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Approach to assess levels of monocytic and PMN MDSC in patient PBMCs.

Patient characteristics per PD-L1 stratification subgroups

Supplementary Data from Phase I Study of Taminadenant (PBF509/NIR178), an Adenosine 2A Receptor Antagonist, with or without Spartalizumab (PDR001), in Patients with Advanced Non–Small Cell Lung Cancer

Supplementary Figure from Phase I Study of Taminadenant (PBF509/NIR178), an Adenosine 2A Receptor Antagonist, with or without Spartalizumab (PDR001), in Patients with Advanced Non–Small Cell Lung Cancer

Purpose:The adenosine 2A receptor (A2AR) mediates the immunosuppressive effects of adenosine in the tumor microenvironment and is highly expressed in non–small cell lung cancer (NSCLC). Taminadenant (PBF509/NIR178) is an A2AR antagonist able to reactivate the antitumor immune response.Patients and Methods:In this phase I/Ib, dose-escalation/expansion study, patients with advanced/metastatic NSCLC and ≥1 prior therapy received taminadenant (80–640 mg, orally, twice a day) with or without spartalizumab (anti–programmed cell death-1, 400 mg, i.v., every 4 weeks). Primary endpoints were safety, tolerability, and feasibility of the combination.Results:During dose escalation, 25 patients each received taminadenant alone or with spartalizumab; 19 (76.0%) and 9 (36.0%) had received prior immunotherapy, respectively. Dose-limiting toxicities (all Grade 3) with taminadenant alone were alanine/aspartate aminotransferase increase and nausea [n = 1 (4.0%) each; 640 mg], and in the combination group were pneumonitis [n = 2 (8.0%); 160 and 240 mg] and fatigue and alanine/aspartate aminotransferase increase [n = 1 (4.0%) each; 320 mg]; pneumonitis cases responded to steroids rapidly and successfully. Complete and partial responses were observed in one patient each in the single-agent and combination groups; both were immunotherapy naïve. In the single-agent and combination groups, 7 and 14 patients experienced stable disease; 7 and 6 patients were immunotherapy pretreated, respectively.Conclusions:Taminadenant, with and without spartalizumab, was well tolerated in patients with advanced NSCLC. The maximum tolerated dose of taminadenant alone was 480 mg twice a day, and 240 mg twice a day plus spartalizumab. Efficacy was neither a primary or secondary endpoint; however, some clinical benefit was noted regardless of prior immunotherapy or programmed cell death ligand-1 status.

Purpose:Histone deacetylase inhibitors (HDACi) enhance tumor immunogenicity through several mechanisms and may improve response to immune checkpoint inhibitors (ICIs). In a phase I/Ib trial, we tested the oral HDACi vorinostat combined with the programmed cell death protein 1 inhibitor pembrolizumab in advanced/metastatic non–small cell lung cancer.Patients and Methods:Patients received intravenous pembrolizumab (200 mg every 3 weeks) plus oral vorinostat (200 or 400 mg/day). Primary endpoint was safety/tolerability. Secondary endpoints included response rate, progression-free survival, disease control rate (DCR), and overall survival. Tumor gene expression changes, T-cell density, and myeloid cell levels were studied in serial tissue specimens.Results:Thirty-three patients were treated (13 in phase I, 20 in phase Ib). In phase I, both ICI-naïve and ICI-pretreated patients were enrolled to determine dose-limiting toxicities (DLT). No DLTs were observed, and the recommended phase I dose was pembrolizumab 200 mg and vorinostat 400 mg. Any-grade adverse events were mainly fatigue (33%) and nausea/vomiting (27%). Of six ICI-naïve and 24 ICI-pretreated patients evaluable for response, four (13%) had partial response [two confirmed, one unconfirmed with subsequent prolonged stable disease (SD), one unconfirmed with subsequent progressive disease (PD)], 16 (53%) had SD, and 10 (33%) had PD for a DCR of 67%. In the ICI-pretreated cohort, three patients (one confirmed, two unconfirmed) had partial response and 10 had SD. Pretreatment CD8+ T-cell presence in tumor stromal regions was associated with treatment benefit.Conclusions:Pembrolizumab plus vorinostat was well tolerated and demonstrated preliminary antitumor activity despite progression on prior ICI treatment.

Background: Arginine deprivation with ADI-PEG20 (pegargiminase) alone or combined with chemotherapy displayed antitumor activity in early phase clinical trials of argininosuccinate synthase 1 (ASS1)-deficient cancers, including pleural mesothelioma (PM). The non-epithelioid subtype of mesothelioma is particularly aggressive and arginine-auxotrophic due to frequent ASS1 loss. ATOMIC-meso is a pivotal phase 2-3 trial comparing standard of care (SOC) chemotherapy plus pegargiminase or placebo for patients (pts) with non-epithelioid PM. Methods: In this double-blind, placebo-controlled, phase 2-3 trial, we randomly assigned ECOG PS 0-1 pts with chemonaïve non-epithelioid PM in an intention-to-treat 1:1 ratio to receive q3 week SOC chemotherapy with pemetrexed (500mg/m2 i.v.) and cisplatin (75mg/m2 i.v.) with q1 week pegargiminase (36 mg/m2 i.m.) or placebo i.m. up to 6 cycles. Carboplatin (AUC5) was permitted in the phase 3 portion instead of cisplatin. Maintenance therapy with pegargiminase or placebo was continued until progression, toxicity or 24 months. The primary end point was median OS (mOS) and secondary end points included median PFS (mPFS), safety, pharmacodynamics and immunogenicity. ORR was assessed by blinded independent central review (BICR) for the phase 2 portion only using modified RECIST or RECIST v1.1. Results: 249 pts with non-epithelioid PM (median age 71, range 28-86; male 82.7%; 48.2% biphasic and 51.8% sarcomatoid) from 5 countries were randomized between Aug 2017 and Aug 2021: 125 pts were assigned to the pegargiminase-chemotherapy group and 124 pts to the placebo-chemotherapy group. The experimental arm showed a superior mOS respect to SOC: 9.3 months (95% confidence interval [CI], 7.9-11.8) vs. 7.7 months (95% CI, 6.1-9.5) (hazard ratio [HR], 0.71; 95% CI, 0.55-0.93; p=0.023). Also, the mPFS was higher in the experimental vs. control arm: 6.2 months (95% CI, 5.8-7.4) vs. 5.6 months (95% CI, 4.14-5.91) ([HR], 0.65; 95% CI, 0.46-0.90; p=0.019). The ORR by BICR was 13.8% in the pegargiminase-chemotherapy group vs. 13.5% in the placebo-chemotherapy group (p=0.95) with more stable disease in the former (71.3% vs. 62.9%). Plasma arginine declined with a reciprocal increase in citrulline. Anti-ADI-PEG20 antibodies were detected in 97.4% of patients by week 25 on pegargiminase. Grade ≥ 3 treatment-related adverse events to pegargiminase occurred in 28.8% and to placebo in 16.9%; grade ≥ 3 drug hypersensitivity and skin reactions occurred in 3.2% and 1.6% in the experimental arm, respectively, and none on placebo. Post-study drug treatment was comparable in both arms (45.6% post-pegargiminase vs. 46.8% post-placebo). Conclusions: In this first randomized trial of an arginine-depleting chemotherapy in cancer, the pegargiminase-pemetrexed-platinum triplet prolonged survival and had a favorable safety profile in pts with non-epithelioid PM (ClinicalTrials.gov Identifier NCT02709512) Citation Format: Peter W. Szlosarek, Ben Creelan, Thomas Sarkodie, Luke Nolan, Paul Taylor, Olga Olevsky, Federica Grosso, Diego Cortinovis, Meenali Chitnis, Amy Roy, David Gilligan, Hedy Kindler, Dionysis Papadatos-Pastos, Giovanni L. Ceresoli, Aaron Mansfield, Anne Tsao, Ken O’Byrne, Anna K. Nowak, Jeremy Steele, Michael Sheaff, Amanda Johnston, John Bomalaski, Marjorie Zauderer, Dean A. Fennell. Phase 2-3 trial of pegargiminase plus chemotherapy versus placebo plus chemotherapy in patients with non-epithelioid pleural mesothelioma [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 CT007.

BACKGROUND LMD from systemic cancer has a dismal prognosis with median survivals of 8-10 weeks. A phase 2 trial of PD-1 inhibitor monotherapy in LMD showed median overall survival (OS) of 3.6 months (Brastianos P et al., 2020). We determined the safety/efficacy of avelumab, a PD-L1 inhibitor with WBRT in patients with LMD (NCT0371768). This combination can treat the tumor directly and increase BBB permeability (Li, 2003; Nordal, 2005) allowing the increased egress of activated T cells into the meninges/CSF. METHODS Patients received concurrent avelumab 800 mg IV q2 weeks for ≤ 5 cycles (unless PD or unacceptable toxicity) with WBRT 3000 cGy in 10 fractions. Primary endpoints are safety/DLTs and OS at 3 months. Secondary endpoints are CSF T-cell/cytokine profiles (scRNAseq, phosophoproteomics etc.). RESULTS A total of 15 patients (7 breast, 7 lung & 1 other) were enrolled (n = 13 F, ages 32-79). Pts receiving anti-PD-1/PD-1L/PD-L2/CD137,CTLA-4 therapy ≤ 6 months prior were excluded. Three of 15 patients had grade 3/4 AEs (diarrhea, lymphopenia, decreased WBC count in 3 patients). Seven patients (50%) were alive at 3 or 6 months. The estimated median follow up in 14 patients is 4.75 months (range, 0.92 – 30.05 months, 95% CI is 1.32 ~ 19.82). The median PFS is 3.75 months (95% CI = 0.85-15.16) and median OS is 6.89 months (95% CI = 1.18-14.7). CONCLUSIONS The combination of avelumab and WBRT is safe, well tolerated, and demonstrates encouraging activity in patients with LMD with an OS that is longer than other published series. Multiple platform interrogation of CSF (analysis underway) will determine mechanisms of LMD therapeutic/resistance effects.

Purpose:The adenosine 2A receptor (A2AR) mediates the immunosuppressive effects of adenosine in the tumor microenvironment and is highly expressed in non–small cell lung cancer (NSCLC). Taminadenant (PBF509/NIR178) is an A2AR antagonist able to reactivate the antitumor immune response.Patients and Methods:In this phase I/Ib, dose-escalation/expansion study, patients with advanced/metastatic NSCLC and ≥1 prior therapy received taminadenant (80–640 mg, orally, twice a day) with or without spartalizumab (anti–programmed cell death-1, 400 mg, i.v., every 4 weeks). Primary endpoints were safety, tolerability, and feasibility of the combination.Results:During dose escalation, 25 patients each received taminadenant alone or with spartalizumab; 19 (76.0%) and 9 (36.0%) had received prior immunotherapy, respectively. Dose-limiting toxicities (all Grade 3) with taminadenant alone were alanine/aspartate aminotransferase increase and nausea [n = 1 (4.0%) each; 640 mg], and in the combination group were pneumonitis [n = 2 (8.0%); 160 and 240 mg] and fatigue and alanine/aspartate aminotransferase increase [n = 1 (4.0%) each; 320 mg]; pneumonitis cases responded to steroids rapidly and successfully. Complete and partial responses were observed in one patient each in the single-agent and combination groups; both were immunotherapy naïve. In the single-agent and combination groups, 7 and 14 patients experienced stable disease; 7 and 6 patients were immunotherapy pretreated, respectively.Conclusions:Taminadenant, with and without spartalizumab, was well tolerated in patients with advanced NSCLC. The maximum tolerated dose of taminadenant alone was 480 mg twice a day, and 240 mg twice a day plus spartalizumab. Efficacy was neither a primary or secondary endpoint; however, some clinical benefit was noted regardless of prior immunotherapy or programmed cell death ligand-1 status.

Abstract 3740 Background: Based upon dramatic improvement in major and complete cytogenetic response with imatinib (STI571) in the phase III International Randomized Study of Interferon Versus STI571 (IRIS) trial, imatinib was approved for first-line treatment in CML. Despite this success, five-year follow up of this trial showed only 69% of patients remained on imatinib. Other long-term studies suggest that up to 50% of patients may require interruption or discontinuation of imatinib due to primary or secondary resistance, drug intolerance, or progression to accelerated phase (AP) or blast crisis (BC). Methods: The Total Cancer Care (TCC) database was used to identify all patients with CML treated with imatinib as first-line therapy between 1992 and 2010 at Moffitt Cancer Center (MCC). “Imatinib-refractory” was defined as absence of complete hematologic response by 3 months, or cytogenetic response by 6 months. “Loss of response” was defined as loss of best response while remaining on the dose of imatinib that was previously therapeutic. Progression-free survival (PFS) was defined as time from treatment to loss of best response, or progression to AP or BC. Descriptive data were reported, chi square test was used for categorical variables, and Kaplan Meier method was used for OS and PFS. Log rank test was used to compare survival times between groups. Statistical analysis was done using SPSS statistical software, version 19. Results: Of a total of 540 CML patients evaluated, 304 (56%) received imatinib as first-line therapy, with 51% being male and 49% female. Five patients were diagnosed before 2001 and median age was 49.5 years. Median time on imatinib was 23 months. With a median follow up of 72 months (95% CI 67–76), the 5-year OS was 78% and median OS was not reached. Of 304 patients, 139 (46%) required a change to second generation TKI's. Causes for imatinib discontinuation included: intolerance in 48 (35%) patients, refractory disease in 34 (24%) patients, loss of response in 26 (19%) patients, and progression to AP or BC in 31 (22%) patients. In patients switched due to intolerance, refractory disease or loss of response median PFS and OS were not reached. Median OS was 53 months (95% CI 5.4–101.3) in patients whose therapy was changed due to progression to AP or BC (P=0.000) (Figure 1). Overall, 82 (27%) patients progressed to AP or BC either on first or second line therapy, and 25 (8%) developed kinase domain mutations (KDM). Of the 25 patients with KDM, 13 (52%) developed T315I mutations. Conclusion: Despite the success of imatinib in improving outcomes in CML, nearly half of all patients will require discontinuation of the drug with a change to second line TKI's. This change does not appear to negatively impact OS, with the exception of therapy changes due to overt progression into AP or BC. Our results suggest that most imatinib failures may be salvaged with second generation TKI's without significant impact upon overall survival. Disclosures: No relevant conflicts of interest to declare.