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Opdivo (nivolumab) Demonstrates Superior Recurrence-Free Survival Versus Yervoy (ipilimumab) for Patients with Resected High-Risk Melanoma in Phase 3 CheckMate -238 Study

On September 10, 2017 Bristol-Myers Squibb Company (NYSE: BMY) reported that treatment with Opdivo (nivolumab) 3 mg/kg resulted in a significant improvement in recurrence-free survival (RFS) compared to Yervoy (ipilimumab) 10 mg/kg in patients with stage IIIb/c or stage IV melanoma following complete surgical resection (Press release, Bristol-Myers Squibb, SEP 10, 2017, View Source [SID1234520456]). Following the July 5 announcement of topline results, detailed findings from the phase 3 CheckMate -238 study will be highlighted on September 11 during the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress in Madrid, Spain as part of the press program at 8:15 a.m. CEST and in Presidential Symposium 3 (LBA8) at 4:30 p.m. CEST. The results are also being published simultaneously in the New England Journal of Medicine.

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At this planned interim analysis, Opdivo met its primary endpoint, showing a statistically significant improvement of 35% in RFS (HR 0.65; 97.56% CI: 0.51 to 0.83; p <0.0001) compared to Yervoy. The 18-month RFS rates for the Opdivo and Yervoy groups, respectively, were 66.4% (95% CI: 61.8 to 70.6) and 52.7% (95% CI: 47.8 to 57.4). Median RFS had not yet been reached for either group at the time of this analysis. This benefit was consistent across key subgroups, including BRAF mutated and BRAF wildtype patients, and no new safety signals were identified in this trial.

"Despite the rapid development of promising new options for advanced melanoma patients in recent years, those patients with high-risk, resectable melanoma still face a poor prognosis and have an unmet need for more effective adjuvant treatments," said Jeffrey S. Weber, M.D., Ph.D., deputy director of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Health, and Professor of Medicine at NYU School of Medicine. "The significant RFS results observed with Opdivo in CheckMate -238 are encouraging and provide physicians with new insights into the potential of Opdivo for the management of adjuvant melanoma."

Adverse events (AEs) leading to discontinuation were reported in 9.7% of subjects in the Opdivo arm compared to 42.6% of patients in the Yervoy group. Treatment-related grade 3/4 AEs were experienced by 14.4% of patients in the Opdivo group and 45.9% in the Yervoy group. The most common all-cause AEs leading to discontinuation in the Opdivo arm were diarrhea (1.5%) and colitis (1.1%). In the Yervoy arm, the most common AEs leading to discontinuation were diarrhea (10.2%), colitis (8.2%), hypophysitis (4.2%), alanine aminotransferase increase (3.5%), aspartate aminotransferase increase (2.9%), hepatitis (1.5%) and pneumonitis (1.5%). There were no treatment-related deaths reported in the Opdivo group and two treatment-related deaths reported in the Yervoy arm that occurred more than 100 days after treatment.

"These data show Opdivo as the first PD-1 to significantly improve RFS and the only I-O agent to demonstrate superior results, including better tolerance, as compared to an active control, in the treatment of adjuvant melanoma," said Vicki Goodman, M.D., head of new asset development, Bristol-Myers Squibb. "These results build upon the significant treatment advance we saw with Yervoy in an adjuvant setting and speak to our leadership and commitment to cancer research through innovative approaches including exploring much-needed treatment options to address earlier stages of disease."

About CheckMate -238

CheckMate -238 is an ongoing phase 3, randomized double-blind study of Opdivo versus Yervoy in patients who have undergone complete resection of stage IIIb/c or stage IV melanoma. The trial randomized 906 patients 1:1 to receive either Opdivo 3 mg/kg intravenously (IV) every two weeks or Yervoy 10 mg/kg IV every three weeks for four doses and then every 12 weeks starting at week 24. Patients were treated until disease recurrence, unacceptable toxicity or consent withdrawal for up to one year. The primary endpoint is RFS defined as the time between randomization and the date of first recurrence or death.

Adjuvant Therapy in Melanoma

Melanoma is separated into five staging categories (stages 0 to 4) based on the in-situ feature, thickness and ulceration of the tumor, whether the cancer has spread to the lymph nodes, and how far the cancer has spread beyond lymph nodes.

Stage 3 melanoma has reached the regional lymph nodes but has not yet spread to distant lymph nodes or to other parts of the body (metastasized), and requires surgical resection of the primary tumor as well as the involved lymph nodes. Some patients may also be treated with adjuvant therapy. Despite surgical intervention and possible adjuvant treatment, most patients experience disease recurrence and progress to metastatic disease. By five years, the majority of stage IIIb and IIIc patients (68% and 89%, respectively) experience disease recurrence.

Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

At Bristol-Myers Squibb, patients are at the center of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational Immuno-Oncology (I-O) medicines for hard-to-treat cancers that could potentially improve outcomes for these patients.

We are leading the scientific understanding of I-O through our extensive portfolio of investigational compounds and approved agents. Our differentiated clinical development program is studying broad patient populations across more than 50 types of cancers with 14 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs position us to advance I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O radiation therapies across multiple tumors and potentially deliver the next wave of therapies with a sense of urgency. We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and how patients’ tumor biology can be used as a guide for treatment decisions throughout their journey.

We understand making the promise of I-O a reality for the many patients who may benefit from these therapies requires not only innovation on our part but also close collaboration with leading experts in the field. Our partnerships with academia, government, advocacy and biotech companies support our collective goal of providing new treatment options to advance the standards of clinical practice.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivo’s leading global development program is based on Bristol-Myers Squibb’s scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has enrolled more than 25,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 60 countries, including the United States, the European Union and Japan. In October 2015, the company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

U.S. FDA-APPROVED INDICATIONS FOR OPDIVO

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-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 confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of adults and pediatric (12 years and older) patients with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated pneumonitis occurred in 6% (25/407) of patients.

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.

Immune-Mediated Hepatitis

OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated hepatitis occurred in 13% (51/407) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%.

Immune-Mediated Neuropathies

In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.

Immune-Mediated Endocrinopathies

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency.

Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO with YERVOY, hypophysitis occurred in 9% (36/407) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO with YERVOY, adrenal insufficiency occurred in 5% (21/407) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO with YERVOY, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving OPDIVO with YERVOY. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO with YERVOY, diabetes occurred in 1.5% (6/407) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. 6 of the 9 patients were hospitalized for severe endocrinopathies.

Immune-Mediated Nephritis and Renal Dysfunction

OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients.

Immune-Mediated Skin Adverse Reactions and Dermatitis

OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated rash occurred in 22.6% (92/407) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.

Immune-Mediated Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. Encephalitis occurred in one patient receiving OPDIVO with YERVOY (0.2%) after 1.7 months of exposure.

Other Immune-Mediated Adverse Reactions

Based on the severity of adverse reaction, permanently discontinue or withhold treatment, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO the following clinically significant immune-mediated adverse reactions occurred in <1.0% of patients receiving OPDIVO: uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), myositis, myocarditis, rhabdomyolysis, motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In patients receiving OPDIVO monotherapy, infusion-related reactions occurred in 6.4% (127/1994) of patients. In patients receiving OPDIVO with YERVOY, infusion-related reactions occurred in 2.5% (10/407) of patients.

Complications of Allogeneic HSCT after OPDIVO

Complications, including fatal events, occurred in patients who received allogeneic HSCT after OPDIVO. Outcomes were evaluated in 17 patients from Checkmate 205 and 039, who underwent allogeneic HSCT after discontinuing OPDIVO (15 with reduced-intensity conditioning, 2 with myeloablative conditioning). Thirty-five percent (6/17) of patients died from complications of allogeneic HSCT after OPDIVO. Five deaths occurred in the setting of severe or refractory GVHD. Grade 3 or higher acute GVHD was reported in 29% (5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of patients. A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in 35% (n=6) of patients. Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic encephalitis without an identified infectious cause, and Grade 3 (n=1) suspected viral encephalitis. Hepatic veno-occlusive disease (VOD) occurred in one patient, who received reduced-intensity conditioned allogeneic HSCT and died of GVHD and multi-organ failure. Other cases of hepatic VOD after reduced-intensity conditioned allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. Cases of fatal hyperacute GVHD have also been reported. 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.

Embryo-Fetal Toxicity

Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- or YERVOY- containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose.

Serious Adverse Reactions

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO . The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration.

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and dyspnea (20%). The most common (≥20%) adverse reactions in the OPDIVO (n=313) arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO were cough and dyspnea at a higher incidence than investigator’s choice. In Checkmate 275, the most common adverse reactions (≥ 20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%).. The most common adverse reactions (≥20%) in patients who received OPDIVO as a single agent were fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia.

In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Please see U.S. Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY.

Checkmate Trials and Patient Populations

Checkmate 067 – advanced melanoma alone or in combination with YERVOY; Checkmate 037 and 066 – advanced melanoma; Checkmate 017 – squamous non-small cell lung cancer (NSCLC); Checkmate 057 – non-squamous NSCLC; Checkmate 025 – renal cell carcinoma; Checkmate 205/039 – classical Hodgkin lymphoma; Checkmate 141 – squamous cell carcinoma of the head and neck; Checkmate 275 – urothelial carcinoma.

Pfizer Presents Positive Pivotal Data for PF-05280014, an Investigational Biosimilar to Herceptin® (trastuzumab), at the European Society for Medical Oncology (ESMO) 2017 Congress

On September 10, 2017 Pfizer Inc. (NYSE:PFE) reported positive findings from REFLECTIONS B327-02 (n=707), a pivotal Phase 3 randomized, double-blind comparative safety and efficacy study of the company’s investigational trastuzumab biosimilar (PF-05280014) versus Herceptin1 (trastuzumab), at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress in Madrid (Press release, Pfizer, SEP 10, 2017, View Source [SID1234520449]). Positive data from a supplemental study, REFLECTIONS B327-04 (n=226), were also presented at the meeting. PF-05280014 is being developed by Pfizer as a potential biosimilar to Herceptin.

Know more, wherever you are:
Latest on ESMO (Free ESMO Whitepaper) Through 1stOncology, book your free 1stOncology demo here.

"Biosimilars are poised to revolutionize the oncology treatment landscape by expanding patient access to high quality and effective therapies," said Dr. Mark Pegram, associate director for clinical research at the Stanford Comprehensive Cancer Institute, and director of the Breast Oncology Program at the Stanford Women’s Cancer Center. "These data are encouraging, and reinforce the future potential of Pfizer’s investigational trastuzumab biosimilar to help meet the needs of cancer patients and their treating physicians as a potentially lower cost option to Herceptin, across all indications."

The REFLECTIONS B327-02 study achieved the primary objective for equivalence in the objective response rate (ORR) of PF-05280014 versus Herceptin in patients receiving first-line treatment, in combination with paclitaxel, for HER2-positive metastatic breast cancer [risk ratio of 0.940; within the pre-specified equivalence margin of 0.8–1.25]. ORR is defined as the proportion of patients with tumor size reduction of a predefined amount and for a minimum period of time.2 Additionally, rates of one year progression-free survival and one year survival were similar across groups (56% and 88.84% vs. 52% and 87.96% for PF-05280017 and Herceptin, respectively).

The REFLECTIONS B327-04 study found there were no clinically meaningful differences between PF-05280014 and Herceptin in terms of efficacy, safety, immunogenicity, and noninferiority in pharmacokinetics, as neoadjuvant treatment taken in combination with docetaxel and carboplatin for patients with operable HER2-positive breast cancer.

"Pfizer is committed to driving significant improvements in patient care through the development of high quality, effective biosimilars. Including PF-05280014, Pfizer’s biosimilars pipeline consists of eight distinct biosimilar molecules in mid to late stage development, with three of these in oncology," said Salomon Azoulay, MD, Senior Vice President, Chief Medical Officer, Pfizer Essential Health. "By continuing to grow our oncology and supportive care presence through both novel therapies and biosimilars, we are able to provide an array of important treatment options for patients, physicians and healthcare systems."

As part of Pfizer’s commitment to expanding its oncology biosimilars pipeline, the company is progressing its biosimilar trastuzumab marketing applications, which have been accepted for review by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

About PF-05280014

PF-05280014 is a monoclonal antibody (mAb) that is in development as a potential biosimilar for all currently approved indications of Herceptin (trastuzumab).

Herceptin is currently approved in the U.S., EU and other markets for HER2-positive breast cancer and gastric cancer.

PF-05280014 is an investigational compound and has not received regulatory approval in any country. Biosimilarity has not yet been established by regulatory authorities and is not yet claimed.

Five Prime Announces Updated Data in Mesothelioma Patients from Ongoing Phase 1b Trial of FP-1039 at ESMO 2017 Congress

On September 10, 2017 Five Prime Therapeutics, Inc. (Nasdaq:FPRX), a clinical-stage biotechnology company focused on discovering and developing innovative immuno-oncology protein therapeutics, reported that updated data from the ongoing Phase 1b trial of FP-1039/GSK3052230 (hereafter FP-1039) in mesothelioma patients were reported today in an oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress in Madrid, Spain (Press release, Five Prime Therapeutics, SEP 10, 2017, View Source [SID1234520447]). The presentation titled "Multicenter, Nonrandomized, Open-Label Phase 1b Study of FP-1039/GSK3052230 with Chemotherapy: Results in Malignant Pleural Mesothelioma (MPM)" by Dr. Jose Trigo et al., is available at View Source

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"We are encouraged by the results of FP-1039 in the front-line treatment of malignant pleural mesothelioma, a rare aggressive cancer with a poor prognosis," said Helen Collins, M.D., Senior Vice President and Chief Medical Officer of Five Prime. "The majority of patients across all dose levels experienced tumor reduction. While this is single-arm data, we believe the findings compare favorably to historical data for chemotherapy alone. In addition to the safety and efficacy results, duration of progression-free survival correlated positively with increasing expression levels of tumoral FGF2."

The mesothelioma arm of the open-label Phase 1b trial evaluated weekly infusions of FP-1039, an FGF ligand trap, in combination with first-line pemetrexed and cisplatin chemotherapy in patients with untreated, unresectable MPM. Following the dose escalation portion of the trial, 15 mg/kg weekly was identified as the maximum tolerated dose (MTD) for FP-1039 and established as the dose for expansion in patients with MPM. The primary study endpoints are safety and overall response rate (ORR), disease control rate (DCR) at 6 months, progression free survival (PFS) and exploratory translational objectives. The poster includes data from MPM patients who had received FP-1039 as of the March 17, 2017 cut-off.

Safety Data

The most common adverse events across all dose levels (AEs; all grades) observed were: nausea (56%), decreased appetite (36%), fatigue (33%) and infusion reaction (36%)

The vast majority of events were Grades 1-2

Three dose-limiting toxicities (DLTs) were observed at the 20 mg/kg dose (Grade 5 bowel perforation/ischemia; Grade 3 elevated creatinine level and Grade 3 infusion reaction)

No DLTs were observed at the 15 mg/kg dose level and so MTD was established at 15 mg/kg

Toxicities associated with small-molecule FGFR inhibitors, such as hyperphosphatemia, retinal detachment and nailbed changes, have not been observed
Efficacy Data

In the 27 patients evaluable as of March 17, 2017, who had received FP-1039 at or below the 15 mg/kg MTD dose level:

Preliminary ORR was 48%, with six-month DCR of 81%, evaluated per mRECIST 1.1

– 13 confirmed Partial Responses (PRs) and 9 durable Stable Disease (SD) (lasting at least six months)

– Evaluable patients are defined as patients who enrolled at least 42 days (2 cycles) prior to the cutoff date

Median PFS at or below the 15 mg/kg MTD dose level was 7.4 months. Historical median time to progression for cisplatin/pemetrexed is 5.7 months.
FGF2 IHC Exploratory Biomarker Data

FGF2 overexpression is associated with worse prognosis in MPM

Statistically significant correlation between PFS and cytoplasmic FGF2 H-score was observed for the 15 mg/kg expansion group
About FP-1039

FP-1039 is a protein drug designed to intervene in FGF signaling. As a ligand trap, FP-1039 binds to FGF ligands circulating in the extracellular space (such as FGF2), preventing these signaling proteins from reaching FGFR1 on the surface of tumor cells. Treatment with FP-1039 treatment has not been shown to cause hyperphosphatemia, a side effect seen with small molecule inhibitors of FGF receptors, which block the activity of both cancer-associated FGFs and FGF-23. GlaxoSmithKline (GSK) was the sponsor of the trial.

Merck’s KEYTRUDA® (pembrolizumab) Continues to Show Overall Survival Benefit Over Chemotherapy with Nearly Two Years Follow-Up in Previously Treated Patients with Advanced Urothelial Carcinoma, Post-Platinum Failure

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).

"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.

IDERA PHARMACEUTICALS PRESENTS POSITIVE PHASE 1 DATA FOR INTRATUMORAL IMO-2125 IN COMBINATION WITH IPILIMUMAB DEMONSTRATING AN OVERALL RESPONSE RATE (ORR) OF 44% IN MELANOMA PATIENTS REFRACTORY TO ANTI-PD1 THERAPY

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.

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.