Anticancer Therapy In Patients Research Articles

Enhancing Immune Response in Non-Small-Cell Lung Cancer Patients: Impact of the 13-Valent Pneumococcal Conjugate Vaccine.

Background: Non-small-cell lung cancer (NSCLC) is one of the most frequently diagnosed diseases among all types of lung cancer. Infectious diseases contribute to morbidity and mortality by delaying appropriate anti-cancer therapy in patients with NSCLC. Methods: The study aimed to evaluate the effectiveness of vaccination with the 13-valent pneumococcal conjugate vaccine (PCV13) in 288 newly diagnosed NSCLC patients. The analysis of the post-vaccination response was performed after vaccination by assessing the frequency of plasmablasts via flow cytometry and by assessing the concentration of specific anti-pneumococcal antibodies using enzyme-linked immunosorbent assays. Results: The results of the study showed that NSCLC patients responded to the vaccine with an increase in the frequencies of plasmablasts and antibodies but to a lesser extent than healthy controls. The immune system response to PCV13 vaccination was better in patients with lower-stage NSCLC. We found higher antibody levels after vaccination in NSCLC patients who survived 5 years of follow-up. Conclusions: We hope that our research will contribute to increasing patients' and physicians' awareness of the importance of including PCV13 vaccinations in the standard of oncological care, which will extend the survival time of patients and improve their quality of life.

750P PFS2 and adjustment of overall survival (OS) for subsequent anticancer therapy in patients (pts) with primary advanced or recurrent endometrial cancer (pA/rEC) treated with dostarlimab plus chemotherapy or chemotherapy alone in the ENGOT-EN3-NSGO/GOG-3031/RUBY trial

750P PFS2 and adjustment of overall survival (OS) for subsequent anticancer therapy in patients (pts) with primary advanced or recurrent endometrial cancer (pA/rEC) treated with dostarlimab plus chemotherapy or chemotherapy alone in the ENGOT-EN3-NSGO/GOG-3031/RUBY trial

27P Amivantamab versus alternative real-world anti-cancer therapies in patients with advanced non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations in the US and Europe

27P Amivantamab versus alternative real-world anti-cancer therapies in patients with advanced non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations in the US and Europe

Abstract OT3-08-01: A phase 1 trial of LOXO-783, a potent, highly mutant-selective, brain-penetrant allosteric PI3Kα H1047R inhibitor in PIK3CA H1047R-mutant advanced breast cancer (aBC) and other solid tumors (PIKASSO-01, trial in progress)

Abstract Background: Phosphoinositide 3-kinase alpha (PI3Kα) H1047R mutations are activating oncogenic events that occur in ~15% of breast cancers (BC). Available PI3Kα inhibitors target both wild-type (WT) and mutant PI3Kα and, as a result, their efficacy may be limited by on-target WT PI3Kα-mediated toxicities, including hyperglycemia, skin rash, and diarrhea. LOXO-783 is an oral, potent and highly mutant-selective, brain-penetrant allosteric PI3Kα H1047R inhibitor. Preclinically, LOXO-783 is highly selective for PI3Kα H1047R over WT PI3Kα and other PI3K isoforms and induces single-agent tumor regressions in ER+, HER2- PI3Kα H1047R-mutant BC models without causing hyperglycemia or increases in plasma insulin/C-peptide. LOXO-783 also demonstrates brain penetration in vivo with dose-dependent tumor growth inhibition in brain metastasis models. This trial investigates LOXO-783 alone and in combination with other anticancer therapies in patients with PIK3CA H1047R-mutant aBC and other solid tumors. Trial Design: This global, first-in-human phase 1a/b study of LOXO-783 includes dose escalation of LOXO-783 monotherapy followed by dose expansion of LOXO-783 alone and in combination with other anticancer therapies (Table). Monotherapy dose escalation will be evaluated using a modified toxicity probability interval-2 (mTPI-2) design. In dose expansion (Parts A-E), each combination cohort will include a safety lead-in of 3-6 patients. Men and premenopausal women with ER+ aBC must receive concomitant treatment with a GnRH agonist. An optional pharmacodynamic (PD) biomarker sub-study will be conducted at select dose levels during dose escalation in patients with ER+, HER2- aBC with soft tissue disease amenable to safe repeat tumor biopsies. Eligibility criteria: Eligible patients must have PIK3CA H1047R-mutant aBC or other solid tumors with measurable disease or non-measurable bone-only disease (aBC patients only). In dose escalation, patients may have received up to 5 prior regimens. In dose expansion, prior therapy requirements are outlined in the Table below. Key exclusion criteria include prior inhibitor(s) of PI3K/AKT/mTOR (except in dose escalation or in select patients with prior intolerance of these inhibitors), colorectal cancer, endometrial cancer with concurrent PI3K/AKT/mTOR and/or RAS/RAF alterations and diabetes mellitus (DM) requiring medication (except in Part C). Study objectives: Recommended phase 2 dose (RP2D) determination; safety and tolerability assessment, PK and PD evaluation, objective response rate and clinical benefit rate assessment per RECIST v1.1. Recruitment is ongoing (PIKASSO-01, NCT05307705). Table. Dose Expansion (Phase 1b) Citation Format: Dejan Juric, Komal Jhaveri, Muralidhar Beeram, Erika Hamilton, Vincent Chau, Matthew P. Hanley, Shiyao Liu, Lillian M. Smyth, Funda Meric-Bernstam. A phase 1 trial of LOXO-783, a potent, highly mutant-selective, brain-penetrant allosteric PI3Kα H1047R inhibitor in PIK3CA H1047R-mutant advanced breast cancer (aBC) and other solid tumors (PIKASSO-01, trial in progress) [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 OT3-08-01.

Profile of Solid Tumor Patients Complicated With Venous Thromboembolism: A 10-Year Retrospective Cross-Sectional Study Based on 1482 Cases

The aim of this single-centre 10-year retrospective observational study was to evaluate the profile of Chinese cancerous patients complicated with venous thromboembolism (VTE) based on demographic features, clinical characteristics, and medication exposure. Consecutive 1482 patients with solid tumor complicated with VTE at a tertiary center between 2012 and 2021 were retrospectively enrolled. Data were collected on demographics, comorbidities, discharge diagnoses, laboratory examination data, treatment details, and imaging description of the lesion. The overall incidence of clinical VTE was 1.35% in hospitalized patients with cancer in our center. Lung cancer was the most frequent tumor subtype for developing VTE events, accounting for 24.83% of all cases. Over half of the patients (66.60%) were observed to have an increased risk of VTE within the first 6 months of cancer diagnosis. Close to half of the patients (46.49%) had received chemotherapy within 6 months prior to the diagnosis of VTE. The frequency of massive ascites group (＞2000 mL) in gynecological patients with VTE was significantly larger than that of nonmassive ascites group (≤2000 mL) (P < .001). Patients with ovarian, vulvar, lung cancers were considered at high risk for VTE. The assessment and monitoring of VTE in patients with cancer within the first 6 months of cancer diagnosis should be strengthened. VTE occurrence was closely related to advanced age and stage, adenocarcinoma, obesity and noval anticancer therapies in patients with cancer. Early detection of VTE-related examination may lead to earlier intervention for patients with gynecological tumors with preoperative massive ascites.

Predictive and Prognostic Potential of Liver Function Assessment in Patients with Advanced Hepatocellular Carcinoma: A Systematic Literature Review

Introduction: We conducted a systematic literature review to assess the utility of liver function assessments for predicting disease prognosis and response to systemic anticancer therapy in patients with advanced hepatocellular carcinoma (aHCC). Methods: This was a PRISMA-standard review and was registered with PROSPERO (CRD42021244588). MEDLINE and Embase were systematically searched (March 24, 2021) to identify publications reporting the efficacy and/or safety of systemic anticancer therapy (vs. any/no comparator) in liver-function-defined subgroups in phase 2 or 3 aHCC trials. Screening was completed by a single reviewer, with uncertainties resolved by a second reviewer and/or the authors. English-language full-text articles and congress abstracts were eligible for inclusion. Included publications were described and assessed for risk of bias using the GRADE methodology. Results: Twenty (of 2,579) screened publications were eligible; seven categorized liver function using the albumin-bilirubin system, nine using the Child-Pugh system, four using both. GRADE assessment classified ten, nine, and one publication(s) as reporting moderate-quality, low-quality, and very-low-quality evidence, respectively. Analyses of cross-trial trends of within-exposure arm analyses (active and control) reported a positive relationship between baseline liver function and overall survival and progression-free survival, supporting liver function as a prognostic marker in aHCC. There were also signals for a modest relationship between more preserved baseline liver function and extent of systemic treatment benefit, and with more preserved liver function and lower incidence of safety events. Conclusion: This review supports liver function as a prognostic variable in aHCC and highlights the value of a priori stratification of patients by baseline liver function in aHCC trials. The predictive value of liver function warrants further study. Findings were limited by the quality of available data.

ZINC SUPPLEMENTATION IN THE MANAGEMENT OF ORAL MUCOSITIS IN HEAD AND NECK CANCER PATIENTS: NARRATIVE LITERATURE REVIEW

<h3>Objectives</h3> The aim of this study was to perform a narrative review about the influence of zinc supplementation in treatment and/or prevention of oral mucositis (OM), the most common side effect of anticancer therapies in patients with head and neck cancer (HNC). <h3>Study Design</h3> A survey of studies related to the definition, treatment, and prevention of OM with nutrients, particularly zinc, was carried out between January 2018 and July 2019 using the PubMed, Cochrane Library, and Scielo databases. Inclusion criteria were human clinical trials and systematic and narrative reviews on nutritional supplements to treat and prevent OM in HNC. Exclusion criteria were animal studies and no association between nutrients and/or supplements to the treatment and/or prevention of OM. Sixty-one scientific papers published between 2004 and 2019 were selected. <h3>Results</h3> Zinc supplementation had positive effects on reducing manifestation and severity of OM due to its antioxidant and immunomodulatory properties. In general, the zinc supplement was well tolerated and did not show significant side effects. However, the ideal dose and possible side effects of its use have not yet been defined. <h3>Conclusions</h3> This study suggests the effectiveness of zinc in preventing and treating OM. Further studies are needed to establish drug administration protocol and to evaluate the effects of its use.

Phase 1 trial of first-line bintrafusp alfa in combination with other anticancer therapies in patients (pts) with locally advanced or advanced cervical cancer.

5528 Background: Until the recent FDA approval of pembrolizumab in combination with chemotherapy ± bevacizumab, there have been limited treatment options that address the underlying biology for pts with persistent, recurrent, or metastatic (P/R/M) or locally advanced (LA) cervical cancer. Persistent HPV infection is associated with 99% of cervical cancers and is linked to upregulation of TGF-β. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1, has shown promising clinical activity and manageable safety in pts with recurrent or metastatic cervical cancer. We report data from a phase 1 trial evaluating safety of first-line bintrafusp alfa plus chemotherapy ± bevacizumab for pts with P/R/M cervical cancer or bintrafusp alfa plus chemoradiotherapy for pts with LA cervical cancer (INTR@PID 046; NCT04551950). Methods: Pts with P/R/M cervical cancer who had not received prior systemic therapy received bintrafusp alfa 2400 mg Q3W plus cisplatin/carboplatin and paclitaxel with (cohort 1A) or without (cohort 1B) bevacizumab. Pts with LA cervical cancer received bintrafusp alfa 2400 mg Q3W plus concurrent weekly cisplatin and radiotherapy followed by maintenance therapy with bintrafusp alfa (cohort 2). Pts were treated until disease progression, death, unacceptable toxicity, or withdrawal. Primary endpoints were safety and tolerability of bintrafusp alfa in combination with current standard-of-care therapies in pts with P/R/M or LA cervical cancer. Results: As of November 25, 2021, 8 pts in cohort 1A, 9 in cohort 1B, and 8 in cohort 2 had received bintrafusp alfa for a median of 11.6, 10.0, and 5.6 cycles, respectively. At the time of this analysis, 11 of 25 pts remained on bintrafusp alfa therapy. Any-grade bintrafusp alfa–related adverse events (AEs) occurred in 75.0%, 100.0%, and 75.0% of pts in cohorts 1A, 1B, and 2, respectively (Table). The most-common grade ≥3 AEs were anemia and hematuria (25.0% each) in cohort 1A and vaginal hemorrhage (22.2%) in cohort 1B. One pt had grade 4 anemia and vaginal hemorrhage in cohort 1B. No treatment-related deaths occurred. AEs led to permanent discontinuation of bintrafusp alfa in 37.5%, 33.3%, and 12.5% of pts in cohorts 1A, 1B, and 2, respectively; the most common any-grade AE was vaginal hemorrhage (22.2%). Conclusions: No new safety signals were observed with first-line bintrafusp alfa plus chemotherapy ± bevacizumab or chemoradiotherapy in pts with P/R/M or LA cervical cancer. Clinical trial information: NCT04551950. [Table: see text]

Oncolytic Virotherapy in Peritoneal Metastasis Gastric Cancer: The Challenges and Achievements.

Gastric cancer (GC) is the fourth most common cancer and the second leading cause of cancer death globally. Although the mortality rate in some parts of the world, such as East Asia, is still high, new treatments and lifestyle changes have effectively reduced deaths from this type of cancer. One of the main challenges of this type of cancer is its late diagnosis and poor prognosis. GC patients are usually diagnosed in the advanced stages of the disease, which is often associated with peritoneal metastasis (PM) and significantly reduces survival. This type of metastasis in patients with GC poses a serious challenge due to limitations in common therapies such as surgery and tumor resection, as well as failure to respond to systemic chemotherapy. To solve this problem, researchers have used virotherapy such as reovirus-based anticancer therapy in patients with GC along with PM who are resistant to current chemotherapies because this therapeutic approach is able to overcome immune suppression by activating dendritic cells (DCs) and eventually lead to the intrinsic activity of antitumor effector T cells. This review summarizes the immunopathogenesis of peritoneal metastasis of gastric cancer (PMGC) and the details for using virotherapy as an effective anticancer treatment approach, as well as its challenges and opportunities.

In vivo inducible reverse genetics in patients\u2019 tumors to identify individual therapeutic targets

High-throughput sequencing describes multiple alterations in individual tumors, but their functional relevance is often unclear. Clinic-close, individualized molecular model systems are required for functional validation and to identify therapeutic targets of high significance for each patient. Here, we establish a Cre-ERT2-loxP (causes recombination, estrogen receptor mutant T2, locus of X-over P1) based inducible RNAi- (ribonucleic acid interference) mediated gene silencing system in patient-derived xenograft (PDX) models of acute leukemias in vivo. Mimicking anti-cancer therapy in patients, gene inhibition is initiated in mice harboring orthotopic tumors. In fluorochrome guided, competitive in vivo trials, silencing of the apoptosis regulator MCL1 (myeloid cell leukemia sequence 1) correlates to pharmacological MCL1 inhibition in patients´ tumors, demonstrating the ability of the method to detect therapeutic vulnerabilities. The technique identifies a major tumor-maintaining potency of the MLL-AF4 (mixed lineage leukemia, ALL1-fused gene from chromosome 4) fusion, restricted to samples carrying the translocation. DUX4 (double homeobox 4) plays an essential role in patients’ leukemias carrying the recently described DUX4-IGH (immunoglobulin heavy chain) translocation, while the downstream mediator DDIT4L (DNA-damage-inducible transcript 4 like) is identified as therapeutic vulnerability. By individualizing functional genomics in established tumors in vivo, our technique decisively complements the value chain of precision oncology. Being broadly applicable to tumors of all kinds, it will considerably reinforce personalizing anti-cancer treatment in the future.

C-REV Retains High Infectivity Regardless of the Expression Levels of cGAS and STING in Cultured Pancreatic Cancer Cells.

Oncolytic virus (OV) therapy is widely considered as a major breakthrough in anti-cancer treatments. In our previous study, the efficacy and safety of using C-REV for anti-cancer therapy in patients during stage I clinical trial was reported. The stimulator of interferon genes (STING)–TBK1–IRF3–IFN pathway is known to act as the central cellular host defense against viral infection. Recent reports have linked low expression levels of cGAS and STING in cancer cells to poor prognosis among patients. Moreover, downregulation of cGAS and STING has been linked to higher susceptibility to OV infection among several cancer cell lines. In this paper, we show that there is little correlation between levels of cGAS/STING expression and susceptibility to C-REV among human pancreatic cancer cell lines. Despite having a responsive STING pathway, BxPC-3 cells are highly susceptible to C-REV infection. Upon pre-activation of the STING pathway, BxPc-3 cells exhibited resistance to C-REV infection. However, without pre-activation, C-REV completely suppressed the STING pathway in BxPC-3 cells. Additionally, despite harboring defects in the STING pathway, other high-grade cancer cell lines, such as Capan-2, PANC-1 and MiaPaCa-2, still exhibited low susceptibility to C-REV infection. Furthermore, overexpression of STING in MiaPaCa-2 cells altered susceptibility to a limited extent. Taken together, our data suggest that the cGAS–STING pathway plays a minor role in the susceptibility of pancreatic cancer cell lines to C-REV infection.

Increased plasma levels of damage-associated molecular patterns during systemic anticancer therapy in patients with advanced lung cancer.

BackgroundImmunogenic cell death (ICD) characterized by the release of damage-associated molecular patterns (DAMPs) from dying cancer cells may contribute to the synergistic antitumor effect of cytotoxic chemotherapy combined with an immune checkpoint inhibitor. The kinetics of circulating DAMP levels in cancer patients have remained largely uncharacterized, however.MethodsWe evaluated the possible effects of various systemic anticancer therapy modalities on the kinetics of plasma DAMP concentrations in a prospective observational study of patients with advanced lung cancer. The plasma concentrations of high-mobility group box 1 (HMGB1), calreticulin (CRT), heat shock protein 70 (HSP70), annexin A1, and histone H3 were thus determined in 121 such patients at four time points during the first cycle of treatment.ResultsThe mean of the maximum fold change in HMGB1, HSP70, or annexin A1 concentration observed during treatment was significantly greater than the corresponding baseline value (P<0.005). The maximum fold changes in HMGB1 and CRT concentrations tended to be associated with clinical response as evaluated by RECIST criteria, although the changes in the levels of these two DAMPs were not correlated, suggestive of differential induction mechanisms. Among the various treatment modalities administered, platinum-based combination or single-agent chemotherapy tended to elicit robust increases in the concentrations of HMGB1 and CRT.ConclusionsSerial monitoring of plasma revealed that systemic anticancer therapy increased the circulating levels of HMGB1 and CRT and that these changes tended to be associated with clinical response, suggesting that agents capable of releasing these DAMPs into plasma might induce ICD in advanced lung cancer patients.

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.

Long non-coding RNA PART1 predicts a poor prognosis and promotes the malignant progression of pancreatic cancer by sponging miR-122

Background and objectivesLong non-coding RNA (lncRNA) prostate androgen-regulated transcript 1 (PART1) was previously shown to exert an oncogenic role in several human cancers. However, whether PART1 is associated with the malignant progression of pancreatic cancer remains unclear. In the current study, we aimed to identify the role and potential mechanism of PART1 in pancreatic cancer.MethodsqRT-PCR was applied to detect PART1 expression in 45 cases of pancreatic cancer patients. The chi-square test was performed to assess the association between PART1 expression and clinicopathologic features, and Kaplan-Meier method was applied to evaluate overall survival. In vitro CCK-8, transwell invasion, and flow cytometry assays were applied to detect the effects of PART1 on cell proliferation, invasion, and apoptosis, respectively. Luciferase reporter and RNA immunoprecipitation assays were used to identify the regulatory mechanism between PART1 and miR-122.ResultsPART1 expression was upregulated in pancreatic cancer tissues and cell lines. High PART1 expression was closely correlated with tumor size, T classification, clinical stage, and vascular invasion, and predicted a poor overall survival. PART1 knockdown significantly suppressed cell proliferation and invasion abilities of pancreatic cancer but promoted cell apoptosis. PART1 was found to serve as a molecular sponge of miR-122, and miR-122 inhibition partially reversed the inhibitory phenotypes of PART1 knockdown on pancreatic cancer cells.ConclusionsPART1 promotes the malignant progression of pancreatic cancer by sponging miR-122. The PART1/miR-122 axis might be a promising target for anticancer therapy in patients with pancreatic cancer.

The Management of Nausea and Vomiting Not Related to Anticancer Therapy in Patients with Cancer.

In cancer patients, the management of nausea and vomiting that is not directly related to treatment is challenging. Much current practice is based on expert opinion and anecdote. Fortunately, over recent years, a number of quality trials have been undertaken to strengthen the evidence base that guides the care of our patients with these distressing symptoms. Much is still unknown however. In this article, we present the latest literature that addresses some of the outstanding issues.

MO01.30 Trial in Progress: A Phase 1b Study of Sotorasib, a KRAS (G12C) Inhibitor, in Combination with other Anticancer Therapies in Patients with Advanced Solid Tumors Harboring KRAS p.G12C Mutation (CodeBreaK101)

MO01.30 Trial in Progress: A Phase 1b Study of Sotorasib, a KRAS (G12C) Inhibitor, in Combination with other Anticancer Therapies in Patients with Advanced Solid Tumors Harboring KRAS p.G12C Mutation (CodeBreaK101)

Myeloid cell leukemia-1 is an important predictor of survival and progression of small cell lung cancer.

BackgroundSmall cell lung cancer (SCLC) is the most fatal malignancy for which more effective therapies are urgently needed. Overexpression of myeloid cell leukemia-1 (Mcl-1) has been demonstrated to be one of the most common genetic alterations among different types of tumor/cancer, which induces resistance against various anti-cancer therapies including cisplatin. The study aimed to explore the role of Mcl-1 in the prognosis and resistance to anti-cancer therapy in patients with SCLC.MethodsPatients with SCLC were recruited from those enrolled/treated in Sun Yat-sen University Cancer Center. Their specimens were collected for immunohistochemical evaluation. We compared the baseline characteristics, response to chemotherapy and overall survival (OS) of the patients with different expression levels of Mcl-1.ResultsThe expression level of Mcl-1 was significantly lower in patients with limited stage SCLC than in those with extensive stage SCLC (P=0.014). Based on the median value of Mcl-1 expression level, the patients were divided into high and low Mcl-1 groups, respectively. Univariate analysis revealed that low Mcl-1 expression was associated with a significant improvement in OS, with a hazard ratio (HR) of 0.538. Multivariate analysis confirmed the independent prognostic value of Mcl-1 expression level (P=0.014). Moreover, we found a significantly close relationship between higher Mcl-1 expression level and shorter time to progression (TTP) of the patients received chemotherapy (P=0.040).ConclusionsOur findings demonstrated that Mcl-1 expression level was a prognostic biomarker for survival outcomes and cancer progression in the patients with SCLC. Thus, it could be used as a valuable biomarker in identifying those patients with high risk of treatment failure.

Outcomes of COVID-19 Infection in Patients Receiving Ruxolitinib and Hypomethylating Agent Therapy

IntroductionThe ongoing novel coronavirus disease 2019 (COVID-19) pandemic has provoked questions about treatment decisions in patients with hematologic malignancies. Of note, several anti-cancer agents have been shown to have preclinical activity against the SARS-CoV-2 virus, including ruxolitinib (Jakafi), as well as the hypomethylating agents (HMA) decitabine (Dacogen) and azacitidine (Vidaza). In addition, ruxolitinib has previously been shown to have potent activity against the cytokine response, similar to that seen in COVID-19 infections. The optimal management of patients on these agents who become infected with COVID-19 is unknown and it is not clear if the use of these agents modifies the clinical course of infection. We describe a case series of patients with hematologic malignancies receiving therapy with these agents while infected with COVID-19.MethodsWe conducted a retrospective chart review of consecutive patients between March 1 and May 21, 2020 who were receiving therapy with ruxolitinib, azacitidine, or decitabine when diagnosed with COVID-19 by SARS-CoV-2 PCR assay within the Mount Sinai Health System. The indications for these agents included acute lymphocytic leukemia, acute myeloid leukemia, myelofibrosis, polycythemia vera, and myelodysplastic syndromes. Patients who last received the agent more than thirty days prior to COVID-19 diagnosis were excluded from our series.ResultsSixteen patients on HMA or ruxolitinib were diagnosed with COVID-19 within our health system during this span. Full patient characteristics and clinical data are described in Tables 1a and 1b. Seven patients were receiving ruxolitinib and nine patients were on HMA: eight on azacitidine and one on decitabine. Of the patients on HMA, eight had therapy held after confirmed COVID-19 infection, and one was continued on therapy. Overall mortality in the HMA cohort was 88.9% (8/9), including 7/8 in the therapy-held group and the one patient for whom therapy was continued. Of the patients on ruxolitinib, three had therapy held and four were continued after confirmed infection. Overall mortality in the ruxolitinib cohort was 57.1% (4/7), with 75% (3/4) in the therapy-held and 33% (1/3) mortality in the therapy-continued groups. All patients who died (n = 12) required either non-invasive positive pressure ventilation or mechanical ventilation. Across all agents, patients who survived (n = 4) required no higher level of supplemental oxygen than non-rebreather mask, and one did not require hospitalization. Cytokine levels were on average higher on admission for the ruxolitinib-held group but were not associated with mortality or increased oxygen requirement.DiscussionHigh mortality rates were observed for both ruxolitinib and HMA in this high-risk group of patients with hematologic malignancy regardless of whether therapy was held. HMA was commonly held at time of infection: further investigation will be needed to elucidate any potential in-vivo anti-SARS-CoV-2 activity for these reagents. Mortality was numerically less in patients in receiving ruxolitinib who continued therapy, however this should be interpreted with caution given our small cohort. Further clinical trials to address the use of ruxolitinib are necessary and are ongoing. These data can help guide further investigation regarding use of anti-cancer therapy in patients with hematologic malignancy diagnosed with COVID-19.DisclosuresMascarenhas:Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution).

One-year survival of patients with high-grade glioma discharged alive from the intensive care unit.

IntroductionOnly limited data are available regarding the long-term prognosis of patients with high-grade glioma discharged alive from the intensive care unit. We sought to quantify 1-year mortality and evaluate the association between mortality and (1) functional status, and (2) management of anticancer therapy in patients with high-grade glioma discharged alive from the intensive care unit. Patients and methodsRetrospective observational cohort study of patients with high-grade glioma admitted to two intensive care units between January 2009 and June 2018. Functional status was assessed by the Karnofsky Performance Status. Anticancer therapy after discharge was classified as (1) continued (unchanged), (2) modified (changed or stopped), or (3) initiated (for newly diagnosed disease). ResultsNinety-one high-grade glioma patients (73% of whom had glioblastoma) were included and 78 (86%) of these patients were discharged alive from the intensive care unit. Anticancer therapy was continued, modified, and initiated in 41%, 42%, and 17% of patients, respectively. Corticosteroid therapy at the time of ICU admission [odds ratio (OR) 0.07] and cancer progression (OR 0.09) was independently associated with continuation of anticancer therapy. The mortality rate 1 year after ICU admission was 73%. On multivariate analysis, continuation of anticancer therapy (OR 0.18) and Karnofsky performance status on admission (OR 0.90) were independently associated with lower 1-year mortality. ConclusionThe presence of high-grade glioma is not sufficient to justify refusal of intensive care unit admission. Performance status and continuation of anticancer therapy are associated with higher survival after intensive care unit discharge. Previous presentationPreliminary results were presented at the most recent congress of the French Intensive Care Society, Paris, 2019.Electronic supplementary materialThe online version of this article (10.1007/s00415-020-10191-0) contains supplementary material, which is available to authorized users.

Trial in progress: A phase Ib study of AMG 510, a specific and irreversible KRASG12C inhibitor, in combination with other anticancer therapies in patients with advanced solid tumors harboring KRAS p.G12C mutation (CodeBreak 101).

TPS3661 Background: Kirsten rat sarcoma viral oncogene homolog (KRAS) p.G12C mutation has been identified as a driver oncogenic mutation in several solid tumors (eg, non-small cell lung cancer [NSCLC], colorectal cancer [CRC]). Development of therapies targeting KRASG12C has been unsuccessful. AMG 510 is a specific and irreversible small molecule inhibitor of KRASG12C. A first-in-human clinical trial of AMG 510 monotherapy in patients with KRAS p.G12C mutant solid tumors is currently ongoing. AMG 510 in combination with additional anticancer therapies may lead to enhanced antitumor efficacy. This study is a master protocol designed to evaluate multiple investigational regimens of AMG 510 in patients with KRAS p.G12C mutant solid tumors. Here, we present two combination cohorts of AMG 510 with a mitogen-activated protein kinase kinase (MEK) inhibitor and an investigational anti-programmed cell death protein-1 (PD-1) therapy, respectively. Additional combination cohorts will be presented at the meeting. Methods: This is a phase 1b, open-label study evaluating AMG 510 in combination with a MEK inhibitor or an investigational anti-PD-1 therapy in pts with KRAS p.G12C mutant solid tumors. The dose exploration phase (part 1; n=20) will evaluate the safety and tolerability of AMG 510 in combination with the MEK inhibitor or anti-PD-1 therapy; this will be followed by a dose expansion phase (part 2; n=40) to verify the safety and tolerability profile of AMG 510 combination therapies and assess antitumor efficacy. Key eligibility criteria include locally-advanced or metastatic malignancy with KRAS p.G12C mutation identified through molecular testing and at least one or multiple lines of prior systemic therapy (eg, ≥2 for advanced/metastatic colorectal cancer). Primary endpoints include dose-limiting toxicities, treatment-emergent or -related adverse events. Secondary endpoints include pharmacokinetic parameters of combination regimens, disease control rate, duration of response, progression-free survival, and duration of stable disease (measured by computed tomography or magnetic resonance imaging and assessed per RECIST 1.1). The study began enrolling pts in December 2019 and is ongoing. For more information, please contact Amgen Medical Information: medinfo@amgen.com . Clinical trial information: NCT04185883 .