Ligand-independent integrin beta1 signaling supports lung adenocarcinoma development

Integrins, the principal extracellular matrix (ECM) receptors of the cell, promote cell adhesion, migration, and proliferation, which are key events for cancer growth and metastasis. To date, most integrin-targeted cancer therapeutics have disrupted integrin-ECM interactions, which are viewed as critical for integrin functions. However, such agents have failed to improve cancer patient outcomes. We show that the highly expressed integrin beta1 subunit is required for lung adenocarcinoma development in a carcinogen-induced mouse model. Likewise, human lung adenocarcinoma cell lines with integrin beta1 deletion failed to form colonies in soft agar and tumors in mice. Mechanistically, we demonstrate that these effects do not require integrin beta1-mediated adhesion to ECM but are dependent on integrin beta1 cytoplasmic tail-mediated activation of focal adhesion kinase (FAK). Together, these studies support a critical role for integrin beta1 in lung tumorigenesis that is mediated through constitutive, ECM-binding independent signaling involving the cytoplasmic tail

Use of meta-analysis of clear cell renal cell carcinoma gene expression to define a variant subgroup and identify gender influences on tumor biology.

412 Background: Clear cell renal cell carcinoma (ccRCC) displays molecular and histological heterogeneity. Previously described subsets of this disease, ccA and ccB, were defined based on multi-gene expression profiles, but it is unclear if these subgroupings reflect the full spectrum of disease or how these molecular subtypes relate to histological descriptions or gender. We sought to determine whether additional subtypes of ccRCC exist, and whether these subtypes are related to VHL inactivation, HIF1/HIF2 expression, tumor histology, or gender. Methods: Six large publically available ccRCC gene expression databases were identified that cumulatively provided data for 480 tumors for meta-analysis via meta-array compilation. Unsupervised consensus clustering was performed on the meta-arrays. Tumors were examined for the relationship of multigene-defined consensus subtypes and expression signatures of VHL mutation and HIF status, tumor histology, and gender. Results: Two dominant subsets of ccRCC were observed. However, a minor third cluster was revealed which correlated strongly with a wild type VHL expression profile and indications of variant histologies. When variant histologies were removed, ccA tumors naturally divided by gender. This technique is limited by potential for persistent batch effect, tumor sampling bias, and restrictions of annotated information. Conclusions: ccA and ccB subsets of ccRCC are robust in meta-analysis among histologically conventional ccRCC tumors. A third group of tumors was identified, which may represent a new variant of ccRCC. Within definitively clear cell tumors, gender may delineate tumors in such a way that could have implications regarding current treatments and future drug development. </jats:p

Optimal treatment by invoking biologic clusters in renal cell carcinoma (OPTIC RCC).

TPS742 Background: The first-line treatment for metastatic clear cell renal cell carcinoma (mccRCC) includes an immuno-oncology (IO) based combination. The current standard regimens include a PD-1 inhibitor plus either (1) an anti-CTLA-4 inhibitor (IO/IO), or (2) an anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) (IO/TKI). Currently, there is no level 1 evidence to guide physician’s choice between an IO/IO versus IO/TKI combination. The phase III IMmotion 151 trial performed RNA-seq from 823 ccRCC tumors and established seven biologically distinct gene expression clusters of ccRCC (Motzer and Rini et al., Cancer Cell 2020). The seven clusters showed differential responses to immune checkpoint inhibitor and may serve as a predictive biomarker to select frontline treatment. Methods: This trial is a phase II, multicenter study using the established biologic clusters to assign patients with mccRCC to either an IO/IO (ipilimumab/nivolumab) or an IO/TKI (nivolumab/cabozantinib) regimen. Patients diagnosed with mccRCC without prior systemic therapy (including in the neoadjuvant or adjuvant setting) and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. RNA-seq will be performed on metastatic tumor specimens and used to assign tumor clusters. Patients with cluster 1/2 tumors will be assigned to the nivolumab/cabozantinib arm; patients with cluster 4/5 tumors will be assigned to the ipilimumab/nivolumab arm. Cluster 3/6/7 will be excluded. The primary endpoint is overall response rate (ORR) per RECIST 1.1. The hypothesis is that use of tumor clusters to assign front-line therapy to either nivolumab/cabozantinib or ipilimumab/nivolumab will lead to a 20% greater ORR compared to unselected historical controls in CheckMate 9ER (ORR: 55%) or CheckMate 214 (ORR: 40%). This trial adopts Simon’s MiniMax two-stage design (power: 80%, one-sided α: 0.1). For the nivolumab/cabozantinib arm, stage I will enroll 12 eligible patients. If there are 7 or more responders in the first 12 patients, the trial will continue for stage II to enroll additional 14 patients (total n=26). The primary endpoint will be met if there are 18 or more responders (ORR ≥75%). For the ipilimumab/nivolumab arm, stage I will enroll 16 eligible patients. If there are 7 or more responders in the first 16 patients, the trial will continue for stage II to enroll additional 12 patients (total n=28). The primary endpoint will be met if there are 15 or more responders (ORR ≥60%). Key secondary endpoints include progression-free survival (PFS), depth of response&gt;80%, and rate of immune-related adverse events (irAEs). This trial is funded by the Department of Defense Kidney Cancer Research Program Clinical Trial Award (W81XWH-22-1-1033) (NCT05361720). Clinical trial information: NCT05361720 . </jats:p

Association between on-treatment eosinophil dynamics and outcomes in metastatic renal cell carcinoma patients treated with ipilimumab/nivolumab.

364 Background: Baseline neutrophil to eosinophil ratio (NER) has been associated with response to immunotherapy in metastatic renal cell carcinoma (mRCC). The association of on-treatment changes in NER and absolute eosinophil count (AEC) during induction with ipilimumab/nivolumab and relation to clinical outcomes are reported. Methods: Patients with mRCC treated with ipilimumab/nivolumab at Vanderbilt-Ingram Cancer Center were identified. Contal and O’Quigley’s method was used to determine the optimal cutpoint associated with improved progression free survival (PFS) and overall survival (OS). Multivariable Cox proportional hazard function was used to assess the association between clinical outcomes and on treatment (week 3/6/9/12) maximum AEC and lowest NER, separately. Results: 63 patients were identified: 81% clear cell histology and 79% male; 24% IMDC favorable risk, 52% intermediate risk, and 24% poor risk. When maximum AEC was coded as a continuous variable, every increase of 100 AEC was associated with improved PFS (HR: 0.89, p-value: 0.017) and OS (HR: 0.87, p-value: 0.053). When the on treatment maximum AEC was dichotomized at the optimal cutpoint of 380 cells/µL, patients with maximum AEC ≥ 380 cells/µL had longer PFS (mPFS: 11.5 months vs 2.7 months, p-value: 0.001) and OS (mOS: 29.6 months vs 16.8 months, p-value: 0.08). When on treatment lowest NER was dichotomized at the optimal cutpoint of 13.2, patients with lowest NER &lt;13.2 had improved PFS (mPFS: 12.5 months vs 2.7 months, p-value:&lt;0.001) and OS (mOS: non-reached vs 16.5 months, p-value: 0.003). After baseline characteristic adjustment (Table), higher on treatment AEC was associated with improved PFS (HR: 0.38, p-value: 0.004), and lower on treatment NER was associated with improved PFS (HR:0.34, p-value:0.002) and OS (HR: 0.38, p-value: 0.036). Conclusions: Higher AEC and low NER while on treatment are associated with improved clinical outcomes in ipilimumab/nivolumab-treated patients with mRCC. Prospective study is warranted to validate these biomarkers.[Table: see text] </jats:p