Standard Anticancer Therapy Research Articles

Feasibility of an exercise-nutrition-psychology integrated rehabilitation model based on mobile health and virtual reality for cancer patients: a single-center, single-arm, prospective phase II study

ObjectiveExplore the feasibility of a mobile health(mHealth) and virtual reality (VR) based nutrition-exercise-psychology integrated rehabilitation model in Chinese cancer patients.MethodsWe recruited cancer patients in the Oncology department of the Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University from October 2022 to April 2023. The rehabilitation program was provided by a team of medical oncologists, dietitians, psychotherapists, and oncology specialist nurses. Participants received standard anti-cancer therapy and integrated intervention including hospitalized group-based exercise classes, at-home physical activity prescription, behavior change education, oral nutrition supplements, and psychological counseling. An effective intervention course includes two consecutive hospitalization and two periods of home-based rehabilitation (8 weeks). Access the feasibility as well as changes in aspects of physical, nutritional, and psychological status.ResultsAt the cutoff date of April 2023, the recruitment rate was 75% (123/165). 11.4%patients were lost to follow-up, and 3.25% withdrew halfway. Respectively, the completion rate of nutrition, exercise, and psychology were 85%,55%, and 63%. Nutrition interventions show the highest compliance. The parameters in nutrition, psychology, muscle mass, and quality of life after the rehabilitation showed significant improvements (P < .05). There was no significant statistical difference (P > .05) in handgrip strength and 6-minute walking speed.ConclusionIt is feasible to conduct mHealth and VR-based nutrition-exercise-psychology integrated rehabilitation model in Chinese cancer patients. A larger multi-center trial is warranted in the future.Trial registrationChiCTR2200065748 Registered 14 November 2022.

Abstract P2-02-06: Adjuvant Denosumab treatment in early breast cancer: a systematic review and meta-analysis of randomized controlled clinical trials

Abstract Background. Adjuvant denosumab treatment improved bone-health related outcomes in early breast cancer (BC) patients with discordant survival results. We undertook a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess efficacy and safety of adjuvant denosumab in addition to standard anticancer therapy. Methods. PubMed, CENTRAL, Scopus, Embase, clinicaltrials.gov and key oncological meetings websites were screened to identify potentially eligible RCTs based on the PICOs model: P) Participant: pre and postmenopausal early BC patients; I) Intervention: adjuvant denosumab; C) Comparator: placebo; O) Outcomes: Disease-free survival (DFS), Bone Metastasis-free survival (BMFS), Overall Survival (OS), fracture incidence and time to first fracture were adopted as survival endpoints, and Adverse Events, Serious Adverse Events, Osteonecrosis of the Jaw (ONJ) and Atypical Femur Fractures (AFF) as safety endpoints; S) Study design: phase III RCTs. Risk of bias was assessed with Cochrane Collaboration Risk of Bias Tool. Pooled hazard ratios (HR), risk ratios (RR), risk differences (RD) and respective confidence intervals (CI) were computed using both a fixed and a random effect model. Subgroup analyses based on menopausal status, hormone receptor and HER2 status and immunophenotype were performed. Results. Two phase III RCTs were included (ABCSG-18, D-CARE), for an overall population of 7929 early BC patients receiving denosumab or placebo. Denosumab addition to standard of care anticancer treatment showed no difference in DFS (HR 0.93; 95% CI 0.75-1.16, p=0.53), BMFS (HR 0.90; 95% CI 0.75-1.07, p=0.23) and OS (HR 0.92; 95% CI 0.72-1.17, p=0.49). In hormone receptor-positive/HER2 negative patients, denosumab significantly prolonged both DFS (HR 0.88; 95% CI 0.78-0.99, p=0.04) and BMFS (HR 0.83; 95% CI 0.71-0.97, p=0.02). No interaction was found between denosumab addition and menopausal status. Fracture incidence (RR 0.79; 95% CI 0.70-0.89, p&amp;lt; 0.01) and time to first fracture (HR 0.76; 95% CI 0.66-0.87, p&amp;lt; 0.01) were also improved with denosumab. No association between denosumab addition and overall toxicity was seen and no difference was observed in terms of ONJ and AFF between the 60mg every 6 months schedule and placebo (RD 0.001, 95% CI from -0.001 to 0.002, p=0.48) Conclusions. Findings from this meta-analysis validate the role of denosumab as a highly effective anti-resorptive agent. We provide robust evidence that its addition to standard anticancer treatment significantly improves survival outcomes in hormone receptor-positive/HER2 negative early BC patients, suggesting that the implementation of denosumab use in combination with endocrine therapy in this patient population should be reconsidered. Systematic Review Registration: https://www.crd.york.ac.uk/prospero, identifier CRD42022332787. Citation Format: Luca Mastrantoni, Giovanna Garufi, Elena Di Monte, Noemi Maliziola, Mariangela Pasqualoni, Letizia Pontolillo, Sergio Pannunzio, Maria Chiara Cannizzaro, Armando Di Bello, Alessandra Fabi, Antonella Palazzo, Emilio Bria, Giampaolo Tortora, Armando Orlandi. Adjuvant Denosumab treatment in early breast cancer: a systematic review and meta-analysis of randomized controlled clinical trials. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-02-06.

Adjuvant denosumab in early breast cancer: a systematic review and meta-analysis of randomized controlled clinical trials.

In early breast cancer (BC) the impact of denosumab on survival outcomes is still unclear. We undertook a systematic review and meta-analysis to assess efficacy and safety of adjuvant denosumab in addition to standard anticancer therapy. PubMed, CENTRAL, Scopus, Embase, and oncological meetings websites were screened to identify potentially eligible randomized controlled trials (RCTs). Survival outcomes were disease-free survival (DFS), bone-metastasis-free survival (BMFS), and overall survival (OS). Fracture incidence and time to first fracture were bone-health outcomes. Osteonecrosis of the jaw (ONJ), atypical femur fractures (AFF), and other adverse events were also evaluated. Pooled hazard ratios (HRs) and risk ratios (RR) with respective 95% confidence interval (95% CI) were computed using a random-effects model. Exploratory subgroup analyses were performed. Two phase III RCTs were included, the Austrian Breast & Colorectal Cancer Study Group-18 (ABCSG-18) and the D-CARE trials, for a total of 7929 patients. In the ABCSG-18 trial, denosumab was administered every 6 months during endocrine therapy (for a median of seven cycles) while the D-CARE trial used an intensive schedule for a total treatment duration of 5 years. Adjuvant denosumab showed no difference in DFS (HR: 0.932; 95% CI: 0.748-1.162), BMFS (HR: 0.9896; 95% CI: 0.751-1.070), and OS (HR: 0.917; 95% CI: 0.718-1.171) compared to placebo in the overall population. In hormone receptor positive/human epidermal growth factor receptor 2 (HER2) negative BC patients, a DFS (HR: 0.883; 95% CI: 0.782-0.996) and BMFS (HR: 0.832; 95% CI: 0.714-0.970) benefit was observed and BMFS was prolonged in all hormone receptor positive patients (HR: 0.850; 95% CI: 0.735-0.983). Fracture incidence (RR: 0.787; 95% CI: 0.696-0.890) and time to first fracture (HR: 0.760; 95% CI: 0.665-0.869) were also improved. No increase in overall toxicity was seen with denosumab and no differences were observed for ONJ and AFF between the 60-mg every 6-month schedule and placebo. Denosumab addition to anticancer treatment does not improve DFS, BMFS, or OS in the overall population, although a DFS improvement was observed in hormone receptor positive/HER2 negative BC patients and a BMFS improvement in all hormone receptor positive patients. Bone-health outcomes were improved with no added toxicity with the 60-mg schedule. PROSPERO identifier: CRD42022332787.

The Efficacy and Safety of Celecoxib in Addition to Standard Cancer Therapy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

The purpose of this meta-analysis was to evaluate the efficacy and safety of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, in addition to standard anticancer therapy. Randomized controlled trials (RCTs) that evaluated the efficacy and safety of celecoxib-combined cancer therapy were systematically searched in PubMed and Embase databases. The endpoints were overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), objective response rate (ORR), disease control rate (DCR), pathological complete response (pCR), and adverse events (AEs). The results of 30 RCTs containing 9655 patients showed limited benefits in celecoxib-combined cancer therapy. However, celecoxib-combined palliative therapy prolonged PFS in epidermal growth factor receptor (EGFR) wild-type patients (HR = 0.57, 95%CI = 0.35–0.94). Moreover, despite a slight increase in thrombocytopenia (RR = 1.35, 95%CI = 1.08–1.69), there was no increase in other toxicities. Celecoxib combined with adjuvant therapy indicated a better OS (HR = 0.850, 95%CI = 0.725–0.996). Furthermore, celecoxib plus neoadjuvant therapy improved the ORR in standard cancer therapy, especially neoadjuvant therapy (overall: RR = 1.13, 95%CI = 1.03–1.23; neoadjuvant therapy: RR = 1.25, 95%CI = 1.09–1.44), but not pCR. Our study indicated that adding celecoxib to palliative therapy prolongs the PFS of EGFR wild-type patients, with good safety profiles. Celecoxib combined with adjuvant therapy prolongs OS, and celecoxib plus neoadjuvant therapy improves the ORR. Thus, celecoxib-combined cancer therapy may be a promising therapy strategy.

The cost of cancer care: how far would you go for a trial?

BackgroundClinical trials are often considered the gold standard in cancer care. However, patients face barriers in trial participation including distances to cancer centres and personal costs including changing employment status, cost of medications, inpatient admissions, and parking tariffs.AimOur aim was to compare the distances patients travelled for clinical trials compared to those receiving standard systemic anticancer therapy (SACT). We also investigated the additional costs associated with this.MethodsThis was a retrospective review of electronic patient medical records. The distance from the patients’ home address to Beaumont was calculated as a one-way journey in kilometres. Patients attending for clinical trials were compared to those receiving standard of care SACT.ResultsA total of 271 patients receiving standard SACT over a 5-day period and 111 patients enrolled on 24 clinical trials were included. The median one-way distance travelled by patients enrolled in clinical trials was 41.4 km, compared to 14 km in those patients’ receiving standard of care SACT. The median estimated cost was €13 vs €4.20 for those enrolled on clinical trials compared to those receiving standard of care treatment, respectively.ConclusionPatients enrolled on clinical trials often travel more than twice as far to receive their anti-cancer treatment compared to those receiving standard of care SACT and incur an increased cost of travel expenses.

Interim Results from the First Clinical Study of CC-95251, an Anti-Signal Regulatory Protein-Alpha (SIRPα) Antibody, in Combination with Rituximab in Patients with Relapsed and/or Refractory Non-Hodgkin Lymphoma (R/R NHL)

Interim Results from the First Clinical Study of CC-95251, an Anti-Signal Regulatory Protein-Alpha (SIRPα) Antibody, in Combination with Rituximab in Patients with Relapsed and/or Refractory Non-Hodgkin Lymphoma (R/R NHL)

Co-Treatment with the Epigenetic Drug, 3-Deazaneplanocin A (DZNep) and Cisplatin after DZNep Priming Enhances the Response to Platinum-Based Therapy in Chondrosarcomas.

Simple SummaryChondrosarcoma is a rare bone tumor characterized by the secretion of a cartilage-like extracellular matrix. Its treatment poses major challenges, since chondrosarcoma is resistant to chemotherapy and radiotherapy. Consequently, chondrosarcoma treatment has been limited over the past 30 years, and consists in the surgical resection of the tumor. Increasing evidence suggests that future cancer therapies will be enhanced by the combination of epigenetic and conventional antitumor agents, leading to further investigations to combine 3-Deazaneplanocin A (DZNep), an epigenetic drug, with existing antitumoral agents. We show by in vitro and in vivo experiments that an optimised DZNep/cisplatin combination reduces chondrosarcoma viability and induces apoptosis more effectively than each of the drugs alone. These results demonstrate the potential use of this epigenetic-chemotherapeutic combination approach for further studies and management of chondrosarcoma treatment.Background: We have previously shown that 3-Deazaneplanocin A (DZNep) induces apoptosis in chondrosarcomas. Herein, we tested whether the combination of this epigenetic drug to a standard anticancer therapy may enhance the response to each drug in these bone tumors. Methods: Two chondrosarcoma cell lines (SW1353 and JJ012) were cultured in the presence of DZNep and/or cisplatin. Cell growth was evaluated by counting viable cells, and apoptosis was determined by Apo2.7 expression by flow cytometry. In vivo, the antitumoral effect of the DZNep/cisplatin combination was assessed through measurements of tumor volume of JJ012 xenografts in nude mice. Results: In vitro, the DZNep/cisplatin combination reduced cell survival and increased apoptosis compared to each drug alone in chondrosarcomas, but not in normal cells (chondrocytes). This enhancement of the antitumoral effect of the DZNep/cisplatin combination required a priming incubation with DZNep before the co-treatment with DZNep/cisplatin. Furthermore, in the chondrosarcoma xenograft mice model, the combination of both drugs more strongly reduced tumor growth and induced more apoptosis in tumoral cells than each of the drugs alone. Conclusion: Our results show that DZNep exposure can presensitize chondrosarcoma cells to a standard anticancer drug, emphasizing the promising clinical utilities of epigenetic-chemotherapeutic drug combinations in the future treatment of chondrosarcomas.

TTI-621 (SIRPαFc), an Immune Checkpoint Inhibitor Blocking the CD47 “Do Not Eat” Signal, Induces Objective Responses in Patients with Advanced, Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

BackgroundCD47 is an immune checkpoint that binds to signal regulatory protein alpha (SIRPα) and delivers a “do not eat” signal to suppress macrophage phagocytosis. Tumor cells frequently overexpress CD47 to evade macrophage-mediated destruction. TTI-621 (SIRPαFc) is an immune checkpoint inhibitor consisting of the CD47 binding domain of human SIRPα linked to the Fc region of human IgG1 designed to both: 1) block the CD47 “do not eat” signal, and 2) engage macrophage Fcγ receptors with IgG1 Fc to enhance phagocytosis and antitumor activity.MethodsA phase 1, open-label, multicenter study is ongoing to evaluate the activity of weekly IV infusions of TTI-621 in multiple cohorts of adult patients (pts) with relapsed or refractory malignancies. Eligible pts are those who have progressed on standard anticancer therapy (including rituximab for pts with B-cell lymphomas), or those for whom no other approved therapy exists (NCT02663518). This data disclosure comprises all consecutively enrolled pts with diffuse large B-cell lymphoma (DLBCL) who received, at a minimum, 0.2 mg/kg/week TTI-621 monotherapy or 0.1 mg/kg TTI-621 in combination with 375 mg/m2/week rituximab for 8 weeks, after which TTI-621 monotherapy was permitted.ResultsAs of June 1, 2017, 14 evaluable pts with DLBCL (7M/7F, age 42-72 years) have been enrolled and treated: 6 pts received TTI-621 monotherapy and 8 pts received TTI-621 plus rituximab. The number of prior systemic therapies ranged from 2 to 13; 6 pts had received prior autograft. Weekly outpatient treatments have been well tolerated. Mild-to-moderate infusion-related reactions were experienced by 9 pts following the first dose of TTI-621. Transient, dose-dependent decreases in platelets and leukocytes were generally without clinical sequelae. Objective responses were observed for 5/14 pts (36%): 1/6 pts treated with TTI-621 monotherapy and 4/8 pts treated with TTI-621 plus rituximab. Two pts attained complete responses (CR). One CR occurred in a pt treated with TTI-621 monotherapy who remains in continued CR at 20+ weeks. The second CR was in a pt treated with TTI-621 plus rituximab who remains in continued CR at 12+ weeks.ConclusionsWeekly IV dosing employing TTI-621 to block the CD47 “do not eat” signal as monotherapy or in combination with rituximab was well tolerated. Treatment was associated with preliminary and promising anti-tumor activity in pts with advanced DLBCL as evidenced by 2 CRs and 3 PRs among 14 pts. DisclosuresAnsell:Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Merck: Research Funding; Celldex: Research Funding; Seattle Genetics: Research Funding. Flinn:Genentech: Research Funding; Janssen: Research Funding; Janssen: Research Funding; Acerta: Research Funding; AbbVie Company: Research Funding; Seattle Genetics: Research Funding; KITE: Research Funding; Verastem: Research Funding; Curis: Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; Agios: Research Funding; Beigene: Research Funding; Forty Seven: Research Funding; Pfizer: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Constellation: Research Funding; Celgene: Research Funding; Pharmacyclics LLC: Research Funding; Takeda: Research Funding; Portola: Research Funding; Trillium: Research Funding; Calithera: Research Funding. O'Connor:Celgene: Honoraria, Research Funding; Trillium Therapeutics: Research Funding. Advani:Pfizer: Consultancy; Takeda/ Millenium: Research Funding. Percival:FLXbio: Research Funding. Johnson:Trillium Therapeutics: Employment. Catalano:Trillium Therapeutics: Employment; Apotex Inc.: Employment. Irwin:Hoffmann La Roche: Employment, Equity Ownership; Trillium Therapeutics: Employment, Equity Ownership. Petrova:Trillium Therapeutics: Employment, Equity Ownership. Uger:Trillium Therapeutics: Employment, Equity Ownership, Patents & Royalties. Sievers:Trillium Therapeutics: Employment, Equity Ownership. Chen:Genentech: Speakers Bureau; Merck: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy; Pharmacyclics: Consultancy, Research Funding; Affimed: Research Funding.

A Single Direct Intratumoral Injection of TTI-621 (SIRPαFc) Induces Antitumor Activity in Patients with Relapsed/Refractory Mycosis Fungoides and Sézary Syndrome: Preliminary Findings Employing an Immune Checkpoint Inhibitor Blocking the CD47 “Do Not Eat” Signal

BackgroundCD47 is an immune checkpoint that binds to signal regulatory protein alpha (SIRPα) and delivers a “do not eat” signal to suppress macrophage phagocytosis. Tumor cells frequently overexpress CD47 to evade macrophage-mediated destruction. TTI-621 (SIRPαFc) is an immune checkpoint inhibitor consisting of the CD47 binding domain of human SIRPα linked to the Fc region of human IgG1 designed to both: 1) block the CD47 “do not eat” signal, and 2) engage macrophage Fcγ receptors with IgG1 Fc to enhance phagocytosis and antitumor activity. It is hypothesized that direct intratumoral injection of TTI-621 may enhance both local and systemic antitumor activity.MethodsA Phase 1, multicenter, open-label study is ongoing to characterize the safety and tolerability of intratumoral injection of TTI-621 (NCT02890368). Eligible patients (pts) are adults with relapsed or refractory mycosis fungoides/Sézary syndrome or percutaneously-accessible solid tumors who have progressed on standard anticancer therapy or for whom no other approved therapy exists. Pts are enrolled in sequential cohorts to receive a single intratumoral injection of TTI-621 at increasing dose levels to characterize safety, pharmacokinetics, pharmacodynamics, and preliminary evidence of antitumor activity. Repeat TTI-621 intratumoral dosing has recently been initiated. Serial, post-injection biopsies are collected to assess the temporal impact of TTI-621 on the tumor microenvironment.ResultsNine pts (6 M/3F, age 57-85 years) have been enrolled as of July 2017. Diagnoses include mycosis fungoides/Sézary syndrome (N=6), melanoma (N=1), leiomyosarcoma (N=1), and squamous cell carcinoma (N=1). A single intratumoral injection of 1 mg, 3 mg, or 10 mg TTI-621 has been well tolerated by all enrolled pts. The most frequently reported adverse events were fatigue in 5 pts, chills in 4 pts, and decreased appetite in 3 pts. All treatment-related AEs were Grade 1 or 2 in severity. No dose limiting toxicity has been observed to date. All 6 pts with mycosis fungoides/Sézary syndrome experienced decreases in tumor size and/or decreased circulating Sézary cells (3 of 3 pts) as determined by a decrease in a peripheral clonal T-cell populationor CD4:CD8 ratio after a single intratumoral injection of TTI-621. Responses ranged from loco-regional to systemic effects. One pt with localized refractory mycosis fungoides on the dorsum of the foot obtained a complete response of the injected lesion that is ongoing after 17+ weeks of follow up. NanoString analysis of peripheral blood and tumor tissue pre- and post-intratumoral injection of TTI-621 indicated alterations in genes associated with activation of the innate immune system and upregulation of IFN-associated genes.ConclusionsThese preliminary Phase 1 data suggest that mycosis fungoides and its leukemic variant, Sézary syndrome, are highly responsive to a single dose of TTI-621 delivered by intratumoral injection. One pt achieved a complete response of the injected lesion and 5 additional pts experienced decreases in tumor size and/or decreased circulating Sézary cells. Intratumoral injections were well tolerated by all pts. Evidence of innate immune activation was documented, consistent with the proposed function of TTI-621 as an innate immune checkpoint inhibitor. DisclosuresQuerfeld:Soligenix: Research Funding; Elorac: Research Funding; Celgene: Honoraria, Research Funding; MiRagen: Honoraria, Research Funding; Actelion: Honoraria, Research Funding; Medivir: Honoraria; Mallinckrodt: Honoraria; Mindera: Consultancy; Kyowa: Research Funding; Trillium Therapeutics: Research Funding; City of Hope: Employment. Thompson:Trillium Therapeutics: Research Funding. Taylor:Blue Print Medicines: Consultancy, Honoraria; Eisai Inc.: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Trillium Therapeutics: Consultancy, Honoraria. Pillai:Trillium Therapeutics: Research Funding. Johnson:Trillium Therapeutics: Employment. Catalano:Trillium Therapeutics: Employment; Apotex Inc.: Employment. Petrova:Trillium Therapeutics: Employment, Equity Ownership. Uger:Trillium Therapeutics: Employment, Equity Ownership, Patents & Royalties. Irwin:Hoffmann La Roche: Employment, Equity Ownership; Trillium Therapeutics: Employment, Equity Ownership. Sievers:Trillium Therapeutics: Employment, Equity Ownership. Akilov:Seattle Genetics: Consultancy; Medivir: Consultancy; Actelion Pharmacuticals: Consultancy, Research Funding; Trillium Therapeutics: Research Funding.

Effects of a Unique Combination of the Whole-Body Low Dose Radiotherapy with Inactivation of Two Immune Checkpoints and/or a Heat Shock Protein on the Transplantable Lung Cancer in Mice.

Non-small cell lung cancer (NSCLC) continues to be the leading cause of cancer death worldwide. Recently, targeting molecules whose functions are associated with tumorigenesis has become a game changing adjunct to standard anti-cancer therapy. As evidenced by the results of preclinical and clinical investigations, whole-body irradiations (WBI) with X-rays at less than 0.1–0.2 Gy per fraction can induce remissions of various neoplasms without inciting adverse side effects of conventional chemo- and radiotherapy. In the present study, a murine model of human NSCLC was employed to evaluate for the first time the anti-neoplastic efficacy of WBI combined with inactivation of CTLA-4, PD-1, and/or HSP90. The results indicate that WBI alone and in conjunction with the inhibition of the function of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the programmed death-1 (PD-1) receptor immune checkpoints (ICs) and/or heat shock protein 90 (HSP90) markedly reduced tumorigenesis in mice implanted by three different routes with the syngeneic Lewis lung cancer cells and suppressed clonogenic potential of Lewis lung carcinoma (LLC1) cells in vitro. These results were associated with the relevant changes in the profile of pro- and anti-neoplastic immune cells recruited to the growing tumors and the circulating anti- and pro-inflammatory cytokines. In contrast, inhibition of the tested molecular targets used either separately or in combination with each other did not exert notable anti-neoplastic effects. Moreover, no significant synergistic effects were detected when the inhibitors were applied concurrently with WBI. The obtained results supplemented with further mechanistic explanations provided by future investigations will help design the effective strategies of treatment of lung and other cancers based on inactivation of the immune checkpoint and/or heat shock molecules combined with low-dose radiotherapy.

Impact of Cancer History on Outcomes Among Hospitalized Patients with COVID-19.

BackgroundEarly reports suggested increased mortality from COVID‐19 in patients with cancer but lacked rigorous comparisons to patients without cancer. We investigated whether a current cancer diagnosis or cancer history is an independent risk factor for death in hospitalized patients with COVID‐19.Patients and MethodsWe identified patients with a history of cancer admitted to two large hospitals between March 13, 2020, and May 10, 2020, with laboratory‐confirmed COVID‐19 and matched them 1:2 to patients without a history of cancer.ResultsMen made up 56.2% of the population, with a median age of 69 years (range, 30–96). The median time since cancer diagnosis was 35.6 months (range, 0.39–435); 80% had a solid tumor, and 20% had a hematologic malignancy. Among patients with cancer, 27.8% died or entered hospice versus 25.6% among patients without cancer. In multivariable analyses, the odds of death/hospice were similar (odds ratio [OR], 1.09; 95% confidence interval [CI], 0.65–1.82). The odds of intubation (OR, 0.46; 95% CI, 0.28–0.78), shock (OR, 0.54; 95% CI, 0.32–0.91), and intensive care unit admission (OR, 0.51; 95% CI, 0.32–0.81) were lower for patients with a history of cancer versus controls. Patients with active cancer or who had received cancer‐directed therapy in the past 6 months had similar odds of death/hospice compared with cancer survivors (univariable OR, 1.31; 95% CI, 0.66–2.60; multivariable OR, 1.47; 95% CI, 0.69–3.16).ConclusionPatients with a history of cancer hospitalized for COVID‐19 had similar mortality to matched hospitalized patients with COVID‐19 without cancer, and a lower risk of complications. In this population, patients with active cancer or recent cancer treatment had a similar risk for adverse outcomes compared with survivors of cancer.Implications for PracticeThis study investigated whether a current cancer diagnosis or cancer history is an independent risk factor for death or hospice admission in hospitalized patients with COVID‐19. Active cancer, systemic cancer therapy, and a cancer history are not independent risk factors for death from COVID‐19 among hospitalized patients, and hospitalized patients without cancer are more likely to have severe COVID‐19. These findings provide reassurance to survivors of cancer and patients with cancer as to their relative risk of severe COVID‐19, may encourage oncologists to provide standard anticancer therapy in patients at risk of COVID‐19, and guide triage in future waves of infection.

ENGOT-EN6/NSGO-RUBY: A phase III, randomized, double-blind, multicenter study of dostarlimab + carboplatin-paclitaxel versus placebo + carboplatin-paclitaxel in recurrent or primary advanced endometrial cancer (EC).

TPS6107 Background: Carboplatin-paclitaxel is considered standard systemic anticancer therapy for recurrent or advanced EC for which surgery and/or radiation are not curative. Dostarlimab (TSR-042) is an anti-programmed cell death (PD)-1 humanized monoclonal antibody that has demonstrated antitumor activity and an acceptable safety profile in patients (pts) with recurrent or advanced EC in the GARNET trial. The RUBY trial was designed to evaluate the efficacy and safety of dostarlimab in combination with carboplatin-paclitaxel in recurrent or primary advanced EC compared with carboplatin-paclitaxel alone. Methods: This is a global, randomized, double-blind, multicenter, placebo-controlled study. Eligible pts must have first recurrent or primary stage III or stage IV EC with a low potential for cure by radiation therapy or surgery alone or in combination. Pts with carcinosarcoma are eligible for enrollment. 470 pts will be enrolled from approximately 160 sites in the ENGOT countries, United States, and Canada. Stratification factors are microsatellite instability (MSI) status (MSI-high [MSI-H] or microsatellite stable [MSS]), prior external pelvic radiotherapy (yes or no), and disease status (recurrent, primary stage III, or primary stage IV). Pts will be randomized 1:1 to receive combination dostarlimab 500 mg or placebo + carboplatin AUC 5 + paclitaxel 175 mg/m2 every 3 weeks for 6 cycles followed by dostarlimab 1000 mg or placebo monotherapy every 6 weeks for up to 3 years in the absence of progressive disease, death, unacceptable toxicity, or patient/physician decision to withdraw from the study. The primary endpoint is progression-free survival (PFS) as assessed by the investigator in the all-comers population and the MSI-H population per RECIST version 1.1. Secondary efficacy endpoints are PFS assessed by blinded independent central review per RECIST version 1.1, overall survival, objective response rate, duration of response, disease control rate, safety and tolerability, and patient-reported outcomes. Clinical trial information: NCT03981796.

Abstract OT3-18-01: Detect III/IV study trial - The multicenter study program in patients with HER2-negative MBC and circulating tumor cells

Abstract Background: The collaborative DETECT study program represents a large program on metastatic breast cancer (MBC) worldwide. The main objective of the DETECT trial is to evaluate the efficacy of individualized breast cancer treatment based on the presence and phenotype setting of circulating tumor cells (CTCs). Thus, the DETECT study program is one of the first clinical trials translating the role of CTC enumeration/phenotyping directly into treatment intervention within different breast cancer subtypes. Trial design: The DETECT-III trial is a multicenter, randomized, phase III study comparing standard therapy alone versus standard therapy plus lapatinib in patients with initially HER2-negative MBC and HER2-positive CTCs. Patients with HER2-negative MBC and only HER2-negative CTCs can be included within the DETECT-IV trial, a prospective, multicenter, open-label, phase II study including patients with HER2-negative MBC. Within the DETECT-IV study setting postmenopausal patients with hormone-receptor positive MBC are treated with the CDK 4/6 inhibitor ribociclib and endocrine therapy, while women with triple negative MBC or a hormone-receptor positive tumor and indication for chemotherapy will receive eribulin. Specific aims: The DETECT study program offers various up-to-date treatment options, generating a wealth of clinical data including long-term follow-up data, evaluated in the controlled setting of a single large clinical trial program. The primary endpoint of the DETECT III trial is the comparison of efficacy as assessed using CTC clearance rate between patients receiving standard anticancer therapy with lapatinib and patients receiving standard anticancer therapy alone. The secondary objective of this trial is to assess the level of compliance to study procedures comparing the efficacy of lapatinib between given treatment groups. The primary objectives of the DETECT- IV trial are to evaluate CTC clearance rate for the ribociclib cohort and progression-free survival (defined as time interval from date of recruitment until progressive disease) for the eribulin cohort. The main focal point of the extensive collaborative translational oncology research projects is to apply innovative biomarkers and assays focusing on molecular characteristics of CTCs. This “biological status” of CTCs may provide new information about their potential function in terms of a repeatedly performed liquid biopsy to assess the patients’ response to therapy. Citation Format: Sabrina Krause, Thomas WP Friedl, Peter A Fasching, Andreas Schneeweiss, Volkmar Müller, Sabine Riethdorf, Klaus Pantel, Florin-Andrei Taran, Arkadius Polasik, Marie Tzschaschel, Amelie de Gregorio, Franziska Meier-Stiegen, Jens Huober, Wolfgang Janni, Tanja Fehm. Detect III/IV study trial - The multicenter study program in patients with HER2-negative MBC and circulating tumor cells [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-18-01.

Honokiol: A Review of Its Anticancer Potential and Mechanisms.

Cancer is characterised by uncontrolled cell division and abnormal cell growth, which is largely caused by a variety of gene mutations. There are continuous efforts being made to develop effective cancer treatments as resistance to current anticancer drugs has been on the rise. Natural products represent a promising source in the search for anticancer treatments as they possess unique chemical structures and combinations of compounds that may be effective against cancer with a minimal toxicity profile or few side effects compared to standard anticancer therapy. Extensive research on natural products has shown that bioactive natural compounds target multiple cellular processes and pathways involved in cancer progression. In this review, we discuss honokiol, a plant bioactive compound that originates mainly from the Magnolia species. Various studies have proven that honokiol exerts broad-range anticancer activity in vitro and in vivo by regulating numerous signalling pathways. These include induction of G0/G1 and G2/M cell cycle arrest (via the regulation of cyclin-dependent kinase (CDK) and cyclin proteins), epithelial–mesenchymal transition inhibition via the downregulation of mesenchymal markers and upregulation of epithelial markers. Additionally, honokiol possesses the capability to supress cell migration and invasion via the downregulation of several matrix-metalloproteinases (activation of 5′ AMP-activated protein kinase (AMPK) and KISS1/KISS1R signalling), inhibiting cell migration, invasion, and metastasis, as well as inducing anti-angiogenesis activity (via the down-regulation of vascular endothelial growth factor (VEGFR) and vascular endothelial growth factor (VEGF)). Combining these studies provides significant insights for the potential of honokiol to be a promising candidate natural compound for chemoprevention and treatment.

Synergistic effect of the combination therapy on ovarian cancer cells under microfluidic conditions

Ovarian cancer belongs to the group of gynecological cancers and indicates the high resistance to many drugs used in standard anticancer therapy. The treatment of ovarian cancer is a big challenge for the present medicine. In our report we tested the effectiveness of the combination anticancer therapy against ovarian cells: human ovarian carcinoma (A2780) and human ovarian fibroblasts (HOF). Two different types of drugs were used: doxorubicin (DOX) and a new-generation photosensitizer, nanoencapsulated meso-tetraphenylporphyrin (nano-TPP). The aim of the research was to compare the effect of the sequential combination therapy (chemotherapy with DOX and photodynamic therapy with nano-TPP) carried out in static and dynamic conditions. To achieve dynamic culture conditions, similar to in vivo environment, we designed a new microfluidic system in which the simultaneous, independent cultures of two cell lines (non-malignant and cancer cells) and their one-step analysis were possible. We observed that the sequential combination of photodynamic therapy (PDT) with chemotherapy allowed to obtain the synergistic effect of the treatment with using low doses of drugs. We also confirmed that the use of microfluidic conditions significantly increased the effectiveness of combination therapy and allowed for maintaining a high selectivity of the action of drugs on cancer cells. To the best of our knowledge, for the first time the microfluidic system was used to carry out sequential combination therapy against ovarian cancer.

Natural Killer Cell Therapy: A New Treatment Paradigm for Solid Tumors.

In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. Compared with cytotoxic T lymphocytes, NK cells take a unique position targeting tumor cells that evade the host immune surveillance by down-regulating self-antigen presentation. Recent findings highlighted that NK cells can even target cancer stem cells. The efficacy of allogeneic NK cells has been widely investigated in the treatment of hematologic malignancies. In solid tumors, both autologous and allogeneic NK cells have demonstrated potential efficacy. In allogeneic NK cell therapy, the mismatch between the killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) can be harnessed to increase the antitumor activity. However, the allogeneic NK cells cause more adverse events and can be rejected by the host immune system after repeated injections. In this regard, the autologous NK cell therapy is safer. This article reviews the published results of clinical trials and discusses strategies to enhance the efficacy of the NK cell therapy. The difference in immunophenotype of the ex vivo expanded NK cells resulted from different culture methods may affect the final efficacy. Furthermore, currently available standard anticancer therapy, molecularly targeted agents, and checkpoint inhibitors may directly or indirectly enhance the efficacy of NK cell therapy. A recent study discovered that NK cell specific genetic defects are closely associated with the tumor immune microenvironment that determines clinical outcomes. This finding warrants future investigations to find the implication of NK cell specific genetic defects in cancer development and treatment, and NK cell deficiency syndrome should be revisited to enhance our understanding. Overall, it is clear that NK cell therapy is safe and promises a new paradigm for the treatment of solid tumors.

778P - Subgroup analyses of a randomized two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with 2 and 4 courses of cisplatin/S-1 (CS) and docetaxel/cisplatin/S-1 (DCS) as neoadjuvant chemotherapy for locally advanced gastric cancer

BackgroundNeoadjuvant chemotherapy is promising to improve the survival of locally advanced gastric cancer. However, optimal regimen and duration of treatment have not been established. We previously reported the primary results of COMPASS-D trial (ASCO-GI 2019). Herein, we report the results of subgroup analyses of efficacy by baseline disease characteristics and demographics. MethodsPatients with M0 and either T4 or T3 in case of junctional cancer or schirrhous type received 2 or 4 courses of cisplatin (60mg/m2 at day 8) / S-1 (80mg/m2 for 21 days with 1 week rest) or docetaxel (40mg/m2 at day 1) / cisplatin (60mg/m2 at day 1) / S-1 (80mg/m2 for 14 days with 2 weeks rest) as neoadjuvant chemotherapy. Then, patients underwent D2 gastrectomy and adjuvant S-1 chemotherapy for 1 year. The primary endpoint was 3-year overall survival. Subgroup analysis was performed in each regimen (CS vs DCS) and duration (2 vs 4 courses), stratified by age, gender, esophageal invasion, macroscopic type, histological type, cT, and cN. ResultsBetween Oct 2011 and Sep 2014, 132 patients were assigned to CS (n=66; 33 in 2-courses and 33 in 4-courses) and DCS (n=66; 33 in 2-courses and 33 in 4-courses). The 3-year OS was 58.1% in 2-courses CS, 58.1% in 4-courses CS, 48.5% in 2-courses DCS, and 71.9% in 4-courses DCS. Subgroup analyses were summarized in the table.Table778PTableSubgroupHR of 4-sourses (95%CI)HR of DCS (95%CI)Overall0.77 (0.43-1.22)0.80 (0.48-1.34)Age < 70 y.o.0.82 (0.45-1.52)0.88 (0.48-1.62)Age=> 70 y.o.0.49 (0.17-1.39)0.68 (0.26-1.76)Male0.53 (0.27-1.05)0.81 (0.42-1.54)Female1.22 (0.51-2.90)0.79 (0.33-1.87)Esophageal invasion-0.72 (0.40-1.31)0.71 (0.39-1.27)Esophageal invasion+0.73 (0.24-2.17)1.06 (0.36-3.16)Schirrhous or large Type30.47 (0.22-1.00)0.82 (0.41-1.63)Non schirrous or large Type30.74 (0.23-2.41)0.50 (0.13-1.87)Differentiated0.37 (0.08-1.66)0.38 (0.09-1.71)Undiffirentiated0.66 (0.32-1.36)1.24 (0.63-2.43)cT3 or T4a0.66 (0.38-1.17)0.76 (0.44-1.32)cT4bN/A2.33 (0.26-21.4)cN00.77 (0.32-1.86)0.74 (0.31-1.80)cN+0.66 (0.34-1.27)0.87 (0.46-1.66) ConclusionsThe DCS regimen and duration 4-courses showed a beneficial tendency as a neoadjuvant setting regardless of disease characteristics and demographics. The 4-courses DCS is widely applicable to future phase III study to confirm of neoadjuvant chemotherapy for locally advanced gastric cancer. Clinical trial identificationUMIN000006378. Legal entity responsible for the studyThe authors. FundingThe Nongovermental Organization, Kanagawa Standard Anti-cancer Therapy Support System. DisclosureAll authors have declared no conflicts of interest.

ALKBH overexpression in head and neck cancer: potential target for novel anticancer therapy

The nine identified human homologues of E. coli AlkB 2-oxoglutarate (2OG) and Fe(II)-dependent dioxygenase, ALKBH1-8 and FTO, display different substrate specificities and diverse biological functions. Here we discovered the combined overexpression of members of the ALKBH family in head and neck squamous cell carcinomas (HNSCC). We found direct correlation of ALKBH3 and FTO expression with primary HNSCC tumor size. We observed unidentified thus far cytoplasmic localization of ALKBH2 and 5 in HNSCC, suggesting abnormal role(s) of ALKBH proteins in cancer. Further, high expression of ALKBHs was observed not only in HNSCC, but also in several cancerous cell lines and silencing ALKBH expression in HeLa cancer cells resulted in dramatically decreased survival. Considering the discovered impact of high expression of ALKBH proteins on HNSCC development, we screened for ALKBH blockers among newly synthetized anthraquinone derivatives and demonstrated their potential to support standard anticancer therapy.

Formononetin: A Review of Its Anticancer Potentials and Mechanisms.

Cancer, a complex yet common disease, is caused by uncontrolled cell division and abnormal cell growth due to a variety of gene mutations. Seeking effective treatments for cancer is a major research focus, as the incidence of cancer is on the rise and drug resistance to existing anti-cancer drugs is major concern. Natural products have the potential to yield unique molecules and combinations of substances that may be effective against cancer with relatively low toxicity/better side effect profile compared to standard anticancer therapy. Drug discovery work with natural products has demonstrated that natural compounds display a wide range of biological activities correlating to anticancer effects. In this review, we discuss formononetin (C16H12O4), which originates mainly from red clovers and the Chinese herb Astragalus membranaceus. The compound comes from a class of 7-hydroisoflavones with a substitution of methoxy group at position 4. Formononetin elicits antitumorigenic properties in vitro and in vivo by modulating numerous signaling pathways to induce cell apoptosis (by intrinsic pathway involving Bax, Bcl-2, and caspase-3 proteins) and cell cycle arrest (by regulating mediators like cyclin A, cyclin B1, and cyclin D1), suppress cell proliferation [by signal transducer and activator of transcription (STAT) activation, phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT), and mitogen-activated protein kinase (MAPK) signaling pathway], and inhibit cell invasion [by regulating growth factors vascular endothelial growth factor (VEGF) and Fibroblast growth factor 2 (FGF2), and matrix metalloproteinase (MMP)-2 and MMP-9 proteins]. Co-treatment with other chemotherapy drugs such as bortezomib, LY2940002, U0126, sunitinib, epirubicin, doxorubicin, temozolomide, and metformin enhances the anticancer potential of both formononetin and the respective drugs through synergistic effect. Compiling the evidence thus far highlights the potential of formononetin to be a promising candidate for chemoprevention and chemotherapy.

Abstract CT086: Interim results from CLASSICAL-Lung, a Phase Ib/II study of VX15/2503 (pepinemab) in combination with avelumab in advanced NSCLC

Abstract Background: Blockade of the PD/PD-L1 pathway is an effective immunotherapy for NSCLC, however rational combination therapies are needed to overcome resistance mechanisms. VX15/2503 (pepinemab) is an IgG4 humanized monoclonal antibody targeting semaphorin 4D (SEMA4D, CD100). In vivo preclinical models demonstrated antibody blockade of SEMA4D promoted immune infiltration and reduced function and recruitment of immunosuppressive myeloid cells within the tumor. Importantly, preclinical combinations of anti-SEMA4D with various immunotherapies enhanced T cell activity and tumor regression. Avelumab is a fully human IgG1 antibody specific for PD-L1 and has been approved for both Merkel cell and urothelial carcinomas. The CLASSICAL-Lung clinical trial tests the combination of pepinemab with avelumab to couple immune activation via checkpoint inhibition with beneficial modifications of the immune microenvironment via pepinemab. Here, we present interim results of the dose escalation portion of the CLASSICAL-Lung study. Methods: This Phase Ib/II, open label, single arm, first-in-human combination study is designed to evaluate the safety, tolerability and efficacy of pepinemab in combination with avelumab in 62 subjects with advanced (IIIB/IV) NSCLC. The trial is split into dose escalation (n=12) and dose expansion (n=50) phases. The dose escalation portion includes patients who are immunotherapy naïve and have either progressed or declined standard first or second-line systemic anticancer therapy. The expansion phase includes a similar patient cohort as well as a second cohort of patients whose tumors progressed during or following immunotherapy. Patients in the dose escalation cohorts received ascending doses of pepinemab (5, 10, 20 mg/kg, Q2W) in combination with avelumab (10mg/kg, Q2W). The primary objective of dose escalation is safety, tolerability, and identification of the RP2D for dose expansion. Secondary objectives include evaluation of efficacy, immunogenicity, and PK/PD, and an exploratory objective is to identify candidate biomarkers of activity. Results / Conclusions: Dose escalation was successfully completed. The combination was found to be well tolerated at all dose levels tested and the RP2D was selected as 10mg/kg pepinemab Q2W (with 10mg/kg avelumab Q2W) for the dose expansion phase. No concerning safety signals have been identified to date. The most frequent related AEs were grades 1 or 2 fatigue, pyrexia, or chills; no grade 3 AE occurred in more than one subject. One DLT, a grade 3 pulmonary embolism occurred in the 10mg/kg pepinemab cohort, resolved and did not recur in that same subject or additional subjects in any cohort. The disease control rate to date in all dose escalation patients treated for at least two months is 90%. More detailed data from the dose escalation cohorts will be presented, as well as an enrollment update for the dose expansion phase. Clinical trial information: NCT03268057 Citation Format: Michael Shafique, Terrence L. Fisher, Elizabeth E. Evans, John E. Leonard, Desa Rae Pastore, Crystal Mallow, Ernest Smith, Maurice Zauderer, Andreas Schröeder, Kevin Chin, Thaddeus Beck, Megan Baumgart, Rachel E. Sanborn, Jonathan W. Goldman. Interim results from CLASSICAL-Lung, a Phase Ib/II study of VX15/2503 (pepinemab) in combination with avelumab in advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT086.