MELANOMA

Combination dabrafenib and trametinib versus combination nivolumab and ipilimumab for patients with advanced BRAF-mutant melanoma: The DREAMseq Trial - ECOG-ACRIN EA6134

Recent findings showed a significant advantage in the 2-year overall survival rate for advanced melanoma patients who first underwent immunotherapy (72% survival rate) versus those who initially received targeted therapies (52% survival rate). In this Phase III trial, patients with treatment-naive BRAF V600-mutant metastatic melanoma were randomized to receive either combination nivolumab/ipilimumab (Arm A) or dabrafenib/trametinib (Arm B) in Step 1, and at disease progression they were enrolled in Step 2 receiving the alternate therapy, dabrafenib/trametinib (Arm C) or nivolumab/ipilimumab (Arm D). The primary endpoint was 2-year overall survival. Secondary endpoints included 3-year overall survival, objective response rate, response duration, progression-free survival, crossover feasibility, and safety. The researchers enrolled 265 patients. Of those, 73 went on to Step 2 (27 Arm C, 46 Arm D). The study was stopped early due to a clinically significant endpoint being achieved, according to the study authors. Data revealed a 2-year overall survival rate of 71.8 percent for patients starting on Arm A compared with 51.5 percent for those in Arm B. Additionally, Step 1 progression-free survival favored Arm A. The study authors reported that crossover occurred in 52 percent of patients with documented disease progression. They also observed that Grade >3 toxicities occurred with similar frequency between arms and regimen toxicity profiles were as expected. "Combination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority of patients," the study authors concluded.

AUTHOR COMMENTARY: "With further analysis of the data since our initial report, we not only know that patients with metastatic BRAF-mutant melanoma in general do better when combination immunotherapy is administered prior to combination targeted therapy, but we also have a better idea as to why," noted study author Michael Atkins, MD, Deputy Director of Georgetown Lombardi Comprehensive Cancer Center. "Specifically, combination immunotherapy, in contrast to targeted therapy, produces more long-lasting tumor shrinkage, reduces the risk of disease progression in the central nervous system, and doesn't interfere with the subsequent effectiveness of the alternative treatment approach."

IMMUNE MODULATOR

Mitigating the prevalence and function of myeloid-derived suppressor cells by redirecting myeloid differentiation using a novel immune modulator

Researchers uncovered a new strategy for correcting immune dysfunction among cancer patients. This research, which included both laboratory studies and an early-phase clinical trial, demonstrated that a novel immune modulator known as VSSP (very small size particle) can significantly reduce myeloid-derived suppressor cells (MDSCs) in advanced kidney cancer (J Immunother Cancer 2022; 10(9):e004710). The investigators sought to find an alternative method for targeting MDSCs using VSSP, a nanoparticle that has been in clinical development in Cuba for more than 10 years and has been incorporated into the formulation of three different cancer vaccine candidates currently at different stages of clinical testing. The endpoints in this study included safety and impact on polymorphonuclear (PMN)-MDSC frequency and function. Data demonstrated that VSSP diminished PMN-MDSCs by shunting granulocyte-monocyte progenitor differentiation toward monocytes/macrophages and dendritic cells with heightened expression of the myeloid-dependent transcription factors interferon regulatory factor-8 and PU.1, according to the study authors. "This skewing was at the expense of expansion of granulocytic progenitors and rendered the remaining MDSCs less suppressive," they reported. "Importantly, these effects were also demonstrated in a clinical setting wherein VSSP monotherapy significantly reduced circulating PMN-MDSCs and their suppressive function." Together, these data showed the potential of VSSP as a "novel regulator of myeloid biology that mitigates MDSCs in cancer patients and reinstates a more normal myeloid phenotype that potentially favors immune activation over immune suppression."

AUTHOR COMMENTARY: "Our findings also suggest that the mechanism by which VSSP is interfering with the immunosuppressive signals coming from the tumor is at early stages of the generation of the myeloid dysfunction," according to Circe Mesa, PhD, Department of Immunoregulation, Immunology and Immunotherapy Direction at the Center for Molecular Immunology in Havana, Cuba. "This may position VSSP as a first-in-class immune-modulating therapy to combine with antitumor therapies dampened by a dysfunctional myeloid compartment."

BREAST CANCER

Elevated c-reactive protein and subsequent patient-reported cognitive problems in older breast cancer survivors: The thinking and living with cancer study

Long-term findings suggest that higher levels of a key inflammatory marker are related to older breast cancer survivors reporting cognitive problems (J Clin Oncol 2022; doi:10.1200/JCO.22.00406). The Thinking and Living with Cancer (TLC) study is one of the first long-term efforts to examine the potential link between chronic inflammation and cognition in breast cancer survivors 60 and older. From September 2010 to March 2020, researchers enrolled English-speaking women 60 years or older who were newly diagnosed with primary breast cancer (Stage 0-III), as well as frequency-matched controls. Women with dementia, neurologic disorders, and other cancers were excluded from the study. Researchers talked to and obtained blood samples from breast cancer survivors and women without cancer up to 6 times over the course of 5 years. The analysis included 400 survivors and 329 controls with C-reactive protein (CRP) specimens and follow-up data (average age: 67.7 years). The study authors measured cognition using the Functional Assessment of Cancer Therapy-Cognitive Function and neuropsychological testing. At each visit, mixed linear effect models tested for survivor-control differences in natural log (ln)-transformed CRP. Random effect-lagged fluctuation models tested directional effects of ln-CRP on subsequent cognition, according to the researchers. Of the survivors, the majority had Stage I (60.9%), estrogen receptor-positive (87.6%) tumors. Data showed that survivors had significantly higher adjusted mean ln-CRP than controls at baseline and 12-, 24-, and 60-month visits. Higher adjusted ln-CRP predicted lower participant-reported cognition on subsequent visits among survivors, but not in the control group, the study authors reported, while also noting that effects were unchanged by depression or anxiety. They observed that survivors overall had adjusted Functional Assessment of Cancer Therapy-Cognitive Function scores that were 9.5 and 14.2 points lower than controls at CRP levels of 3.0 and 10.0 mg/L. "Longitudinal relationships between CRP and cognition in older breast cancer survivors suggest that chronic inflammation may play a role in development of cognitive problems," the study authors concluded. "CRP testing could be clinically useful in survivorship care."

AUTHOR COMMENTARY: "Blood tests for CRP are used routinely in the clinic to determine risk of heart disease," said lead study author Judith Carroll, PhD, Associate Professor of Psychiatry and Biobehavioral Sciences and Faculty Member of the Cousins Center for Psychoneuroimmunology at UCLA. "Our study suggests this common test for inflammation might also be an indicator of risk for cognitive problems reported by breast cancer survivors."