“Immunotherapy has led a transformation for melanoma care but combinations of anti–PD-1 and CTLA-4 agents are toxic and biomarkers are not available to help personalized treatment, calling for further research into less toxic and more effective options, according to a presentation by Caroline Robert, MD, PhD, at the 2017 World Congress of Melanoma.
“At this point, the only approved immunotherapy combination remains the PD-1 inhibitor nivolumab (Opdivo) and the CTLA-4 inhibitor ipilimumab (Yervoy). However, research into combination approaches is now focusing on triplets of anti–PD-1 therapies and new checkpoints, such as IDO. Additionally, ongoing research continues to search of a biomarker of response for immunotherapy in melanoma.”
“The combination of the programmed death receptor 1 (PD-1) inhibitor nivolumab at a reduced dose (1 mg/kg) with the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab at standard dose (3 mg/kg) for four doses followed by standard-dose nivolumab alone is a standard of care for patients with advanced, previously untreated melanoma. This is based on results from the phase III CheckMate-067 trial that confirmed combination therapy is significantly more effective than single-agent nivolumab or ipilimumab. However, improvement in efficacy is associated with increased treatment-related grade 3/4 adverse events and treatment discontinuation in nearly 40% of patients.”
“Whether a melanoma patient will better respond to a single immunotherapy drug or two in combination depends on the abundance of certain white blood cells within their tumors, according to a new study conducted by UC San Francisco researchers joined by physicians from UCSF Health. The findings provide a novel predictive biomarker to identify patients who are most likely to respond well to a combination of immunotherapy drugs known as checkpoint inhibitors—and to protect those who won’t respond from potentially adverse side effects of combination treatment.
” ‘Combination immunotherapy is super-expensive and very toxic,’ said Adil Daud, MD, director of Melanoma Clinical Research at the UCSF Helen Diller Family Comprehensive Cancer Center and senior author of the new study. ‘You’re putting patients at a lot of extra risk if they don’t need it, and you can adjust for that risk by knowing in advance who can benefit.’ ”
“Bristol-Myers got a much-needed boost with the earlier-than-expected news that Opdivo beat out Yervoy in a Phase III study focused on a particular niche for adjuvant melanoma therapy. And an analyst who’s been following the data says it could be worth a billion dollars in added annual sales.
“The big biotech says an interim analysis of Checkmate-238 provided researchers with proof that the PD-1 drug outperformed Yervoy, Bristol-Myers’ CTLA-4 drug, among advanced Stage IIIb or IV patients, cutting the recurrence rate for those who have undergone surgery. There are no bottom line numbers in the statement, but Bristol-Myers says they’ll be able to release data at an upcoming conference to show that Opdivo provided a significantly lower risk of disease recurrence.”
“Bristol-Myers Squibb (BMS) and AstraZeneca have each announced separate delays in the development of PD-1 and CTLA-4 inhibitor combinations as first-line therapies for patients with advanced or metastatic non–small cell lung cancer (NSCLC), according to statements from each of the companies.
“In its statement, BMS noted that it would not be pursuing an accelerated approval for the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) as a frontline therapy for NSCLC. Instead, the company plans to delay the submission of data to the FDA until findings from a phase III study are available, most likely from the phase III CheckMate-227 trial.”
New targeted and immunotherapy drugs have changed the diagnosis of metastatic melanoma from a death sentence into a disease that can potentially be managed and even cured. Nevertheless, these new drugs do not work in all patients, or they may stop working after a transient response. This post (part one of two) will describe ongoing efforts to find drug combinations with higher efficacy than single drugs and decipher the mechanisms underlying drug resistance. Continue reading…
“With the development of novel targeted and immunotherapeutic agents that are more efficacious than traditional chemotherapy, treatment paradigms in melanoma have undergone major changes. Current recommendations for first-line systemic therapy for patients with advanced or metastatic melanoma consider BRAF mutation status, tumor growth rate, and the presence or absence of cancer-related symptoms.
“Immunotherapies with agents that block CTLA-4 or PD-1/PD-L1 checkpoints have been associated with durable responses in a subset of patients, and are often considered for patients with low-volume, asymptomatic metastatic melanoma. Targeted therapies, on the other side, are preferred for patients with BRAF-mutant tumors who have symptomatic disease and benefit from the rapid response associated with these agents.”
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“Despite its initial running start, the continuing development of immunotherapies in the field of non-small cell lung cancer (NSCLC) won’t be slowing down anytime soon, according to Naiyer Rizvi, MD.
“ ‘The field is changing so fast,’ said Rizvi, director of Thoracic Oncology and Immunotherapeutics, Columbia University Medical Center, in an exclusive interview with Targeted Oncology. ‘Soon, we will have a better understanding of the first-line use of PD-1 agents, Then, maybe a year later, the data on the combination of PD-1/PD-L1 and CTLA-4 will come out. It is going to be a busy year. The NCCN [National Comprehensive Cancer Network] is going to be busy rewriting their guidelines every 6 months at this rate.’
“One immunotherapy currently being investigated is the anti–PD-1 agent pembrolizumab (Keytruda), in the KEYNOTE-024 study. The study is looking at pembrolizumab in the first-line setting for patients with stage IV metastatic NSCLC whose tumors express PD-L1.”
“A combination of the anti–PD-L1 immune checkpoint inhibitor durvalumab (MEDI4736) with the anti–CTLA-4 monoclonal antibody tremelimumab showed improved tumor response in patients with advanced non–small cell lung cancer (NSCLC) over single-agent therapy.
“The study, published in the Journal for ImmunoTherapy of Cancer, was a phase I, open-label, dose-escalation/expansion study that contained 84 patients. Of these patients, 48 had two or more prior lines of therapy. Data from the study showed improved tumor response regardless of PD-L1 status, with an overall response rate of 25% and 35% of PD-L1-negative patients receiving a response (0% tumor cell staining).”