Malignant peritoneal mesothelioma (MPeM) is a rare but aggressive malignancy with limited treatment options. VEGF inhibition enhances efficacy of immune-checkpoint inhibitors by reworking the immunosuppressive tumor milieu. Efficacy and safety of combined PD-L1 (atezolizumab) and VEGF (bevacizumab) blockade (AtezoBev) was assessed in 20 patients with advanced and unresectable MPeM with progression or intolerance to prior platinum–pemetrexed chemotherapy. The primary endpoint of confirmed objective response rate per RECISTv1.1 by independent radiology review was 40% [8/20; 95% confidence interval (CI), 19.1–64.0] with median response duration of 12.8 months. Six (75%) responses lasted for >10 months. Progression-free and overall survival at one year were 61% (95% CI, 35–80) and 85% (95% CI, 60–95), respectively. Responses occurred notwithstanding low tumor mutation burden and PD-L1 expression status. Baseline epithelial–mesenchymal transition gene expression correlated with therapeutic resistance/response (r = 0.80; P = 0.0010). AtezoBev showed promising and durable efficacy in patients with advanced MPeM with an acceptable safety profile, and these results address a grave unmet need for this orphan disease. Significance: Efficacy of atezolizumab and bevacizumab vis-à-vis response rates and survival in advanced peritoneal mesothelioma previously treated with chemotherapy surpassed outcomes expected with conventional therapies. Biomarker analyses uncovered epithelial–mesenchymal transition phenotype as an important resistance mechanism and showcase the value and feasibility of performing translationally driven clinical trials in rare tumors. See related commentary by Aldea et al., p. 2674. This article is highlighted in the In This Issue feature, p. 2659

IMPORTANCETherapies for patients with advanced well-differentiated neuroendocrine tumors (NETs) have expanded but remain inadequate, with patients dying of disease despite recent advances in NET therapy. While patients with other cancers have seen long-term disease control and tumor regression with the application of immunotherapies, initial prospective studies of single-agent programmed cell death 1 inhibitors in NET have been disappointing.OBJECTIVE To evaluate the response rate following treatment with the combination of the vascular endothelial growth factor inhibitor bevacizumab with the programmed cell death 1 ligand 1 inhibitor atezolizumab in patients with advanced NETs. DESIGN, SETTING, AND PARTICIPANTS This single-arm, open-label nonrandomized clinical study in patients with rare cancers included 40 patients with advanced, progressive grade 1 to 2 NETs (20 with pancreatic NETs [pNETs] and 20 with extrapancreatic NETs [epNETs]) treated at a tertiary care referral cancer center between March 31, 2017, and February 19, 2019. Data were analyzed from June to September 2021. INTERVENTIONS Patients received intravenous bevacizumab and atezolizumab at standard doses every 3 weeks until progression, death, or withdrawal. MAIN OUTCOMES AND MEASURESThe primary end point was objective radiographic response using Response Evaluation Criteria in Solid Tumors, version 1.1, with progression-free survival (PFS) as a key secondary end point. RESULTSFollowing treatment of the 40 study patients with bevacizumab and atezolizumab, objective response was observed in 4 patients with pNETs (20%; 95% CI, 5.7%-43.7%) and 3 patients with epNETs (15%; 95% CI, 3.2%-37.9%). The PFS was 14.9 (95% CI, 4.4-32.0) months and 14.2 (95% CI, 10.2-19.6) months in these cohorts, respectively. CONCLUSIONS AND RELEVANCEIn this nonrandomized clinical trial, findings suggest that clinical responses in patients with NET may follow treatment with the combination of bevacizumab and atezolizumab, with a PFS consistent with effective therapies.

BACKGROUND Checkpoint inhibitor therapy has demonstrated overall limited efficacy in the treatment of GBM. Mechanisms of resistance to checkpoint blockade need to be better elucidated. Analysis of the tumor microenvironment is critical to identify correlates of response to immune checkpoint blockade. 60 newly diagnosed GBM patients unselected for MGMT status underwent treatment with concurrent atezolizumab with radiation therapy and TMZ followed by adjuvant atezolizumab and TMZ (NCT03174197). Clinical data has been reported previously. METHODS Tissue image immunoprofiling was conducted using 2 multiplex immunofluorescence (mIF) panels against; CD3, CD8, PD-1, PD-L1, Granzyme B, FOXP3, CD45RO, CD68, and GFAP antibodies. PDL-1 (Clone SP263) malignant cells expression was assessed by immunohistochemistry. Correlations between mIF biomarkers co-expressions, IHC PD-L1, and clinical outcome including OS, radiographic response, and PFS were evaluated. RESULTS Of 60 patients enrolled, image immunoprofiling was performed successfully on pre-treatment tissue in 48 patients. 20 of 60 patients underwent re-resection for suspected recurrent disease of which 10 patients had immunoprofiling performed successfully on pre and post treatment samples. An analysis of CD3CD8+ cytotoxic T lymphocytes was consistent with prior work, showing no or relatively low levels at baseline, and no association with clinical outcome. PDL-1 expression by IHC, at thresholds of >1% or >5%, was not associated with clinical outcome. Tumors with a higher number of GFAP-expressing cancer cells had a significantly lower tumor response (p< 0.05) and median OS (430 vs. 799 days, p< 0.01). CONCLUSIONS For newly diagnosed GBM patients treated with standard of care radiation and temozolomide in combination with atezolizumab, T-cell levels and PDL-1 expression were not predictive of outcome. GFAP may represent a novel predictive biomarker of overall survival. Ongoing studies to evaluate the gut microbiome and tumor genomic (WES, CNA) and transcriptomic (RNAseq) features of these and matched tumors are underway.

Purpose: Preclinical evidence supporting immunomodulatory effect of MEK inhibition that augments anti-tumor activity of PD-1 inhibitors is a compelling rationale for investigating combined MEK and PD-L1 inhibition in advanced microsatellite-stable (MSS) SBA wherein immune checkpoint inhibitors (ICIs) have little clinical benefit. We conducted a prospective, phase 2 trial evaluating efficacy and safety of COTEZO regimen in treatment refractory SBA. Procedures: Patients aged ≥ 18 years with metastatic MSS SBA, ECOG PS 0 - 2, and disease progression on prior systemic chemotherapy were enrolled and treated with cobimetinib (60 mg orally once daily for days 1 - 21) and atezolizumab (840 mg intravenously every 2 weeks) every 28-day cycle. The primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. by independent radiology review. Key pre-specified secondary endpoints were safety, disease control rate (DCR), progression-free (PFS) and overall (OS) survival. Pre/on-treatment biopsies were examined for response biomarkers. Results: Between 4/2017 and 7/2020, 20 patients were enrolled. The confirmed ORR per RECISTv1.1 was 10% [2/20; 95%CI: 1.2 - 31.7] (1 complete response and 1 partial response). Seven patients had stable disease for a DCR of 45% (95%CI: 23.1 - 68.5). Median PFS and OS were 2.4 (95% CI 1.3-3.5) and 8.8 (95% CI 5.6 - 12) months, respectively. Grade 3 treatment-emergent adverse events (no grade 4/5) occurred in 7 (35%) patients; most common being elevated CPK (15%) and vomiting (10%). One (5%) patient had grade 3 vomiting, necessitating treatment discontinuation. There appeared to be a marked difference in OS between patients with increased pre-treatment tumor immune infiltration as compared to those lacking immune infiltration amongst patients with RNASeq data available (n=13). Specifically, increased immune infiltration as assessed by computational deconvolution of RNASeq data pointed to increased macrophage and monocyte infiltration as prognostic factors. This was additionally assessed via application of a global “immune score” algorithm, ESTIMATE. In order to generalize our findings, we expanded our computational deconvolution analysis to include additional small bowel adenocarcinoma patients who received standard-of-care treatment (n=7). For the combined standard-of-care and experimentally treated patients we saw that those with immune infiltration had significantly better OS (9 months vs greater than 3 years, HR 5.7, Padj = 0.017), suggesting that immune infiltration is a prognostic, rather than predictive biomarker. Conclusions: Although our study did not meet its primary endpoint of ORR, we identified tumor immune infiltration as a prognostic biomarker in SBA, which could select patients with better outcomes on immunotherapy. Citation Format: Nicholas Hornstein, John P. Shen, Andrew J. Pellatt, Suyu Liu, Mark Knafl, Anneleis F. Willett, Haifeng Zhu, Dipen M. Maru, Walter Darbonne, Ignacio I. Wistuba, Andy Futreal, James C. Yao, Scott E. Woodman, Michael J. Overman, Kanwal P. Raghav. Efficacy, safety, and biomarker analysis of combined MEK (Cobimetinib) and PD-L1 (Atezolizumab) inhibition (COTEZO) in advanced small bowel adenocarcinoma (SBA) [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 CT148.

2006 Background: Checkpoint inhibitor (CPI) therapy has demonstrated overall limited efficacy in the treatment of GBM. Sixty newly diagnosed GBM patients unselected for MGMT status underwent treatment with concurrent atezolizumab with radiation therapy and TMZ followed by adjuvant atezolizumab and TMZ (NCT03174197). Clinical data has been reported previously. Methods: Genomic (WES with somatic mutation and SCNA determination N = total 42 samples, 33 baseline, 9 TP-2), transcriptomic (RNA seq N = total 72 samples, 54 baseline, 18 TP-2), and metagenomic sequencing of fecal samples (N = total 45 samples, 26 pre samples, 13 post RT samples, six 6m samples) analyses were conducted on pre-treatment samples. Findings were correlated with clinical outcome including OS and PFS. Twenty of the 60 patients underwent re-resection for suspected recurrent disease of which nine patients had WES and RNA seq performed successfully on paired pre and post treatment samples. Results: Somatic mutation, copy number and ploidy profiles were consistent with known aberrations in GBM. An unsupervised molecular network-based stratification of pre-treatment tumor mutations resulted in patients being grouped in 3 clusters with survival difference. Patients with GBM harboring an EGFR aberrancy were associated with a relatively worse mOS following treatment compared to patients with tumors enriched with PTEN alterations, while patients with IDH1 mutations had the longest mOS. Gene set enrichment analysis of gene expression in tumors from patients ( < mOS vs ≥mOS) identified genes associated with lymphocyte activation and immune response in patients with longer survival (p < 0.01) Unsupervised hierarchical clustering of bacterial taxa demonstrated two distinct clusters with significant difference by OS. Survival analysis and Analysis of Compositions of Microbiomes with Bias Correction (ANCOM-BC) revealed distinct taxa associated with OS ( Ruminococcus spp.) and response to treatment ( Eubacterium spp.), respectively. Conclusions: In this small CPI-treated GBM cohort, WES, SCNA and RNA seq identified pre-treatment tumor features that separated patients by survival. The fecal microbiome observations in our GBM cohort warrants further investigation. Clinical trial information: NCT03174197.