Blogs

FROM JUNE 6, 2022

Effects of pembrolizumab for specific patient subgroups in KEYNOTE-826

5506. Pembrolizumab + chemotherapy in patients with persistent, recurrent, or metastatic cervical cancer: Subgroup analysis of KEYNOTE-826.

Krishnansu Sujata Tewari (University of California, Irvine) provided analysis of data from the 27-month follow-up of the KEYNOTE-826 clinical trial, with a focus on specific patient subgroups. KEYNOTE-826 showed addition of pembrolizumab (pembro) to standard of care (SOC) chemotherapy (chemo) +/- bevacizumab (bev) provided statistically significant improvements in overall survival (OS; 12-mo rate 74.8% vs 63.6%; HR 0.67) and progression free survival (PFS; 12-mo rate 44.7% v 33.5%; HR 0.65) in patients with persistent, recurrent, or metastatic cancer. Baseline characteristics were evenly distributed between the pembro + chemo +/- bev arm (Pembro Arm; n=308) and the placebo + chemo +/- bev arm (Placebo Arm; n=309). Approximately 88% of patients had a PD-L1 CPS score >= 1. Approximately 48% of patients had received chemoradiotherapy (CRT) only prior to therapy, 30% of patients in each arm had stage II disease at initial diagnosis (FIGO 2009), and approximately 63% received bev during the study. All patients included in analyses from the 27-month follow-up had CPS > 1. Adding pembrolizumab to chemotherapy increased PFS and OS for all subgroups included in the study:

• Median PFS for squamous tumors was 6.9 mos for the Placebo Arm (n=211) vs.10.4 mos for the Pembro Arm (n=236; HR = 0.63); median OS was 14.2 mos for the Placebo Arm vs. 23.5 mos for the Pembro Arm (HR=0.61)
• Median PFS for non-squamous tumors were 8.4 mos for the Placebo Arm (n=98) vs. 11.6 mos for the Pembro Arm (n=71; HR 0.66); median OS was 21.3 mos for the Placebo Arm and not yet reached for the Pembro Arm (HR = 0.76)
• Median PFS for patients who received carboplatin was 7.4 mos for the Placebo Arm (n=249) vs. 10.2 mos for the Pembro Arm (n=246; HR=0.69); median OS was 15.9 mos for the Placebo Arm vs. 21.4 mos for the Pembro Arm (HR=0.69)
• Median PFS for patients who received cisplatin was 8.4 mos for the Placebo Arm (n=59) vs. 15.2 mos for the Pembro Arm (n=61; HR = 0.47); median OS was 21.3 mos for the Placebo Arm and not yet reached for the Pembro Arm (HR = 0.59).
• Median PFS for patients who received Bevacizumab was 10.2 mos for the Placebo Arm (n=193) vs. 15.2 mos for the Pembro Arm (n=196; HR = 0.61); median OS was 24.7 mos for the Placebo Arm (n=193) and not yet reached for the Pembro Arm (n=196; HR=0.63)
• Median PFS for patients who did not receive bevacizumab was 6.2 mos for the Placebo Arm (n=116) vs. 6.3 mos for the Pembro Arm (n=112; HR=0.74); median OS was 12.6 mos for the Placebo Arm and 16.8 mos for the Pembro Arm (HR=0.74)
• Median PFS for patients who received prior CRT only was 6.3 mos for the Placebo Arm (n=118) vs. 10.3 mos for the Pembro Arm (n=125; HR = 0.62); median OS 12.6 mos for the Placebo Arm vs. 21.3 mos for the Pembro Arm (HR = 0.64)
• Median PFS for patients who had not received CRT was 8.4 mos for the Placebo Arm (n=191) vs. 10.4 mos for the Pembro Arm (n=183; HR=0.69); median OS was 19.4 mos for the Placebo Arm and not yet reached for the Pembro Arm (HR=0.71)

The addition of pembro also improved objective response rates for all subgroups. The benefit of pembro was consistent across a broad range of patient subgroups, including histology, platinum use, beva use, and prior CRT exposure. This analysis provides further support for pembro + chemo as the new SOC for persistent, recurrent, or metastatic cervical cancer.

Combination therapies with antibody-drug conjugates for cervical cancer

5507. Tisotumab vedotin (TV) + pembrolizumab (pembro) in first-line (1L) recurrent or metastatic cervical cancer (r/mCC): Interim results of ENGOT Cx8/GOG 3024/innovaTV 205

Ignace Vergote (Belgium and Luxembourg Gynaecological Oncology Group (BGOG), Leuven Cancer Institute, and University Hospital Leuven) presented findings from the ENGOT Cx8/GOG 3024/innovaTV205 trial which explored tisotumab vedotin (TV)-based combination therapy for recurrent or metastatic cervical cancer (r/m cc). TV as an antibody-drug conjugate targeting tissue factor, and MMAE, the payload drug of TV, induces apoptosis of tumor cells. It has been hypothesized that destruction of tumor cells stimulates T cell activation, thus TV could potentially enhance the anti-tumor activity of the immune checkpoint inhibitor pembrolizumab. Results from the dose expansion phase of this trial were reported. The trial consisted of three cohorts: first-line therapy with TV + pembrolizumab (1L TV + pembro, n=32); second- or third-line therapy with TV + pembrolizumab (2L/3L TV + pembro, n=34); first line therapy with TV + carboplatin (1L TV + carbo, n=33). Confirmed objective response rate (ORR) for the 1L TV + Pembro arm at a median follow-up time of 18.8 months was 40.6%. 5 patients (15.6%) achieved complete response (CR), and 8 patients (25.0%) achieved a partial response (PR). Median duration of response has not been determined, and median time to response was 1.4 months. At the 18.8-month follow-up, 7/13 responders had maintained their response. Confirmed ORR for the 2L/3L TV + Pembro arm was 38.2%. 3 (8.8%) patients achieved CR, and 10 (29.4%) achieved PR. Median DOR was 14.0 months, and median time to response was 1.4 months. At the 1- month follow-up, 5/13 responders had maintained their response. Confirmed ORR of the 1L TV + Carbo arm was 54.5%. 4 patients (12.1%) achieved CR, and 14 (42.4%) achieved PR. Median DOR was 8.6 months, and median time to response was 1.4 months. At the 14.6-month follow-up, 5/18 responders had maintained their response. Most treatment emergent adverse events (TEAEs) were grade 1 or 2, and TEAEs that were of special interest to TV included ocular events (dry eye, conjunctivitis), bleeding (anemia and epistaxis), and peripheral neuropathy. These TEAEs were primarily grades 1 or 2 and appeared consistently across all three cohorts. Data from this study suggest that TV-based combination regimens could potentially improve clinical outcomes in first line r/m cc. A clinical trial to evaluate a triple combination therapy (TV + carbo + pembro +/- bevacizumab) in first line r/m cc is ongoing.

 
Dendritic cell vaccination for glioblastoma

2005. Reproducibility of outcomes in sequential trials using CMV-targeted dendritic cell vaccination for glioblastoma.

Kristen A Batich (Duke University Medical Center) reported on three studies to improve the efficacy of dendritic cell (DC) vaccines for primary and recurrent glioblastoma (GBM). In the phase II ATTAC study (n = 12), patients with newly diagnosed GBM received cytomegalovirus (CMV)-specific DC vaccines against the GBM pp65 antigen. Half of the patients received vaccine site preconditioning with tetanus-diptheria (Td) toxoid, and half of the patients received unpulsed DCs at the vaccine site. Median overall survival for the patients that received Td preconditioning was 41.4 months from diagnosis, compared to 18.5 months for the patients who received unpulsed DCs. ATTAC-GM was an expanded cohort trial that included 11 patients receiving CMV DC vaccine with granulocyte-macrophage colony stimulating factor (GM-CSF). At the 5-year follow-up for ATTAC and ATTAC-GM, overall survival (OS) was 33.3% and 36.4%, respectively. 6 long-term survivors from ATTAC (n=2) and ATTAC-GM (n-4) were alive at the 5-year follow-up. Td preconditioning was associated with significant increases in DC migration to draining lymph nodes, and increased DC migration was associated with gains in OS. A similar pattern in Td preconditioning and increased DC migration was also seen in the ELEVATE trial (n=36), a confirmatory validation study assessing Td-mediated DC migration and survival. 3-year OS rates for patients receiving Td was 34%, compared to 6% for patients receiving unpulsed DCs (p=0.026). Median OS for the Td arm was 24 months, compared to 18 months for the unpulsed DC arm. Td pre-conditioning was associated with enhanced pp65 DC vaccine migration. Data from these three sequential trials show that CMV pp65 DC vaccines are safe and effective. Preconditioning with Td is associated with long-term survival and increased migration of DC vaccines, and the benefits of DC migration on clinical outcomes have been shown to be reproducible.

Correlative studies of patient samples before and after treatment of glioblastoma with immune checkpoint inhibitors

2006. Baseline tumor genomic and gut microbiota association with clinical outcomes in newly diagnosed glioblastoma (GBM) treated with atezolizumab in combination with temozolomide (TMZ) and radiation.

Shiao-Pei S. Weathers (The University of Texas MD Anderson Cancer Center) presented results from correlative studies related to a phase I/II study (n=60) that investigating the safety and efficacy of concurrent atezolizumab with radiation therapy and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM). Genomic (whole exome sequencing), transcriptomic (RNA seq), and metagenomic (sequencing of fecal samples) were performed on baseline and post-treatment samples. Pre-treatment tumor mutations were grouped into clusters that correlated with differences in survival. Patients with tumors with EGFR mutations/copy number variants were associated with lower median overall survival (mOS) rates. Patients with PTEN mutations/copy number variants were associated with intermediate mOS. Low tumor mutational burden was associated with higher OS for patients with GB, compared to high tumor mutational burden. Genes associated with lymphocyte activation and immune response, when overexpressed in the tumor, resulted in significantly higher mOS, compared to tumors with underexpressed genes. Analysis of fecal samples showed no differences in species diversity with regards to survival status. Distinct bacteria species were differentially enriched in survivors compared to non-survivors, and some of these species have been associated with response to immune checkpoint blockade in melanoma. Results from this small study suggest that pre-treatment genomic analyses of tumors and/or gut microbiota may have the potential to identify patients with GBM who are more likely to respond to immunotherapy.

Can CD8 and PD-L1 densities and spatial proximities predict immunotherapy outcomes?

2509. Efficacy of anti-PD1/PD-L1 immunotherapy in non–small cell lung cancer is dependent upon Immunoscore IC CD8 and PD-L1 status.

François Ghirnghelli (Georges François Leclerc Cancer Center, Dijon) reported the development of a duplex immunohistocheomstry (IHC) and digital pathology-based analysis of CD8 and PD-L1 double staining to identify prognostic markers for patients with non-small cell lung cancer (NSCLC) who receive PD-(L)1 inhibitors. The staining protocol and analysis allowed for quantification of CD8 and PD-L1 density and spatial proximity. The HDX3 antibody was used for PD-L1 staining, and digital pathology analyses of PD-L1 staining were in concordance with laboratory assessments. Immunoscore IC (IS-IC), an in vitro diagnostic test (CE-IVD), was derived by a multivariate Cox model with five significant covariates: CD8 free of PD-L1, CD8 clusters, CD8 cells in proximity of PD-L1 cells, CD8 number, PD-L1 cells in proximity of CD8 cells. An IS-IC–based model discriminated patients into 2 categories or 3 categories. The training cohort for the models consisted of patients with metastatic NSCLC (n=133) treated with anti-PD-(L)1 at one hospital. The independent evaluation cohort consisted of patients with metastatic NSCLC (n=132) treated with anti PD-(L)1 at two independent care centers. In 2 categories, the IS-IC risk score was significantly associated with patients’ PFS (p < 0.0001) and OS (p < 0.0001) in the training cohort and in the validation cohort (PFS: p = 0.0047, OS: p < 0.0001). Low IS-IC risk score corresponded with short PSF and low OS, and High IS-IC corresponded with prolonged PSF and OS. Independent PD-L1 IHC evaluation in the laboratory on the same cohorts did not yield any significant associations with PSF or OS. These data suggest IS IC is a promising predictive biomarker to identify patients most likely to respond to immune checkpoint inhibitor therapy, but this strategy needs to be further validated in randomized studies for clinical use.

VIGex gene expression profile and circulating tumor DNA as predictive biomarkers for immunotherapy

2510. External validation of the VIGex gene-expression signature (GES) as a novel predictive biomarker for immune checkpoint treatment (ICT).

Alberto Hernando-Calvo (Princess Margaret Cancer Centre) reported on a validation study for VIGex, a 12-gene expression profile of genes involved in immune activation and suppression, as a potential predictive biomarker for treatment with immune checkpoint inhibitors. VIGex classifies samples into Hot, intermediate-Cold (I-Cold) and Cold subgroups. Preliminary studies have shown that the Hot subgroup as defined by VIGex has been associated with better progression free survival (PFS) in patients treated with ICT. Tumor biopsies were sampled from 106 patients from the Phase II INSPIRE trial who were treated with pembrolizumab for a variety of cancers, including triple negative breast cancer, ovarian cancer, metastatic melanoma, head and neck cancer, and other mixed solid tumors. RNAseq was available for samples from 76 patients. VIGex signatures were developed for the samples and classified as Cold (n=9), Intermediate cold (iCold; n=21) or Hot (n=46). VIGex HOT score was significantly associated with benefits in progression-free survival (PFS) and overall survival (OS) in the INSPIRE trial (PFS: p = 0.036, OS: p=0.009). This association with immunotherapy benefit was independent of TMB, PD-L1 levels, and tumor types. VIGex subscores were combined with changes in circulating tumor DNA (ctDNA) levels from baseline to cycle 3. Hot tumors that showed decreased ctDNA in week 3 of treatment were significantly associated with gains in PFS and OS (PFS: HR = 0.49, p = 0.004; OS: HR = 0.43, p < 0.001). Hot tumors with increased ctDNA significantly corresponded with decreased OS (p = 0.015). Of the ten patients that showed complete clearance of ctDNA from baseline to week 3 of treatment, 9 were categorized as Hot in VIGex. VIGex has the potential to be a predictive biomarker for immunotherapy outcomes, independent of PD-L1 levels and TMB and adding changes in ctDNA levels during treatment could improve its predictive power.

Gut microbiota, B cells and tertiary lymphoid structures in the TME, and patient response to immunotherapy

2511. Identifying gut microbial signatures associated with B cells and tertiary lymphoid structures (TLS) in the tumor microenvironment (TME) in response to immune checkpoint blockade (ICB).

Elise F Nassif (The University of Texas MD Anderson Cancer Center) reported on a study that investigated the association of the gut microbiome with tertiary lymphoid structure (TLS) and B cells in the tumor microenvironment (TME) in response to immune checkpoint blockade (ICB). Patient specimens from three randomized phase 2 trials of neoadjuvant treatment with ICB (nivolumab +/- ipilimumab) for melanoma (n=23), non-small cell lung cancer (n=33), and sarcoma (n=17) were analyzed, and patients were categorized as responders (n=22) or non-responder (n=51) based on major pathologic response. Profiling of baseline fecal samples via 16S rRNA gene sequencing from all three cohorts showed no significant difference in microbial diversity or structure in responders vs. non-responders. Ruminococcus species were in significantly higher abundance in the fecal samples of responders vs. non-responders. Transcriptomic signatures of B cells and TLS from tumors at baseline and post-ICB neoadjuvant treatment showed a significant increase in B-cell and TLS signatures in sarcoma and melanoma post-ICB. Sarcoma and melanoma patients with a higher abundance of Ruminococcus species in their fecal samples showed significantly higher levels of B-cell signatures and numerically higher TLS signatures from baseline to post-ICB (B-cell: p = 0.002; TLS: p = 0.052). No changes in B-cell and TLS signatures were observed in sarcoma and melanoma patients with lower abundance of Ruminococcus. These data suggest that the microbiota of the gut may promote migration of B-cells and formation of TLS in the TME, which enhances patient response to ICB. Studies to further characterize the influence of the gut on the TME and ICB response are ongoing.