This twice-monthly newsletter highlights the research endeavors at Dana-Farber Cancer Institute, noting recently published papers available from PubMed where Dana-Farber faculty are listed as first or senior authors. If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know at: [email protected].

Blood

Increased COVID-19 Breakthrough Infection Risk in Patients with Plasma Cell Disorders

La J, Wu JT, Branch-Elliman W, Huhmann L, Han SS, Brophy M, Do NV, Lin AY, Fillmore NR,
Munshi NC
Patients with multiple myeloma (MM) are at increased risk of infection and severe outcomes from COVID-19 infection, partly owing to inadequate protection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Their susceptibility stems from both immune-suppressive treatments used for MM and underlying immune-deficiency from the disease itself. However, it is unknown how much risk is shared by patients with monoclonal gammopathy of undetermined significance (MGUS), a precursor state to MM that does not require immune-suppressive treatment but may be associated with immune-deficiency. Here, we measured the risk of breakthrough infections among vaccinated patients with MM or MGUS relative to the patients without MM or MGUS in the national Veterans Affairs (VA) health care system and described the association of MM-specific treatments with breakthrough risk.

Cancer Cell
Personalized Neoantigen Vaccine NEO-PV-01 with Chemotherapy and Anti-PD-1 as First-Line Treatment for Non-Squamous Non-Small Cell Lung Cancer

Awad MM
Neoantigens arising from mutations in tumor DNA provide targets for immune-based therapy. Here, we report the clinical and immune data from a Phase Ib clinical trial of a personalized neoantigen-vaccine NEO-PV-01 in combination with pemetrexed, carboplatin, and pembrolizumab as first-line therapy for advanced non-squamous non-small cell lung cancer (NSCLC). This analysis of 38 patients treated with the regimen demonstrated no treatment-related serious adverse events. Multiple parameters including baseline tumor immune infiltration and on-treatment circulating tumor DNA levels were highly correlated with clinical response. De novo neoantigen-specific CD4+ and CD8+ T cell responses were observed post-vaccination. Epitope spread to non-vaccinating neoantigens, including responses to KRAS G12C and G12V mutations, were detected post-vaccination. Neoantigen-specific CD4+ T cells generated post-vaccination revealed effector and cytotoxic phenotypes with increased CD4+ T cell infiltration in the post-vaccine tumor biopsy. Collectively, these data support the safety and immunogenicity of this regimen in advanced non-squamous NSCLC.

Journal of Clinical Oncology

Point/Counterpoint: Is It Time for Universal Germline Genetic Testing for All GI Cancers?

Yurgelun MB
Use of germline genetic testing among patients with cancer is increasing because of (1) the availability of multigene panel tests that include multiple cancer susceptibility genes in a single test, (2) decreased costs of these tests and improvements in insurance coverage, and (3) US Food and Drug Administration-approval of genotype-directed therapies such as poly(ADP-ribose) polymerase inhibitors for individuals with certain cancers and pathogenic germline variants in BRCA1 and BRCA2 (with possible benefits with other genes in the homologous repair deficiency pathway). In addition, National Comprehensive Cancer Network guidelines have already endorsed germline genetic testing for all patients with certain cancer types (epithelial ovarian cancer, exocrine pancreatic cancer, and high-grade/metastatic prostate cancer), regardless of age or personal/family history of cancer. Herein, we debate the pros and cons of offering germline multigene panel testing to all patients diagnosed with any GI cancer. The authors agree that it may just be a matter of time before germline multigene panel testing is offered to all patients with cancer; however, this article will highlight some of the benefits, risks, and limitations of this approach so that research can help fill some of the gaps to ensure that genetic medicine continues to be implemented in ways that improve real-world patient care and outcomes.

Journal of Clinical Oncology
Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer

Bardia A, Tolaney SM

PURPOSE: Hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) endocrine-resistant metastatic breast cancer is treated with sequential single-agent chemotherapy with poor outcomes. Sacituzumab govitecan (SG) is a first-in-class antibody-drug conjugate with an SN-38 payload targeting trophoblast cell-surface antigen 2, an epithelial antigen expressed in breast cancer.
METHODS: In this global, randomized, phase III study, SG was compared with physician's choice chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine) in endocrine-resistant, chemotherapy-treated HR+/HER2- locally recurrent inoperable or metastatic breast cancer. The primary end point was progression-free survival (PFS) by blinded independent central review.
RESULTS: Patients were randomly assigned to receive SG (n = 272) or chemotherapy (n = 271). The median age was 56 years, 95% had visceral metastases, and 99% had a prior cyclin-dependent kinase 4/6 inhibitor, with three median lines of chemotherapy for advanced disease. Primary end point was met with a 34% reduction in risk of progression or death (hazard ratio, 0.66 [95% CI, 0.53 to 0.83; P = .0003]). The median PFS was 5.5 months (95% CI, 4.2 to 7.0) with SG and 4.0 months (95% CI, 3.1 to 4.4) with chemotherapy; the PFS at 6 and 12 months was 46% (95% CI, 39 to 53) v 30% (95% CI, 24 to 37) and 21% (95% CI, 15 to 28) v 7% (95% CI, 3 to 14), respectively. Median overall survival (first planned interim analysis) was not yet mature (hazard ratio, 0.84; P = .14). Key grade 3 treatment-related adverse events (SG v chemotherapy) were neutropenia (51% v 38%) and diarrhea (9% v 1%).
CONCLUSION: SG demonstrated statistically significant PFS benefit over chemotherapy, with a manageable safety profile in patients with heavily pretreated, endocrine-resistant HR+/HER2- advanced breast cancer and limited treatment options.

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