ESMO 2024: Novel Therapies Show Promise in Bladder, Lung, Kidney, and Gastric Cancers
Key Insights
Circulating tumor DNA (ctDNA) clearance may predict favorable outcomes in cisplatin-ineligible bladder cancer (search) patients treated with durvalumab, tremelimumab, and enfortumab vedotin.
AMG 193, a PRMT5 inhibitor, demonstrated antitumor activity in MTAP (search)-deleted advanced solid tumors, including lung and pancreatic (search) cancers, with a manageable safety profile.
Ipilimumab plus nivolumab significantly improved overall survival in non-clear cell renal cell carcinoma (search), particularly in patients with PD-L1 (search) expression.
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 (search), a novel treatment for MTAP (search)-deleted solid tumors, an immunotherapy combination for non–clear cell renal cancer, and first-line combinations with an antibody-drug conjugate in HER2 (search)-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 (search). 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 (search)-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 (search), pancreatic (search), biliary, and non–small cell lung cancers (NSCLC (search)). 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 (search) (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 (search) (RCC). The 12-month overall survival rate was 78.3% with the immunotherapy doublet and 68.3% with standard agents (P = .029). PD-L1 (search) 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 (search)-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.