Purpose: Up to 17% of patients with pancreatic ductal adenocarcinoma (PDAC) harbor pathogenic (germline or somatic) mutations in a homologous recombination, DNA damage response and repair (HR-DDR) gene, such as BRCA1/2, or PALB2. Platinum-based chemotherapy, or treatment with PARP inhibitors are of particular benefit in these patients. However, there may be even greater benefit when platinums and PARP inhibitors are combined. Patients and Methods: We performed a single-arm, open-label, phase...
Thu Oct 01, 2020 10:05
Purpose: The prognosis for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is poor, and only a minority of patients benefit from checkpoint immunotherapy. Talimogene laherparepvec (T-VEC), an oncolytic immunotherapy approved for advanced melanoma, in combination with pembrolizumab may yield enhanced antitumor activity over either agent alone. Patients and Methods: This was a phase Ib/III, multicenter trial testing intratumoral T-VEC combined with intravenous...
Thu Oct 01, 2020 10:05
Purpose: Combination therapy with reduced-dose programmed death 1 inhibitor plus standard-dose cytotoxic T-lymphocyte–associated antigen 4 inhibitor demonstrated efficacy, but substantial toxicity, in melanoma. We present long-term results of part 1B of KEYNOTE-029, which assessed safety and efficacy of standard-dose pembrolizumab plus reduced-dose ipilimumab in advanced melanoma. Patients and Methods: Part 1B was an expansion cohort of the open-label, phase Ib portion of KEYNOTE-029. Eligible...
Thu Oct 01, 2020 10:05
Gastrointestinal stromal tumor (GIST) provides a paradigm to evaluate new molecularly targeted therapies and to identify structural and functional mechanisms for drug response and resistance. Drug development in GIST has successfully exploited the high reliance on KIT/PDGFRA oncogenic signaling as a therapeutic vulnerability. The recent arrival of avapritinib and ripretinib to the GIST arena has aimed to further improve on precision kinase inhibition and address tumor heterogeneity in imatinib-resistant...
Thu Oct 01, 2020 10:05
Purpose: T-cell immunoglobulin and ITIM domain (TIGIT), a member of the immune checkpoint family, is important in normal T-cell biology. However, the phenotypical profile and clinical relevance of TIGIT in follicular lymphoma is largely unknown. Experimental Design: Biopsy specimens from a cohort of 82 patients with follicular lymphoma were analyzed using mass cytometry to explore the phenotype and biological and clinical significance of TIGIT+ T cells. Results: TIGIT is highly expressed...
Thu Oct 01, 2020 10:05
Immune checkpoint inhibitors (ICI) may overcome cancer cells' ability to evade the immune system and proliferate. The long-term benefit of ICI in the metastatic setting led to evaluate neoadjuvant ICI approaches in several tumor types such as melanoma, non–small cell lung cancer, and breast and bladder cancer. We summarize the current evidence for the efficacy of neoadjuvant ICI in cancer and discuss several unresolved challenges, including the role of adjuvant treatment after neoadjuvant ICI, the...
Thu Oct 01, 2020 10:05
Purpose: 124I-PU-H71 is an investigational first-in-class radiologic agent specific for imaging tumor epichaperome formations. The intracellular epichaperome forms under cellular stress and is a clinically validated oncotherapeutic target. We conducted a first-in-human study of microdose 124I-PU-H71 for PET to study in vivo biodistribution, pharmacokinetics, metabolism, and safety; and the feasibility of epichaperome-targeted tumor imaging. Experimental Design: Adult patients with cancer...
Thu Oct 01, 2020 10:05
On September 17, 2019, FDA granted accelerated approval to pembrolizumab plus lenvatinib for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation. The submission and review of this application was conducted through an FDA Oncology Center of Excellence initiative named Project Orbis...
Thu Oct 01, 2020 10:05
Purpose: Pembrolizumab improved survival in patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this study were to determine if pembrolizumab would be safe, result in pathologic tumor response (pTR), and lower the relapse rate in patients with resectable human papillomavirus (HPV)–unrelated HNSCC. Patients and Methods: Neoadjuvant pembrolizumab (200 mg) was administered and followed 2 to 3 weeks later by surgical tumor ablation. Postoperative...
Thu Oct 01, 2020 10:05
In the CheckMate 275 study, composite biomarkers appear to better predict response to immunotherapy over individual ones. Nevertheless, the path forward needs consensus guidelines for biomarker interpretation. Thereafter, prospective validation with real-time, serial biospecimen collection along with the development of composite biomarker models leads to the goal of personalized therapy. See related article by Galsky et al., p. 5120
Thu Oct 01, 2020 10:05
Purpose: No biomarker to personalize treatment in locally advanced rectal cancer (LARC) is currently available. We assessed in LARC whether a diagnostic biopsy-adapted immunoscore (ISB) could predict response to neoadjuvant treatment (nT) and better define patients eligible to an organ preservation strategy ("Watch-and-Wait"). Experimental Design: Biopsies from two independent cohorts (n1 = 131, n2 = 118) of patients with LARC treated with nT followed by radical surgery were immunostained...
Thu Oct 01, 2020 10:05
Given the modest clinical benefits observed with immune checkpoint blockade in advanced prostate cancer, there is a renewed interest in exploring other forms of immunotherapy. Here, the authors report the use of a novel plasmid DNA vaccine encoding the androgen receptor, called pTVG-AR, in men with metastatic hormone-sensitive prostate cancer. See related article by Kyriakopoulos et al., p. 5162
Thu Oct 01, 2020 10:05
Purpose: Treatment approaches using Hsp90 inhibitors at their maximum tolerated doses (MTDs) have not produced selective tumor toxicity. Inhibition of Hsp90 activity causes degradation of client proteins including those involved in recognizing and repairing DNA lesions. We hypothesized that if DNA repair proteins were degraded by concentrations of an Hsp90 inhibitor below those required to cause nonspecific cytotoxicity, significant tumor-selective radiosensitization might be achieved. Experimental...
Thu Oct 01, 2020 10:05
Purpose: Preclinical studies demonstrated that a DNA vaccine (pTVG-AR, MVI-118) encoding the androgen receptor ligand-binding domain (AR LBD) augmented antigen-specific CD8+ T cells, delayed prostate cancer progression and emergence of castration-resistant disease, and prolonged survival of tumor-bearing mice. This vaccine was evaluated in a multicenter phase I trial. Patients and Methods: Patients with metastatic castration-sensitive prostate cancer (mCSPC) who had recently begun androgen...
Thu Oct 01, 2020 10:05
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