On December 5, 2016 Bristol-Myers Squibb Company (NYSE:BMY) reported updated findings from the Phase 1b trial, CheckMate -012, in chemotherapy-naïve advanced non-small cell lung cancer patients evaluating Opdivo monotherapy, or in combination with Yervoy, at different doses and schedules (Press release, Bristol-Myers Squibb, DEC 5, 2016, View Source [SID1234516912]). Data from this trial have been previously reported. These updated results, with a median follow-up of 16 months, include pooled efficacy findings for the Opdivo and Yervoy combination cohorts (Opdivo 3 mg/kg every two weeks plus Yervoy 1 mg/kg every six [Q6W] or 12 weeks [Q12W]). Schedule your 30 min Free 1stOncology Demo! In the pooled combination cohorts, the median progression-free survival in patients with PD-L1 expression ≥1% (n=46) was 12.7 months (95% CI: 7.8, 23.0) and was not reached in patients with PD-L1 expression ≥50% (n=13; 95% CI: 7.8, NR). For patients with ≥50% PD-L1 expression (n=13), the one-year overall survival rate was 100% in the pooled combination cohorts. In addition, the confirmed objective response rates in all treated patients (n=77) was 43%, nearly double the response rate reported with Opdivo monotherapy (23%; n=52), with six patients (8%) achieving a complete response, three of which were in patients with PD-L1 expression <1%. The Grade 3/4 treatment-related adverse events were 42% and 31% for the Q12W and Q6W combination cohorts, respectively.
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Scott N. Gettinger, M.D., associate professor of medicine, Yale Cancer Center, New Haven, Conn., commented, "With longer follow-up in the CheckMate -012 trial, we observe that the Opdivo and Yervoy combination resulted in encouraging progression-free survival. We are also excited to see the consistent near doubling of response rates with the combination relative to Opdivo alone in both PD-L1 expressors and non-expressors, and the previously reported response rates of over 50% and 90%, respectively, among patients with at least 1% and 50% tumor PD-L1 expression. We look forward to further evaluating Opdivo plus Yervoy in the first line treatment setting for advanced lung cancer."
Results from CheckMate -012 will be presented today at the International Association for the Study of Lung Cancer 17th World Conference on Lung Cancer (WCLC) in Vienna, Austria, during an Oral Session at 11:00 a.m. CET.
Nick Botwood, M.D., development lead, Lung, Bristol-Myers Squibb, commented, "The updated results from CheckMate -012 continue to be promising, and we look forward to advancing the Opdivo and Yervoy combination in the ongoing CheckMate -227 Phase 3 trial for first-line advanced lung cancer, with the hope of confirming these findings."
About CheckMate -012
CheckMate -012 is a multi-arm Phase 1b trial evaluating the safety and tolerability (primary endpoints) of Opdivo as monotherapy or in combination with Yervoy at different doses and schedules in patients with chemotherapy-naïve advanced non-small cell lung cancer. The secondary endpoints include confirmed objective response rate (ORR) and progression-free survival (PFS) rates at 24 weeks. Exploratory endpoints include overall survival (OS) and efficacy by PD-L1 expression.
The updated data presented at WCLC include a median follow-up of 16 months for the two combination cohorts – Opdivo 3 mg/kg every two weeks plus Yervoy 1 mg/kg every six weeks (Q6W) (n=39) and 12 weeks (Q12W) (n=38). In the study, both PD-L1 expressors >1% and non-expressors <1% were enrolled. The majority of patients with quantifiable baseline PD-L1 expression in each cohort had PD-L1 tumor expression of ≥1%, including 72% in the Q6W cohort and 70% in the Q12W cohort.
The pooled PFS and OS findings for the combination cohorts in all-treated patients and by tumor PD-L1 expression are reported below.
Nivo 3 Q2W +
Ipi 1 Q6/12W All-Treated (n=77) PD-L1 >1% (n=46) PD-L1 >50% (n=13)
Median PFS, mo (95%, CI) 8.0 (4.1, 13.2) 12.7 (7.8, 23.0) NR (7.8, NR)
1-year OS rate, % 76 87 100
Additional efficacy findings were reported for the Q6W and Q12W cohorts in patients with tumor PD-L1 expression ≥1% at WCLC. These findings are summarized below.
Q12W (n = 23) Q6W (n = 23)
ORR, % (n/N) 57 (13/23) 57 (13/23)
Median PFS, mo (95%, CI) 10.4 (6.4, NR) 13.2 (3.5, 23.0)
1-year OS rate, % 91 83
The rates of treatment-related adverse events (AEs) with Opdivo plus Yervoy remained similar to those previously reported. Treatment related AEs of any grade were 84% and 74% for the Q12W and Q6W combination cohorts, respectively. The Grade 3/4 AEs were 42% and 31% for the Q12W and Q6W combination cohorts, respectively. Treatment-related AEs of any grade led to discontinuation in 18% of patients in Q12W and Q6W combination cohorts. Treatment-related Grade 3/4 AEs led to discontinuation in 8% of patients in the Q12W and Q6W combination cohorts.
About Lung Cancer
Lung cancer is the leading cause of cancer deaths globally, resulting in more than 1.5 million deaths each year, according to the World Health Organization. Non-small cell lung cancer (NSCLC) is one of the most common types of the disease and accounts for approximately 85% of cases. About 25% to 30% of all lung cancers are squamous cell carcinomas, and non-squamous NSCLC accounts for approximately 50% to 65% of all lung cancer cases. Survival rates vary depending on the stage and type of the cancer when it is diagnosed. Globally, the five-year survival rate for Stage I NSCLC is between 47% and 50%; for Stage IV NSCLC, the five-year survival rate drops to 2%.
Bristol-Myers Squibb: At the Forefront of Immuno-Oncology Science & Innovation
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 that will raise survival expectations in hard-to-treat cancers and will change the way patients live with cancer.
We are leading the scientific understanding of I-O through our extensive portfolio of investigational and approved agents, including the first combination of two I-O agents in metastatic melanoma, and our differentiated clinical development program, which is studying broad patient populations across more than 20 types of cancers with 11 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs uniquely position us to advance the science of combinations across multiple tumors and potentially deliver the next wave of I-O combination regimens 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 inform which patients will benefit most from I-O therapies.
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 57 countries, including the United States, the European Union and Japan. In October 2015, the company’s Opdivo + Yervoy combination was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 47 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 patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin. 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.
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 4.9% (13/263) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 3.4% (9/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=8).
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, among all patients (safety population [n=263]), adverse reactions leading to discontinuation (4.2%) or to dosing delays (23%) occurred. The most frequent serious adverse reactions reported in ≥1% of patients were infusion-related reaction, pneumonia, pleural effusion, pyrexia, rash and pneumonitis. Ten patients died from causes other than disease progression, including 6 who died from complications of allogeneic HSCT. Serious adverse reactions occurred in 21% of patients in the safety population (n=263) and 27% of patients in the subset of patients evaluated for efficacy (efficacy population [n=95]). 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 infections, and sepsis.
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, among all patients (safety population [n=263]) and the subset of patients in the efficacy population (n=95), respectively, the most common adverse reactions (≥20%) were fatigue (32% and 43%), upper respiratory tract infection (28% and 48%), pyrexia (24% and 35%), diarrhea (23% and 30%), and cough (22% and 35%). In the subset of patients in the efficacy population (n=95), the most common adverse reactions also included rash (31%), musculoskeletal pain (27%), pruritus (25%), nausea (23%), arthralgia (21%), and peripheral neuropathy (21%). 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 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%).
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.
Please see U.S. Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY.
Karyopharm Presents Updated Phase 2b STORM Data at the American Society of Hematology 2016 Annual Meeting
On December 4, 2016 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, reported updated results from its Phase 2b STORM study of selinexor (KPT-330), including robust rates and duration of response, compelling overall survival and a favorable safety profile, in patients with heavily pretreated refractory multiple myeloma (MM) at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2016 annual meeting held December 3-6, 2016 in San Diego (Filing, 8-K, Karyopharm, DEC 4, 2016, View Source [SID1234516967]). Selinexor is the Company’s lead, novel, oral Selective Inhibitor of Nuclear Export (SINE) compound, in development for the treatment of a variety of malignancies, including MM and acute myeloid leukemia (AML).
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"The data presented today further support the rationale for selinexor as a promising new treatment for patients with refractory myeloma with no clearly beneficial treatment options," said Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm. "Based on the exciting STORM data and the existing unmet medical need, we have expanded the study to include additional patients with penta-refractory myeloma and expect to report top-line data from this study in early 2018."
Updated Phase 2b STORM Clinical Data in Refractory Multiple Myeloma
In an oral presentation titled, "Selinexor and Low Dose Dexamethasone in Patients with Lenalidomide, Pomalidomide, Bortezomib, Carfilzomib and Anti-CD38 Ab Refractory MM STORM Study," Dan T. Vogl, MD, MSCE, Assistant Professor of Medicine, Perelman School of Medicine, University of Pennsylvania, presented updated clinical data from the ongoing Phase 2b STORM study, a single-arm clinical trial evaluating selinexor in combination with low-dose dexamethasone in patients with quad-refractory or penta-refractory myeloma. Patients with quad-refractory disease have previously received two proteasome inhibitors (PIs) (bortezomib (Velcade) and carfilzomib (Kyprolis)) and two immunomodulatory drugs (IMiDs) (lenalidomide (Revlimid) and pomalidomide (Pomalyst)), and their disease is refractory to at least one PI, at least one IMiD, and has progressed following their most recent therapy. Patients with penta-refractory myeloma have quad-refractory disease that is also refractory to an anti-CD38 monoclonal antibody, such as daratumumab (Darzalex) or isatuximab.
Phase 2b STORM Efficacy
Category
N1 ORR (%) CBR (%) VGPR (%) PR (%) MR (%) SD (%) PD (%) NE (%)
Overall
78 16 (21% ) 26 (33% ) 4 (5% ) 12 (15% ) 10 (13% ) 27 (35% ) 9 (12% ) 16 (21% )
Quad
48 10 (21% ) 14 (29% ) 2 (4% ) 8 (17% ) 4 (8% ) 21 (44% ) 4 (8% ) 9 (19% )
Penta
30 6 (20% ) 12 (40% ) 2 (7% ) 4 (13% ) 6 (20% ) 6 (20% ) 5 (17% ) 7 (23% )
6 Doses/month
51 10 (20% ) 15 (29% ) 3 (6% ) 7 (14% ) 5 (10% ) 21 (41% ) 4 (8% ) 11 (2% )
8 Doses/month
27 6 (22% ) 11 (41% ) 1 (4% ) 5 (19% ) 5 (19% ) 6 (22% ) 5 (19% ) 5 (19% )
ORR=Objective Response Rate (VGPR+PR), CBR=Clinical Benefit Rate (VGPR+PR+MR), VGPR=Very Good Partial Response,
PR=Partial Response, MR=Minor Response, SD=Stable Disease, PD=Progressive Disease, NE=Non-Evaluable
1 One patient not included, did not have active myeloma
1
LOGO Targeting Disease at the Nuclear Pore
All responses were adjudicated by an Independent Review Committee (IRC). Among the 78 evaluable patients (median seven prior treatment regimens), the overall response rate (ORR) was 21%, and included very good partial responses (VGPR) and partial responses (PR). Among the 48 patients in the quad-refractory group, the ORR was 21%. For comparison, in a similar quad-refractory patient population, the anti-CD38 monoclonal antibodies Darzalex and isatuximab had ORRs of 21% and 20%, respectively. Among the 30 patients in the penta-refractory group, the ORR was 20%. Clinical benefit rate (ORR + MR) was 32% (all patients), 29% (quad-refractory), and 37% (penta-refractory). To the Company’s knowledge, no other agents have reported response rates in patients with penta-refractory MM. Median overall survival (OS) was 9.3 months for all patients, greater than 11 months (median not reached) for patients with ³MR, and 5.7 months for patients who did not have any response (£SD). Median duration of response (DOR) was 5 months. Grade ³3 cytopenias were the most common side effects and were generally not associated with clinical sequellae. Nausea, anorexia and fatigue were the most common non-hematological side effects, primarily Grades 1 and 2, and were treatable with supportive care and/or dose modification. There were low rates of Grade ³3 non-hematologic toxicities, with no new safety signals identified. In particular, there was one reported case of Grade 4 infection (1.3%), one case of Grade 2 neuropathy (1.3%) and one reported case of sepsis (1.3%).
Dr. Vogl commented, "The quad- and penta-refractory populations are continuing to expand as patients live longer and cycle through a variety of treatment options, including immunomodulatory drugs, proteasome inhibitors, or anti-CD38 monoclonal antibodies, before their disease ultimately becomes refractory and non-responsive. In my experience, selinexor is the first agent to be specifically investigated in in this difficult to treat and currently underserved population. The response rate and duration suggest that selinexor has the potential to be an exciting new option for myeloma treatment."
Karyopharm to Host Multiple Myeloma-focused Dinner Reception and Webcast at ASH (Free ASH Whitepaper) 2016
On Monday, December 5, 2016, Karyopharm will host an investor and analyst dinner reception, which will feature a moderated panel discussion with recognized experts in the treatment of MM, updated selinexor data in MM, and a live Q&A session. Confirmed external speakers include:
• Daniel Auclair, PhD (Moderator), Multiple Myeloma Research Foundation
• Nizar Bahlis, MD, University of Calgary, Southern Alberta Cancer Research Institute
• Paul G. Richardson, MD, Dana Faber Cancer Institute, Jerome Lipper Multiple Myeloma Center
• Ravi Vij, MD, MBA, Washington University School of Medicine in St. Louis, Oncology Division
• Dan T. Vogl, MD, Abramson Cancer Center Clinical Research Unit, University of Pennsylvania
In addition, Michael Kauffman, MD, PhD, CEO of Karyopharm Therapeutics will be joining.
The event will take place during the ASH (Free ASH Whitepaper) 2016 annual meeting and interested parties can access a live webcast of the event beginning Monday, December 5, 2016 at 8:15 p.m. PT under "Events & Presentations" in the "Investors" section of the company’s website at View Source A replay of the webcast will be archived on the company’s website for 90 days following the event.
About Selinexor
Selinexor (KPT-330) is a first-in-class, oral Selective Inhibitor of Nuclear Export / SINE compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor
Targeting Disease at the Nuclear Pore
suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. To date, over 1,800 patients have been treated with selinexor and it is currently being evaluated in several mid- and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in combination with low-dose dexamethasone (STORM) and backbone therapies (STOMP), and in acute myeloid leukemia (SOPRA), diffuse large B-cell lymphoma (SADAL), and liposarcoma (SEAL), among others. Karyopharm plans to initiate a pivotal randomized Phase 3 study of selinexor in combination with bortezomib (Velcade) and low-dose dexamethasone (BOSTON) in patients with multiple myeloma in early 2017. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with one or more approved therapies in a variety of tumor types to further inform the Company’s clinical development priorities for selinexor. The latest clinical trial information for selinexor is available at www.clinicaltrials.gov.
Data on Proprietary BTK Inhibitor, ARQ 531, Demonstrating Inhibition of Wild Type and C481S Mutant BTK and Superiority to Ibrutinib in TCL1 Mouse Model Presented at the American Society of Hematology Annual Meeting
On December 4, 2016 ArQule, Inc. (Nasdaq: ARQL) reported that preclinical data was presented on Bruton’s tyrosine kinase (BTK) inhibitor, ARQ 531, in a poster presentation by The Ohio State University at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting. The presentation highlighted preclinical studies of ARQ 531 in Chronic Lymphocytic Leukemia (CLL) (Press release, ArQule, DEC 4, 2016, View Source [SID1234516920]). ARQ 531 is an investigational, orally bioavailable, potent and reversible BTK inhibitor.
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ARQ 531 Poster Presentation Highlights
Title: The Bruton’s Tyrosine Kinase (BTK) Inhibitor ARQ 531 Effectively Inhibits Wild Type and C481S Mutant BTK and Is Superior to Ibrutinib in a Mouse Model of Chronic Lymphocytic Leukemia
Multi-targeted inhibition of cytokine, chemokine, and BCR pathways by ARQ 531 decreases activation, migration, and viability of CLL cells.
Unlike ibrutinib, ARQ 531 inhibits activation of C481S mutated BTK variants and maintains cytotoxicity in ibrutinib resistant clones.
ARQ 531 demonstrates remarkable efficacy in an in vivo TCL1 adoptive transfer model, improving survival to a greater extent than ibrutinib and restoring granulocyte production.
The company plans to complete preclinical studies and file an Investigational New Drug (IND) application in early 2017 to begin clinical testing later in the year.
The presentation can be viewed at View Source
"Irreversible kinase inhibitors directed at BTK have really changed the landscape of CLL but at extended follow up, we are beginning to see a subset of high risk patients who are relapsing," said Dr. Jennifer Woyach, M.D., of The Ohio State University College of Medicine. "Small molecules that target BTK that are not dependent upon the C481 site represent an exciting option for future clinical trials. We are excited to be working with ArQule on this project and look forward to initiating the first in man study with ARQ 531."
"We began our BTK discovery program in 2011 which ultimately lead to the selection of ARQ 531, a potent reversible inhibitor of both wild type and mutant BTK," said Dr. Giovanni Abbadessa, M.D., PhD., Vice President of Clinical Development, Translational Medicine and Medical Affairs at ArQule. "With the recent emergence in 2015 of BTK resistance we concentrated our efforts in this growing CLL patient population. We are pleased to be working with The Ohio State University to finish preclinical studies on this exciting program. We remain on track to file an IND application early next year."
About BTK and ARQ 531
ARQ 531 is an investigational, orally bioavailable, potent and reversible Bruton’s tyrosine kinase (BTK) inhibitor. Biochemical and cellular studies have shown that ARQ 531inhibits both the wild type and C481S-mutant forms of BTK. The C481S mutation is a known emerging resistance mechanism for first generation irreversible BTK inhibitors. ARQ 531 has high oral bioavailability as well as good ADME, pharmacokinetic and metabolic properties. The company plans to file an IND for ARQ 531 in early 2017. BTK is a therapeutic target that has been clinically proven to inhibit B-cell receptor signaling in blood cancers.
Roche’s Gazyva/Gazyvaro Helped People With Previously Untreated Follicular Lymphoma Live Significantly Longer Without Their Disease Worsening Compared to MabThera/Rituxan
On December 5, 2016 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported data from the positive, pivotal Phase III GALLIUM study that compared Gazyva/Gazyvaro (obinutuzumab) plus chemotherapy followed by Gazyva/Gazyvaro alone head-to-head against MabThera/Rituxan (rituximab) plus chemotherapy followed by MabThera/Rituxan alone for people with previously untreated follicular lymphoma. At a pre-planned interim analysis in May 2016, an independent data monitoring committee determined that the study met its primary endpoint early. The results showed Gazyva/Gazyvaro-based treatment reduced the risk of disease worsening or death (progression-free survival; PFS, as assessed by investigator) by 34 percent compared to MabThera/Rituxan-based treatment (HR=0.66; 95% CI 0.51-0.85, p=0.0012). Median PFS was not yet reached. Adverse events with either Gazyva/Gazyvaro or MabThera/Rituxan were consistent with those seen in previous studies.
"Follicular lymphoma, the most common slow-growing form of non-Hodgkin lymphoma, is an incurable blood cancer characterized by cycles of remission and disease progression, and becomes harder to treat with every relapse," said Sandra Horning, M.D., Roche’s Chief Medical Officer and Head of Global Product Development. "This study of Gazyva/Gazyvaro-based treatment is the first and only Phase III trial to date to show superior progression-free survival compared to MabThera/Rituxan-based treatment, the current standard of care, in previously untreated follicular lymphoma."
The primary results from the GALLIUM study (Abstract #6) were presented during the Plenary Scientific Session of the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego by Dr. Robert Marcus, King’s College Hospital, London and the National Cancer Research Institute (NCRI), on Sunday, December 4 at 2:00 P.M. PST. Additionally, an analysis of minimal residual disease (MRD) status in the GALLIUM study (Abstract #613) was presented in a separate oral session by Dr. Christiane Pott, University Hospital Schleswig-Holstein, Kiel, Germany, and the German Low Grade Lymphoma Study Group (GLSG) on Monday, December 5 at 7:00 A.M. PST.
GALLIUM is the third positive Phase III study for Gazyva/Gazyvaro, following the CLL11 study in patients with previously untreated chronic lymphocytic leukaemia (CLL) and the GADOLIN study in patients with indolent (slow-growing) non-Hodgkin lymphoma whose disease progressed during or within six months of prior MabThera/Rituxan-based therapy. The results of the GALLIUM study will be submitted to health authorities around the world for approval consideration.
About the GALLIUM study
GALLIUM (NCT01332968) is a global Phase III open-label, multi-centre, randomised two-arm study examining the efficacy and safety of Gazyva/Gazyvaro plus chemotherapy followed by Gazyva/Gazyvaro alone for up to two years, as compared head-to-head against MabThera/Rituxan plus chemotherapy followed by MabThera/Rituxan alone for up to two years. Chemotherapies used were CHOP, CVP or bendamustine and were selected by each participating study site prior to beginning enrolment. GALLIUM included 1401 patients with previously untreated indolent non-Hodgkin lymphoma (iNHL), of which 1202 patients had follicular lymphoma. The primary endpoint of the study was investigator-assessed PFS in patients with follicular lymphoma, with secondary endpoints including PFS assessed by independent review committee (IRC), PFS in the overall study population (iNHL), response rate (overall response, ORR; and complete response, CR), overall survival (OS), and safety. The GALLIUM study is being conducted in cooperation with the GLSG (Germany), the East German Study Group Hematology and Oncology (OSHO; Germany) and the NCRI (United Kingdom).
A summary of the GALLIUM study results presented at ASH (Free ASH Whitepaper) is included below.
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1 Primary endpoint is PFS as assessed by investigator; median follow-up of 34.5 months
2 Measured by computerized tomography (CT) scans
3 MRD-negativity means no cancer can be detected in the blood or bone marrow using a specific highly sensitive test
4 Defined as any AE occurring during or within 24 hours of infusion of Gazyva/Gazyvaro or MabThera/Rituxan and considered drug-related
About Gazyva/Gazyvaro (obinutuzumab)
Gazyva/Gazyvaro is an engineered monoclonal antibody designed to attach to CD20, a protein expressed on certain B cells, but not on stem cells or plasma cells. Gazyva/Gazyvaro is designed to attack and destroy targeted B-cells both directly and together with the body’s immune system.
Gazyva/Gazyvaro is currently approved in more than 80 countries in combination with chlorambucil, for people with previously untreated chronic lymphocytic leukaemia. The approvals were based on the CLL11 study, showing significant improvements with Gazyva/Gazyvaro plus chlorambucil across multiple clinical endpoints, including PFS, overall response rate (ORR), complete response rate (CR), and minimal residual disease (MRD) when compared head-to-head with MabThera/Rituxan plus chlorambucil.
In February 2016, Gazyva was approved by the US Food and Drug Administration in combination with bendamustine followed by Gazyva alone for people with follicular lymphoma who did not respond to a Rituxan-containing regimen, or whose follicular lymphoma returned after such treatment. In June 2016, Gazyvaro was approved by the European Commission in combination with bendamustine followed by Gazyvaro maintenance in people with follicular lymphoma who did not respond or who progressed during or up to six months after treatment with MabThera or a MabThera-containing regimen. Both approvals were based on the phase III GADOLIN study, showing a significant improvement in progression-free survival with Gazyva/Gazyvaro-based therapy compared to bendamustine alone. Gazyva is marketed as Gazyvaro in the EU and Switzerland.
Additional combination studies investigating Gazyva/Gazyvaro with other approved or investigational medicines, including cancer immunotherapies and small molecule inhibitors, are underway across a range of blood cancers.
About follicular lymphoma
Follicular lymphoma is the most common indolent (slow-growing) form of non-Hodgkin lymphoma (NHL), accounting for about one in five cases of NHL.2 It is considered incurable and relapse is common. It is estimated that more than 75,000 people are diagnosed with follicular lymphoma each year worldwide.3
Favorable Response Rates Suggest Promise of Ibrutinib (IMBRUVICA®) Combination Therapy in Two Common Types of Non-Hodgkin’s Lymphoma
On December 4, 2016 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported encouraging efficacy and safety findings from two separate studies evaluating ibrutinib (IMBRUVICA) as a combination therapy in two of the most common types of non-Hodgkin’s lymphoma: diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) (Press release, AbbVie, DEC 4, 2016, View Source [SID1234516911]). IMBRUVICA, a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor, is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.
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In a Phase 1b study of patients with relapsed/refractory (R/R) DLBCL, the investigational combination of ibrutinib, rituximab, and escalating doses of lenalidomide were tested (abstract #473). Preliminary efficacy results demonstrated the highest response rate was observed in patients with the worst prognosis subtype (non-GCB) and in patients with transformed disease.1 These data will be presented today in an oral presentation at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego, CA.
"Though standard therapy can cure over half of patients with diffuse large B-cell lymphoma (the most common form of aggressive lymphoma), patients with relapsed or refractory disease do overall poorly with only less than a quarter of patients efficiently salvaged with current strategies including stem cell transplantation," said Andre Goy, M.D., Chairman and Executive Director at John Theurer Cancer Center at Hackensack University Medical Center in New Jersey and lead investigator of the study.* "We are encouraged by these results in a heavily pretreated and refractory population and look forward to further evaluating the efficacy of ibrutinib combination therapy with rituximab and lenalidomide in the Phase 2 portion of the study."
Separately at the meeting, data from a Phase 2 multicenter study showed that the combination of ibrutinib and rituximab produced favorable response rates in patients with previously untreated FL (abstract #1804). At a median time on study of 22 months, the overall response rate (ORR) was 85%, with 35% of patients achieving a complete response (CR).2 The data were presented in a poster presentation on Saturday, December 3.
"We are highly encouraged by this longer-term data showing strong and durable responses that appear to improve with an extended treatment duration," said Nathan Fowler, M.D., Associate Professor, Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX and lead investigator of the study.* "The results of the study to date suggest that the addition of ibrutinib to rituximab in the front-line follicular lymphoma setting provides enhanced outcomes over rituximab alone."
DLCBL is an aggressive B-cell lymphoma and the most common subtype of non-Hodgkin’s lymphoma. Despite 50-60% of patients being cured with standard chemo-immunotherapy, patients who relapse have poor outcomes.3 FL is the most common subtype of indolent non-Hodgkin’s lymphoma. It is often slow-growing, but is considered incurable in advanced stages. Over time, about one-third of FL cases advance to the fast-growing DLBCL.4
"The response rates observed with ibrutinib combination therapy in treatment-naïve follicular lymphoma and relapsed/refractory diffuse large B-cell lymphoma show promise for patients with two different types of non-Hodgkin’s lymphoma," said Darrin Beaupre, M.D., Ph.D., Head of Early Development and Immunotherapy at Pharmacyclics LLC, an AbbVie company. "We pioneered the development of BTK inhibition with ibrutinib, and we continue to progress our robust development program. Based on the encouraging Phase 2 study results in FL, we are initiating a Phase 3 study of the combination of ibrutinib and rituximab in the first-line setting."
About the Studies
Abstract #473: A multicenter, open-label phase 1b/2 study of ibrutinib in combination with lenalidomide and rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma (Oral Presentation; Sunday, December 4, 4:30 PM PT)
Subjects with R/R DLBCL were treated with the investigational combination of ibrutinib 560 mg once daily, rituximab 375 mg/m2 on day one for six cycles and escalating doses of lenalidomide. Preliminary data for 45 patients showed responses on 15 mg, 20 mg, and 25 mg lenalidomide, with responses for patients with the non-GCB subtype (response-evaluable population) seen in more than half of the subjects. Patients with transformed disease also showed favorable responses. Overall, the treatment combination was tolerable. The most frequent Grade 3 or 4 adverse events (AEs) were neutropenia (38%), thrombocytopenia (11%), and maculopapular rash (11%). Based on safety data from this portion of the study, the Phase 2 portion of the trial is being initiated.1
Abstract #1804: Ibrutinib combined with rituximab in treatment-naïve patients with follicular lymphoma: Arm 1 + arm 2 results from a multicenter, open-label phase 2 study (Poster Presentation; Saturday, December 3, 5:30 PM – 7:30 PM PT)
Updated data were presented for 80 patients with FL receiving two different administration schedules of ibrutinib and rituximab (Arm 1, 60 patients; Arm 2, 20 patients). In Arm 1 at a median time on study of 22 months, the ORR was 85%, with 35% CR. Median time to best response was 2.7 months. With a median time on study of 15 months in Arm 2, ORR was 75%, with 35% CR. Median time to best response was 4.3 months. Median duration of response (DOR), progression-free survival (PFS) and overall survival (OS) were not reached in either arm.2
In Arm 1, patients received ibrutinib 560 mg once daily until disease progression or unacceptable toxicity and rituximab 375 mg/m2 once weekly for four weeks. In Arm 2, patients received ibrutinib 560 mg once daily for eight weeks, then concurrent rituximab once weekly for four weeks, followed by ibrutinib 560 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed ORR. Secondary endpoints included DOR, PFS and OS.2
Treatment was well tolerated, with no new safety signals with longer follow up. AEs were primarily Grade 1 or 2. The most common AEs included fatigue (68%), diarrhea (52%), nausea (47%), headache (30%), cough, myalgia, maculopapular rash (28% each), and muscle spasms (23%) in Arm 1, and fatigue (80%), diarrhea (60%), nausea (55%), myalgia (45%), maculopapular rash (35%), and headache, cough and muscle spasms (25% each) in Arm 2. Common Grade 3 or 4 AEs in either Arm 1 or 2 included maculopapular rash (5% and 10%, respectively), fatigue (7% and 5%), pyrexia (3% and 10%) and diarrhea (2% and 10%).2
About IMBRUVICA
IMBRUVICA is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton’s tyrosine kinase (BTK). BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.5,6 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.5
IMBRUVICA is approved to treat patients with CLL/SLL including patients with 17p deletion, patients with mantle cell lymphoma who have received at least one prior therapy and patients with Waldenström’s macroglobulinemia. Accelerated approval was granted for the MCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.5
IMBRUVICA was one of the first medicines to receive U.S. FDA approval via the new Breakthrough Therapy Designation pathway.
IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA has one of the most robust clinical oncology development programs for a single molecule in the industry with nearly 30 (n=27) company-sponsored trials underway, 14 of which are Phase 3. In addition, there are more than 40 (n=44) investigator-sponsored trials taking place around the world. To date, more than 65,000 patients around the world have been treated with IMBRUVICA in clinical practice and clinical trials.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage – Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA.
The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and postsurgery depending upon the type of surgery and the risk of bleeding.
Infections – Fatal and nonfatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Evaluate patients for fever and infections and treat appropriately.
Cytopenias – Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19% to 29%), thrombocytopenia (range, 5% to 17%), and anemia (range, 0% to 9%) based on laboratory measurements occurred in patients treated with single agent IMBRUVICA. Monitor complete blood counts monthly.
Atrial Fibrillation – Atrial fibrillation and atrial flutter (range, 6% to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.
Hypertension – Hypertension (range, 6% to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new-onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA. Adjust existing antihypertensive medications and/or initiate antihypertensive treatment as appropriate.
Second Primary Malignancies – Other malignancies (range, 5% to 16%) including non-skin carcinomas (range, 1% to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4% to 13%).
Tumor Lysis Syndrome – Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (eg, high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.
Embryo-Fetal Toxicity – Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
ADVERSE REACTIONS
The most common adverse reactions (?20%) in patients with B-cell malignancies (MCL, CLL/SLL, and WM) were neutropenia** (64%), thrombocytopenia** (63%), diarrhea (43%), anemia** (41%), musculoskeletal pain (30%), rash (29%), nausea (29%), bruising (29%), fatigue (27%), hemorrhage (21%), and pyrexia (21%).
**Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).
The most common Grade 3 or 4 non-hematologic adverse reactions (?5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%).
Approximately 6% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse reactions.
Approximately 4%-10% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse reactions. Most frequent adverse reactions leading to discontinuation were pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each) in CLL patients and subdural hematoma (1.8%) in MCL patients.
DRUG INTERACTIONS
CYP3A Inhibitors – Avoid coadministration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.
CYP3A Inducers – Avoid coadministration with strong CYP3A inducers.
SPECIFIC POPULATIONS
Hepatic Impairment – Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA dose.
Please see Full Prescribing Information: View Source