Ahmad Awada

The NeoRHEA was a single-arm phase 2 study that included patients with estrogen receptor positive / human epidermal factor receptor 2 negative early breast cancer that received 4 cycles of neoadjuvant palbociclib and endocrine therapy. The primary outcome was baseline biomarkers of treatment resistance and secondary outcome was post-treatment transcriptional and epigenetic changes of tumor, immune and stromal cells. E2F targets and G2M checkpoint proliferation-related genes gene sets were enriched in baseline samples from resistant patients., Downregulation of E2F targets and G2M checkpoint post treatment was observed in tumor, endothelial and T cells. Gene Set Enrichment Analyses (GSEA) based on genes residing in the differentially accessible peaks revealed similar effects,. Moreover, decreases in CD8 + CD103+ tissue-resident memory cell marker genes were observed post-treatment and validated by multiplex immunohistochemistry. Our data reveal that treatment with palbociclib and endocrine therapy diminishes adaptive anti-tumor immunity by decreasing T cell proliferation and the presence of tissue-resident memory T cells NCT03065621.

Purpose:IL1 pathway upregulation is implicated in pancreatic ductal adenocarcinoma (PDAC) progression, therapy resistance, and survival. Nadunolimab is an IL1 receptor accessory protein (IL1RAP)–targeting antibody with enhanced antibody-dependent cellular cytotoxicity that blocks IL1α/IL1β signaling. We investigated efficacy and safety of nadunolimab in PDAC, in combination with gemcitabine/nab-paclitaxel (GN).Patients and Methods:Patients with previously untreated locally advanced/metastatic PDAC received nadunolimab (1.0–7.5 mg/kg) every 2 weeks with standard GN. The primary objective was safety; secondary objectives were antitumor response, progression-free survival, and overall survival (OS). Correlations between serum and tumor biomarkers and clinical response were explored.Results:Seventy-six patients were enrolled; the median age was 63 years (range, 43–89), 42% were female, 97% had metastatic disease, and 9% had received adjuvant chemotherapy. The most frequent grade ≥3 adverse event was neutropenia (66%), typically during cycle 1. Infusion-related reactions occurred in 29% (grade 3, 3%). Only 1 of the 76 patients had grade 3 or above peripheral neuropathy. No marked dose-dependent differences in safety or efficacy were observed among the four dose groups. The median OS was 13.2 months (95% confidence interval, 11.0–15.6), and the 1-year survival rate was 58%. The median immune PFS (immune Response Evaluation Criteria in Solid Tumours) was 7.1 months (95% confidence interval, 5.2–7.4). Treatment efficacy was higher in patients with high versus low tumor baseline IL1RAP expression (OS 14.2 vs. 10.6 months; P = 0.012). A reduction in serum IL8 on treatment correlated with prolonged OS.Conclusions:Nadunolimab combined with GN shows promising efficacy and manageable safety in locally advanced/metastatic PDAC. Higher tumor baseline IL1RAP expression correlated with better outcome.

Supplementary methods and results

Purpose: IL1 pathway upregulation is implicated in pancreatic ductal adenocarcinoma (PDAC) progression, therapy resistance, and survival. Nadunolimab is an IL1 receptor accessory protein (IL1RAP)–targeting antibody with enhanced antibody-dependent cellular cytotoxicity that blocks IL1α/IL1β signaling. We investigated efficacy and safety of nadunolimab in PDAC, in combination with gemcitabine/nab-paclitaxel (GN). Patients and Methods: Patients with previously untreated locally advanced/metastatic PDAC received nadunolimab (1.0–7.5 mg/kg) every 2 weeks with standard GN. The primary objective was safety; secondary objectives were antitumor response, progression-free survival, and overall survival (OS). Correlations between serum and tumor biomarkers and clinical response were explored. Results: Seventy-six patients were enrolled; the median age was 63 years (range, 43–89), 42% were female, 97% had metastatic disease, and 9% had received adjuvant chemotherapy. The most frequent grade ≥3 adverse event was neutropenia (66%), typically during cycle 1. Infusion-related reactions occurred in 29% (grade 3, 3%). Only 1 of the 76 patients had grade 3 or above peripheral neuropathy. No marked dose-dependent differences in safety or efficacy were observed among the four dose groups. The median OS was 13.2 months (95% confidence interval, 11.0–15.6), and the 1-year survival rate was 58%. The median immune PFS (immune Response Evaluation Criteria in Solid Tumours) was 7.1 months (95% confidence interval, 5.2–7.4). Treatment efficacy was higher in patients with high versus low tumor baseline IL1RAP expression (OS 14.2 vs. 10.6 months; P = 0.012). A reduction in serum IL8 on treatment correlated with prolonged OS. Conclusions: Nadunolimab combined with GN shows promising efficacy and manageable safety in locally advanced/metastatic PDAC. Higher tumor baseline IL1RAP expression correlated with better outcome.

Purpose We aimed to assess the impact of surgery of primary tumor in overall survival (OS) of women with de novo metastatic breast cancer. Methods Nationwide, population-based retrospective cohort study of women diagnosed with de novo metastatic breast cancer in Belgium, between Jan/2010-Dec/2014. Data was obtained from the Belgian Cancer Registry and administrative databases. “Surgery” group was defined by surgery of primary tumor up to nine months after diagnosis. We excluded women who did not receive systemic treatment or did not complete nine months follow-up after diagnosis. All the subsequent analyses reporting on overall survival and the stratified outcome analyses were performed based on this nine-month landmark cohort. OS was estimated using Kaplan-Meier method and compared using adjusted Cox proportional hazards models controlling for confounders with 95% confidence intervals (CI). We performed a stratified analysis according to surgery timing and a propensity score matching analysis. Results 1985 patients, 534 (26.9%) in the “Surgery” and 1451 (73.1%) in the “No Surgery” group. Patients undergoing surgery were younger (p < 0.001), had better performance status (PS) (p < 0.001), and higher proportion of HER2-positive and triple-negative breast cancer (p = 0.012). Median follow-up was 86.0 months (82.6–88.5). Median OS was 60.1 months (57.1–68.2) in the “Surgery” vs. 41.9 months (39.8–44.2) in the “No Surgery” group (adjusted HR 0.56; 0.49–0.64). OS was similar when surgery was performed upfront or after systemic treatment. Propensity score matching analysis confirmed the same findings. Conclusion Among patients receiving systemic treatment for de novo metastatic breast cancer and surviving nine months or more, those who received surgery of the primary tumor within nine months of diagnosis have longer subsequent survival than those who did not.

Despite important advances in the treatment of metastatic melanoma with the development of MAPK-targeted agents and immune checkpoint inhibitors, the majority of patients either do not respond to therapies or develop acquired resistance. Furthermore, there is no effective targeted therapy currently available for BRAF wild-type melanomas (approximately 50% of cutaneous melanoma). Thus, there is a compelling need for new efficient targeted therapies. Prohibitins (PHBs) are overexpressed in several types of cancers and implicated in the regulation of signaling networks that promote cell invasion and resistance to cell apoptosis. Herein, we show that PHBs are highly expressed in melanoma and are associated with not only poor survival but also with resistance to BRAFi/MEKi. We designed and identified novel specific PHB inhibitors that can inhibit melanoma cell growth in 3D spheroid models and a large panel of representative cell lines with different molecular subtypes, including those with intrinsic and acquired resistance to MAPKi, by significantly moderating both MAPK (CRAF-ERK axis) and PI3K/AKT pathways, and inducing apoptosis through the mitochondrial pathway and up-regulation of p53. In addition, autophagy inhibition enhances the antitumor efficacy of these PHB ligands. More important, these ligands can act in synergy with MAPKi to more efficiently inhibit cell growth and overcome drug resistance in both BRAF wild-type and mutant melanoma. In conclusion, targeting PHBs represents a very promising therapeutic strategy in melanoma, regardless of mutational status.