Novel therapeutic strategies and combinations are showing promise across a spectrum of cancers, according to presentations at the European Society for Medical Oncology (ESMO) Congress 2024. Studies highlighted potential biomarkers in bladder cancer, a novel treatment for MTAP-deleted solid tumors, an immunotherapy combination for non–clear cell renal cancer, and first-line combinations with an antibody-drug conjugate in HER2-positive upper gastrointestinal cancers.
ctDNA Clearance as a Biomarker in Bladder Cancer
An exploratory analysis of the VOLGA trial's safety run-in suggests that circulating tumor DNA (ctDNA) clearance correlates with improved outcomes in cisplatin-ineligible patients with bladder cancer. The study, led by Alexandra Drakaki, MD, PhD, involved 17 patients treated with neoadjuvant durvalumab, tremelimumab, and enfortumab vedotin. ctDNA negativity increased from 37.5% at baseline to 78.6% after neoadjuvant therapy. Notably, 7 of 10 patients achieved ctDNA clearance after treatment, with five of those seven showing a pathologic complete response at surgery. Patients with persistent ctDNA positivity experienced disease upstaging. ctDNA clearance was associated with prolonged event-free survival. Dr. Drakaki emphasized the need for continued ctDNA collection in the main VOLGA trial to validate these findings, stating that ctDNA analysis could offer a noninvasive method to assess treatment efficacy and adjust therapeutic strategies in real time.
AMG 193 in MTAP-Deleted Solid Tumors
AMG 193, a first-in-class MTA-cooperative PRMT5 inhibitor, has demonstrated activity in patients with MTAP-deleted advanced solid tumors, according to a phase I study presented by Adrian Sacher, MD, MMSc, FRCPC. MTAP deletion occurs in approximately 10% to 15% of cancers, including glioblastoma, pancreatic, biliary, and non–small cell lung cancers (NSCLC). AMG 193 selectively targets MTAP-deleted tumor cells, potentially avoiding dose-limiting hematologic toxicities seen with first-generation PRMT5 inhibitors. The study reported an acceptable safety profile, with nausea, vomiting, and fatigue as the most common treatment-related adverse events. Partial responses were observed in NSCLC (5 of 17 patients), pancreatic cancer (5 of 23 patients), biliary cancer (2 of 19 patients), and gastroesophageal cancer (2 of 6 patients). The median duration of response was 8.3 months, with a median duration of disease control of 9.2 months. ctDNA analysis showed that 83% of patients with stable disease had more than 50% ctDNA reduction. Transcriptomic analysis revealed a significant impact on cell-cycle arrest, attenuation of DNA damage response, and increased alternative splicing events. The 1,200 mg once-daily dose is being further evaluated in dose-expansion cohorts, both as monotherapy and in combination with standard-of-care therapies for NSCLC and pancreatic cancer.
Ipilimumab/Nivolumab in Non–Clear Cell Renal Cancer
In the phase II SUNNIFORECAST trial, ipilimumab plus nivolumab significantly improved the 12-month overall survival rate compared to standard-of-care therapies in patients with non–clear cell renal cell carcinoma (RCC). The 12-month overall survival rate was 78.3% with the immunotherapy doublet and 68.3% with standard agents (P = .029). PD-L1 expression was important for benefit, with the hazard ratio (HR) for overall survival favoring the combination arm among patients with a PD-L1 combined positive score (CPS) of at least 1% (HR = 0.56; P = .008). Median overall survival was 33.2 months and 25.2 months, respectively (P = .163). Objective response rates favored the doublet: 32.8% (8.0% complete responses) vs 19.6% (1.6% complete responses) (P = .001). According to Lothar Bergmann, MD, the SUNNIFORECAST trial underlines a relevant clinical benefit of the combination in non–clear cell RCC and may represent a new standard in these entities.
T-DXd Combinations in HER2-Positive Gastric Cancers
Updated results from the phase I/II DESTINY-Gastric03 study indicate that first-line combinations with the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd) show efficacy in HER2-positive esophageal, gastric, and gastroesophageal junction (GEJ) cancers. The highest objective response rate (78%) was reported in patients receiving full doses of T-DXd and fluoropyrimidine. With a median follow-up of 21 months, the median duration of response was 20 months, and the median progression-free survival was 20 months. However, this cohort experienced grade ≥ 3 adverse events in 76% of patients, with drug-related interstitial lung disease (ILD) developing in 12%. A reduced-dose triplet regimen of T-DXd (5.4 mg/kg), fluoropyrimidine (750 mg/m2), and pembrolizumab is being further evaluated due to improved tolerability. Yelena Y. Janjigian, MD, noted that several studies are planned to evaluate the combination of T-DXd with fluoropyrimidine and immunotherapies in HER2-positive, CPS-positive tumors.
