Cancer/HCC Immunotherapies/PD1 Inhibitors - Nivolumab targets a protein called the programmed death-1 (PD-1) receptor & for HCC/Liver Cancer
The PD-1 pathway plays an important role in controlling the immune system to prevent inadvertent immune cell activation and autoimmune disease.
There continues to be a buzz about immunotherapy, and particularly the programmed death (PD) inhibitors, such as nivolumab (Opdivo, Bristol-Myers Squibb Company) and pembrolizumab (Keytruda, Merck & Co, Inc). Both these drugs have already been launched, but there are similar drugs coming through the pipeline, including MPDL3280A (Genentech/Roche), MEDI4736 and MED10680 (Medimmune Inc), avelumab (Merck Serono), pidilizumab (CureTech), and others......http://www.medscape.com/viewarticle/845163
Immunotherapy for Genitourinary Cancers Still in Infancy -
Immunotherapies at ASCO....May 27, 2015......http://www.onclive.com/conference-coverage/asco-2015/ASCO-Highlights-Include-Phase-III-Findings-in-Multiple-Tumor-Types.......Findings from large, late-stage clinical trials in melanoma, non-small cell lung cancer (NSCLC), and several hematologic malignances are expected to rank among the most clinically significant research findings presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, according to industry analysts.
"Liver cancer can be added to the tumor types that have responded to the immunotherapy nivolumab (Opdivo, Bristol-Myers Squibb).....The programmed death-1 (PD-1)"
Opdivo (nivolumab) First PD-1 Inhibitor to Demonstrate Superior Overall Survival Versus Standard of Care (docetaxel) in Previously-Treated Non-Squamous Non-Small Cell Lung Cancer in Pivotal Phase III Trial......http://news.bms.com/press-release/opdivo-nivolumab-first-pd-1-inhibitor-demonstrate-superior-overall-survival-versus-sta&t=635685709624226643
Bristol-Myers Squibb to Present Data at 2015 American Society of Clinical Oncology (ASCO) Annual Meeting that Demonstrate the Promise of its Broad Immuno-Oncology Portfolio Across Solid Tumors and Blood Cancers Including Multiple Myeloma.........http://asco2015.bms.com/news/news-at-asco/press-release-details/2015/Bristol-Myers-Squibb-to-Present-Data-at-2015-American-Society-of-Clinical-Oncology-ASCO-Annual-Meeting-that-Demonstrate-the-Promise-of-its-Broad-Immuno-Oncology-Portfolio-Across-Solid-Tumors-and-Blood-Cancers-Including-Multiple-Myeloma/default.aspx
Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma.......http://www.nejm.org/doi/full/10.1056/NEJMoa1414428.....
Phase I/II Opdivo (nivolumab) Trial Shows Bristol-Myers Squibb's PD-1 Immune Checkpoint Inhibitor is First to Demonstrate Anti-Tumor Activity In Patients With Hepatocellular Carcinoma
Interim results show favorable safety profile of Opdivo, and durable responses in previously-treated patients
Overall survival rate of 62% at 12 months observed at this interim analysis
Hepatocellular carcinoma is the second most frequent cause of cancer-related death worldwide and remains an area of significant unmet medical need
Patients with hepatocellular carcinoma who have relapsed or have disease progression, following standard of care, have a median survival with best supportive care of ~7 to 8 months
Friday, May 29, 2015 2:02 pm EDT
"Bristol-Myers Squibb's experience in hepatitis and Immuno-Oncology make us poised as leaders to advance Opdivo into additional studies of hepatocellular carcinoma"
PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) today announced results from an interim analysis of CA209-040, a Phase I/II dose-ranging trial evaluating the safety and anti-tumor activity of Opdivo (nivolumab) in previously-treated patients with hepatocellular carcinoma (HCC) or advanced liver cancer. Initial findings demonstrated that the estimated survival rate in evaluable patients (n=47) was 62% at 12 months. Results also show the safety profile of Opdivo is generally consistent with that previously-reported for Opdivo in other tumor types. These data will be featured today, May 29, during the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) press briefing at 1:00 - 2:00 p.m. CDT and presented on Saturday, May 30 from 8:27 a.m. - 8:39 a.m. CDT (Late Breaking Abstract #101).
"Hepatocellular carcinoma is an aggressive and fatal cancer, comprising 90 percent of all liver cancer in adults worldwide with limited therapeutic options for patients with advanced stage disease; no treatment advances have been made for patients who fail to respond or progress on the current standard of care," said Anthony B. El-Khoueiry, MD, lead study author and associate professor of clinical medicine and phase I program director at the University of Southern California Norris Comprehensive Cancer Center. "These preliminary data are encouraging and support the ongoing evaluation of nivolumab in this patient population, as they show promising preliminary survival data, and durable partial or complete response in one out of five nivolumab-treated patients, with many others experiencing stable disease."
More than 700,000 people around the world are diagnosed with HCC each year with a majority of all HCC cases caused by infection with the hepatitis B virus (HBV) or hepatitis C virus (HCV), making HBV/HCV the most common risk factor for liver cancer worldwide. Patients with advanced HCC receiving the current standard of care have a median overall survival of less than 1 year. For patients who have relapsed or have disease progression, median survival with best supportive care is approximately 7 to 8 months.
"Bristol-Myers Squibb's experience in hepatitis and Immuno-Oncology make us poised as leaders to advance Opdivo into additional studies of hepatocellular carcinoma," said Michael Giordano, senior vice president, Head of Development, Oncology, Bristol-Myers Squibb. "Opdivo has demonstrated improvements in survival in a number of different tumor types. We are excited that this trial has shown the potential that this may extend to advanced liver cancer and hope to confirm these findings in future trials."
About the CA209-040
CA209-040 is a Phase I/II dose-ranging trial that evaluated the safety and anti-tumor activity of Opdivo in patients with HCC, the majority of whom had received prior treatment. The trial included 47 HCC patients who were enrolled into one of three treatment arms depending on whether or not they were infected with HCV or HBV. Patients enrolled in the trial received Opdivo doses ranging from 0.1 - 10 mg/kg intravenously every 2 weeks for up to 2 years. The primary objective was safety, tolerability, dose limiting toxicities, and maximum tolerated dose. Anti-tumor activity was a secondary objective (using RECIST 1.1 criteria), and overall survival was an exploratory objective.
As of this interim analysis, 62% of patients in the study were still alive after 12 months. Eight (19%) patients (of 42 evaluable patients) achieved a complete or partial response, meaning that the size of their tumors measured at baseline decreased by 30-100% with Opdivo treatment. In patients with response, duration of response ranged from more than 1.4 - 12.5 months. Seventeen patients remained on study treatment and 30 discontinued treatment due to progressive disease (n=26), complete response (n=2), or adverse events (n=2).
CA209-040 is the first trial to characterize the safety profile of Opdivo monotherapy in patients with HCC, including those with HCV and HBV infections.
In the trial, safety and tolerability were well-characterized, with the frequency and intensity of treatment-related adverse events (AEs) being consistent across Opdivo dose levels. The majority of side effects were mild to moderate in nature with abnormal liver enzymes (19% AST and 15% ALT), rash (17%) and elevation of amylase (15%) and lipase (17%) being the most common; the abnormal liver enzymes and elevated amylase and lipase were not accompanied by any significant clinical symptoms. Grade 3-4 treatment-related AEs were infrequent (19%). There were no treatment-related deaths reported.
Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials - as monotherapy or in combination with other therapies - in which more than 8,000 patients have been enrolled worldwide.
Opdivo became the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world on July 4, 2014 when Ono Pharmaceutical Co. announced that it received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma. In the U.S., the U.S. Food and Drug Administration (FDA) granted its first approval for Opdivo for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. On March 4, 2015, Opdivo received its second FDA approval for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.
IMPORTANT SAFETY INFORMATION
· Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 1 or Trial 3.
In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO; one with Grade 3 and five with Grade 2. In Trial 3, immune-mediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO, including, five Grade 3 and two Grade 2 cases. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.
· In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy.
Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; five with Grade 3 and one with Grade 2. In Trial 3, diarrhea occurred in 21% (24/117) of patients receiving OPDIVO. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor patients for immune-mediated colitis.
Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO.
· In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO; two with Grade 3 and one with Grade 2. In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis.
Immune-Mediated Nephritis and Renal Dysfunction
· In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. In Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.
Immune-Mediated Hypothyroidism and Hyperthyroidism
· In Trial 1, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. In Trial 3, hypothyroidism occurred in 4.3% (5/117) of patients receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients, including one Grade 2 case. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.
Other Immune-Mediated Adverse Reactions
· In Trial 1 and 3 (n=385), the following clinically significant immune-mediated adverse reactions occurred in <2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyeliniation, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified:
hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-BarrŽ syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone- replacement therapy.
· Based on its mechanism of action, OPDIVO 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 OPDIVO and for at least 5 months after the last dose of OPDIVO.
· It is not known whether OPDIVO 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 OPDIVO, advise women to discontinue breastfeeding during treatment.
Serious Adverse Reactions
· In Trial 1, serious adverse reactions occurred in 41% of patients receiving OPDIVO. 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 Trial 3, serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.
Common Adverse Reactions
· The most common adverse reactions (≥20%) reported with OPDIVO in Trial 1 were rash (21%) and in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).
Please see U.S. Full Prescribing Information for OPDIVO.
Immuno-Oncology at Bristol-Myers Squibb
Surgery, radiation, cytotoxic or targeted therapies have represented the mainstay of cancer treatment over the last several decades, but long-term survival and a positive quality of life have remained elusive for many patients with advanced disease.
To address this unmet medical need, Bristol-Myers Squibb is leading research in an innovative field of cancer research and treatment known as Immuno-Oncology, which involves agents whose primary mechanism is to work directly with the body's immune system to fight cancer. The company is exploring a variety of compounds and immunotherapeutic approaches for patients with different types of cancer, including researching the potential of combining Immuno-Oncology agents that target different pathways in the treatment of cancer.
Bristol-Myers Squibb is committed to advancing the science of Immuno-Oncology, with the goal of changing survival expectations and the way patients live with cancer.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.
Bristol-Myers Squibb Forward-Looking Statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee Opdivo will receive regulatory approval for an additional indication in hepatocellular carcinoma or advanced liver cancer. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2014 in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.
Study Opens Door for Nivolumab in HCC
May 29, 2015
Anita T. Shaffer
Nivolumab (Opdivo) generated antitumor responses in nearly 20% of patients with advanced hepatocellular carcinoma (HCC) in a small study that suggests a promising role for the immunotherapy agent in a malignancy with dismal outcomes,1 researchers said at the 2015 ASCO Annual Meeting.
Eight of 42 evaluable patients who participated in the phase I/II study achieved a complete (n = 2) or partial (n = 6) response, as defined by RECIST criteria, lead investigator Anthony B. El-Khoueiry, MD, said during a press briefing.
El-Khoueiry is an associate professor of clinical medicine and the phase I program director at the University of Southern California Norris Comprehensive Cancer Center in Los Angeles.
Notably, El-Khoueiry said, the responses were durable, extending beyond 9 months in 7 of the 8 responders. Tumor growth stabilized in 48% of patients, with the longest duration extending beyond 17 months. Additionally, 62% of patients in the study were still surviving with HCC at 12 months.
The study is the first to demonstrate that a PD-1 inhibitor can be effective in patients with HCC and, even though the study cohort was small, the results compare favorably with existing treatment options, El-Khoueiry indicated. He said the next step in the research is an expansion phase of the trial that will evaluate the drug in a larger group of patients.2
El-Khoueiry noted that sorafenib, which inhibits VEGFR and other kinases, is the only FDA-approved systemic therapy for patients with advanced HCC, with an average overall survival of 7 months to 11 months. "The response rate with the standard of care, which is sorafenib, is 2% to 3%," he said. "In the setting of patients who have already been treated with sorafenib it's about 30% who are usually alive at 12 months."
There is a pressing need for new therapies for patients with HCC, most of whom present with advanced disease, El-Khoueiry indicated. He said HCC is the second most frequent cause of cancer-related death worldwide, and that approximately 780,000 new cases are diagnosed annually.
Patients Stratified by Viral Status
As of mid-March 2015, the CA209-040 study, as it is labeled, enrolled 47 patients with advanced HCC with Child-Pugh scores ≤B7 whose disease progressed after sorafenib treatment or who were intolerant of sorafenib. Overall, 75% of the patients in the study had previously undergone systemic treatment, including 68% who had received sorafenib.
Participants were then divided into three treatment groups depending on whether they had been infected with either hepatitis B (n = 11) or hepatitis C (n = 12), which are risk factors for HCC, or showed no signs of either viral strain (n = 24).
Nivolumab was administered intravenously at doses ranging from 0.1 mg/kg to 10 mg/kg every 2 weeks for up to 2 years.
El-Khoueiry said no maximum-tolerated dose was identified. He also said responses occurred regardless of hepatitis infection status.
In the area of safety signals, treatment-related adverse events (AEs) of any grade were reported in 68% of the total patient population (N = 47), chiefly increases in aspartate aminotransferase (AST), lipase, alanine aminotransferase (ALT), and amylase. Rash of any grade was reported in 17% of patients and pruritis was observed in 13% of participants, although no cases of either AE fell into the grade 3/4 category. Grade 3/4 events were reported in 19% of participants, including increases in AST, ALT, and lipase.
"The safety profile of nivolumab in this study is generally consistent with that previously reported with nivolumab in other types of tumors," said El-Khoueiry, adding that there were no treatment-related deaths.
Lynn M. Schuchter, MD, FASCO, who served as moderator of the press briefing, placed the study of nivolumab in HCC in the context of immunotherapy advances across a broad range of malignancies. "These are cancers that we previously never thought about using immunotherapy for," said Schuchter, chief of the division of hematology/oncology at Penn Medicine in Philadelphia, the University of Pennsylvania's health system.
Currently, the FDA has approved nivolumab for the treatment of patients with unresectable or metastatic melanoma and for individuals with metastatic squamous non-small cell lung cancer.
El-Khoueiry said more study is needed to assess what role nivolumab might play in the treatment paradigm for HCC, as well as whether immunotherapies can be safely and effectively combined with other drugs. He said preclinical studies in mice suggest that pretreatment with sorafenib might enhance the chance of responding to anti-PD-1 therapy.
The expansion phase of the CA209-040 study is seeking to recruit approximately 400 patients into three cohorts stratified by hepatitis viral status, with an estimated completion date of July 2018.2 Primary endpoints include the incidence of worst adverse events and clinical laboratory test abnormalities.
1. El-Khoueiry AB, Melero I, Crocenzi TS, et al. Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040. J Clin Oncol. 2015 (suppl; abstr LBA101).
2. NIH Clinical Trials Registry. www.ClinicalTrails.gov. Identifier: NCT01658878
Add Liver Cancer to Nivolumab's List of Victims
May 29, 2015
CHICAGO - Liver cancer can be added to the tumor types that have responded to the immunotherapy nivolumab (Opdivo, Bristol-Myers Squibb).
The programmed death-1 (PD-1) inhibitor demonstrated an unprecedented overall response rate for a systemic therapy in advanced liver cancer, according to phase 1/2 data presented here at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting.
However, the results are early, the sample size is small, and the patient population had relatively high liver function, experts caution.
Nevertheless, eight of 42 (19%) evaluable patients responded to nivolumab (tumor reduction beyond 30%), including two with complete responses, reported lead study author Anthony B. El-Khoueiry, MD, from the University of Southern California Norris Comprehensive Cancer Center in Los Angeles.
The results compare favorably with the only systemic treatment approved by the US Food and Drug Administration for advanced liver cancer, sorafenib (Nexavar, Onyx/Bayer), which is a multitargeted tyrosine kinase inhibitor. The response rate with sorafenib in this setting is only 2%.
In the study, nivolumab was given intravenously every 2 weeks for up to 2 years.
Notably, responses to nivolumab have been durable in six of eight responders, and have surpassed 12 months in four patients.
Also, 20 (48%) of the patients had stable disease, with the longest lasting 17 months.
The overall survival rate at 12 months was 62% with nivolumab. The average overall survival rate at 12 months is about 30% with sorafenib, Dr El-Khoueiry said during a press briefing.
He also gave a big-picture perspective of the results.
"While we have to verify this early signal in larger studies, this is one of the first signs that immunotherapy with immune checkpoint inhibitors will have a role in the treatment of liver cancer," he said in a press statement.
Another medical oncologist echoed this perspective.
"PD-1 immunotherapies continue to break new ground in diseases where nothing else seems to work well. The fact that this drug might stop advanced liver cancer in its tracks for months, even a year, is great news for patients." said ASCO expert Lynn Schuchter, MD, a medical oncologist at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia.
PD-1 immunotherapies continue to break new ground.
Larger trials are needed to understand the full impact of immunotherapy in liver cancer, she added.
Closer Look: Child-Pugh Score
All the study patients had histologically confirmed advanced hepatocellular carcinoma (HCC) and a Child-Pugh score of B7 or below.
The exclusion of patients with higher Child-Pugh scores is important, said Arturo Loaiza-Bonilla, MD, who treats liver cancer patients at Penn and was asked for comment.
Essentially, the patients in the nivolumab study are Child-Pugh A, and thus "more fit and healthier," he told Medscape Medical News in an email.
Child-Pugh A patients have a better prognosis than other liver cancer patients.
The study is also unusual in that it required a confirmatory tissue biopsy of the liver. "Currently, most of the diagnosis of HCC is made with imaging studies and AFP levels," said Dr Loaiza-Bonilla.
Tissue biopsy is preferable, he explained, because it allows molecular and biomarker assessment, which are needed to move the field forward and eventually aid patient treatment selection.
Liver cancer is the second leading cause of cancer death worldwide, said Dr El-Khoueiry.
In this study, the population was largely pretreated, with 75% of the enrolled patients having received previous systemic therapy, including 68% who had received sorafenib.
The 47 patients were a mix of those infected with hepatitis B or C (n = 23) and those uninfected (n = 24).
The primary end point of the study was safety, and nivolumab was "safe and well tolerated" even in patients with ongoing hepatitis B or C infections, Dr El-Khoueiry reported.
There have not been any safety concerns related to flares of hepatitis B infection or worsening viral infection, according to meeting press materials.
Drug-related adverse events of any grade occurred in 68%, and 19% were grade 3/4.
Grade 3 and 4 adverse events that affected at least 5% of patients were aspartate aminotransferase increase (12%), alanine aminotransferase increase (10%), and lipase increase (5%).
Abnormal liver enzymes and elevated amylase and lipase of any grade occurred in less than 20% of patients; these were not accompanied by any significant clinical symptoms, Dr El-Khoueiry observed.
A dose-limiting toxicity occurred in an uninfected patient at 10 mg/kg, but no maximum tolerated dose was defined in any cohort in the dose-escalation study.
Nivolumab is currently approved in the United States for the treatment of non-small cell lung cancer and melanoma.
These new findings indicate that a new class of drugs works in liver cancer. The results "provide strong justification for more studies of nivolumab and other immunotherapy approaches for patients with advanced liver cancer," Dr El-Khoueiry said.
This study was funded by Bristol-Myers Squibb. Dr El-Khoueiry reports financial ties to multiple pharmaceutical companies, including Bristol-Myers Squibb. Some of his coauthors report financial relationships with pharmaceutical companies, and one is an employee of Bristol-Myers Squibb. Dr Schuchter reports receiving research funding from multiple pharmaceuticals, including Bristol-Myers Squibb.
American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstract LBA101. Presented May 30, 2015.
Monoclonal antibody nivolumab improves survival rates of melanoma patients
Published on May 29, 2015 at 4:42 AM
The monoclonal antibody nivolumab has shown promise as a therapeutic agent, particularly by improving the survival rates of melanoma patients. Jeffrey S. Weber, M.D., Ph.D., director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt Cancer Center will be presenting data from a retrospective analysis of the safety of nivolumab in 4 ongoing phase I-III studies in melanoma patients at the 2015 American Society of Clinical Oncology Annual Meeting in Chicago.
Nivolumab targets a protein called the programmed death-1 (PD-1) receptor. The PD-1 pathway plays an important role in controlling the immune system to prevent inadvertent immune cell activation and autoimmune disease. PD-1 is found on immune cells called T cells, while its ligand PD-L1 is expressed on antigen presenting cells. Binding of PD-L1 to PD-1 inhibits the replication and activity of immune cells and prevents an immune response. Melanoma cells express high levels of PD-L1 to avoid immune detection and improve their survival potential.
The Moffitt team and their collaborators analyzed safety data from 576 patients who received at least one dose of nivolumab. They report that drug-related adverse events were primarily low-grade. The most common adverse events included fatigue (25 percent), pruritus (17 percent), diarrhea (13 percent), and rash (13 percent). Grade 3/4 adverse events occurred in 10 percent of the patients, and prior treatment with the CTLA-4 inhibitor ipilimumab did not affect the incidence of subsequent adverse events with nivolumab.
The adverse events that occurred during nivolumab treatment were manageable. Immunomodulatory (IM) drugs were administered to resolve toxicity to 166 out of 474 patients on the phase III studies, with 114 patients receiving corticosteroids. Resolution of symptoms was dependent on the type of adverse event, with a median time of resolution of 3 weeks for hepatic adverse events and 29 weeks for skin adverse events. Only 1 patient out of 21 who had a select grade 3/4 adverse event did not have resolution following IM treatment.
Importantly, treatment with IM agents did not affect response rates; 44 percent of patients who received an IM for an adverse event responded to therapy, while 36 percent of patients who did not receive an IM responded.
The safety analysis of nivolumab in melanoma patients will be presented during a poster discussion session on Monday, June 1, 4:45 to 6 p.m. in room S100bc. There will also be a poster session on Monday, June 1, 1:15 to 4:45 p.m. in S Hall A.
H. Lee Moffitt Cancer Center & Research Institute
Bristol's Opdivo cuts risk of lung cancer death for some
By Deena Beasley
Chicago May 29 (Reuters) - Bristol-Myers Squibb Co's drug, Opdivo, improved survival in a trial of patients with the most common form of lung cancer, but it did not work in patients who tested negative for a specific protein in their tumors, leading to a nearly 7 percent sell-off in the company's shares on Friday.
The Phase III trial found that Opdivo, part of a new class of drugs that harness the immune system to fight cancer, reduced by 27 percent the risk of death from advanced non-squamous non-small cell lung cancer (NSCLC), compared with chemotherapy. The benefit reached 60 percent for patients with the highest levels of the PD-L1 protein.
"Opdivo did not work in PD-L1 negative patients," said Amit Roy, an analyst at research group Foveal. "That is nearly half of the non-squamous patients."
He said many investors had expected that the drug might be effective regardless of PD-L1 levels, but the results indicate regulators would likely restrict usage to patients who test positive for the protein.
The Bristol drug was approved by U.S. regulators in December to treat advanced melanoma and competes with Keytruda from Merck & Co Inc. The current approvals for both drugs do not require testing patients for PD-L1.
Investors have been keeping a close eye on Opdivo's performance in lung cancer, the most common form of the disease worldwide, and a far larger market. Opdivo was cleared in March to treat the less-common squamous type of NSCLC. Between 85 percent and 90 percent of all lung cancers are NSCLC, and more than two-thirds of those are the non-squamous type, according to the American Cancer Society.
Bristol shares fell $4.55, or 6.6 percent, to close at $64.60 on the New York Stock Exchange.
This latest trial, presented at the annual meeting of the American Society of Clinical Oncology, involved 582 previously treated patients with non-squamous NSCLC.
"This marks the end of the chemotherapy era in second-line treatment of lung cancer," said Fouad Namouni, who oversees Opdivo development at Bristol-Myers.
He said the company is talking with the Food and Drug Administration about applying to expand approval for Opdivo, or nivolumab, to include advanced non-squamous NSCLC. Bristol is also studying Opdivo on its own and in combination with another immunotherapy called Yervoy as an initial treatment for lung cancer.
The trial results showed median overall survival of 12.2 months for the Opdivo group compared with 9.4 months for patients treated with docetaxel. For the subgroup of patients with high levels of PD-L1, which is used by tumors to evade the body's defenses, median survival exceeded 17 months with Opdivo, compared with 9 months for chemotherapy patients.
One in 10 Opdivo patients in the trial experienced serious side effects, compared with more than half of patients in the chemotherapy group.
Roy said eventual use of rival immunotherapy drugs being developed by Roche Holding AG, AstraZeneca Plc and Pfizer Inc will also likely be restricted based on biomarker levels.
The ASCO conference also featured results from an early-stage study of Opdivo showing that 19 percent of patients with advanced liver cancer responded to the antibody with tumor shrinkage of more than 30 percent.
Researchers said that compares with a response rate of just 2 percent for Nexavar, the only currently approved systemic treatment for advanced liver cancer. Nexavar is produced by subsidiaries of Bayer AG and Amgen Inc (Editing by Andre Grenon)