STELLAR Trial Research Articles

Prognostic and Predictive Value of a Modified Diagnostic Biopsy–Adapted Immunoscore in Patients with Rectal Cancer After Neoadjuvant Treatment: A Translational Study From the STELLAR Trial

BackgroundThe purpose of this study was to assess the prognostic significance of the modified diagnostic biopsy-adapted immunoscore (mISb) in determining the outcomes for patients with locally advanced rectal cancer (LARC) in a neoadjuvant setting. MethodsWe included 181 LARC patients from a single subcenter of a prospective study comparing total neoadjuvant therapy (TNT) based on short-course radiotherapy with long-term chemoradiotherapy (CRT). Tumor biopsies at baseline were stained for CD8+ and CD3+ T-cell densities. The mISb was developed using mean percentile of CD8+ T-cell density and CD8/CD3 ratios. Patients were classified into low (0%-25%), intermediate (>25%-70%), and high (>70%-100%) in both groups. The relativity among different lymphocytes and their correlation with survival were illustrated. Survival analyses and Cox regression models were used to compare the prognostic value of mISb and ISb for survival outcomes, and to assess the role of mISb in TNT and CRT subgroups respectively. ResultsIn this study, 151 (83.4%) patients received surgery and 30 (16.6%) followed a watch and wait strategy. A strong correlation was found between CD8+ and CD3+ T-cell densities (R=0.86, P<0.001), while a weak correlation witnessed between CD8+ and CD8/CD3 ratio (R=0.45). The 3-year disease-free survival (DFS) for the entire cohort was 69.9%, with 57.2%, 68.6%, and 85.5% for the low, intermediate, and high mISb groups respectively (P=0.01), while ISb failed to distinguish survival outcomes. Multivariate analysis revealed mISb to be an independent prognostic factor for DFS in surgically treated patients (P=0.01). Specifically, patients with high mISb score showed longer PFS than other subgroups in the TNT cohort (P=0.049), but no significant difference was found in the CRT population. ConclusionsIn this study, mISb demonstrates significant prognostic value in LARC patients receiving preoperative therapies, especially in the TNT subgroup. These findings may help tailor the intensity of neoadjuvant therapy for patients.

Number of lymph nodes retrieved in patients with locally advanced rectal cancer after total neoadjuvant therapy: post-hoc analysis from the STELLAR trial.

The current gold standard for extraperitoneal locally advanced rectal cancer is total neoadjuvant therapy (TNT) followed by total mesorectal excision. This research explored the number of lymph nodes in patients with locally advanced rectal cancer after TNT and its correlation with survival. This is a post-hoc analysis based on the STELLAR trial, including patients with locally advanced rectal cancer from 16 tertiary centres who were randomized for short-term radiotherapy followed by chemotherapy (TNT group) or long-term concurrent chemotherapy group followed by total mesorectal excision between 2015 and 2018. This lymph node-related analysis is based on the TNT group. Subgroups were differentiated based on the lymph node harvest (below the median number: limited lymphadenectomy group, and greater than/equal to the median number: extended lymphadenectomy group). The primary outcomes were overall survival and disease-free survival (DFS). Correlations with clinical/pathological variables, lymphadenectomy categories and use of adjuvant chemotherapy were explored. Among the 451 patients enrolled in the STELLAR trial, 227 patients (50.3%) were assigned to the TNT group, including 29.5% females. The median number of lymph nodes retrieved in the TNT group was 11.0. Patients in the limited lymphadenectomy subgroup exhibited worse overall survival than those with extended lymphadenectomy (HR 2.95 (95% c.i. 1.47 to 5.92), P = 0.001). The overall survival was similar in the ypN0-limited and ypN1-extended subgroups (HR 0.38 (95% c.i. 0.11 to 1.30), P = 0.109). Adjuvant chemotherapy was associated with better overall survival and DFS than no adjuvant chemotherapy overall (P < 0.001) and in the limited lymphadenectomy subgroup (P < 0.001). However, there was no significant difference in overall survival or DFS with or without adjuvant chemotherapy in the extended lymphadenectomy subgroup (P = 0.887 and P = 0.192, respectively). In the STELLAR trial, the median number of lymph nodes harvested was 11. In patients with limited lymphadenectomy, the use of adjuvant therapy after TNT was beneficial and correlated with better prognosis compared with patients who did not receive adjuvant chemotherapy.

(161) - Consistency of the Efficacy and Safety Profile of Sotatercept across Baseline Cardiac Index Subgroups: A Pooled Analysis of STELLAR and PULSAR Trials

(161) - Consistency of the Efficacy and Safety Profile of Sotatercept across Baseline Cardiac Index Subgroups: A Pooled Analysis of STELLAR and PULSAR Trials

(648) - Mean Pulmonary Artery Pressure and Disability in Pulmonary Hypertension: An Analysis of the STELLAR Trial

(648) - Mean Pulmonary Artery Pressure and Disability in Pulmonary Hypertension: An Analysis of the STELLAR Trial

Abstract 13038: Predictive Value of Cardiac Function Parameters and NT-proBNP in Patients With Pulmonary Arterial Hypertension (PAH) Treated With Sotatercept in the STELLAR Trial

Background: Sotatercept is an activin signaling inhibitor under investigation for PAH. Goal: Evaluate the prognostic utility of hemodynamic and cardiac function parameters in PAH patients receiving sotatercept vs placebo. Methods: Participants in STELLAR, a phase 3 trial (NCT04576988), were randomized 1:1 to sotatercept (0.3 up to 0.7 mg/kg once every 3 weeks) or placebo added to background therapies. Eligible participants had WHO functional class II-III, pulmonary vascular resistance ≥400 dyn·s·cm -5 , and 6-minute walk distance 150-550 m. This post-hoc analysis assessed clinical worsening events at last measurement by baseline echocardiography (ECHO), right heart catheterization (RHC), and NT-proBNP parameters. Clinical worsening events were assessed up to week 60. Uni-/multivariate-adjusted Cox models identified baseline parameters significantly (p&lt;0.05) associated with events. Parameters with p-values &lt;0.10 were carried forward to multivariate model. Receiver operating characteristic curves assessed discriminatory utility of cutoff values. Results: Of the significant univariate predictors, only study treatment and log2 NT-proBNP were significant independent predictors of clinical worsening in multivariate model (Table). Each unit increase in log2 NT-proBNP at baseline was associated with a 61% increase in risk (HR 1.61, 95% CI 1.39, 1.88; p&lt;0.001). The AUC for log2 NT-proBNP (0.76 [95% CI 0.67, 0.85]) showed good performance. The optimal NT-proBNP cutoff value was 322 pg/mL. Sotatercept treatment was associated with an 81% reduction in risk vs placebo (HR 0.19, 95% CI 0.10 to 0.38; p&lt;0.001), even after adjusting for NT-proBNP. Conclusions: This post-hoc analysis demonstrated that NT-proBNP is a strong predictor of clinical worsening events in PAH patients. Sotatercept treatment offered protection beyond that achieved with standard therapies alone, even after adjusting for the impact of NT-proBNP.

Population Health Model Predicting the Long-Term Impact of Sotatercept on Morbidity and Mortality in Patients with Pulmonary Arterial Hypertension (PAH).

Pulmonary arterial hypertension (PAH) is a rare, progressive disease associated with significant morbidity and mortality. The phase 3 STELLAR trial tested sotatercept plus background therapy (BGT) versus placebo plus BGT. BGT was comprised of mono-, double-, or triple-PAH targeted therapy. Building on STELLAR findings, we employed a population health model to assess the potential long-term clinical impact of sotatercept. Based on the well-established ESC/ERS 4-strata risk assessment approach, we developed a six-state Markov-type model (low risk, intermediate-low risk, intermediate-high risk, high risk, lung/heart-lung transplant, and death) to compare the clinical outcomes of sotatercept plus BGT versus BGT alone over a lifetime horizon. State-transition probabilities were obtained from STELLAR. Risk stratum-adjusted mortality and lung/heart-lung transplant probabilities were based on COMPERA PAH registry data, and the post-transplant mortality probability was obtained from existing literature. Model outcomes were discounted at 3% annually. Sensitivity analyses were conducted to examine model robustness. In the base case, sotatercept plus BGT was associated with longer life expectancy from model baseline (16.5 vs 5.1years) versus BGT alone, leading to 11.5years gained per patient. Compared with BGT alone, sotatercept plus BGT was further associated with a gain in infused prostacyclin-free life years per patient, along with 683 PAH hospitalizations and 4 lung/heart-lung transplant avoided per 1000 patients. According to this model, adding sotatercept to BGT increased life expectancy by roughly threefold among patients with PAH while reducing utilization of infused prostacyclin, PAH hospitalizations, and lung/heart-lung transplants. Real-world data are needed to confirm these findings. ClinicalTrials.gov identifier, NCT04576988 (STELLAR).

Cost-Effectiveness of Short-Course Radiotherapy Based Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer in China

The phase III STELLAR (NCT02533271) trial demonstrated that four cycles of chemotherapy after short-course radiotherapy (SCRT-TNT) were not inferior to the standard care of long-course concurrent radiotherapy (LCRT) in patients with locally advanced rectal cancer (LARC). This study assessed the cost-effectiveness of SCRT-TNT versus LCRT in locally advanced rectal cancer in China on the basis of the STELLAR trial. A Markov model was used to synthesize the healthcare costs and benefits of LARC patients based on results from the STELLAR trial. The model assumes that LARC who meet the inclusion criteria of the STELLAR trial experience four possible states: No Evidence of Disease (NED), locally recurrence, distant metastases, or any death from rectal cancer or other unrelated causes, where local recurrence continues to be classified as resectable and unresectable. The transition status period is 3 month, and 5 years is used to calculate direct medical costs and health benefits. The probabilities of states transition after SCRT-TNT or LCRT were derived from the results of the STELLAR trial and previous published article (Table.1). Costs were evaluated from the Chinese payer's perspective reported in early 2022 US dollars (US$1 = 6.78 Chinese Yuan). Sensitivity analyses were performed for key variables. Cost-effectiveness was evaluated using the incremental cost-effectiveness ratio and net monetary benefits. Effectiveness was defined as quality-adjusted life-years (QALYs). Willingness-to-pay (WTP) threshold was set at $43500/QALY. Data were collected from October 3, 2020, to September 20, 2021, and analyzed from November 15, 2020, to October 25, 2021. During the 5-year horizon, for the base case scenario, SCRT-TNT incurred a lower total cost and higher QALYs compared with LCCRT. The total cost was $65767 and QALYs were 1.77 for SCRT-TNT; for LCCRT, the total cost was $72802 and QALYs were 1.64. This resulted in an ICER of -$ 55470.69 per QALY. Therefore, SCRT-TNT was a cost-saving and dominating treatment strategy compared with LCRT. Sensitivity analysis showed that ICERs were most sensitive to the parameters of distant metastases risk after treatment. SCRT-TNT in locally advanced rectal cancer can be a cost-effective alternative to LCRT in China, and should be considered in appropriately selected patients.

Prognostic Role and Time Varying Failure Hazard of Neoadjuvant Rectal (NAR) Scores in the Stellar Randomized Phase 3 Trial

This study examined the prognostic role of the neoadjuvant rectal (NAR) score on disease-free survival (DFS) in the STELLAR phase III trial and assessed time-varying failure hazard. The study included patients from the STELLAR trial who underwent total mesorecta excision and had calculable NAR scores. Chi-square tests were used to analyze the distribution of demographic information, treatment information, and NAR scores. Kaplan-Meier and Cox regression analyses assessed DFS, while smoothed hazard plots evaluated hazard variations. Of 461 patients, 231 received total neoadjuvant therapy (TNT) and 229 received concurrent chemoradiotherapy (CRT). With a median follow-up of 37 months, 3-year DFS rates for low, intermediate, and high NAR scores were 86.2%, 72.671.8%, and 53.153.6%, respectively (P <0.001). In the TNT group, rates for the corresponding NAR score groups were 87.3%, 67.6%, and 52.4% while in the CRT group, rates were 84.7%, 76.0%, and 53.4% (both P <0.001). Multivariate analysis showed NAR scores as independent prognostic factors for DFS (intermediate vs. low, hazard ratio (HR) = 2.452.55, 95% confidence interval (CI): 1.347 - 4.4675, P <0.003; high vs. low, HR = 4.2668, 95% CI: 2.5133 - 8.727.79, P <0.001). The DFS hazardrisk rates for different NAR score groups initially increased and then decreased, peaking in the second year with rates of 5.04.6%, 11.62%, and 21.52% for low, intermediate, and high NAR scores, respectively. After the fourth year, the high NAR score still had a higher failure hazardrisk (12.5%), while the intermediate and low NAR score had a lower relapse hazardrisk (<3%). The NAR score was a strong prognostic factor for DFS in the STELLAR trial, irrespective of TNT or CRT modalities. Hazard variations at different NAR score levels offer insights for personalized monitoring and warrant further investigation in clinical trials using NAR scores as endpoints. (NCT02533271).

Effects of sotatercept on haemodynamics and right heart function: analysis of the STELLAR trial.

In the phase 3 STELLAR trial, sotatercept, an investigational first-in-class activin signalling inhibitor, demonstrated beneficial effects on 6-min walk distance and additional efficacy endpoints in pre-treated participants with pulmonary arterial hypertension (PAH). This post hoc analysis evaluated data from right heart catheterisation (RHC) and echocardiography (ECHO) obtained from the STELLAR trial. Changes from baseline in RHC and ECHO parameters were assessed at 24 weeks. An analysis of covariance (ANCOVA) model was used to estimate differences in least squares means with treatment and randomisation stratification (mono/double versus triple therapy; World Health Organization functional class II versus III) as fixed factors, and baseline value as covariate. Relative to placebo, treatment with sotatercept led to significant (all p<0.0001 except where noted) improvements from baseline in mean pulmonary artery (PA) pressure (-13.9 mmHg), pulmonary vascular resistance (-254.8 dyn·s·cm-5), mean right atrial pressure (-2.7 mmHg), mixed venous oxygen saturation (3.84%), PA elastance (-0.42 mmHg·mL-1·beat-1), PA compliance (0.58 mL·mmHg-1), cardiac efficiency (0.48 mL·beat-1·mmHg-1), right ventricular (RV) work (-0.85 g·m) and RV power (-32.70 mmHg·L·min-1). ECHO showed improvements in tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure ratio (0.12 mm·mmHg-1), end-systolic and end-diastolic RV areas (-4.39 cm2 and -5.31 cm2, respectively), tricuspid regurgitation and RV fractional area change (2.04% p<0.050). No significant between-group changes from baseline were seen for TAPSE, heart rate, cardiac output, stroke volume or their indices. In pre-treated patients with PAH, sotatercept demonstrated substantial improvements in PA pressures, PA compliance, PA-RV coupling and right heart function.

Abstract CT139: The STELLAR trial: A phase II/III study of high-dose intermittent sunitinib in patients with recurrent glioblastoma

Abstract Background: Treatment options for patients with recurrent glioblastoma (rGBM) are limited. The lack of effectiveness from oral multi-targeted tyrosine kinase inhibitors, like sunitinib, might be due to a restricted blood-brain barrier penetration. We previously found that standard daily dosed sunitinib resulted in relatively low tumor drug concentrations in patients with GBM (PMID: 35165100). Based on these results, we here tested whether an alternatively scheduled, high-dose intermittent sunitinib treatment strategy with the aim to increase tumor drug concentrations, would improve the outcome of patients with rGBM compared to standard therapy with lomustine. Preliminary efficacy and safety results of the trial are presented. Methods: The STELLAR-trial is a randomized multicenter phase II/III clinical study for patients with rGBM (NCT03025893). Patients were randomized 1:1 to high-dose intermittent sunitinib (300mg once every week (Q1W) in part 1 or 700mg once every two weeks (Q2W) in part 2) or to standard therapy with lomustine (110mg/m2 once every 6 weeks). Adult patients with de novo or secondary glioblastoma with first recurrence after a maximum of one line of chemotherapy and ≥ 3 months since completion of radiotherapy were eligible. The primary endpoint of the trial was progression-free survival (PFS). Secondary endpoints included overall survival (OS), six-month progression-free survival (PFS6) and tolerability of the treatment. A pre-planned interim analysis for futility was performed after inclusion of 25% of patients in both part 1 and part 2. Results: At the pre-planned interim analysis, after inclusion of 26 and 29 patients in part 1 and 2, respectively, the trial was terminated for futility. The median PFS (mPFS) for sunitinib 300mg Q1W was 1.5 months (95% CI 1.4 - 1.7) as compared to 1.5 months (95% CI 1.4 - 1.6) for lomustine (HR 1.24, 95% CI 0.55 - 2.79; p=0.60). For sunitinib dosed at 700mg Q2W, the mPFS was 1.4 months (95% CI 1.3 - 1.5) as compared to 1.5 months (95% CI 1.3 - 1.7) for lomustine (HR 0.96, 95% CI 0.44 - 2.10; p=0.92). The median OS (mOS) for sunitinib 300 mg Q1W was 6.5 months (95% CI 4.5 - 8.5) compared to 4.7 (95% CI 3.3 - 6.0) for lomustine (log rank p=0.83). For sunitinib 700mg Q2W the mOS was 4.7 months (95% CI 3.8 - 5.6) compared to 6.8 months (95% CI 1.7 - 12.0) for lomustine (log rank p=0.65). The percentage of patients that were progression free at 6 months was 8% for both sunitinib groups and 15% for the lomustine group. In general, both treatment strategies with either high-dose intermittent sunitinib or lomustine were tolerated well with maximal grade 3 toxicities in respectively 8% and 15% of patients. Conclusion: Alternative high-dose intermittent sunitinib treatment failed to improve the outcome of patients with rGBM when compared to standard lomustine therapy. Since lomustine remains a poor treatment strategy in rGBM, novel, more effective therapies are urgently needed. Citation Format: Jorien B. Janssen, Cyrillo Brahm, Chantal M. Driessen, Janine Nuver, Mariette Labots, Mathilde C. Kouwenhoven, Esther S. Aliaga, Roelien H. Enting, Jan Cees de Groot, Johannes Berkhof, Annemiek M. Walenkamp, Henk M. Verheul, Myra E. van Linde. The STELLAR trial: A phase II/III study of high-dose intermittent sunitinib in patients with recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT139.

Performance of Noninvasive Tests of Fibrosis Among Asians, Hispanic, and non-Hispanic Whites in the STELLAR Trials

The effect of race on routinely available noninvasive tests of fibrosis is incompletely understood. This study evaluated the performance of noninvasive tests among white and Asian patients in the STELLAR trials (NCT03053050 and NCT03053063), which evaluated selonsertib in patients with advanced (F3-F4) fibrosis due to nonalcoholic steatohepatitis (NASH). Baseline liver biopsies were centrally read using the NASH Clinical Research Network system, and 4 noninvasive tests (Nonalcoholic fatty liver disease fibrosis score [NFS], Fibrosis-4 index [FIB-4], Enhanced Liver Fibrosis test [ELF], and liver stiffness by vibration-controlled transient elastography) were measured. The performance of these tests to discriminate advanced fibrosis was evaluated using areas under the receiver operating characteristics curves with 5-fold cross-validation repeated 100 times. Among 3207 patients screened with evaluable liver histology, 2281 were whites and 762 were Asians. Seventy-two percent of whites and 67% of Asians had advanced fibrosis. The areas under the receiver operating characteristics curves of the noninvasive tests for advanced fibrosis were similar in whites and Asians: 0.73 and 0.75 for NFS, 0.78 and 0.80 for FIB-4, 0.79 and 0.81 for ELF, and 0.80 and 0.83 for liver stiffness, respectively. At the published cutoffs, the tests had similar sensitivities and specificities in the 2 groups. However, the sensitivities of NFS, FIB-4, and ELF were low in both white and Asian patients younger than 40 years. In the global phase III STELLAR trials, the diagnostic performance of routinely available noninvasive tests for the detection of advanced fibrosis due to NASH was acceptable and similar between white and Asian patients.

Derivation and validation of the nonalcoholic fatty liver disease cirrhosis score (NCS) to distinguish bridging fibrosis from cirrhosis

Separation of bridging fibrosis from cirrhosis in non-alcoholic fatty liver disease (NAFLD) is critical to guide management. Therefore, it was the aim of this study to develop an easy-to-perform score distinguishing F3 and F4 fibrosis in NAFLD. A derivation cohort comprising 251 NAFLD patients with F3 or F4 was used to develop the NAFLD Cirrhosis Score (NCS). The NCS was validated in three independent cohorts with liver histology comprising 1666 participants from the STELLAR trials, 47 patients from China and 2058 patients from the European NAFLD Registry. A model including INR, gGT, ALT, platelets and age discriminated best between patients with bridging fibrosis and cirrhosis with an area under the curve (AUC) of 0.733 (95%CI 0.671–0.795). The diagnostic performance of the NCS was similar in the STELLAR studies (AUC 0.700; 95%CI 0.680–0.730) and a smaller cohort from China (AUC 0.727; 95%CI 0.533–0.921). In the European NAFLD Registry, spanning all histological fibrosis stages, the NCS exhibited an AUC of 0.798 (95%CI 0.766–0.830) to detect cirrhosis. We derived two NCS cut-off values (<64.5 and >79.17) to classify patients at low, intermediate, or high risk for the presence of cirrhosis. Using these cut-offs, further diagnostic workup could be avoided by ruling in or ruling out cirrhosis in approximately half of the patients. Furthermore, NCS identified patients at risk for progression to cirrhosis in the F3 cohort and liver-related outcomes in the F4 cohort. ConclusionThe NCS is a simple tool to improve the identification of compensated cirrhosis within the large group of advanced disease stage and provides prognostic information. Overall, the differentiation of F3 from F4 disease using standard laboratory remains difficult and does not exceed moderate accuracy.

QR‐421a RNA therapy in retinitis pigmentosa due to mutations in USH2A: Stellar trial Phase[AP1] 1b/2 interim results

AbstractPurposeTo report Phase 1b/2 interim results of QR‐421a RNA therapy promoting USH2A exon 13 skipping. USH2A exon 13 mutations lead to non‐syndromic Retinitis Pigmentosa &amp; Usher syndrome type 2.MethodsStellar (NCT03780257) is a 24‐month, multicenter Phase 1b/2 single‐dose trial assessing 3 dose levels (50, 100, 200 μg) of QR‐421a in patients aged ≥18 years with biallelic USH2A pathogenic mutations with at least one in exon 13. Cohorts 1 &amp; 2 included subjects randomized to sham‐procedure or QR‐421a. Primary endpoints: frequency &amp; severity of adverse events (AEs). Secondary endpoints: change in best‐corrected visual acuity (BCVA), static perimetry &amp; ellipsoid zone [EZ] area.Results20 subjects were enrolled, 14 received QR‐421a &amp; 6 received sham. Response to QR‐421a was similar for all doses. No serious AE or inflammation was observed. Two subjects had worsening of pre‐existing conditions: one with cataracts (not treatment‐related) &amp; one with cystoid macular edema (being managed with standard care). BCVA stabilization was observed in QR‐421a‐treated eyes (TE), versus a decline in untreated eyes (UE). At week 48, mean BCVA benefit was 6.0 &amp; 9.3 letters in all QR‐421a‐treated &amp; advanced subjects (n = 6; baseline BCVA of &lt;70 letters) respectively. No BCVA benefit was observed in sham‐treated eyes (SE). Mean change from baseline of the EZ‐area was +15.0% in TE, –26.4% in UE, &amp; –12.5% in SE at week 24. For static perimetry at week 12, the mean number of locations (loci) that improved by ≥7 dB compared to baseline was 9.2 loci versus 6.1 loci in TE versus UE in all QR‐421a‐treated subjects &amp; 12.9 loci versus 6.9 loci in early moderate‐stage subjects (n = 8; baseline BCVA of ≥70 letters). SE responded similarly to UE.ConclusionsQR‐421a was well tolerated &amp; demonstrated evidence of disease stabilization in visual acuity, &amp; improvements in retinal sensitivity &amp; retinal structural imaging data. An open‐label extension trial &amp; 2 Phase 2/3 trials are planned.

Abstract P248: The tyrosine kinase inhibitor XL092 promotes an immune-permissive tumor microenvironment and enhances the anti-tumor activity of immune checkpoint inhibitors in preclinical models

Abstract Background: Cabozantinib, an inhibitor of MET, VEGFR2, AXL, and MER, has shown significant clinical activity in multiple solid tumors, both alone and in combination with immune checkpoint inhibitors (ICIs). XL092 has a similar target profile to cabozantinib but with a significantly shorter clinical half-life and pharmacokinetic properties suitable for once daily oral dosing (Hsu, Eur J Cancer, 2020). In preclinical studies, the combination of XL092 and anti–PD-1 exhibited greater anti-tumor activity than either agent alone. Here, we describe further preclinical characterization of XL092 in combination with ICIs, including modulation of immune cells in vivo and in vitro. Methods: Pharmacodynamic activity was evaluated in the MC38 syngeneic tumor model following treatment with XL092 alone or in combination with anti–PD-1 or anti–PD-L1. Tumor CD31+ microvessel density and CD8+ T cell infiltration were assessed by immunohistochemistry, and circulating immune cells were measured by FACS. Macrophage repolarization and efferocytosis were evaluated in vitro using primary human macrophages. Results: Treatment of MC38 tumor-bearing mice with XL092 inhibited tumor angiogenesis in a dose-dependent manner, and combination treatment with XL092 and anti–PD-1 increased CD8+ lymphocyte tumor cell infiltration compared with either agent alone. XL092 and ICIs also promoted significant changes in peripheral immune cell subsets in the MC38 model. Treatment with XL092 alone or in combination with ICIs increased circulating levels of CD4+ and CD8+ T cells and B cells, and combination treatment with anti–PD-1 decreased levels of proliferating and IFNg-producing effector T cells in circulation. While the level of peripheral NK cells was unaffected by these treatments, XL092 alone or in combination with ICIs decreased levels of proliferating and GrzB+ effector cells in circulation. Treatment with XL092 alone or in combination with ICIs reduced the levels of circulating myeloid cells, including myeloid-derived suppressor cells, dendritic cells, and macrophages. In vitro treatment of human macrophages with XL092 inhibited macrophage efferocytosis with IC50 ~81 nM and promoted repolarization from an M2 anti-inflammatory to an M1 pro-inflammatory phenotype. Conclusions: Immune cell profiling showed that treatment with XL092 and ICIs promotes CD8+ T cell tumor infiltration, increases in peripheral lymphocytes, decreases in peripheral myeloid cells, and macrophage repolarization, suggesting that XL092 promotes an immune-permissive tumor microenvironment. Consistent with these immunomodulatory effects, the combination of XL092 and ICIs has shown greater anti-tumor activity in syngeneic tumor models than either agent alone. XL092 is currently being evaluated in multiple solid tumors as a single agent and in combination with ICIs in the phase 1/1b STELLAR trials (NCT03845166). Citation Format: Jeff Hsu, Colin Chong, Jeffrey Serrill, Sharon Wu, Kevin Leong, Ted Yun, Lynne Bannen, Peter Lamb, Wei Xu, Peiwen Yu. The tyrosine kinase inhibitor XL092 promotes an immune-permissive tumor microenvironment and enhances the anti-tumor activity of immune checkpoint inhibitors in preclinical models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P248.

P24.08 Radiological Response to TTFields Plus Chemotherapy for Malignant Pleural Mesothelioma from the Phase 2 STELLAR Trial

P24.08 Radiological Response to TTFields Plus Chemotherapy for Malignant Pleural Mesothelioma from the Phase 2 STELLAR Trial

P25.10 Computational Simulations on Safety of Tumor Treating Fields Delivered to the Lungs in Mesothelioma and NSCLC

Tumor Treating Fields (TTFields) inhibit cancer cell division by utilizing low intensity alternating electric fields in the intermediate frequency. TTFields are FDA-approved for glioblastoma and malignant pleural mesothelioma (MPM). The phase 2 trial STELLAR trial (Ceresoli et al, Lancet Onc 2019; NCT02397928) demonstrated promising results with a median overall survival of 18.2 months (95% CI 12.1‍–‍25.8) in patients with MPM treated with TTFields plus standard of care chemotherapy. The efficacy of TTFields therapy depends on the frequency of the electric field: 150 kHz is the optimal frequency for MPM and Non-Small-Cell lung cancer (NSCLC). Preclinical studies suggest that treatment efficacy increases with the intensity of the electric field. The higher the field intensity, the larger the therapeutic effect, with a therapeutic threshold of 0.7 V/cm above which TTFields exert a significant anti-mitotic effect. However, Delivery of an electric field to the body unavoidably leads to deposition of heat in the tissue, and it is important to insure that TTFields are delivered in an optimal manner so as not to lead to thermal damage of the patient’s tissues. Here we performed numerical simulations to determine the thermal safety of TTFields at therapeutic levels delivered to the upper torso. Delivery of TTFields to the thorax of computational models using the Optune Lua device was simulated. Male, female, and obese models (Virtual Population, IT’IS foundation) were used. Numerical simulations were performed using Sim4life (v3.0, ZMT Zurich). The field intensities within the lungs of the models were evaluated. Thermal safety was analyzed using specific absorption rate (SAR), which is a metric for assessing heating due to electromagnetic absorption. The simulations showed that for all 3 models, the Optune Lua device delivers TTFields at therapeutic intensities greater than 0.7 V/cm RMS to cover at least 76% of the lungs. SAR values within the internal organs were generally below the levels at which thermal damage occurs (10 W/kg) as set out in the ICNIRP guidelines for occupational exposure (Health Phys 1998;74:494–522) with maximum SAR levels not exceeding 20 W/kg. In the superficial body layers higher SAR values were observed. However, the Optune Lua device incorporates temperature control that prevents the skin from heating to levels at which thermal damage can occur. The results of this study support the observations that Optune Lua delivers TTFields to the lungs at therapeutic levels in a manner that is unlikely to cause thermal damage in patients. Optune Lua is safe for use in MPM and NSCLC. These data will help in ongoing and planned NSCLC clinical trials, such as the phase 3 LUNAR trial [NCT02973789] that is currently investigating the efficacy of TTFields therapy combined with immune checkpoint inhibitors or docetaxel.

Effectiveness and Safety of Tumor Treating Fields (150 kHz) plus Cisplatin or Pemetrexed Combination in Mesothelioma: in Vitro and in Vivo Findings

Malignant pleural mesothelioma (MPM) is an aggressive thoracic cancer linked to asbestos exposure with a poor prognosis and limited treatment options. Tumor Treating Fields (TTFields) are a noninvasive, antineoplastic treatment delivered locoregionally to the tumor bed via low intensity (1-3 V/cm), intermediate frequency (100-500 kHz), alternating electric fields. TTFields are FDA-approved as a first line therapy with pemetrexed plus platinum-based agent for unresectable MPM. TTFields with this combination was evaluated in the phase 2 STELLAR clinical trial (Ceresoli et al, Lancet Oncology 2019) in patients with unresectable MPM, demonstrating a promising median overall survival of ∼18.2 months (vs ∼12 months; historical control) without increases in systemic toxicity. Utilizing in vitro and in vivo models, we investigated the effects of TTFields alone and in combination with cisplatin or pemetrexed in MPM. Using the inovitroTM system, cells from human MPM cell lines (NCI-H2052 and MSTO-211H) were treated at various frequencies of TTFields for 72 hours. The combined treatment of TTFields with cisplatin or pemetrexed was tested by applying TTFields at the 150 kHz optimal frequency with various concentrations of cisplatin (80–5120 nM) or pemetrexed (2–4096 nM). Cell counts, clonogenic potential, and apoptosis induction were determined. TTFields (150 kHz) were applied to Fisher rats with IL-45 intrapleural tumors cells for 8 days and to C57BL/6 mice with RN5 S.C. tumors for 7 days. Tumor volume was determined using MRI. To determine treatment safety, TTFields (2–3 V/cm) were applied to the torsos of Sprague-Dawley rats at 150 kHz for 2 weeks and all major internal organs were histologically compared. The optimal TTFields frequency was 150 kHz in both NCI-H2052 and MSTO-211H human MPM cell lines. TTFields (150 kHz; 1.1 V/cm) application for 72 hours led to a 45-51% reduction in cell counts and a 46-64% additional decrease in clonogenic potential. TTFields plus cisplatin or pemetrexed significantly reduced the cell count, the clonogenic potential and induced apoptosis versus each treatment alone (P <0.0001). Tumor volume was significantly decreased in the TTFields plus pemetrexed plus cisplatin combination group versus the control group in both tumor models. Histological analysis of major internal organs showed no increase in pathological findings when TTFields were applied to the rat torso. These in vitro and in vivo data demonstrate that the optimal TTFields frequency to inhibit MPM is 150 kHz. TTFields alone showed effectiveness and safety, and combined with cisplatin or pemetrexed demonstrated enhanced effectiveness with no increased safety concerns in the torso. Findings were consistent with efficacy and safety findings in the STELLAR trial.

Abstract 92: Increasing TTFields treatment efficacy by targeting G2 cell cycle checkpoint

Abstract Introduction; Tumor Treating Fields (TTFields) is a novel non-invasive anticancer treatment modality utilizing alternating electric fields. TTFields is FDA approved for glioblastoma patients after demonstrating a 5 months increase in overall survival, and for unresectable mesothelioma patients after the STELLAR trial showed an overall survival of 18 months without increasing the toxicity. While the effectiveness of TTFields is initially attributed to the effects of TTFields during cell division, studies are ongoing analysing its interphase effects and impact on the tumor (micro)environment. Our aim is to further exploit the working mechanism of TTFields by analysing its effect on the cell cycle and identify targets to increase its efficacy. Material and Methods; To analyse the effect of TTFields on the cell cycle, A172 glioblastoma cells were synchronized in S-phase by double thymidine block. Six hours post-release, cells were subjected to TTFields treatment (200kHz; 4,5V/cm). Cell cycle analysis was performed by flow cytometry (PI, α-phospho-histone H3Ser10). Efficacy of combination strategies were tested in 3 different glioblastoma cells lines (A172, U251 and SNB-19). Efficacy was quantified by colony formation assay (CFA) testing the cell reproductive death after treatment (i.e. only viable cells after treatment are replated to analyse the colony forming capacity). Results: TTFields treatment of synchronized A172 cells showed that TTFields causes an accumulation of cells in G2 phase and delayed entry into mitosis with less than 1% of the cells in mitosis 4 hours after TTFields exposure (versus 5% of mitotic cells in the control arm, p&amp;lt;0.001). This arrest can be abrogated by Wee1 inhibition (AZD1775) increasing the mitotic population to more than 35% at 4 hours after TTFields exposure (p&amp;lt;0.001). To test the efficacy of targeting the G2 checkpoint during TTFields treatment, cells were treated with TTFields and a Wee1 (AZD1775, PD0166285) or Chk1 (AZD7762) inhibitor for 72 hours and then replated for CFA. We observed an impressive synergistic effect between TTFields and any of these G2 cell cycle interfering drugs in all three cell lines (p&amp;lt;0.001). Conclusion: The underlying mechanism of the G2 checkpoint activation and the synergistic effect of TTFields plus G2 checkpoint targeting agents is subject of ongoing research. By any means, the combination of TTFields and G2 checkpoint targeting agents causes a synergistic treatment effect and is a very promising strategy. Citation Format: Paul Slangen, Mariska van Geldorp, Mark de Gooijer, Olaf van Tellingen, Gerben Borst. Increasing TTFields treatment efficacy by targeting G2 cell cycle checkpoint [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 92.

THU033 - Incidence and risk factors for cardiovascular events in patients with advanced fibrosis due to non-alcoholic steatohepatitis: data from the phase 3 STELLAR trials

THU033 - Incidence and risk factors for cardiovascular events in patients with advanced fibrosis due to non-alcoholic steatohepatitis: data from the phase 3 STELLAR trials

Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trials

Apoptosis signal-regulating kinase 1 (ASK1) plays a key role in hepatocyte injury, inflammation, and fibrosis in non-alcoholic steatohepatitis (NASH). We evaluated the safety and antifibrotic effect of selonsertib, a selective inhibitor of ASK1, in patients with advanced fibrosis due to NASH. We conducted 2 randomized, double-blind, placebo-controlled, phase III trials of selonsertib in patients with NASH and bridging fibrosis (F3, STELLAR-3) or compensated cirrhosis (F4, STELLAR-4). Patients were randomized 2:2:1 to receive selonsertib 18 mg, selonsertib 6 mg, or placebo once daily for 48 weeks. Liver biopsies were performed at screening and week 48 and non-invasive tests of fibrosis (NITs) were evaluated. The primary efficacy endpoint was the proportion of patients with ≥1-stage improvement in fibrosis without worsening of NASH at week 48. Additional endpoints included changes in NITs, progression to cirrhosis (in STELLAR-3), and liver-related clinical events. Neither trial met the primary efficacy endpoint. In STELLAR-3, fibrosis improvement without worsening of NASH was observed in 10% (31/322, p= 0.49 vs. placebo), 12% (39/321, p= 0.93 vs. placebo), and 13% (21/159) of patients in the selonsertib 18 mg, selonsertib 6 mg, and placebo groups, respectively. In STELLAR-4, the primary endpoint was achieved in 14% (51/354; p= 0.56), 13% (45/351; p= 0.93), and 13% (22/172) of patients, respectively. Although selonsertib led to dose-dependent reductions in hepatic phospho-p38 expression indicative of pharmacodynamic activity, it had no significant effect on liver biochemistry, NITs, progression to cirrhosis, or adjudicated clinical events. The rates and types of adverse events were similar among selonsertib and placebo groups. Forty-eight weeks of selonsertib monotherapy had no antifibrotic effect in patients with bridging fibrosis or compensated cirrhosis due to NASH. Patients with non-alcoholic steatohepatitis (NASH) can develop scarring of the liver (fibrosis), including cirrhosis, which increases the risks of liver failure and liver cancer. We tested whether 48 weeks of treatment with selonsertib reduced fibrosis in patients with NASH and advanced liver scarring. We did not find that selonsertib reduced fibrosis in these patients. Clinicaltrials.gov numbers NCT03053050 and NCT03053063.