“Pamela L. Kunz, MD, assistant professor of Medicine (Oncology), Stanford University School of Medicine, discusses the potential of immunotherapy in the treatment of patients with neuroendocrine tumors (NETs).
“There are currently some clinical trials under development looking at immunotherapy in NETs both at Stanford University School of Medicine and University of Pennsylvania, Kunz explains. One phase I/II trial will examine the safety and efficacy of intratumoral injection of ipilimumab combined with an anti—PD-L1 agent in these patients.”
“It is possible that immunotherapy agents could be agnostic to disease sites, Kunz says. Though it was originally believed that PD-1/PD-L1 expression is a requirement to be a predictive biomarker, additional research could show that it may not be necessary.”
“The combination of nivolumab and ipilimumab has received accelerated FDA approval as a treatment for patients with BRAF V600 wild-type (WT) unresectable or metastatic melanoma, based on findings from the phase II CheckMate-069 study.
” ‘Historically, metastatic melanoma has been a difficult disease to treat. Now, a new treatment option based on the combination of two valued immuno-oncology agents demonstrates significant efficacy versus ipilimumab in metastatic melanoma,’ said Jedd D. Wolchok, MD, PhD, chief, Melanoma and Immunotherapeutics Service, Department of Medicine and Ludwig Center at Memorial Sloan Kettering Cancer Center, in a statement. ‘Today’s approval represents a step forward for the melanoma community, providing hope for patients with metastatic melanoma.’ ”
“The FDA has accepted a supplemental biologics license application for the Opdivo plus Yervoy regimen to include data from a phase 3 trial of patients with previously untreated advanced melanoma, according to a press release from Bristol-Myers Squibb.
“The agency also granted priority review of the application, with a target action date of Jan. 23, according to the release
” ‘Findings from CheckMate -067 provide additional evidence that the combination of the two immuno-oncology agents, Opdivo [nivolumab] and Yervoy [ipilimumab], may provide improved outcomes for patients with advanced melanoma, and has the potential to become the basis of how this devastating disease is treated,’ Michael Giordano, senior vice president, head of development for oncology at Bristol-Myers Squibb, said in a press release. ‘We saw significant clinical benefit from the Opdivo+Yervoy regimen in these patients, including an increase in the time patients lived without disease progression, and we look forward to working with the FDA to review this data.’ “
“Patients with advanced melanoma skin cancer survive for longer without their disease progressing if they have been treated with a combination of two drugs, nivolumab and ipilimumab, than with either of these drugs alone. New results show that these patients also do better regardless of their age, stage of disease and whether or not they have a cancer-driving mutation in the BRAF gene.
“Dr James Larkin, a Consultant Medical Oncologist at The Royal Marsden, London, UK, told the 2015 European Cancer Congress, that results from the CheckMate 067 phase III clinical trial had already shown that the combination of the two drugs, which target two different pathways that regulate the immune system, improved the progression-free survival in patients with melanoma who had not received any other treatment. However, until now it was not known whether this remained the case when the results were analysed according to genetic status, age and how advanced was their disease.
“Nivolumab is an inhibitor of the programmed cell death protein 1 (known as PD-1), which functions as an immune checkpoint, playing an important role in the immune system. Ipilimumab inhibits the CTLA-4 checkpoint, which also plays a role in the immune system.”
“Nivolumab (Opdivo) and ipilimumab (Yervoy), a chemotherapy-free regimen, showed activity as a first-line therapy for patients who have advanced non-small cell lung cancer (NSCLC), according to a preliminary clinical trial that was presented at this year’s World Conference on Lung Cancer.
“Four different regimens of nivolumab, the PD-1 inhibitor, and ipilimumab, the anti-CTLA-4 antibody, led to response rates of 13% to 39% in 148 patients with no prior exposure to systemic therapy. The combination produced deep and durable responses, with a low rate of treatment-emergent grade 3/4 adverse events (AEs) leading to discontinuation.
“ ‘Clinical activity was observed regardless of tumor PD-L1 expression,’ said lead investigator Naiyer A. Rizvi, MD, director of Thoracic Oncology and Immunotherapeutics at Columbia University Medical Center. ‘We have preliminary evidence of greater activity in tumors that have 1% or greater PD-L1 expression. The median disease control rate [response plus stable disease] was not reached in any arm, regardless of PD-L1 expression.’ “
“Bristol-Myers Squibb Company (NYSE:BMY) today announced updated results from the Opdivo (nivolumab)+Yervoy (ipilimumab) arms in CheckMate -012, a multi-arm Phase 1b trial evaluating Opdivo in patients with chemotherapy-naïve advanced non-small cell lung cancer (NSCLC). In this study, Opdivo was administered as monotherapy or as part of a combination with other agents, including Yervoy, at different doses and schedules. Results from other cohorts in CheckMate -012 have been previously-unreported. These updated results include findings from the administration of four new dosing schedules of Opdivo+Yervoy (n=148), which resulted in confirmed objective response rates (ORR) ranging from 13% to 39% depending on the administered regimen. Median duration of response was not reached in any of these arms with a median follow-up of 6.2 months to 16.6 months, and median progression-free survival (PFS) ranged from 4.9 months to 10.6 months.”
“Adverse events related to immune activation with ipilimumab (Yervoy, Bristol-Myers Squibb Company) may be higher than clinical trials have previously suggested, according to a study of real-world clinical data from patients treated at Memorial Sloan Kettering Cancer Center, in New York City. The study was published online August 17 in the Journal of Clinical Oncology.
“Ipilimumab was the first of the novel immunotherapies launched for melanoma, and so far it is the only one that is an anticytotoxic T-cell lymphocyte-4 (anti-CTLA-4) antibody. It can cause immune activation and adverse reactions, such as diarrhea, rash, hepatitis, and pituitary inflammation. These reactions are often treated with steroids; severe reactions may require treatment with an anti–tumor necrosis factor alpha (anti-tNFα), such as infliximab (Remicade, Janssen Biotech, Inc).
” ‘Among our small group of physicians highly experienced with ipilimumab, we felt that 35% of the patients required systemic steroids to treat adverse events,’ commented lead author Paul Chapman, MD, a specialist in metastatic melanoma at Memorial Sloan Kettering Cancer Center.”
“Jason J. Luke, MD, FACP, assistant professor of medicine, The University of Chicago, discusses the efficacy of PD-1/PD-L1 inhibitors in melanoma. The combination of these inhibitors, nivolumab and ipilimumab, was used to treat patients with previously untreated, unresectable or metastatic melanoma, in the Checkmate 069 study.
“Luke says PD-L1 is very complex and difficult when developing immunohistochemical assays. Since several pharmaceutical companies conduct different assays that test various things, a particular patient may be positive in one case, but not in another. For this reason, patients become very confused.
“Luke also mentions that there is no validated method across the board, so it is difficult to determine the next steps going forward.”
Of all cancer types, melanoma is the most investigated in terms of its potential to be treated through immune system-based approaches. More immunotherapy drugs are approved for melanoma than for any other type of cancer, and more are in development. Recent additions to the immunotherapy arsenal are the ‘anti-PD-1’ immune checkpoint blockade drugs pembrolizumab (Keytruda) and nivolumab (Opdivo). Continue reading…