The UPMC Hillman Cancer Center (Hillman), previously titled the University of Pittsburgh Cancer Institute (UPCI), is a National Cancer Institute (NCI)-designated Comprehensive Cancer Center located in the Hillman Cancer Center in the Shadyside neighborhood of Pittsburgh, Pennsylvania, United States, adjacent to UPMC Shadyside. The only NCI-designated cancer center in Western Pennsylvania, Hillman is composed of collaborative academic and research efforts between the University of Pittsburgh, the University of Pittsburgh Medical Center (UPMC), and Carnegie Mellon University. Hillman provides clinical cancer care to some 74,000 patients treated at its facilities at both the Hillman Cancer Center location in the Shadyside neighborhood of Pittsburgh and at UPMC-affiliated sites throughout Pennsylvania, New York, Ohio, and overseas locations. Founded in 1984, Hillman became the youngest cancer center in history to achieve NCI-designation. As of 2007, Hillman had received nearly $200 million in funding from the National Cancer Institute, which ranks it as one of the top ten cancer research institutes.
TPS3634 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage III A, B (all pts) and stage II, IIIC (ctDNA+ only) CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (SignateraTM, bespoke assay), those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP) + oxaliplatin (Ox) for 3-6 mos per established guidelines vs. serial ctDNA monitoring. Patients who are ctDNA+ post-operatively or with serial monitoring (Cohort B) will be randomized to FP+Ox vs. more intensive AC with addition of irinotecan (I) for 6 mos. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate vs. delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox vs FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June 2022. NCT#: NCT05174169. Support: U10-CA-180868, -180822; UG1CA-189867; Natera, Inc. Clinical trial information: NCT05174169 .
Immune checkpoint blockade-based multimodal therapy is widely used across oncology; yet drivers of resistance in most cancer types are not well understood. Here, we comprehensively characterized the tumor genome, microenvironment and microbiome in a phase 3 international randomized trial ( NCT02952586 ) to identify factors that shape outcomes to anti-PD-L1 avelumab plus standard-of-care chemoradiotherapy versus placebo/chemoradiotherapy in individuals with locally advanced head and neck cancer. Patients receiving avelumab whose tumors contained distinct immunologic and genetic features had superior outcomes compared to those receiving placebo. By contrast, patients with increased myeloid/neutrophil activities had worse outcomes with avelumab than those treated with placebo. Strikingly, these tumors possessed telltale intratumoral bacteria, elevated tumor-associated neutrophils, high systemic neutrophil-to-lymphocyte ratios and suppressed adaptive immunity. We define tumor ecosystems associated with benefit to chemoimmunotherapy. Our data demonstrate how intratumoral bacteria affect immune checkpoint blockade response within a randomized trial. These discoveries enhance our understanding of combination immunotherapy, provide a useful multiomic resource and identify unanticipated interactions that may guide future therapeutic strategies. Chan and colleagues report that tumor ecosystem and microbiome features are associated with response to anti-PD-L1 avelumab plus chemoradiotherapy in patients with locally advanced head and neck cancer.
PURPOSE:Unsatisfactory outcomes in pancreatic ductal adenocarcinoma (PDAC) highlight the need to identify precision-based treatment modalities. We aimed to utilize patient-derived organoids (PDO) to predict the most effective individual components of potential combination therapies. EXPERIMENTAL DESIGN:Autologous αβ- and γδ-enriched tumor-infiltrating lymphocyte (TIL) and PDO cultures were established from resected PDAC tissue. PDOs were characterized by immunostaining, targeted next-generation sequencing, and drug screening with standard-of-care multidrug chemotherapeutic regimens. Expanded TIL cultures were profiled through flow cytometry, sequencing, and potency against autologous PDOs. RESULTS:PDO cultures were established with an 80% success rate. In addition to faithfully recapitulating molecular and histologic features of the parental tumor, PDOs were sufficiently expanded for pharmacotyping within a clinically relevant time frame of 36 days. Notably, PDO chemotherapeutic sensitivity profiles correlated with patient serum CA 19-9 dynamics and recurrence-free survival. Furthermore, expanded γδ-enriched TILs supported the activation of αβ TCR+ cells and demonstrated more potent functionality in response to autologous PDO targets. Importantly, infiltration of γδ T cells within pancreatic tumor tissue was associated with improved overall survival. CONCLUSIONS:We confirm the feasibility of generating PDOs within a clinically relevant time frame and provide evidence of their utility for advancing therapeutic success in PDAC.
TPS6113 Background: HPV-negative head and neck squamous cell carcinoma (HNSCC) is an aggressive disease characterized by high rates of recurrence, metastasis, and resistance to standard treatments. Over 80% of HPV-negative HNSCC cases overexpress TGF-β, a key driver of poor survival and treatment resistance. Ficerafusp alfa, a first-in-class bifunctional antibody, targets epidermal growth factor receptor (EGFR) while neutralizing TGF-β in the tumor microenvironment. In a Phase 1/1b trial (NCT04429542), ficerafusp alfa demonstrated promising efficacy and a manageable safety profile in first-line recurrent/metastatic (R/M) HNSCC. The ongoing FORTIFI-HN01 study (NCT06788990) is a randomized, double-blind, placebo-controlled Phase 2/3 trial designed to assess the efficacy and safety of ficerafusp alfa combined with pembrolizumab versus placebo plus pembrolizumab in patients with PD-L1 positive first-line R/M HPV-negative HNSCC. Methods: Eligible patients must have histologically confirmed R/M HNSCC with primary lesions in the oral cavity, larynx, or hypopharynx, or OPSCC, excluding HPV-positive OPSCC confirmed by central laboratory testing. Additional criteria include no prior systemic therapy for R/M disease, PD-L1 positive tumors (CPS ≥1), measurable disease per RECIST v1.1 assessed by BICR, and ECOG performance status of 0 or 1. The Phase 2 objective is to determine the optimal biological dose (OBD) of ficerafusp alfa through an integrated analysis of safety, tolerability, PK, PD, and efficacy. Subjects will be randomized 1:1:1 to receive high-dose ficerafusp alfa, low-dose ficerafusp alfa, or placebo, each combined with pembrolizumab. Randomization is stratified by PD-L1 CPS (1-19 vs. ≥20) and disease extent (local/regional recurrence only, distant metastasis only, or both). After OBD determination, the trial will transition seamlessly into Phase 3 with a 2:1 randomization (OBD vs. control).Patients will receive pembrolizumab (200 mg i.v. every 3 weeks for up to 35 cycles) and either ficerafusp alfa (1500 mg or 750 mg) or placebo weekly until disease progression or unacceptable toxicity. Tumor imaging will occur every 6 weeks during the first year and every 9 weeks thereafter. The primary endpoints are objective response rate (ORR) per RECIST v1.1 (BICR) and overall survival (OS). Secondary endpoints include safety, additional efficacy measures, and patient-reported outcomes (PROs). The trial is actively recruiting, with a planned enrollment of (NCT06788990). Clinical trial information: NCT06788990 .
PURPOSE:Relapse is a major cause of failure in human papillomavirus-independent head and neck squamous cell carcinoma. Clinicopathologic criteria for adjuvant treatment remain imprecise and have not changed for decades. We investigated whether ctDNA in lymphatic exudate collected via surgical drains ("lymph") 24 hours after surgery identified molecular residual disease (MRD) and compared its performance with time-matched plasma. EXPERIMENTAL DESIGN:Using an ultra-sensitive tumor-informed sequencing approach, tumor variants were called in lymph and plasma to classify patients as ctDNA positive or ctDNA negative, trained in an initial cohort of 36 patients, and replicated in an independent cohort of 37 patients. Progression-free survival was compared in ctDNA(+) versus ctDNA(-) patients. RESULTS:Lymph identified MRD in two independent multi-site cohorts (initial cohort sensitivity = 76% and specificity = 63%; log-rank P = 0.01; replication cohort sensitivity = 65% and specificity = 70%; log-rank P = 0.04). Lymph performance was enhanced in locoregional relapse (sensitivity = 78% and specificity = 67%; log-rank P = 0.0004) and generalized to early-stage patients. Analysis of matched plasma collected at this early timepoint was not predictive of recurrence (sensitivity = 35% and specificity = 72%; log-rank P = 0.7). In patients with intermediate-risk pathology, lymph ctDNA was associated with recurrence (sensitivity = 88% and specificity = 67%; log-rank P = 0.0008), suggesting an opportunity for improved stratification of patients who may benefit from additional adjuvant treatment. CONCLUSIONS:Postoperative lymph is a novel, proximal, and early source of MRD with the potential to introduce more precision into adjuvant therapy decision-making and improve outcomes, especially for patients with intermediate-risk human papillomavirus-independent head and neck squamous cell carcinoma.
