Combining BRAF Inhibition, Anti-PD-1 No Help in BRAF-Mutant Melanoma

Excerpt:

“Patients with BRAF-mutant melanoma obtained no survival benefit from combined treatment of anti-BRAF therapy and an immune checkpoint inhibitor, a retrospective analysis showed.

“Median progression-free survival (PFS) was 6.0 to 6.5 months in BRAF-inhibitor naive patients who received a PD-1/PD-L1 inhibitor alone or with a BRAF inhibitor. Patients with prior exposure to a BRAF inhibitor had a median PFS of 8.0 months with anti–PD-1 therapy and 4.5 months with combined treatment. Median overall survival was 10.5 to 12 months with a PD-1/PD-L1 inhibitor alone or in combination with a BRAF inhibitor, regardless of prior BRAF inhibitor exposure status.

“ ‘BRAF inhibitor-refractory patients derived no additional benefit with anti-PD therapy in combination with BRAF inhibition,’ Wen-Jen Hwu, MD, of MD Anderson Cancer Center in Houston, and colleagues concluded in a poster presentation at the 2016 ASCO Annual Meeting in Chicago. ‘Clinical findings are similar with either anti-PD alone or in combination with BRAF inhibition in terms of objective response rate (ORR), disease control rate (DCR), and overall survival (OS).’ ”

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Avelumab Promising in Unresectable Mesothelioma

Excerpt:

“The novel anti-PD-L1 agent avelumab showed some promising clinical activity and was generally well tolerated in a phase I trial of patients with unresectable, previously treated mesothelioma. Results of the trial were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, held June 3–7 in Chicago.

“ ‘Approximately 3,000 new cases of malignant mesothelioma are diagnosed each year in the United States,’ said Raffit Hassan, MD, of the National Cancer Institute in Bethesda, Maryland, who presented the study. The current standard treatment of pemetrexed and cisplatin yields a median overall survival of 12.1 months, and there is no US Food and Drug Administration (FDA)-approved therapy for patients progressing after first-line chemotherapy.

“Avelumab is a fully human anti-PD-L1 IgG1 antibody; it is under investigation in multiple malignancies. PD-L1 is expressed on the surface of mesothelioma cells, providing a rationale for avelumab’s use in this malignancy. In the new JAVELIN study, more than 1,600 patients have been treated with the drug across a variety of malignancies; in this analysis, 53 patients with unresectable pleural or peritoneal mesothelioma were included. All patients had progressed after a platinum/pemetrexed-containing regimen; they were unselected for PD-L1 expression.”

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Distinct Features Associated With Benefit for BRAF/MEK Inhibition

Excerpt:

“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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FDA Grants Priority Review for Genentech’s Cancer Immunotherapy Atezolizumab in Specific Type of Lung Cancer

Excerpt:

“Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that the U.S. Food and Drug Administration (FDA) has accepted the company’s Biologics License Application (BLA) and granted Priority Review for atezolizumab (anti-PDL1; MPDL3280A) for the treatment of people with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease expresses the protein PD-L1 (programmed death ligand-1), as determined by an FDA-approved test, and who have progressed on or after platinum-containing chemotherapy.

“ ‘In a study of atezolizumab in people with previously treated advanced lung cancer, PD-L1 expression correlated with how well they responded to the medicine,’ said Sandra Horning, M.D., chief medical officer and head of Global Product Development. ‘The goal of PD-L1 as a biomarker is to identify people most likely to benefit from atezolizumab alone.’ ”

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Relevancy of PD-L1 as a Biomarker for Immunotherapies in NSCLC

“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.”


AZ Cancer Immunotherapy Combo Impresses in Lung Cancer Trial

“Two immuno-oncology drugs in development at AstraZeneca (AZ) have shown potential as a dual therapy for non-small cell lung cancer, according to a new study.

“The phase II trial – reported in Lancet Oncology – found that combining anti-PD-L1 antibody durvalumab with anti-CTLA-4 antibody tremelimumab achieved an overall response rate (ORR) of 23%, significantly higher than has previously been seen with durvalumab alone in this setting.

“The trial was small and focused primarily on safety, but the preliminary efficacy signal – albeit in just 26 patients – is encouraging, according to an editorial accompanying the study by Edward Garon of the David Geffen School of Medicine at the University of California, Los Angeles.”


Putting Immune Checkpoint Blockade to the Test in Breast Cancer


About 10 months ago, we asked: Is There a Future for Immunotherapy in Breast Cancer? Now, we can answer this question with a qualified “yes.” The data show why:

Triple-negative breast cancer (TNBC)

TNBC has long been considered to be more amenable to immune system-based treatments than other types of breast cancer because it is more immunogenic; that is, relatively high levels of immune cells accumulate within or adjacent to TNBC tumors. These immune cells could be triggered to attack tumors if properly activated. TNBC tumors are also likely to have a higher mutational burden (number of genetic mutations). This is one of the predictors of sensitivity to a type of treatment called immune checkpoint blockade.  Drugs known as checkpoint inhibitors block the proteins PD-1 or PD-L1. In cancer, PD-L1 proteins on tumor cells bind to PD-1 proteins on immune T cells and inhibit their tumor-killing activity. Immune checkpoint drugs disable this interaction and enable activation of T cells. These drugs are actively being explored in TNBC in clinical trials.

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Video: Dr. Saeed Rafii on the Phase Ib JAVELIN Trial Examining Avelumab in Breast Cancer

“Saeed Rafii, MD, PhD, MRCP, medical oncologist, medical director, Sarah Cannon Research Institute, London, discusses the phase Ib JAVELIN solid tumor trial. The trial looks at the anti-PD-L1 antibody avelumab (MSB0010718C) in patients with locally advanced or metastatic breast cancer. Rafii said the trial looked at 168 patients, regardless of the subtype of their breast cancer.

“Patients enrolled in the trial must have had 3 or fewer lines of chemotherapy prior to receieving avelumab. Rafii said of the patients, 10% experiences immune-related events. He also added that 8 patients had to stop due to treatment-related toxicities and that there were 2 mortalities. One of the 2 mortalities were from acute hepatic failure and another from respitority distress.”

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Video: Dr. Kunz on Potential of Immunotherapy in Neuroendocrine Tumors

“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.”

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