Purpose: The stimulator of IFN genes (STING) is a transmembrane protein that plays a role in the immune response to tumors. Single-agent STING agonist MIW815 (ADU-S100) has demonstrated immune activation but limited antitumor activity. This phase Ib, multicenter, dose-escalation study assessed the safety and tolerability of MIW815 plus spartalizumab (PDR001), a humanized IgG4 antibody against PD-1, in 106 patients with advanced solid tumors or lymphomas. Patients and Methods: Patients were treated with weekly intratumoral injections of MIW815 (50–3,200 μg) on a 3-weeks-on/1-week-off schedule or once every 4 weeks, plus a fixed dose of spartalizumab (400 mg) intravenously every 4 weeks. Results: Common adverse events were pyrexia (n = 23; 22%), injection site pain (n = 21; 20%), and diarrhea (n = 12; 11%). Overall response rate was 10.4%. The MTD was not reached. Pharmacodynamic biomarker analysis demonstrated on-target activity. Conclusions: The combination of MIW815 and spartalizumab was well tolerated in patients with advanced/metastatic cancers, including in patients with anti-PD-1 refractory disease. Minimal antitumor responses were seen.

Background: In order to counteract fatigue, physical activity (PA) is recommended for all stages of cancer. However, only few advanced cancer patients (ACP) are physically active. Quantitative data with high numbers of ACP reporting barriers to PA are missing. This study aimed to identify barriers to PA in ACP with tiredness/weakness and investigate their motivation towards it. Methods: Outpatients with metastatic cancer receiving cancer care at a German Cancer Center reporting moderate/severe tiredness/weakness during self-assessment (MIDOS II) were enrolled. We assessed Fatigue-(FACF-F) and Depression (PHQ8) Scores, demographics, cancer-specific parameters, motivation for PA, physical, psychological and social barriers. Results: 141 of 440 eligible patients (32.0%) with different diagnoses agreed to participate. Patients frequently reported “I feel weakened due to my tumor therapy” (n = 108; 76.6%), physical symptoms (tiredness, weakness, dyspnea, joint-problems, pain, nausea [n = 107; 75.9%]) and fatigue (n = 99; 70.2%) as barriers to PA. However, no significant group differences regarding these barriers were found between physically active and inactive patients. Social barriers were rarely chosen. Motivated patients were 5.6 times more likely to be physically active (p < 0.001), also motivation turned out to be the strongest predictor for a physically active behavior (β = 1.044; p = 0.005). Motivated attitude towards PA was predicted by fatigue (β = − 2.301; p = 0.008), clinically relevant depression (β = − 1.390, p = 0.039), knowledge about PA and quality of life (QoL) (β = 0.929; p = 0.002), PA before diagnosis (β = 0.688; p = 0.005 and Interest in exercise program (β = 0.635; p = 0.008). Conclusion: “I feel weakened due to my tumor therapy” is the most reported barrier to PA among both, physically and inactive patients. Motivation for PA is the strongest predictor of performing PA. Interest in PA, knowledge about PA/QoL and PA before diagnosis are main predictors of a motivated attitude. Absence/presence of social barriers did not associate with motivation, fatigue and depression proved to be a negative predictor. Programs including information, motivational counseling and individualized training should be offered for ACP to overcome barriers and reduce fatigue. Trial registration: German Register of Clinical Trials DRKS00012514, registration date: 30.5.2017.

Patients suffering from acute myeloid leukemias (AML) bearing FMS-like tyrosine kinase-3-internal tandem duplications (FLT3-ITD) have poor outcomes following cytarabine- and anthracyclin-based induction therapy. To a major part this is attributed to drug resistance of FLT3-ITD-positive leukemic cells. Against this background, we have devised an antibody array approach to identify proteins, which are differentially expressed by hematopoietic cells in relation to activated FLT3 signaling. Selective upregulation of antiapoptotic myeloid cell leukemia-1 (MCL-1) was found in FLT3-ITD-positive cell lines and primary mononuclear cells from AML patients as compared with FLT3-wild-type controls. Upregulation of MCL-1 was dependent on FLT3 signaling as confirmed by its reversion upon pharmacological inhibition of FLT3 activity by the kinase inhibitor PKC412 as well as siRNA-mediated suppression of FLT3. Heterologously expressed MCL-1 substituted for FLT3 signaling by conferring resistance of hematopoietic cells to antileukemia drugs such as cytarabine and daunorubicin, and to the proapoptotic BH3 mimetic ABT-737. Conversely, suppression of endogenous MCL-1 by siRNA or by flavopiridol treatment sensitized FLT3-ITD-expressing hematopoietic cells to cytotoxic and targeted therapeutics. In conclusion, MCL-1 is an essential effector of FLT3-ITD-mediated drug resistance. Therapeutic targeting of MCL-1 is a promising strategy to overcome drug resistance in FLT3-ITD-positive AML.

Purpose: Treatment options for recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) after failure of immune checkpoint inhibitor treatment and platinum-based chemotherapy are limited. Preliminary data suggested that monalizumab plus cetuximab had clinical activity in R/M HNSCC. Patients and Methods: INTERLINK-1 (NCT04590963) was a double-blind, phase III study. Participants with R/M HNSCC who had received immune checkpoint inhibitor therapy and progressed despite platinum-based chemotherapy were randomized 2:1 to monalizumab (750 mg, every 2 weeks) or placebo, plus cetuximab (400 mg/m2 loading dose, then 250 mg/m2, weekly). The primary endpoint was overall survival (OS) in participants with non-oropharyngeal cancer or human papillomavirus (HPV)-negative oropharyngeal cancer (HPV-unrelated analysis set). Secondary endpoints included progression-free survival and objective response rate. Results: At data cutoff, 216 participants were randomized in the HPV-unrelated analysis set: 145 to monalizumab plus cetuximab and 71 to placebo plus cetuximab. Median OS was 8.8 months for monalizumab plus cetuximab versus 8.6 months for placebo plus cetuximab (HR, 1.00; 95% confidence interval, 0.66–1.54); median progression-free survival was 3.6 versus 3.8 months, respectively (HR, 1.11; 95% confidence interval, 0.79–1.57); and the objective response rate was 15.2% versus 23.9%, respectively. INTERLINK-1 was terminated after a preplanned interim analysis showed that futility criteria were met (predetermined futility HR >0.874). Grade 3/4 treatment–related adverse events were reported in 18.3% and 17.2% of participants treated in the monalizumab and placebo arms, respectively. Conclusions: Monalizumab plus cetuximab did not improve OS compared with placebo plus cetuximab. The safety profile of the combination was consistent with safety observations for cetuximab monotherapy.

Most metastatic colorectal cancer (mCRC) patients succumb to refractory disease due to secondary chemotherapy resistance. To elucidate the molecular changes associated with secondary resistance, we recruited 64 patients with mCRC and hepatic metastases before standard first-line chemotherapy between 2014 and 2018. We subjected DNA from primary tumor specimens (P), hepatic metastasis specimens after treatment (M), and liquid biopsies (L) taken prior to (pre), during (intra), and after (post) treatment to next generation sequencing. We performed Nanostring expression analysis in P and M specimens. Comparative bioinformatics and statistical analysis revealed typical mutational patterns with frequent alterations in TP53, APC, and KRAS in P specimens (n = 48). P and pre-L (n = 42), as well as matched P and M (n = 30), displayed a similar mutation spectrum. In contrast, gene expression profiles classified P (n = 31) and M (n = 23), distinguishable by up-regulation of immune/cytokine receptor and autophagy programs. Switching of consensus molecular subtypes from P to M occurred in 58.3% of cases. M signature genes SFRP2 and SPP1 associated with inferior survival, as validated in an independent cohort. Molecular changes during first-line treatment were detectable by expression profiling rather than by mutational tumor and liquid biopsy analyses. SFRP2 and SPP1 may serve as biomarkers and/or actionable targets.

Purpose: The prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remains dismal. New cytotoxic agents such as nab-paclitaxel and liposomal irinotecan (nal-Iri) have extended the armamentarium of therapeutic options in the last years. Nowadays, sequential therapeutic strategies with moderately toxic chemotherapeutic protocols can be administered to the patients. However, prognostic and predictive biomarkers are still missing to identify those patients, which profit most from a “continuum of care” concept rather than receiving intensive first-line protocols such as FOLFIRINOX. To this end, we retrospectively evaluated the impact of the systemic inflammation as one essential hallmark of cancer in patients with advanced PDAC treated with sequential systemic. Methods: A cohort of 193 PDAC patients treated at our center from January 2005 to August 2011 were retrospectively evaluated for the following systemic inflammatory response (SIR) markers: neutrophil–lymphocyte ratio (NLR), lymphocyte–monocyte ratio (LMR) C-reactive protein (CRP), and the modified Glasgow Prognostic Score (mGPS). SIR markers were correlated with clinico-pathological findings, response to chemotherapy and overall survival (OS) using Kaplan–Meier curves and Cox proportional models. Results: All evaluated SIR markers were significantly associated with OS in patients with metastatic disease but not in patients with locally advanced PDAC. Interestingly, all SIR markers were only prognostic in patients not receiving antibiotics as surrogate marker for systemic bacterial infections. Based on the evaluated SIR markers, we propose a new Systemic Inflammation Score (SIS), which significantly correlated with reduced OS (HR: 3.418 (1.802–6.488, p < 0.001)) and the likelihood of receiving further-line systemic therapies (p = 0.028). Conclusion: Routinely assessed SIR biomarkers have potential to support therapeutic decision making in patients with metastatic PDAC.