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Background: Impaired apoptosis is a common feature of cancer cells and may contribute to chemoresistance. LCL161 is an oral small molecule antagonist of Inhibitor of Apoptosis Proteins (IAPs) that sensitizes a subset of tumors from diverse lineages to treatment with cytotoxic therapies, including paclitaxel. Multiple breast cancer models are sensitive to LCL161 as a single agent and LCL161 acts synergistically with paclitaxel in these models. A phase I study established an LCL161 dose of 1800 mg once weekly as well tolerated, with strong evidence of pharmacodynamic activity at doses ≥320 mg. This ongoing phase Ib study defines the dose limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, and pharmacokinetics (PK) of LCL161 in combination with weekly paclitaxel. Methods: Patients with advanced/metastatic solid tumors were treated with paclitaxel 80 mg/m² each week followed by escalating doses of LCL161 administered once weekly immediately following paclitaxel. PK and biomarker sampling was performed. Results: Thirty-two patients have received LCL161 doses of 600 mg (n = 3), 1200 mg (n = 5), 1500 mg (n = 4), and 1800 mg (n = 20). The most frequent adverse events considered LCL161-related included diarrhea (n = 11; 1 Grade 3), nausea (n = 8), fatigue (n = 7; 2 Grade 3), peripheral neuropathy (n = 6; 1 Grade 3), vomiting (n = 6), decreased appetite (n = 5), alopecia (n = 4), and anemia (n = 4). The principal DLTs were neutropenia, fatigue, and neuropathy. Significant cytokine release syndrome, the DLT of single-agent LCL161, has not been observed likely due to the use of dexamethasone as a premedication. No PK interaction between LCL161 and paclitaxel was observed. RECIST partial responses have been observed in 4 patients with diverse tumor types, including breast cancer. Preliminary antitumor activity in the expansion cohort with breast cancer patients will be presented. Discussion: LCL161 and paclitaxel combination therapy is well tolerated, with manageable toxicities and no evidence of a PK interaction that might interfere with the activity of either agent. Enrollment of additional patients with breast and ovarian cancer into an expansion cohort is ongoing, utilizing an approach to identify those more likely to respond to treatment with IAP antagonists. [ABSTRACT FROM AUTHOR]

Abstract: Cutaneous T-cell lymphoma (CTCL) is a rare cancer of skin-homing T cells. A subgroup of patients develops large cell transformation with rapid progression to an aggressive lymphoma. Here, we investigated the transformed CTCL (tCTCL) tumor ecosystem using integrative multiomics spanning whole-exome sequencing (WES), single-cell RNA sequencing, and immune profiling in a unique cohort of 56 patients. WES of 70 skin biopsies showed high tumor mutation burden, UV signatures that are prognostic for survival, exome-based driver events, and most recurrently mutated pathways in tCTCL. Single-cell profiling of 16 tCTCL skin biopsies identified a core oncogenic program with metabolic reprogramming toward oxidative phosphorylation (OXPHOS), cellular plasticity, upregulation of MYC and E2F activities, and downregulation of MHC I suggestive of immune escape. Pharmacologic perturbation using OXPHOS and MYC inhibitors demonstrated potent antitumor activities, whereas immune profiling provided in situ evidence of intercellular communications between malignant T cells expressing macrophage migration inhibitory factor and macrophages and B cells expressing CD74., Significance: Our study contributes a key resource to the community with the largest collection of tCTCL biopsies that are difficult to obtain. The multiomics data herein provide the first comprehensive compendium of genomic alterations in tCTCL and identify potential prognostic signatures and novel therapeutic targets for an incurable T-cell lymphoma. This article is highlighted in the In This Issue feature, p. 1171., (©2022 American Association for Cancer Research.)