Immune checkpoint inhibitors are associated with immune-related adverse events (irAEs), including arthritis (arthritis-irAE). Management of arthritis-irAE is challenging because immunomodulatory therapy for arthritis should not impede antitumor immunity. Understanding of the mechanisms of arthritis-irAE is critical to overcome this challenge, but the pathophysiology remains unknown. Here, we comprehensively analyze peripheral blood and/or synovial fluid samples from 20 patients with arthritis-irAE, and unmask a prominent Th1-CD8+ T cell axis in both blood and inflamed joints. CX3CR1hi CD8+ T cells in blood and CXCR3hi CD8+ T cells in synovial fluid, the most clonally expanded T cells, significantly share TCR repertoires. The migration of blood CX3CR1hi CD8+ T cells into joints is possibly mediated by CXCL9/10/11/16 expressed by myeloid cells. Furthermore, arthritis after combined CTLA-4 and PD-1 inhibitor therapy preferentially has enhanced Th17 and transient Th1/Th17 cell signatures. Our data provide insights into the mechanisms, predictive biomarkers, and therapeutic targets for arthritis-irAE.
9105 Background: The aurora kinase and mTOR pathways are implicated in resistance to EGFR inhibitor osimertinib. Here, we investigated the safety and efficacy of the aurora kinase inhibitor alisertib and the mTOR inhibitor sapanisertib in combination with osimertinib. Methods: This is a phase 1b study with dose finding and expansion portions (NCT04479306). The dose finding portion used a Bayesian optimal interval (BOIN) design to assess two arms: osimertinib 80 mg daily in combination with alisertib 20 mg, 30 mg, and 40 mg daily day 1-21 of 28-day cycle (osi-ali arm) and osimertinib 80 mg daily in combination with sapanisertib 2 mg and 3 mg daily (osi-sapa arm). Dose limiting toxicities (DLTs) were predefined in the protocol. Patients with EGFR (L858R/exon 19 deletion) mutant NSCLC whose disease have progressed on osi and up to one additional line of systemic therapy were assigned, at investigator discretion, to either study arm. Tumor biopsy was mandatory at study entry and optional upon progression. Results: As of February 1, 2022, 40 patients are enrolled (20 in each arm). One DLT was observed in each arm: grade 3 nausea in ali-osi arm and grade 3 AST elevation in osi-sapa arm. Grade 3 treatment emergent adverse events (TEAEs) occurred in 10% of each arm, and no grade 4 TEAEs were observed. The most common TEAEs in osi-ali arm was leucopenia (45%) and anemia (35%) while in osi-sapa arm, hyperglycemia (45%) and stomatitis (40%). In osi-ali arm (n = 20), median progression free survival (mPFS) was 1.9 months while objective response rate (ORR) and disease control rate (DCR) were 5% (95% CI: 0.1 ̃ 24.9%) and 40% (95% CI: 19.1 ̃ 63.9%), respectively. In osi-sapa arm (n = 16, evaluated for response to date), mPFS was 4.6 months while ORR and DCR were 12.5% (95% CI: 1.6 ̃ 38.3%) and 68.7% (95% CI: 35.7 ̃ 82.7%), respectively. Conclusions: Osimertinib with alisertib or sapanisertib is well tolerated in osimertinib-resistant, EGFR mutant NSCLC. The sapanisertib combination, but not the alisertib combination, demonstrates antitumor activity suggesting that mTOR inhibition warrants further exploration in this population. Biomarker analysis is ongoing to identify the molecular determinants of response and resistance to sapasertib. Clinical trial information: NCT04479306.
Background: Von Hoff et al. demonstrated survival improvement with gemcitabine (GEM) + nabpaclitaxel (NabP) for metastatic pancreatic ductal adenocarcinoma (PDAC) compared to GEM alone. GEM + NabP resulted in a median overall survival (OS) and progression-free survival (PFS) of 8.5 and 5.5 months, respectively. Patients with baseline hyperbilirubinemia were excluded. Primary objective was OS. Secondary objectives included time on treatment (TOT), disease control rate, dosing practices, delays/admissions, and adverse effects. Methods: Patients with borderline resectable, locally advanced, or metastatic PDAC who initiated frontline GEM-NabP during July 01, 2013-July 01, 2017 were reviewed. Patients with a baseline total bilirubin≥2 mg/dL were included. Results: Twelve patients total were included. Median age was 71 years old. Median baseline total bilirubin was 2.4 mg/dL (range, 2.1-5.2 mg/dL). 58% had metastatic disease. Median doses were NabP 100 mg/m 2 + GEM 600 mg/m 2 IV with a fixed-dose rate infusion (10 mg/m 2 /min). GEM-NabP was given biweekly or 3 weeks on 1 week off. Median OS, TOT, and disease control rate were 13.9, 5.2 months, and 58%, respectively. Fifty percent of patients required a dose delay. Metastatic patients only (n=7) had median OS and TOT of 6.9 and 2.1 months, respectively. No admissions related to toxicity were found.Conclusions: Our analysis revealed safety with NabP (median dose =100 mg/m 2 ) + GEM (median dose =600 mg/m 2 at fixed-dose rate) given predominately biweekly in patients with a baseline elevated total bilirubin (≥2 mg/dL).
9049 Background: Primary resistance to immune checkpoint inhibitor (ICI) therapy remains a major challenge in clinical oncology. Here, we describe the clinical outcome of patients who experienced radiologic progression within 12 weeks of therapy with nivolumab and ipilimumab (I+N) for metastatic non-small cell lung cancer (mNSCLC). Methods: The LONESTAR study is an ongoing phase III study (NCT03391869). Study enrolls patients with immunotherapy naïve mNSCLC (prior chemotherapy is allowed). All patients receive I+N for 12 weeks and are randomized to experimental therapy vs. control arm if they did not have disease progression. Patients who experience radiologic progression per RECIST v1.1 are not randomized and removed from the study. Treatment beyond progression is allowed if they clinically benefit from the systemic therapy. We prospectively collected clinicopathologic and radiologic outcome data from patients who experienced radiologic progression within 12 weeks of I+N therapy and have not randomized to investigational therapy. We described the primary progression pattern. We collected subsequent treatment, radiologic, and toxicity data and calculated clinical outcomes, including progression-free survival (PFS) and overall survival (OS). Results: Of the 194 patients who received at least one dose of I+N therapy, 72 patients had clinical and/or radiologic progression at ≤ 12 weeks. Thirty-five (35; 48%) patients did not receive subsequent treatment, 21 (29%) patients received subsequent 2nd line systemic therapy, and 16 (22%) patients were continued on I+N beyond radiologic progression due to ongoing clinical benefit. Among patients treated with 2nd line therapy, 13 patients were treated with platinum doublet +/- anti-PD-(L)1, seven (7) patients were treated with single-agent chemotherapy +/- VEGF inhibitor, and one (1) patient was treated with targeted therapy. The PFS for the 2nd line therapy was 6.5 months (95%CI: 4.8, 8.9), and OS was 10.4 months (95%Cl: 6.6, 16.1). Among the 16 patients treated with I+N beyond progression, 13 had a mixed response to induction therapy, where primary progression was most frequently observed in mediastinal lymph nodes. LCT with radiotherapy was utilized with I+N in 10 patients. The median duration of post-progression treatment with I+N plus LCT was 8.7 months (95%Cl: 5.9, 22.3) and 5.6 months (95%Cl 4.4, 11.5) with I+N alone. The OS was 19.5 months (95% CI: 6.2,18.7). Conclusions: In this study cohort, primary resistance to I+N was observed in 37% of the patients, and in a subset of these patients treated with post-progression I+N, either alone or in combination with LCT, durable clinical benefit was observed. Further studies are warranted to identify which patients are most likely to benefit from post-progression I+N. Clinical trial information: NCT03391869.
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