The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights of the latest advances in immunotherapy emerging from the ASCO 2024 Annual Meeting. Below is a recap of highlighted research presented from Tuesday, June 4, 2024.
2024 Scientific Highlights
Safety and efficacy of immune checkpoint inhibitor atezolizumab in patients with advanced solid tumors with high tumor mutation burden
LBA2509. Atezolizumab in patients (pts) with tumor mutational burden (TMB)–high tumors from the TAPISTRY trial.
Rafal Dziadziuszko (Department of Oncology & Radiotherapy and Early Phase Clinical Trials Centre, Medical University of Gdańsk, Gdańsk, Poland) reported efficacy and safety data from Cohort D of the phase II multi cohort basket trial TAPISTRY, investigating atezolizumab in adult and pediatric patients with tumor mutation burden (TMB)-high advanced or metastatic solid tumors. Prior studies indicate that patients with TMB-high tumors may benefit from the anti-PD-L1 immune checkpoint inhibitor atezolizumab, but these studies have used inconsistent TMB cutoffs making it a challenge to fully understand the relevance of TMB as a biomarker for immune checkpoint inhibitor therapy. The TAPISTRY study used two TMB cutoffs, TMB >= 13 mutations (mut)/Mb and TMB >=16 mut/Mb. 148 Patients with advanced unresectable or metastatic PD-L1 inhibitor naïve TMB-high (>=13 mut/Mb) tumors were given atezolizumab every 21 days. A wide range of solid tumors was represented, including colorectal (n=40), breast (n=11), gastroesophageal (n=11), and hepatobiliary (n=9) cancers. Response rates were similar for the two TMB cutoff groups. Among the efficacy evaluable population of patients with TMB >= 16 mut/Mb (n=111), the ORR was 22.5%, with 4 patients achieving a complete response and 21 patients achieving a partial response. The overall response rate (ORR) of patients with TMB >= 13 mut/Mb (n=129) was 20.2% , with 4 patients achieving a complete response and 22 patients achieving a partial response. Responses were observed across a variety of tumor types, including colorectal and prostate cancers which are typically immune-refractory. The median duration of response (DoR) was not reached for either TMB cutoff group, indicating that patients who responded had responses that lasted for a long period of time. Median progression free survival (PFS) was relatively short, likely due to fast disease progression in non-responders. The median PFS for patients with TMB >=16 mut/Mb and TMB>=13 mut/MB was 2.8 months and 2.7 months, respectively, and median overall survival (OS) was 15.0 months (TMB >= 16 mut/Mb) and 16.1 months (TMB >= 13 mut/Mb). The safety profile of the study was consistent with the known profile of atezolizumab. Data from this study indicates that atezolizumab is safe and leads to long-lasting anti-tumor responses in patients with high TMB burden of 13 mutations/Mb or higher, even in patients with tumors that are typically immune-refractory.
ctDNA as a prognostic and predictive biomarker for patients receiving immune checkpoint inhibitors for metastatic solid tumors
2510. Prognostic and predictive value of ultrasensitive ctDNA monitoring in a metastatic pan-cancer cohort treated with immune checkpoint inhibitors in the context of phase 1 clinical trials.
Rodrigo De Almeida Toledo (Medical Oncology Department, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain) presented a retrospective study investigating the association of baseline and on-treatment circulating tumor DNA (ctDNA) levels and patient response to immune checkpoint inhibitors. The study included samples from 124 patients with refractory metastatic tumors representing 18 different cancer types. Patients had received 1-3 successive lines of immune checkpoint inhibition (ICI) therapy in the context of phase I clinical trials. The majority of patients (75%) had received combination therapies involving ICIs. The best responses to ICI therapy among this patient population were 1 complete response, 6 partial responses, 58 with stable disease, and 59 with progressive disease. ctDNA was profiled using NeXT Personal assay, a tumor-informed liquid biopsy platform that enables detection of molecular residual disease (MRD) down to a detection threshold of 1 part per million (PPM) of ctDNA. Baseline levels of ctDNA were detected in 98% of patients, with levels ranging from 3.26 to 517,000 PPM. Low levels of ctDNA (less than the median 41,817 PPM) at baseline correlated with significantly increased progression free survival (PFS) (HR 0.57, log-rank p=0.017) and overall survival (OS) (HR 0.45; log-rank p<0.001). Early molecular response (mR), defined by a 30% reduction of ctDNA from baseline by cycle 3 of therapy was also associated with longer PFS (HR 0.36, log-rank p<0.0001) and longer OS (HR 0.45, log-rank p=0.006). Patients attaining ctDNA clearance at any point during treatment had median PFS that was 3.4 times higher than the PFS of patients who remained ctDNA-positive (median PFS 6.4 months and 1.9 months, respectively; HR 0.22, log-rank p=0.0001). The median OS among patients who attained ctDNA clearance was not reached by the 60-month data cutoff, and median OS for patients who did not clear ctDNA was 8.3 months (HR 0.32; log-rank p=0.0004). Longitudinal monitoring of ctDNA levels indicated that molecular tumor progression, defined as a 20% increase in ctDNA levels, preceded radiologic progression by an average of 81 days. This study demonstrates that sensitive ctDNA monitoring can act as an early predictor of disease response, disease progression, and survival outcomes. Given its increased sensitivity, increased lead time, and ease of sample collection in comparison to radiographic monitoring, ctDNA-based monitoring holds high potential to inform decisions and improve clinical management of patients receiving ICIs for solid tumors.
For a study of ctDNA dynamics in patients receiving ICI combination therapy for mismatch repair deficient colorectal cancer, read this paper by Kasi et al that was published in JITC.
Association of a radiomics signature estimating T cell infiltration of tumors with tumor progression and survival benefits in patients with lung cancer treated with durvalumab
2511. CD8 radiomics signature to assess inter-lesion spatial heterogeneity and cold liver lesions in advanced non-small cell lung cancers treated with durvalumab.
Roger Sun (Gustave Roussy, Department of Radiation Oncology, Université Paris-Saclay, UMR 1030, ImmunoRadAI, Villejuif, France) presented a study investigating a previously validated radiomics signature to estimate CD8 T cell infiltration of the tumor and its potential utility to evaluate patient inter-lesion heterogeneity and predict clinical outcomes for patients treated with durvalumab for non-small cell lung cancer. Data from 1137 lesions from 188 patients participating in the phase I/II trial Study 1108. Tumor radiomic features were extracted from CT scans, and a validated CD8 radiomics score were analyzed for the cohort of 188 patients. Low CD8 radiomics score at baseline was associated with a significantly higher risk of progression of the lesion (AUC=0.59, p<0.001), especially regarding liver lesions (AUC=0.66, p<0.001). At the patient level, the CD8 radiomics score of the least CD8-infiltrated lesion was found to have predictive value for survival: CD8 radiomics scores were positively associated with overall survival (OS; HR 0.7, p=0.029) and progression-free survival (PFS; HR 0.68, p=0.014). When patients were stratified by the presence of liver metastases and by immunologically “cold” versus “hot” liver lesions, the presence of cold liver lesions significantly decreased PFS and OS compared to patients with hot liver lesions, patients with cold non-liver lesions, and patients with hot non-liver lesions. Although more prospective clinical trials are needed to further validate this model, the CD8 radiomics score has potential to track disease progression and to predict patient prognosis in patients receiving durvalumab for non-small cell lung cancer.
Elucidating the associations of immune-related adverse events to patient response to immune checkpoint inhibitors
2512. High-dimensional longitudinal immune profiling uncovers a dual role of the CXCL9/CXCR3, CXCL13/CXCR5, and CCL11/CCL3 axis in the coupling of immune-related adverse events to immune checkpoint inhibitor response.
Michel Obeid (CHUV, Lausanne, Switzerland) reported on a study of immune signatures and immunophenotypes linking immune-related adverse events (irAEs) to immune checkpoint inhibitor (ICI) therapy to patient response to ICI therapy. Multiple studies have identified shared mechanisms between severe irAEs and patient response to ICI therapy including T cell activation and cytokine release. The goal of this study was to identify immunophenotypes and related biomarkers associated with irAEs and response to ICI, ultimately improving the efficacy and safety of ICI therapy. Comprehensive immune profiling analyses were performed on whole blood and peripheral blood mononuclear cells from 165 patients with cancer at baseline (prior to starting ICI therapy) and after they experienced an irAE. The 135 patients who experienced an irAE represented a variety of events, including pneumonitis (n=25), arthritis (n=24), colitis (n=34), cytokine release syndrome (CRS; n=33) and myocarditis (n=19). Serum concentrations of CCL3 were significantly increased during development of CRS, myocarditis, and pneumonitis, increased CXCL9 was increased upon onset of arthritis, colitis, CRS, myocarditis, and pneumonitis, CXCL13 was upregulated in CRS and pneumonitis, HGF was upregulated in colitis, CRS, and myocarditis. CCL11 upregulation was not associated with any irAEs. To examine patterns of irAEs and patient response, patients were subgroups based on irAE. In the ir-colitis subgroup (n=34), high levels of HGF were associated with significant increases in overall survival (OS; HR 9.22, p=0.008), and HGF and CXCL9 were found to be univariate predictors of OS in ir-colitis. 5-year OS also significantly higher in CXCL9-high patients (HR 3.47, p=0.032). High HGF was also found to be an indicator of severe ir-colitis. Similarly, in the CRS cohort (n=33), high CSCL9 was associated with significant gains in 2-year OS (HR 4.236, p=0.0259) and with more severe CRS. Low levels of CXCL13 was associated with increased survival (HR 5.97, p=0.029) in the ir-myocarditis cohort (n=19), and low CCL3/high CCL 11 was predictive of increased survival (HR 4.48, p=0.0162) in the ir-pneumonitis cohort (n=25). These early results strongly suggest that distinct and novel immunophenotypes may potentially serve as predictors of irAEs and survival. Studies of a larger validation cohort and characterization of early biomarkers before irAE onset are ongoing.
For an additional study on predictors of immune-related adverse events, read this article by Ostmeyer et al published in JITC.
Comparison of an HPV16-targeting immunotherapeutic vaccine in combination with cemiplimab versus cemiplimab monotherapy for HPV16-positive oropharyngeal cancer
6003. Results of a randomized, double-blind, placebo-controlled, phase 2 study (OpcemISA) of the combination of ISA101b and cemiplimab versus cemiplimab for recurrent/metastatic (R/M) HPV16-positive oropharyngeal cancer (OPC).
Caroline Even (Head and Neck Department, Gustave Roussy, Villejuif, France) reported a phase 2 study of ISA101b (peltopepimut-S), a therapeutic vaccine targeting the HPV16 E6/E7 oncoproteins in combination with the anti-PD-1 immune checkpoint inhibitor cemiplimab. Previous studies indicate that ISA101b induces activation and expansion of T helper cells and CD8+ cytotoxic T cells, thus it was hypothesized that ISA101b combined with an immune checkpoint inhibitor would generate a synergistic anti-tumor response. Patients with recurrent or metastatic HPV16-positive oral pharyngeal cancer (OPC) were assigned 1:1 to receive three doses of ISA101b with cemiplimab every three weeks for up to 24 months (ISA101b arm; n=98) or three doses of placebo with cemiplimab every three weeks for up to 24 months (placebo arm; n=100). The overall response rate (ORR) for the full analysis set (FAS), representing all patients who received one or more dose of ISA101b/placebo, was not significantly different between the two arms, 25.3% in the ISA101b arm and 22.9% in the placebo arms. In the per protocol set (PPS) of patients with centrally confirmed HPV16-positive disease and who received all three doses of IS101b or placebo and no major protocol deviations, the ORR was numerically improved in both treatment arms (38.9% for ISA101b and 27.3% for placebo), but the difference between the two arms was not statistically significant. Among patients with PD-L1-high (CPS >=20), ORR in FAS was significantly higher in the ISA101b arm compared to the placebo arm (51.7% vs. 25.8%, respectively; p=0.062) and in the PPS (70.0% for ISA1b vs. 29.2% for PPS; p=0.014). Overall survival (OS) benefits were also observed among patients with tumors that were PD-L1-high. In FAS ISA101b numerically improved median OS (34.8 months) compared to placebo (28.8 months), but this difference was not statistically significant. In the PPS population, ISA101b was associated with a statistically significant increase in median OS compared to placebo (not reached vs 23.3 months (p=0.0324). Addition of ISA101b to treatment did not increase toxicities; 31.6% of patients in the IS101b arm experienced serious treatment-emergent adverse events, compared to 33.0% of patients in the placebo arm. Although the primary endpoint of the study, ORR, was not met, these results indicate that three full doses of ISA101b combined with cemiplimab is associated with a strong clinical benefit against in patients with OPC that is PD-L1 high. A phase 3 study of IS101b in patients with HPV16-positive recurrent or metastatic OPC that is PD-L1-high is being planned.