Autoimmunity Against Surfactant Protein B Is Associated with Pneumonitis During Checkpoint Blockade.

RATIONALE: Immune checkpoint inhibitor-related pneumonitis is a serious autoimmune event affecting up to 20% of patients with non-small cell lung cancer, yet the factors underpinning its development in some patients and not others are poorly understood. OBJECTIVES: To investigate the role of autoantibodies and autoreactive T cells against surfactant-related proteins in the development of pneumonitis. METHODS: The study cohort consisted of non-small cell lung cancer patients who gave blood samples before and during immune checkpoint inhibitor treatment. Serum was used for proteomics analyses and to detect autoantibodies present during pneumonitis. T cell stimulation assays and single-cell RNA sequencing were performed to investigate the specificity and functionality of peripheral autoreactive T cells. The findings were confirmed in a validation cohort comprising patients with non-small cell lung cancer and patients with melanoma. MEASUREMENTS AND MAIN RESULTS: Across both cohorts, patients who developed pneumonitis had higher pre-treatment levels of immunoglobulin G autoantibodies targeting surfactant protein-B. At the onset of pneumonitis, these patients also exhibited higher frequencies of CD4+ interferon-gamma-positive surfactant protein B-specific T cells, and expanding T cell clonotypes recognizing this protein, accompanied by a pro-inflammatory serum proteomic profile. CONCLUSIONS: Our data suggest that the co-occurrence of surfactant protein-B-specific immunoglobulin G autoantibodies and CD4+ T cells is associated with the development of pneumonitis during ICI therapy. Pre-treatment levels of these antibodies may represent a potential biomarker for elevated risk of developing pneumonitis and on-treatment levels may provide a diagnostic aid.

Paclitaxel therapeutic drug monitoring - International association of therapeutic drug monitoring and clinical toxicology recommendations.

Paclitaxel, one of the most frequently used anticancer drugs, is dosed by body surface area, which leads to substantial inter-individual variability in systemic drug exposure. We evaluated clinical evidence regarding the scientific rationale and clinical benefit of individualized paclitaxel dosing based on measured systemic concentrations, known as therapeutic drug monitoring (TDM). In retrospective studies, higher systemic exposure is associated with greater toxicity and efficacy of paclitaxel treatment across several disease types and dosing regimens. In prospective trials, TDM reduces variability in systemic exposure, and has been demonstrated to reduce toxicity while retaining treatment efficacy for 3-weekly dosing in patients with advanced non-small cell lung cancer. Despite the demonstrated benefits of paclitaxel TDM, clinical adoption has been limited due to the challenges with sample collection and analysis. Based on our review, we strongly recommend TDM for patients receiving every 3-week paclitaxel in combination with a platinum agent for advanced NSCLC, due to the prospectively demonstrated clinical benefits, and find moderate evidence to recommend TDM for paclitaxel 3-hour infusions for other tumor types and preliminary evidence suggesting potential usefulness for paclitaxel administered by 1-hour infusions.

TLD-1, a novel liposomal doxorubicin, in patients with advanced solid tumors: Dose escalation and expansion part of a multicenter open-label phase I trial (SAKK 65/16).

BACKGROUND: TLD-1 is a novel liposomal doxorubicin that compared favorably to conventional doxorubicin liposomal formulations in preclinical models. This phase I first-in-human study aimed to define the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety and preliminary activity of TLD-1 in patients with advanced solid tumors. PATIENTS AND METHODS: We recruited patients with advanced solid tumors who failed standard therapy and received up to 3 prior lines of palliative systemic chemotherapy. TLD-1 was administered intravenously every 3 weeks up to a maximum of 9 cycles (6 for patients with prior anthracyclines) from a starting dose of 10 mg/m2, according to an accelerated titration design followed by a modified continual reassessment method. RESULTS: 30 patients were enrolled between November 2018 and May 2021. No dose-limiting toxicities (DLT) were observed. Maximum administered dose of TLD-1 was 45 mg/m2, RP2D was defined at 40 mg/m2. Most frequent treatment-related adverse events (TRAE) of any grade included palmar-plantar erythrodysesthesia (PPE) (50% of patients), oral mucositis (50%), fatigue (30%) and skin rash (26.7%). Most common G3 TRAE included PPE in 4 patients (13.3%) and oral mucositis in 2 (6.7%). Overall objective response rate was 10% in the whole population and 23.1% among 13 patients with breast cancer; median time-to-treatment failure was 2.7 months. TLD-1 exhibit linear pharmacokinetics, with a median terminal half-life of 95 h. CONCLUSIONS: The new liposomal doxorubicin formulation TLD-1 showed a favourable safety profile and antitumor activity, particularly in breast cancer. RP2D was defined at 40 mg/m2 administered every 3 weeks. (NCT03387917).

Relevance of tumor markers for prognosis and predicting therapy response in non-small cell lung cancer patients: A CEPAC-TDM biomarker substudy.

BACKGROUND: Protein tumor markers are released in high amounts into the blood in advanced non-small cell lung cancer (NSCLC). OBJECTIVE: To investigate the relevance of serum tumor markers (STM) for prognosis, prediction and monitoring of therapy response in NSCLC patients receiving chemotherapy. METHODS: In a biomarker substudy of a prospective, multicentric clinical trial (CEPAC-TDM) on 261 advanced NSCLC patients, CYFRA 21-1, CEA, SCC, NSE, ProGRP, CA125, CA15-3 and HE4 were assessed in serial serum samples and correlated with radiological response after two cycles of chemotherapy and overall (OS) and progression-free survival (PFS). RESULTS: While pretherapeutic STM levels at staging did not discriminate between progressive and non-progressive patients, CYFRA 21-1, CA125, NSE and SCC at time of staging did, and yielded AUCs of 0.75, 0.70, 0.69 and 0.67 in ROC curves, respectively. High pretherapeutic CA15-3 and CA125 as well as high CYFRA 21-1, SCC, CA125 and CA15-3 levels at staging were prognostic for shorter PFS and OS -also when clinical variables were added to the models. CONCLUSIONS: STM at the time of first radiological staging and pretherapeutic CA15-3, CA125 are predictive for first-line treatment response and highly prognostic in patients with advanced NSCLC.

Implementing physics-based digital patient twins to tailor the switch of oral morphine to transdermal fentanyl patches based on patient physiology.

Fentanyl transdermal patches are widely implemented for cancer-induced pain treatment due to the high potency of fentanyl and gradual drug release. However, transdermal fentanyl up-titration for opioid-naïve patients is difficult, which is why opioid treatment is often started with oral/iv morphine. Based on the daily dose of morphine, the initial dose of the fentanyl patch is decided upon. After reaching a stable level of pain, the switch is made from oral/iv morphine to transdermal fentanyl. There are standard calculation tools for transferring from oral/iv morphine to transdermal fentanyl, which is the same for all patients. By considering the variations in the physiology of the patients, a unique switching strategy cannot meet the needs of different patients. This study explores the outcome in terms of pain relief and minute ventilation during opioid therapy. For this, we used physics-based simulations on a virtually-generated population of patients, and we applied the same therapy to all patients. We could show that patients' physiology, such as gender, age, and weight, greatly impact the outcome of the therapy; as such, the correlation coefficient between pain intensity and age is 0.89, and the correlation coefficient between patient's weight and maximum plasma concentration of morphine and fentanyl is -0.98 and -0.97. Additionally, a different combination of the duration of overlap between morphine and fentanyl therapy with different doses of fentanyl was considered for the virtual patients to find the best opioid-switching strategy for each patient. We explored the impact of combining physiological features to determine the best-suited strategy for virtual patients. Our findings suggest that tailoring morphine and fentanyl therapy only based on a limited number of features is insufficient, and increasing the number of impactful physiological features positively influences the outcome of the therapy.

Effects of CTLA-4 Single Nucleotide Polymorphisms on Toxicity of Ipilimumab-Containing Regimens in Patients With Advanced Stage Melanoma.

Single nucleotide polymorphisms (SNPs) in the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) gene, an inhibitor of T-cell priming, are associated with auto and alloimmunity. Studies implied a role for these SNPs as surrogate markers for immunotherapy-outcome in patients with melanoma. However, no predictive SNPs are defined to date. We analyzed different CTLA-4 SNPs in a large multicenter cohort of patients with ipilimumab-treated melanoma and investigated possible correlations with treatment-related outcomes. Archival blood and/or tumor tissue samples were collected from 361 patients with advanced-stage ipilimumab-treated (±nivolumab) in 6 Swiss and Dutch hospitals. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry based DNA genotyping was performed for 10 different CTLA-4 SNPs: 49A>G, CT60G>A, Jo27T>C, Jo30G>A, Jo31G>T, -658C>T, -1722T>C, -1661A>G, 318C>T, and C>T rs1863800. Associations between different allele genotypes and occurrence of grade ≥3 adverse events (AEs) and survival were tested using univariable logistic regressions or Cox proportional hazard models. 262/361 (73%) patients could be analyzed; 65% of those were males, the median age was 58 years, 39% showed a partial or complete response, and 65% had ≥1 AEs. A TT-genotype of -1722T>C SNP was significantly associated with a lower incidence of grade ≥3 AEs (P = 0.049), whereas the GG-genotype of CT60G>A correlated with a higher incidence of grade ≥3 AEs (P = 0.026). The TT-genotype of Jo27T>C SNP (P = 0.056) and GG-genotype of Jo31G>T (P = 0.046) were associated with overall survival. CTLA-4 SNPs might predict treatment-related outcomes in patients with melanoma receiving ipilimumab. Confirmatory studies are needed to fully exploit those findings as predictive biomarkers for ipilimumab AEs.

First-line durvalumab in patients with PD-L1 positive, advanced non-small cell lung cancer (NSCLC) with a performance status of 2 (PS2). Primary analysis of the multicenter, single-arm phase II trial SAKK 19/17.

INTRODUCTION: The safety and efficacy of first-line durvalumab in PS2 patients with advanced NSCLC is unknown. Here, we present the primary analysis of first-line durvalumab in PS2 patients, unsuitable for combination chemotherapy. METHODS: In this single-arm, multicenter, phase II trial patients with PD-L1 positive (tumor proportional score ≥25%), advanced NSCLC with PS2, received four-weekly durvalumab 1500 mg. The primary endpoint was overall survival (OS) at 6 months. RESULTS: Forty-eight patients were included. Median follow-up was 23.3 months (95% CI: 14.3-28.6). OS at 6 months was 60% (95% CI: 45-74%). Median OS was 8.5 months (95%CI: 4.4-16.7). Objective response rate and median progression free survival were 17% (95% CI: 8-30%) and 2.5 months (95% CI: 1.8-7.1), respectively. Thirty-three deaths were observed at the time point of the analysis. Seven early fatal events considered not treatment-related occurred during the first 5 weeks of treatment. Four out of the first 7 early fatal events (4/7; 57%) were respiratory failure in patients with advanced symptomatic primary lung tumors. Three more early fatal events occurred after exclusion of patients with grade ≥ 3 dyspnea. Treatment-related AEs ≥G3 were reported in 9 patients (19%) and included colonic perforation in one patient (grade 5), colitis in 4 patients (8%), increased lipase in 3 patients (6%), and hepatitis in 2 patients (4%). CONCLUSIONS: First-line durvalumab in PS2 patients with advanced PD-L1 positive NSCLC results in a high number of early fatal events. When patients with grade ≥ 3 dyspnea are excluded a promising 6-month OS with an acceptable toxicity profile can be observed. Durvalumab could be an option instead of single agent chemotherapy for PS2 patients who are not candidates for platinum doublet chemotherapy provided they are well selected.

Missing prognostic value of soluble PD-1, PD-L1 and PD-L2 in lung cancer patients undergoing chemotherapy - A CEPAC-TDM biomarker substudy.

BACKGROUND: Programmed cell death receptors and ligands in cancer tissue samples are established companion diagnostics for immune checkpoint inhibitor (ICI) therapies. OBJECTIVE: To investigate the relevance of soluble PD-1, PD-L1 and PD-L2 for estimating therapy response and prognosis in non-small cell lung cancer patients (NSCLC) undergoing platin-based combination chemotherapies. METHODS: In a biomarker substudy of a prospective, multicentric clinical trial (CEPAC-TDM) on advanced NSCLC patients, soluble PD-1, PD-L1 and PD-L2 were assessed in serial serum samples by highly sensitive enzyme-linked immunosorbent assays and correlated with radiological response after two cycles of chemotherapy and with overall survival (OS). RESULTS: Among 243 NSCLC patients, 185 achieved response (partial remission and stable disease) and 58 non-response (progression). The distribution of PD-1, PD-L1 and PD-L2 at baseline (C1), prior to staging (C3) and the relative changes (C3/C1) greatly overlapped between the patient groups with response and non-response, thus hindering the discrimination between the two groups. None of the PD markers had prognostic value regarding OS. CONCLUSIONS: Neither soluble PD-1, PD-L1 nor PD-L2 did provide clinical utility for predicting response to chemotherapy and prognosis. Studies on the relevance of PD markers in ICI therapies are warranted.

Geriatric evaluation methods in oncology and their use in clinical studies: A systematic literature review.

INTRODUCTION: Therapeutic options in oncology keep on expanding. Nonetheless, older adults are underrepresented in clinical trials and those enrolled often have a better health status than their average peers, resulting in a lack of representative evidence for this heterogenous population. The inclusion of older patients and a uniform categorization of "frailty" is becoming increasingly urgent. Standardized tools could contribute to the quality and comparability of clinical trials and facilitate clinical decisions. The aim of this literature review was to elaborate an overview of the use of geriatric evaluation (GE) methods in clinical cancer research. MATERIALS AND METHODS: We performed a literature review of the PubMed database. Clinical pharmacotherapy studies that applied or evaluated a clearly defined system for the GE of oncological patients were included. Data retrieved encompassed the applied GE method(s), cancer type(s), and pharmacotherapy investigated, the number of included patients, study type, year of publication, as well as the primary purpose of the GE. The GEs used most frequently were depicted in more depth. RESULTS: In this literature review, 103 publications were selected for inclusion. The biggest proportion of studies (36%, n = 34) used clearly defined, but not previously validated, GE methods (study-specific GE). Standardized GE methods encountered in at least five publications were the G8 screening test (applied in 18% of included studies, n = 17), the Balducci score (7%, n = 7), and a geriatric assessment based on Hurria (5%, n = 5). The primary purpose of GE was predominantly an appraisal of its potential role in pharmacotherapy optimization. The GE also served as baseline and outcome measure, inclusion/exclusion criterion, factor for stratified randomization, and to determine treatment allocation. DISCUSSION: The wide range of GE methods used across studies make direct comparisons difficult, and many methods are poorly characterized and/or not previously validated. The further inclusion of representative older patients in clinical trials combined with the use of a standardized GE could help clinicians in the decision-making process.

C-Reactive Protein as an Early Predictor of Efficacy in Advanced Non-Small-Cell Lung Cancer Patients: A Tumor Dynamics-Biomarker Modeling Framework.

In oncology, longitudinal biomarkers reflecting the patient's status and disease evolution can offer reliable predictions of the patient's response to treatment and prognosis. By leveraging clinical data in patients with advanced non-small-cell lung cancer receiving first-line chemotherapy, we aimed to develop a framework combining anticancer drug exposure, tumor dynamics (RECIST criteria), and C-reactive protein (CRP) concentrations, using nonlinear mixed-effects models, to evaluate and quantify by means of parametric time-to-event models the significance of early longitudinal predictors of progression-free survival (PFS) and overall survival (OS). Tumor dynamics was characterized by a tumor size (TS) model accounting for anticancer drug exposure and development of drug resistance. CRP concentrations over time were characterized by a turnover model. An x-fold change in TS from baseline linearly affected CRP production. CRP concentration at treatment cycle 3 (day 42) and the difference between CRP concentration at treatment cycles 3 and 2 were the strongest predictors of PFS and OS. Measuring longitudinal CRP allows for the monitoring of inflammatory levels and, along with its reduction across treatment cycles, presents a promising prognostic marker. This framework could be applied to other treatment modalities such as immunotherapies or targeted therapies allowing the timely identification of patients at risk of early progression and/or short survival to spare them unnecessary toxicities and provide alternative treatment decisions.

Phase I/Ib, open-label, multicenter, dose-escalation study of the anti-TGF-ß monoclonal antibody, NIS793, in combination with spartalizumab in adult patients with advanced tumors.

BACKGROUND: NIS793 is a human IgG2 monoclonal antibody that binds to transforming growth factor beta (TGF-ß). This first-in-human study investigated NIS793 plus spartalizumab treatment in patients with advanced solid tumors. METHODS: Patients received NIS793 (0.3-1 mg/kg every 3 weeks (Q3W)) monotherapy; following evaluation of two dose levels, dose escalation continued with NIS793 plus spartalizumab (NIS793 0.3-30 mg/kg Q3W and spartalizumab 300 mg Q3W or NIS793 20-30 mg/kg every 2 weeks [Q2W] and spartalizumab 400 mg every 4 weeks (Q4W)). In dose expansion, patients with non-small cell lung cancer (NSCLC) resistant to prior anti-programmed death ligand 1 or patients with microsatellite stable colorectal cancer (MSS-CRC) were treated at the recommended dose for expansion (RDE). RESULTS: Sixty patients were treated in dose escalation, 11 with NIS793 monotherapy and 49 with NIS793 plus spartalizumab, and 60 patients were treated in dose expansion (MSS-CRC: n=40; NSCLC: n=20). No dose-limiting toxicities were observed. The RDE was established as NIS793 30 mg/kg (2100 mg) and spartalizumab 300 mg Q3W. Overall 54 (49.5%) patients experienced ≥1 treatment-related adverse event, most commonly rash (n=16; 13.3%), pruritus (n=10; 8.3%), and fatigue (n=9; 7.5%). Three partial responses were reported: one in renal cell carcinoma (NIS793 30 mg/kg Q2W plus spartalizumab 400 mg Q4W), and two in the MSS-CRC expansion cohort. Biomarker data showed evidence of target engagement through increased TGF-ß/NIS793 complexes and depleted active TGF-ß in peripheral blood. Gene expression analyses in tumor biopsies demonstrated decreased TGF-ß target genes and signatures and increased immune signatures. CONCLUSIONS: In patients with advanced solid tumors, proof of mechanism of NIS793 is supported by evidence of target engagement and TGF-ß pathway inhibition. TRIAL REGISTRATION NUMBER: NCT02947165.

Early Identification of Patients at Risk of Cabazitaxel-induced Severe Neutropenia.

BACKGROUND: Cabazitaxel frequently causes severe neutropenia. A higher cabazitaxel systemic exposure is related to a lower nadir absolute neutrophil count (ANC). OBJECTIVE: To describe the effect of cabazitaxel systemic exposure on ANC by a population pharmacokinetic/pharmacodynamic (POP-PK/PD) model, and to identify patients at risk of severe neutropenia early in their treatment course using a PK threshold. DESIGN, SETTING, AND PARTICIPANTS: Data from five clinical studies were pooled to develop a POP-PK/PD model using NONMEM, linking both patient characteristics and cabazitaxel systemic exposure directly to ANC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A PK threshold, predictive of severe neutropenia (grade ≥3), was determined using a receiver operating characteristic curve. RESULTS AND LIMITATIONS: Ninety-six patients were included with a total of 1726 PK samples and 1081 ANCs. The POP-PK/PD model described both cabazitaxel PK and ANC accurately. A cabazitaxel plasma concentration of >4.96 ng/ml at 6 h after the start of infusion was found to be predictive of severe neutropenia, with a sensitivity of 76% and a specificity of 65%. CONCLUSIONS: Early cabazitaxel plasma levels are predictive of severe neutropenia. Implementation of the proposed PK threshold results in early identification of almost 76% of all severe neutropenias. If prospectively validated, patients at risk could benefit from prophylactic administration of granulocyte colony stimulating factors, preventing severe neutropenia in an early phase of treatment. Implementation of this threshold permits a less restricted use of the 25 mg/m2 dose, potentially increasing the therapeutic benefit. PATIENT SUMMARY: Treatment with cabazitaxel chemotherapy often causes neutropenia, leading to susceptibility to infections, which might be life threatening. We found that a systemic cabazitaxel concentration above 4.96 ng/ml 6 h after the start of infusion is predictive of the occurrence of severe neutropenia. Measurement of systemic cabazitaxel levels provides clinicians with the opportunity to prophylactically stimulate neutrophil growth.

Non-pharmaceutical interventions to optimize cancer immunotherapy.

The traditional picture of cancer patients as weak individuals requiring maximum rest and protection is beginning to dissolve. Too much focus on the medical side and one's own vulnerability and mortality might be counterproductive and not doing justice to the complexity of human nature. Unlike cytotoxic and lympho-depleting treatments, immune-engaging therapies strengthen the immune system and are typically less harmful for patients. Thus, cancer patients receiving checkpoint inhibitors are not viewed as being vulnerable per se, at least not in immunological and physical terms. This perspective article advocates a holistic approach to cancer immunotherapy, with an empowered patient in the center, focusing on personal resources and receiving domain-specific support from healthcare professionals. It summarizes recent evidence on non-pharmaceutical interventions to enhance the efficacy of immune checkpoint blockade and improve quality of life. These interventions target behavioral factors such as diet, physical activity, stress management, circadian timing of checkpoint inhibitor infusion, and waiving unnecessary co-medication curtailing immunotherapy efficacy. Non-pharmaceutical interventions are universally accessible, broadly applicable, instantly actionable, scalable, and economically sustainable, creating value for all stakeholders involved. Most importantly, this holistic framework re-emphasizes the patient as a whole and harnesses the full potential of anticancer immunity and checkpoint blockade, potentially leading to survival benefits. Digital therapeutics are proposed to accompany the patients on their mission toward change in lifestyle-related behaviors for creating optimal conditions for treatment efficacy and personal growth.

Randomized Phase II Cabazitaxel Dose Individualization and Neutropenia Prevention Trial in Patients with Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: There is ongoing controversy about the recommended dose of cabazitaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: This multicenter phase II open-label, randomized, parallel-group study compared 3-weekly cabazitaxel at 25 mg/m2 (conventional arm A) with cabazitaxel therapeutic drug monitoring (experimental arm B) in mCRPC. The primary objective was to improve the clinical feasibility rate (CFR), defined as the absence of grade 4 neutropenia or thrombocytopenia, any thrombocytopenia with bleeding, febrile neutropenia, severe nonhematologic toxicity, withdrawal for cabazitaxel-related toxicity, or death. A total of 60 patients had to be randomized to detect a difference in CFR of 35% (power 80%, two-sided alpha 10%). RESULTS: A total of 40 patients were randomized to arm A and 33 patients to arm B. CFR was 69.4% in arm A and 64.3% in arm B (P = 0.79). Week-12 PSA response was 38.5% in both arms. A radiological response by RECIST v.1.1 was seen in 3 (9.7%) patients in arm A versus 6 (23.1%) patients in arm B (P = 0.28), disease progression was higher in arm A compared with arm B (61.3% vs. 30.8%, P = 0.05). Median progression-free survival was longer in arm B compared with arm A (9.5 vs. 4.4 months; HR = 0.46; P = 0.005). Median overall survival was higher in arm B compared with arm A (16.2 vs. 7.3 months; HR = 0.33; P < 0.0001). CONCLUSIONS: Pharmacokinetic-guided dosing of cabazitaxel in patients with mCRPC is feasible and improves clinical outcome due to individual dose escalations in 55% of patients.

Safety and anti-tumor activity of lisavanbulin administered as 48-hour infusion in patients with ovarian cancer or recurrent glioblastoma: a phase 2a study.

PURPOSE: Lisavanbulin (BAL101553) is the prodrug of avanbulin (BAL27862), a microtubule-destabilizing agent. The goal of this study (NCT02895360) was to characterize the safety, tolerability and antitumor activity of lisavanbulin administered as a 48-hour intravenous (IV) infusion at the recommended Phase 2 dose (RP2D) of 70 mg/m2. Results from the Phase 1 dose-escalation portion of the study identifying the RP2D have been previously reported. Here, we present the findings from the Phase 2a portion of this study. Methods. This multi-center, open-label study included patients with ovarian, fallopian-tube, or primary peritoneal cancer that was either platinum-resistant or refractory (11 patients), or with first recurrence of glioblastoma (12 patients). Lisavanbulin was administered as a 48-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle. Results. Lisavanbulin was well tolerated in both patient cohorts. Thirteen patients (56.5%) developed 49 adverse events assessed as related to study treatment. The majority were mild or moderate; four were grade 3/4. Sixteen SAEs were reported in nine patients (39.1%), with none considered related to study treatment. No AEs led to permanent treatment discontinuation. Three patients in the ovarian cancer cohort had stable disease with lesion size reductions after two cycles of treatment; in the glioblastoma cohort, one patient showed partial response with a > 90% glioblastoma area reduction as best response, and one patient had stable disease after eight cycles of treatment. Conclusion. This study demonstrated a favorable safety and tolerability profile of 48-hour continuous IV infusion of lisavanbulin in patients with solid extracranial tumors or glioblastoma. Clinicaltrials.gov registration: NCT02895360.

HPV and RAD51 as Prognostic Factors for Survival in Inoperable Oral and Oropharyngeal Cancer in Patients Unfit for Chemotherapy Treated with Hyperfractionated Radiotherapy.

INTRODUCTION: The incidence of advanced oral cavity and oropharyngeal cancers is generally high. Treatment outcomes for patients, especially those unfit for comprehensive cancer treatment, are unsatisfactory. Therefore, the search for factors to predict response to treatment and increase overall survival is underway. OBJECTIVE: This study aimed to analyze the presence of 32 HPV genotypes in tumor samples of 34 patients and the effect of HPV status and RAD51 on overall survival. METHOD: Tumor samples of 34 patients with locally advanced oropharyngeal or oral cavity cancer treated with accelerated radiotherapy in monotherapy were analyzed using reverse hybridization and immunohistochemistry for the presence of HPV and RAD51. Its effect on overall survival was examined. RESULTS: Only two types of HPV were identified-HPV 16 (dominant) and HPV 66 (two samples). The HPV positivity was associated with a borderline insignificant improvement in 2-year (p = 0.083), 5-year (p = 0.159), and overall survival (p = 0.083). Similarly, the RAD51 overexpression was associated with borderline insignificant improvement in 2-year (p = 0.083) and 5-year (p = 0.159) survival. CONCLUSION: We found no statistically significant differences but detected trends toward improvement in the survival of HPV-positive and RAD51 overexpressing patients unfit for surgical treatment or chemotherapy treated with hyperfractionated radiotherapy. The trends, however, indicate that in a larger group of patients, the effects of these two parameters would likely be statistically significant.

A prognostic baseline blood biomarker and tumor growth kinetics integrated model in paclitaxel/platinum treated advanced non-small cell lung cancer patients.

Paclitaxel/platinum chemotherapy, the backbone of standard first-line treatment of advanced non-small cell lung cancer (NSCLC), exhibits high interpatient variability in treatment response and high toxicity burden. Baseline blood biomarker concentrations and tumor size (sum of diameters) at week 8 relative to baseline (RS8) are widely investigated prognostic factors. However, joint analysis of data on demographic/clinical characteristics, blood biomarker levels, and chemotherapy exposure-driven early tumor response for improved prediction of overall survival (OS) is clinically not established. We developed a Weibull time-to-event model to predict OS, leveraging data from 365 patients receiving paclitaxel/platinum combination chemotherapy once every three weeks for ≤six cycles. A developed tumor growth inhibition model, combining linear tumor growth and first-order paclitaxel area under the concentration-time curve-induced tumor decay, was used to derive individual RS8. The median model-derived RS8 in all patients was a 20.0% tumor size reduction (range from -78% to +15%). Whereas baseline carcinoembryonic antigen, cytokeratin fragments, and thyroid stimulating hormone levels were not significantly associated with OS in a subset of 221 patients, and lactate dehydrogenase, interleukin-6 and neutrophil-to-lymphocyte ratio levels were significant only in univariate analyses (p value < 0.05); C-reactive protein (CRP) in combination with RS8 most significantly affected OS (p value < 0.01). Compared to the median population OS of 11.3 months, OS was 128% longer at the 5th percentile levels of both covariates and 60% shorter at their 95th percentiles levels. The combined paclitaxel exposure-driven RS8 and baseline blood CRP concentrations enables early individual prognostic predictions for different paclitaxel dosing regimens, forming the basis for treatment decision and optimizing paclitaxel/platinum-based advanced NSCLC chemotherapy.

Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs. METHODS: In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs. FINDINGS: When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-γ (IFN-γ) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67+ regulatory T cells (Tregs) and Ki-67+ CD8+ T cells is also likely to be associated with increased risk of irAEs. CONCLUSIONS: We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs. FUNDING: This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen.

Phase 1 first-in-human dose-escalation study of ANV419 in patients with relapsed/refractory advanced solid tumors.

BACKGROUND: ANV419 is a stable antibody-cytokine fusion protein consisting of interleukin-2 (IL-2) fused to an anti-IL-2 monoclonal antibody that sterically hinders binding of IL-2 to the α subunit of its receptor but has selective affinity for the receptor ßγ subunits. Thus, ANV419 preferentially stimulates CD8+ effector T cells and natural killer cells which are associated with tumor killing, while minimizing the activation of immunosuppressive regulatory T cells. METHODS: ANV419-001 is an open-label, multicenter, phase 1 study to evaluate the safety, tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ANV419. Secondary objectives were to characterize the pharmacokinetics, pharmacodynamics and tumor response. Adult patients with advanced solid tumors and disease progression after ≥1 previous line of systemic therapy were enrolled. ANV419 was administered by intravenous infusion once every 2 weeks, with a planned treatment duration of 12 months. The dose escalation part of the study explored doses 3, 6 and 12 µg/kg as single patient cohorts followed by 24-364 µg/kg in a 3+3 design. Interim results are reported here (data cut-off: March 22, 2023). RESULTS: Forty patients were enrolled and received at least one dose of ANV419. The MTD and RP2D were determined to be 243 µg/kg. The most common ANV419-related treatment-emergent adverse events were Grade 1 and 2 fever (31 (77.5%)), chills (23 (57.5%), vomiting (14 (35.0%)), cytokine release syndrome and nausea (12 (30.0%) each). Transient and self-limiting lymphopenia due to lymphocyte redistribution was observed in all patients. In the RP2D cohort, Grade ≥3 thrombocytopenia and fever were reported by one patient (12.5%) each. All events were manageable with standard supportive care. At doses of 243 µg/kg (RP2D/MTD), the estimated T1/2 was approximately 12 hours. At ANV419 doses ≥108 µg/kg, 64% of patients had a best response of at least SD (15 SD and 1 confirmed PR). CONCLUSIONS: ANV419 at doses up to 243 µg/kg (the RP2D) was well tolerated and showed signs of antitumor activity in a heavily pretreated patient population with advanced solid tumors. TRIAL REGISTRATION NUMBER: NCT04855929.