell lung cancer (NSCLC) whose cancer has progressed on or after platinum-based chemotherapy. Additionally, it is approved with FOLFIRI as a treatment for people with metastatic colorectal cancer (mCRC) whose cancer has progressed on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

Ramucirumab is being investigated in a broad global development program that has enrolled more than 10,000 patients across more than 70 trials worldwide. There are several studies underway or planned to investigate ramucirumab as a single agent and in combination with other anti-cancer therapies for the treatment of multiple tumor types.

Ramucirumab is an antiangiogenic therapy. It is a vascular endothelial growth factor (VEGF) Receptor 2 antagonist that specifically binds and blocks activation of VEGF Receptor 2 by blocking the binding of VEGF receptor ligands VEGF-A, VEGF-C, and VEGF-D. Ramucirumab inhibited angiogenesis in an in vivo animal model.

About Angiogenesis and VEGF Protein
Angiogenesis is the process of making new blood vessels. In a person with cancer, angiogenesis creates new blood vessels that give a tumor its own blood supply, allowing it to grow and spread.

Some tumors create proteins called VEGF. These proteins attach to the VEGF receptors of blood vessel cells causing new blood vessels to form around the tumors, enabling growth. Blocking the VEGF protein from linking to the blood vessels helps to inhibit tumor growth by slowing angiogenesis and the blood supply that feeds tumors. Of the three known VEGF receptors, VEGF Receptor 2 is linked most closely to VEGF-induced tumor angiogenesis.

INDICATIONS
Gastric Cancer
CYRAMZA, as a single agent or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic, gastric or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

Non-Small Cell Lung Cancer
CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.

Colorectal Cancer
CYRAMZA, in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA

WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND
IMPAIRED WOUND HEALING

Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

Warnings and Precautions

Hemorrhage

In study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In study 2, which evaluated CYRAMZA plus paclitaxel in advanced gastric cancer, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in studies 1 and 2. In study 3, which evaluated CYRAMZA plus docetaxel in metastatic non-small cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other antiplatelet therapy other than once-daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from study 3. In study 4, which evaluated CYRAMZA plus FOLFIRI in metastatic colorectal cancer, the incidence of severe bleeding was 2.5% for CYRAMZA plus FOLFIRI and 1.7% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience severe bleeding.
Arterial Thromboembolic Events (ATEs)

Serious, sometimes fatal, ATEs including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials. Permanently discontinue CYRAMZA in patients who experience a severe ATE.
Hypertension

An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%), in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), and in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%). Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.
Infusion-Related Reactions (IRRs)

Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, IRRs occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for grade 3 or 4 IRRs.
Gastrointestinal Perforations

Four of 570 patients (0.7%) who received CYRAMZA as a single agent in advanced gastric cancer clinical trials experienced gastrointestinal perforation. In study 2, the incidence of gastrointestinal perforation was 1.2% for CYRAMZA plus paclitaxel as compared to 0.3% for placebo plus paclitaxel. In study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel as compared to 0.3% for placebo plus docetaxel. In study 4, the incidence of gastrointestinal perforation was 1.7% for CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.
Impaired Wound Healing

CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA has the potential to adversely affect wound healing. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.
Clinical Deterioration in Child-Pugh B or C Cirrhosis

Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

RPLS has been reported at a rate of < 0.1% in clinical studies with CYRAMZA. Discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.
Proteinuria Including Nephrotic Syndrome

In study 4, severe proteinuria occurred more frequently in patients treated with CYRAMZA plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with CYRAMZA plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are ≥2 g over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to < 2 g over 24 hours. Permanently discontinue CYRAMZA for urine protein levels > 3 g over 24 hours or in the setting of nephrotic syndrome.
Thyroid Dysfunction

Monitor thyroid function during treatment with CYRAMZA. In study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in the CYRAMZA plus FOLFIRI-treated patients and 0.9% in the placebo plus FOLFIRI-treated patients.
Embryofetal Toxicity

Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at least 3 months after the last dose of CYRAMZA.
Most Common Adverse Reactions—Single Agent

The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in study 1 were hypertension (16% vs 8%; 8% vs 3%), diarrhea (14% vs 9%; 1% vs 2%), headache (9% vs 3%; 0% vs 0%), and hyponatremia (6% vs 2%; 3% vs 1%).
The most common serious adverse events with CYRAMZA in study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo.
Clinically relevant adverse reactions reported in ≥1% and < 5% of CYRAMZA-treated patients vs placebo in study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%).
Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.
Most Common Adverse Reactions—Combination With Paclitaxel

The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus paclitaxel and ≥2% higher than placebo plus paclitaxel in study 2 were fatigue/asthenia (57% vs 44%; 12% vs 6%), neutropenia (54% vs 31%; 41% vs 19%), diarrhea (32% vs 23%; 4% vs 2%), epistaxis (31% vs 7%; 0% vs 0%), hypertension (25% vs 6%; 15% vs 3%), peripheral edema (25% vs 14%; 2% vs 1%), stomatitis (20% vs 7%; 1% vs 1%), proteinuria (17% vs 6%; 1% vs 0%), thrombocytopenia (13% vs 6%; 2% vs 2%), hypoalbuminemia (11% vs 5%; 1% vs 1%), and gastrointestinal hemorrhage events (10% vs 6%; 4% vs 2%).
The most common serious adverse events with CYRAMZA plus paclitaxel in study 2 were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors.
Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in study 2 were neutropenia (4%) and thrombocytopenia (3%).
Clinically relevant adverse reactions reported in ≥1% and < 5% of the CYRAMZA plus paclitaxel-treated patients in study 2 were sepsis (3.1% for CYRAMZA plus paclitaxel vs 1.8% for placebo plus paclitaxel) and gastrointestinal perforations (1.2% for CYRAMZA plus paclitaxel vs 0.3% for placebo plus paclitaxel).
Most Common Adverse Reactions—Combination With Docetaxel

The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus docetaxel and ≥2% higher than placebo plus docetaxel in study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), stomatitis/mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; < 1% vs < 1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs < 1%), thrombocytopenia (13% vs 5%; 3% vs < 1%), lacrimation increased (13% vs 5%; < 1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%).
The most common serious adverse events with CYRAMZA plus docetaxel in study 3 were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel.
In patients ≥65 years of age, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients < 65 years of age, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel.
Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA in study 3 were infusion-related reaction (0.5%) and epistaxis (0.3%).
For patients with nonsquamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of grade ≥3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for grade ≥3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of grade ≥3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for grade ≥3 pulmonary hemorrhage for placebo plus docetaxel.
Clinically relevant adverse reactions reported in ≥1% and < 5% of CYRAMZA plus docetaxel-treated patients in study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).
Most Common Adverse Reactions—Combination With FOLFIRI

The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus FOLFIRI and ≥2% higher than placebo plus FOLFIRI in study 4 were diarrhea (60% vs 51%; 11% vs 10%), neutropenia (59% vs 46%; 38% vs 23%), decreased appetite (37% vs 27%; 2% vs 2%), epistaxis (33% vs 15%; 0% vs 0%), stomatitis (31% vs 21%; 4% vs 2%), thrombocytopenia (28% vs 14%; 3% vs < 1%), hypertension (26% vs 9%; 11% vs 3%), peripheral edema (20% vs 9%; < 1% vs 0%), proteinuria (17% vs 5%; 3% vs < 1%), palmar-plantar erythrodysesthesia syndrome (13% vs 5%; 1% vs < 1%), gastrointestinal hemorrhage events (12% vs 7%; 2% vs 1%), hypoalbuminemia (6% vs 2%; 1% vs 0%). Twenty percent of patients treated with CYRAMZA plus FOLFIRI received granulocyte colony-stimulating factors.
The most common serious adverse events with CYRAMZA plus FOLFIRI were diarrhea (3.6%), intestinal obstruction (3.0%), and febrile neutropenia (2.8%).
Treatment discontinuation of any study drug due to adverse reactions occurred more frequently in CYRAMZA plus FOLFIRI-treated patients (29%) than in placebo plus FOLFIRI-treated patients (13%). The most common adverse reactions leading to discontinuation of any component of CYRAMZA plus FOLFIRI as compared to placebo plus FOLFIRI were neutropenia (12.5% versus 5.3%) and thrombocytopenia (4.2% versus 0.8%). The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (1.5%) and gastrointestinal perforation (1.7%).
Clinically relevant adverse reactions reported in ≥1% and < 5% of CYRAMZA plus FOLFIRI-treated patients in study 4 consisted of gastrointestinal perforation (1.7% CYRAMZA plus FOLFIRI versus 0.6% for placebo plus FOLFIRI).
Thyroid-stimulating hormone (TSH) was evaluated in 224 patients (115 CYRAMZA plus FOLFIRI-treated patients and 109 placebo plus FOLFIRI-treated patients) with normal baseline TSH levels. Increased TSH was observed in 53 (46%) patients treated with CYRAMZA plus FOLFIRI compared with 4 (4%) patients treated with placebo plus FOLFIRI.
Drug Interactions

No pharmacokinetic interactions were observed between ramucirumab and paclitaxel, between ramucirumab and docetaxel, or between ramucirumab and irinotecan or its active metabolite, SN-38.
Use in Specific Populations

Pregnancy: Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA use in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and pediatric development, and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA.
Lactation: Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA.
Females of Reproductive Potential: Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.
Please see full Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage, gastrointestinal perforation, and impaired wound healing.
RB-P-HCP ISI 16FEB2017