Tatiana Hernández

PURPOSE: Integrin beta-6 (IB6) is highly expressed in non–small cell lung cancer (NSCLC) and other solid tumors and potentially associated with poor outcomes. Sigvotatug vedotin (SV), a novel IB6-directed antibody-drug conjugate, demonstrated acceptable safety and encouraging antitumor activity in dose escalation. We report updated results for dose-expansion regimens in advanced NSCLC (aNSCLC). METHODS: SGNB6A-001 is an open-label, multicenter, dose-escalation/dose-expansion phase I study evaluating safety, tolerability, pharmacokinetics (PK), and antitumor activity of SV in patients with select advanced solid tumors. After dose escalation, dose expansion further explored three regimens: 1.25 mg/kg total body weight (TBW) on Days 1 and 8 of a 21-day cycle, 1.5 mg/kg TBW on Days 1 and 15 of a 28-day cycle (once every 2 weeks), and 1.8 mg/kg adjusted ideal body weight (AiBW) once every 2 weeks. Eligible patients had prior chemotherapy and immunotherapy or targeted therapy if indicated. Primary end points were safety and determination of an optimal dosing schedule. Secondary end points were antitumor activity, PK, and immunogenicity. RESULTS: As of November 26, 2024, 117 patients with aNSCLC were treated in the above cohorts. Any-grade and grade ≥3 treatment-emergent adverse events occurred in 98% and 48% of all patients, respectively, and in 94% and 35% of patients receiving SV 1.8 mg/kg AiBW once every 2 weeks. Modeling revealed that the AiBW regimen resulted in lower PK variability than TBW regimens. The objective response rate and median duration of response were 19% and 11.3 months in the overall population, respectively, and 29% and 12.8 months in patients with nonsquamous, taxane-naïve NSCLC. CONCLUSION: SV demonstrated a manageable safety profile and promising antitumor activity with durable responses in aNSCLC. PK and clinical data support further investigation with the recommended 1.8-mg/kg AiBW once every 2 weeks dosing regimen.

PURPOSE: Performance status (PS) assessment is used to determine clinical trial eligibility among patients with cancer, but may be inaccurately assessed by oncology clinicians. Wearable accelerometers may allow objective assessment of physical activity, a proxy for PS. In this analysis of two prospective studies, we derive and externally validate objective PS (OPS) by measuring the association between daily physical activity and overall survival among patients with metastatic cancer. MATERIALS AND METHODS: For the derivation cohort, we prospectively measured daily physical activity using a wearable accelerometer among patients with metastatic cancer during the screening period for a phase 1 clinical trial in Spain. We used univariable survival analysis, AUCs, and Youden's index to derive an OPS cutoff in mean daily distance walked. We used a multivariable Cox model to calculate the association between OPS and 180-day mortality. We subsequently externally validated OPS in a separate prospective trial of patients with metastatic lung and GI cancers receiving chemotherapy at a large academic health center in the United States. RESULTS: Full data were available for 123 patients (70 derivation; 53 validation). In the derivation cohort, we defined an OPS cutoff at 1,200 m walked per day. Poor OPS was associated with higher mortality than good OPS in the derivation (180-day mortality, 81.6% v 38.4%; adjusted hazard ratio [aHR], 6.82 [95% CI, 3.44 to 13.5]; P < .001) and external validation cohorts (180-day mortality, 36% v 8%; aHR, 7.07 [95% CI, 1.37 to 36.6]; P = .02). CONCLUSION: OPS is an independent, externally validated prognostic indicator and could serve as an objective surrogate for traditional methods of PS assessment in clinical trials and choice of therapy for patients with cancer.

Supplementary Figure 1: Overall Response Over Time on JNJ-64619178 Treatment A. Dose Cohorts 0.5 mg - 1.5 mg (schedule A&B). B. Dose Cohorts 2.0 mg - 4.0 mg (schedule A&B)

The synergy between SWI/SNF and Polycomb Repressive Complexes (PRCs) has been a topic of extensive research. The demonstrated heightened preclinical sensitivity of SWI/SNF gene mutations to EZH2 inhibition together with the accelerated approval of Tazemetostat for selected EZH2 mutant tumors by the FDA, has significantly expanded our understanding of chromatin remodeling complexes and their vulnerabilities. Here we report a durable response in a patient with PBRM1 mutated cholangiocarcinoma treated with Tazemetostat. We provide hypothesis-generating mechanistic findings into the relationship between PBRM1 mutations and EZH2 inhibition and the interplay between the SWI/SNF and PRC2 complexes.

Graph of % change in PARylated protein (PAR) expression against % change in PSA from baseline (pre-treatment) for olaparib and olaparib plus degarelix cohorts.

Additional RNA sequencing analysis performed from CANCAP03 study.

Figure S3 from Cambridge Neoadjuvant Cancer of the Prostate (CANCAP03): A Window Study into the Effects of Olaparib ± Degarelix in Primary Prostate Cancer

Purpose: The purpose was to investigate combined PARP and androgen inhibition in primary prostate cancer and understand the biological mechanisms underlying clinical efficacy, especially in the absence of mutations in homologous recombination (HR) repair pathways. Patients and Methods: The primary objective was to measure PARP inhibition, and the secondary objectives were to assess safety and feasibility. Participants received olaparib for 2 weeks before prostatectomy and were randomly assigned or not assigned (1:1) to degarelix. We analyzed diagnostic biopsy and radical prostatectomy samples for PARylated protein expression using IHC. Exploratory analyses included tumor gene sequencing, mutation analysis, and RNA sequencing (RNA-seq) using both bulk and single-cell RNA-seq performed on pretreatment and posttreatment tissues. Results: PARylated protein expression was significantly reduced in both cohorts, with no drug-related delays in radical prostatectomy. The gene set enrichment analysis identified distinct treatment response signatures related to olaparib in both cohorts and showed downregulation of androgen response genes after olaparib + degarelix treatment. Transcript profiling revealed an upregulation of the p53 hallmark, which was more pronounced with the combination treatment. Canonical cell-cycle progression hallmarks, including E2F targets and the G2–M checkpoint, were suppressed across all cases, correlating with a HR-deficient transcriptional signature. Single-nuclear RNA-seq indicated a greater increase in inflammatory response pathway activity within tumor epithelia after combination treatment. Conclusions: Transcriptomic analysis identified common hallmark alterations reflecting the combined impact of PARP inhibitor and androgen blockade on cell-cycle progression. We observed a shared phenotypic response to combination therapy across prostate cancers without known HR repair gene alterations. This suggests alternative mechanisms rather than antiandrogen-induced HR deficiency.