Chemotalk Newsletter

Chemotalk Newsletter, Vol. 110 June 1, 2017

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Much is new this month, and even more will be forthcoming next month, with the oncology conventions in progress.  As I've said before, skip over what you don't understand because there's plenty you will.  So here goes:

SURVIVALIN MDS EQUIVALENT WITH REDUCED-INTENSITY CONDITIONING

By Leah Lawrence

    Patients with MYELODYSPLASTIC SYNDROME (MDS) undergoing a reduced­intensity conditioning (RIC) regimen prior to allogeneic stem-cell transplantation had similar 2-year relapse-free and overall survival as patients who underwent myeloablative conditioning (MAC), according to the results of the RICMAC trial.

    "The role of conditioning regimen intensity before allogeneic stem-cell transplantation for MDS has not been studied prospectively and recommendations are based on retrospective single-center or registry studies," wrote Nicolaus Kröger, MD, department of stem cell transplantation, University Medical Center Hamburg-Eppendorf, and colleagues in a study published in the Journal of Clinical Oncology. "The rationale for using RIC before allogeneic stem-cell transplantation is to shift from high-dose chemotherapy that is aimed at maximizing cytotoxic leukemia killing to a more immune-mediated effect by harvesting the graft-vs-tumor effect to eradicate the disease."

    In this study, the researchers enrolled 129 patients with MDS or secondary acute myeloid leukemia and randomly assigned them 1:1 to a busulfan-based RIC or MAC.

    At 1 year, the non-relapse mortality was 17% in patients assigned RIC compared with 25% in patients assigned MAC (P = .29). The cumulative incidence of relapse at 2 years was 17% for RIC and 14.8% for MAC. This resulted in a 2-year relapse-free survival of 62.4% for RIC and 58.3% for MAC.

    "In a multivariate analysis for overall survival, RIC resulted in a significant survival benefit at 2 years," the researchers wrote. The 2-year overall survival was 76% for RIC and 63% for MAC.

    "Improved survival after RIC might be a result of lower mortality after relapse," they added. "Whereas after MAC six of nine patients who experienced relapse died, in the RIC arm, only two of 11 patients who experienced relapse died."

    In the low-risk group, treatment with RIC resulted in a lower non-relapse mortality (HR, 0.30). However, in patients with intermediate- and high-risk disease, treatment with RIC resulted in a higher non-relapse mortality (HR, 1.17; and HR, 2.14). The researchers noted that "conclusive answer for this observation cannot be given, but a possible explanation would be that low-risk patients are protected from relapse and are thus more at risk for death without relapse."

    Acute grade 2 to grade 4 and grade 3 and 4 graft-vs-host disease occurred in 32.3% and 15% of patients in the RIC arm and 37.5% and 14% of patients in the MAC arm, respectively. The cumulative incidence of chronic graft-vs-host disease was 61.6% after RIC and 64.7% after MAC.

    The researchers concluded by writing, "our study shows that RIC and MAC followed by allogeneic stem-cell transplantation resulted in at least an equivalent survival trend for a better 2-year overall survival, especially in the cytogenetic low-risk group," suggesting that RIC "can be offered as an alternative to a myeloablative regimen."

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C3d PROTEIN REVERSES TUMOR-MEDIATED IMMUNE SUPPRESSION

By Bryant Furlow

    Vaccination with the immune complement component C3d protein blocks tumor-mediated immunosuppression, enhancing antitumor immune response‹an "entirely new" approach to countering tumor immune suppression and evasion, according to authors of a new preclinical study of mice with LYMPHOMA and MELANOMA.

    Free C3d reversed tumor immune suppression and led to remarkable 80% to 90% reductions in tumor burden among mice with murine lymphoma and melanoma, the team reported. The findings were published in the journal JCI Insight.

    "Our cancer therapy blocks tumor-induced immunosuppression," said coauthor Marilia Cascalho, MD, PhD, associate professor of surgery, microbiology, and immunology at University of Michigan Medicine in Ann Arbor, Michigan. "The biggest surprise is that free C3d cancer vaccination produced long-lived antitumor immunity."

    The work stemmed from unexpected findings in human immunodeficiency virus vaccine research.

    Free, circulating C3d enhanced antitumor immunity "independently of B cells, NK [natural killer] cells, or antibodies, but it does so by increasing tumor infiltrating CD8-positive lymphocytes, by depleting Tregs [regulatory T cells], and by suppressing expression of programmed cell death protein 1 (PD-1) by T cells," Cascalho and colleagues reported.

    C3d vaccination might circumvent the need to identify and target tumor-specific neoantigens. "Free C3d doesn¹t require prior knowledge of any specific cancer antigens," Cascalho explained.

    Cascalho disclosed a pending patent application for C3d as an anticancer agent.

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CERITINIB GETS FIRST-LINE FDA APPROVAL FOR ALK-POSITIVE LUNG CANCER

By Dave Levitan

    Ceritinib is now approved as a first-line treatment in patients with m...
The US Food and Drug Administration (FDA) has expanded the approval for ceritinib. The agent is now approved as a first-line treatment in patients with metastatic, ALK-POSITIVE, NON-SMALL-CELL LUNG CANCER (NSCLC).

    Ceritinib (Zykadia, Novartis) was previously approved in 2014 for ALK-positive metastatic NSCLC in patients who had progressed or were intolerant to crizotinib. The agent is a selective oral ALK inhibitor, with a potency twenty times that of crizotinib.

    The new indication is based on results of the ASCEND-4 trial, results of which were published in January of this year in Lancet. The trial randomized
376 patients with metastatic NSCLC with ALK rearrangements to either ceritinib (189 patients) or to platinum-pemetrexed doublet therapy (187 patients).

    The primary endpoint was progression-free survival, and ceritinib was more effective. The median progression-free survival was 16.6 months with the study drug, compared with 8.1 months in the chemotherapy arm, for a hazard ratio of 0.55 (95% CI, 0.42­0.73; P < .0001).

    The overall response rate was also better, at 73% with ceritinib and 27% with CHEMOTHERAPY. The median response duration was 23.9 months with ceritinib and 11.1 months with platinum/pemetrexed. At this point, overall survival data remain immature. Ceritinib was granted Breakthrough Therapy designation by the FDA, along with a priority review for first-line therapy in this patient population.

    The ASCEND-4 study also examined response rates in patients with measurable central nervous system lesions. The confirmed intracranial response rate was 57% with ceritinib, compared with 22% with chemotherapy.

    Serious adverse events (AEs) occurred in 38% of patients treated with ceritinib, and AEs leading to discontinuation of the drug occurred in 12%.
Dose interruptions due to AEs were seen in 77% of ceritinib patients, and 66% required dose reductions. The most common AEs with the drug in ASCEND-4 included diarrhea, nausea, vomiting, fatigue, and abdominal pain.

    "Today¹s approval represents the next step in the development of Zykadia as a treatment option for ALK-positive metastatic NSCLC, bringing this important medication to a patient population where a need still exists," said Novartis Oncology¹s CEO Bruno Strigini, in a press release.

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Until July...

 

And if you have any thoughts of how this newsletter could be improved, please email me directly, at Elaine@elainejesmer.com.

Elaine Jesmer

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