GLIOBLASTOMA
Repeated blood-brain barrier opening with an implantable ultrasound device for delivery of albumin-bound paclitaxel in patients with recurrent glioblastoma: a phase 1 trial
A first-in-human clinical trial demonstrated that low-intensity pulsed ultrasound with concomitant administration of intravenous microbubbles (LIPU-MB), using a novel, skull-implantable ultrasound device, opens the blood-brain barrier, which allows for safe, repeated penetration of cytotoxic drugs into the brain. As a result of these findings, which were published in The Lancet Oncology, a Phase II study was initiated that is currently exploring the combination of LIPU-MB and albumin-bound paclitaxel plus carboplatin (2023; doi: 10.1016/S1470-2045(23)00112-2).
The research team conducted a dose-escalation Phase I clinical trial, which included adults with recurrent glioblastoma who had a tumor diameter of 70 mm or smaller and a Karnofsky performance status of at least 70. After tumor resection, a nine-emitter ultrasound device was implanted into a skull window. LIPU-MB with intravenous albumin-bound paclitaxel infusion was administered to patients every 3 weeks for up to 6 cycles. The researchers evaluated six dose levels of albumin-bound paclitaxel. Seventeen patients-nine men and eight women-were included in the study.
At data cutoff, the median follow-up was 11.89 months. Study authors reported that one patient was treated per dose level of albumin-bound paclitaxel for levels 1-5 (40-215 mg/m2). Twelve patients received dose level six (260 mg/m2). At a dose of 260 mg/m2, the study authors observed encephalopathy (Grade 3) in one of 12 patients during the first cycle, which was considered a dose-limiting toxicity. It also occurred in one other patient during the second cycle (Grade 2). The toxicity was resolved in both cases and treatment continued at a lower dose. Additionally, Grade 2 peripheral neuropathy was reported in one patient during the third cycle of dose level six. The researchers noted that there were no progressive neurological deficits attributed to LIPU-MB. The most common Grade 3-4 treatment-emergent adverse events were neutropenia, leukopenia, and hypertension. During the study, no treatment-related deaths occurred. Imaging analysis revealed blood-brain barrier opening in the regions targeted by LIPU-MB, according to the study authors who reported that this diminished over the first hour following sonication.
AUTHOR COMMENTARY: "This is potentially a huge advance for glioblastoma patients," said lead investigator Adam Sonabend, MD, Associate Professor of Neurological Surgery at Northwestern University Feinberg School of Medicine, in a statement. "While we have focused on brain cancer, this opens the door to investigate novel drug-based treatments for millions of patients who suffer from various brain diseases."
RENAL CELL CARCINOMA
Cabozantinib Plus Nivolumab & Ipilimumab in Renal Cell Carcinoma
Findings from a Phase III, double-blind trial showed that advanced renal cell carcinoma patients with intermediate or poor prognostic risk who were treated with cabozantinib plus nivolumab and ipilimumab had significantly longer progression-free survival compared with those who did not receive cabozantinib (N Engl J Med 2023; doi: 10.1056/NEJMoa2212851). Patients enrolled in this trial had not previously undergone treatment for their disease. They were randomly assigned to receive nivolumab and ipilimumab combined with either 40 mg cabozantinib daily (experimental group) or matched placebo (control group). Nivolumab (3 mg per kilogram of body weight) and ipilimumab (1 mg per kilogram) were given to study participants once every 3 weeks for 4 cycles. Patients were then administered nivolumab maintenance therapy (480 mg once every 4 weeks) for up to 2 years.
Of the 855 randomized patients, 428 were assigned to the experimental group and 427 to the control group. Patients who received the three-drug combination had a 27 percent lower risk of progression or death compared to those who were treated with nivolumab and ipilimumab alone, according to the study authors. The median progression-free survival was not yet reached in the experimental group. Comparatively, data showed a median progression-free survival of 11.3 months for patients in the control group. In terms of safety, the researchers reported Grade 3 or 4 adverse events in 79 percent of patients in the experimental group versus 56 percent in the control group.
AUTHOR COMMENTARY: "This is the first study to evaluate a triplet therapy against a contemporary immune-oncology doublet control, and it was designed to answer an important question of whether adding cabozantinib to dual checkpoint inhibition can improve outcomes for this patient population," said lead author Toni Choueiri, MD, Director of the Lank Center for Genitourinary Cancer at Dana-Farber Cancer Institute, in a press release. "The initial findings provide a clear look at the efficacy and safety profile of this triplet therapy and demonstrate a significant progression-free survival benefit."
MELANOMA
Prior anti-CTLA-4 therapy impacts molecular characteristics associated with anti-PD-1 response in advanced melanoma
New findings suggest that anti-PD-1 response in patients with advanced melanoma is impacted by previous anti-CTLA-4 therapy (Cancer Cell 2023; doi: 10.1016/j.ccell.2023.03.010). The study authors analyzed seven molecular datasets of samples from patients with advanced melanoma (N=514) who underwent treatment with immune checkpoint inhibitors. Clinical, genomic, and transcriptomic features of anti-PD-1 response in cutaneous melanoma were investigated in this analysis.
The study authors reported an association between previous anti-CTLA-4 therapy and differences in genomic, individual gene, and gene signatures in anti-PD-1 responders. Data showed that anti-CTLA-4-experienced melanoma tumors that respond to PD-1 blockade exhibit the following characteristics: increased tumor mutational burden, inflammatory signatures, and altered cell cycle processes.
"The reported, harmonized dataset presented in this study sets a foundation for investigating the heterogeneity of clinical responses to immune checkpoint inhibitors in melanoma," the researcher concluded. "These harmonized molecular and clinical annotation efforts enabled us to focus on specific questions related to anti-PD-1 response in cutaneous melanoma, with the appropriate account of critical clinical and technical batch effects."
AUTHOR COMMENTARY: "Since the current treatment paradigm for melanoma involves combinations or sequential use of immune checkpoint therapies, our study supports how these therapies may work together to effectively treat melanoma," noted co-senior author Antoni Ribas, MD, Director of the Tumor Immunology Program at UCLA Jonsson Comprehensive Cancer Center and the Parker Institute for Cancer Immunotherapy Center at UCLA. "It also highlights the importance of a patient's prior treatment history as a modifying factor to consider when planning a treatment strategy."