Robert M. Wenham

A Phase III Study of Pafolacianine Injection (OTL38) for Intraoperative Imaging of Folate Receptor–Positive Ovarian Cancer (Study 006)

PURPOSE The adjunctive use of intraoperative molecular imaging (IMI) is gaining acceptance as a potential means to improve outcomes for surgical resection of targetable tumors. This confirmatory study examined the use of pafolacianine for real-time detection of folate receptor–positive ovarian cancer. METHODS This phase III, open-label, 11-center study included subjects with known or suspected ovarian cancer, scheduled to undergo cytoreductive surgery. The objectives were to confirm safety and efficacy of pafolacianine (0.025 mg/kg IV), given ≥ 1 hour before intraoperative near-infrared imaging to detect macroscopic lesions not detected by palpation and normal white light. RESULTS From March 2018 through April 2020, 150 patients received a single infusion of pafolacianine (safety analysis set); 109 patients with folate receptor–positive ovarian cancer comprised the full analysis set for efficacy. In 33.0% of patients (95% CI, 24.3 to 42.7; P < .001), pafolacianine with near-infrared imaging identified additional cancer on tissue not planned for resection and not detected by white light assessment and palpation, exceeding the prespecified threshold of 10%. Among patients who underwent interval debulking surgery, the rate was 39.7% (95% CI, 27.0 to 53.4; P < .001). The sensitivity to detect ovarian cancer was 83%, and the patient false-positive rate was 24.8%. Investigators reported achieving complete R0 resection in 62.4% (68 of 109) of patients. Drug-related adverse events were reported by 30% of patients (45 of 150) and most commonly included nausea, vomiting, and abdominal pain. No drug-related serious adverse events or deaths were reported. CONCLUSION This phase III study of pafolacianine met its primary efficacy end point, identifying additional cancers not otherwise identified or planned for resection. Pafolacianine may offer an important real-time adjunct to current surgical approaches for ovarian cancer.

Olfactory Receptor OR2H1 Is an Effective Target for CAR T Cells in Human Epithelial Tumors

Abstract Although chimeric antigen receptor (CAR)-expressing T cells have proven success in hematologic malignancies, their effectiveness in solid tumors has been largely unsuccessful thus far. We found that some olfactory receptors are expressed in a variety of solid tumors of different histologic subtypes, with a limited pattern of expression in normal tissues. Quantification of OR2H1 expression by qRT-PCR and Western blot analysis of 17 normal tissues, 82 ovarian cancers of various histologies, eight non–small cell lung cancers (NSCLCs), and 17 breast cancers demonstrated widespread OR2H1 expression in solid epithelial tumors with expression in normal human tissues limited to the testis. CAR T cells recognizing the extracellular domain of the olfactory receptor OR2H1 were generated with a targeting motif identified through the screening of a phage display library and demonstrated OR2H1-specific cytotoxic killing in vitro and in vivo, using tumor cells with spontaneous expression of variable OR2H1 levels. Importantly, recombinant OR2H1 IgG generated with the VH/VL sequences of the CAR construct specifically detected OR2H1 protein signal in 60 human lung cancers, 40 ovarian carcinomas, and 73 cholangiocarcinomas, at positivity rates comparable with mRNA expression and without OR2H1 staining in 58 normal tissues. CRISPR/Cas9-mediated ablation of OR2H1 confirmed targeting specificity of the CAR and the tumor-promoting role of OR2H1 in glucose metabolism. Therefore, T cells redirected against OR2H1-expressing tumor cells represent a promising therapy against a broad range of epithelial cancers, likely with an admissible toxicity profile.

Durvalumab with carboplatin/paclitaxel and bevacizumab followed by durvalumab and bevacizumab with or without olaparib maintenance in newly diagnosed non-BRCA-mutated advanced ovarian cancer

Despite treatment advances in newly diagnosed advanced-stage ovarian cancer (aOC), improved outcomes are needed. DUO-O (NCT03737643), a phase III placebo-controlled trial, enrolled patients with newly diagnosed aOC. Following one cycle of carboplatin/paclitaxel ± bevacizumab, patients without a tumor BRCA mutation (non-tBRCAm) were randomly assigned (1 : 1 : 1) at cycle 2 to carboplatin/paclitaxel plus bevacizumab followed by bevacizumab (control); carboplatin/paclitaxel, bevacizumab plus durvalumab followed by bevacizumab plus durvalumab (durvalumab arm); or carboplatin/paclitaxel, bevacizumab plus durvalumab followed by bevacizumab, durvalumab plus olaparib (durvalumab + olaparib arm). Investigator-assessed progression-free survival (PFS; primary endpoint) was tested for the durvalumab + olaparib arm versus control in the non-tBRCAm homologous recombination deficiency (HRD)-positive and non-tBRCAm intention-to-treat (ITT) populations. One thousand one hundred and thirty patients were randomly allocated to the study. The prespecified interim PFS analysis [data cut-off (DCO): 5 December 2022] qualified as the primary analysis; PFS hazard ratio (HR) for the durvalumab + olaparib arm versus control was 0.49 [95% confidence interval (CI) 0.34-0.69, P < 0.0001; median (m) PFS 37.3 versus 23.0 months] in the non-tBRCAm HRD-positive and 0.63 (95% CI 0.52-0.76, P < 0.0001; mPFS 24.2 versus 19.3 months) in the non-tBRCAm ITT population. For the durvalumab arm versus control, PFS HR was 0.87 (95% CI 0.73-1.04, P = 0.13; mPFS 20.6 versus 19.3 months) in the non-tBRCAm ITT population. At final PFS and interim overall survival (OS) analysis (DCO: 18 September 2023), PFS results were consistent with primary analysis; interim OS HR for the durvalumab + olaparib arm versus control was 0.95 (95% CI 0.76-1.20, P = 0.68; 39.0% maturity) in the non-tBRCAm ITT population. Safety was generally consistent with the profiles of the individual agents. DUO-O met its primary PFS endpoints for first-line durvalumab plus carboplatin/paclitaxel and bevacizumab followed by durvalumab, bevacizumab plus olaparib maintenance versus carboplatin/paclitaxel and bevacizumab followed by bevacizumab in the non-tBRCAm HRD-positive and non-tBRCAm ITT populations. Further insight into long-term benefit is anticipated with additional follow-up.

OTL38 for Intra-operative Imaging of Folate Receptor Positive Ovarian Cancer

This is a phase 3, randomized, multi-center, single dose, open label, pivotal study in patients diagnosed with, or with high clinical suspicion of, ovarian cancer scheduled to undergo primary surgical cytoreduction, interval debulking, or recurrent ovarian cancer surgery.