In addition to our in-depth analysis of important clinical trials presented at the European Society for Medical Oncology (ESMO) Congress 2024, there is always room for more coverage from The ASCO Post, including these brief summaries of other presentations of interest. They focus on a potential biomarker in bladder cancer treatment, a novel treatment in 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.
Potential Biomarker in Bladder Cancer Treatment
A recent exploratory analysis of the VOLGA trial safety run-in has revealed significant correlations between circulating tumor DNA (ctDNA) clearance and improved outcomes in cisplatin-ineligible patients with bladder cancer.1
Alexandra Drakaki, MD, PhD
According to lead study author Alexandra Drakaki, MD, PhD, Associate Professor of Hematology/Oncology and Urology Division, David Geffen School of Medicine, UCLA Health, “these findings suggest ctDNA clearance during neoadjuvant therapy may be indicative of favorable outcomes in cisplatin-ineligible patients receiving the combination of the monoclonal antibodies durvalumab and tremelimumab plus the antibody-drug conjugate enfortumab vedotin in the neoadjuvant setting.” Dr. Drakaki, underscored the importance of continued ctDNA collection as part of the main VOLGA trial to further validate these findings. The safety run-in of the global phase III VOLGA trial was consistent of patients with bladder cancer who were cisplatin-ineligible and received this novel three-drug regimen. The analysis presented at the ESMO Congress focused on 17 patients who received at least one cycle of this combination in the neoadjuvant setting, with 14 proceeding to cystectomy. Plasma samples were collected at baseline and prior to surgery for ctDNA analysis using the GRAIL platform.
Key findings from the study showed that ctDNA negativity increased from 37.5% at baseline to 78.6% after neoadjuvant therapy. Of note, said Dr. Drakaki, 7 of 10 patients achieved ctDNA clearance after treatment. Among those with ctDNA clearance, five of seven patients showed pathologic complete response at the time of surgery. Conversely, patients with persistent ctDNA positivity were found to have disease upstaging. One of the most significant outcomes was the association between ctDNA clearance and prolonged event-free survival compared with persistently positive cases.
“This exploratory analysis provides valuable insights into the potential use of liquid biopsies in monitoring treatment response and predicting outcomes in patients with bladder cancer,” Dr. Drakaki concluded. “The integration of ctDNA analysis into treatment protocols may offer a noninvasive method to assess treatment efficacy and potentially adjust therapeutic strategies in real time, ultimately leading to improved care for patients with bladder cancer.”
Novel PRMT5 Inhibitor in MTAP-Deleted Solid Tumors
Adrian Sacher, MD, MMSc, FRCPC
AMG 193, a first-in-class MTA-cooperative PRMT5 inhibitor, demonstrated activity in patients with MTAP-deleted advanced solid tumors in a phase I study presented at an ESMO Presidential Session by Adrian Sacher, MD, MMSc, FRCPC. Dr. Sacher is a thoracic oncologist and affiliate scientist at the Princess Margaret Cancer Centre and Assistant Professor in the Departments of Medicine and Immunology at the University of Toronto.2
“These promising results suggest AMG 193 may offer a new targeted therapeutic approach for patients with MTAP-deleted solid tumors, potentially addressing a significant unmet need in oncology,” commented Dr. Sacher.
AMG 193 targets a specific vulnerability in MTAP-deleted tumors, which occurs in approximately 10% to 15% of cancers, including difficult-to-treat types such as glioblastoma, pancreatic, biliary, and non–small cell lung cancers (NSCLC). Unlike first-generation PRMT5 inhibitors, AMG 193 selectively targets MTAP-deleted tumor cells while sparing normal cells, potentially avoiding dose-limiting hematologic toxicities.
The study enrolled patients with histologically confirmed metastatic or locally advanced solid tumors with MTAP deletion. Key findings included the following:
- Safety Profile: AMG 193 demonstrated an acceptable safety profile, with nausea, vomiting, and fatigue being the most common treatment-related adverse events. Of note, no clinically significant myelosuppression was observed.
- Efficacy: Antitumor activity was observed across various solid tumors. Partial responses were seen in 5 of 17 patients with NSCLC, 5 of 23 patients with pancreatic cancer, 2 of 19 patients with biliary cancer, and 2 of 6 patients with gastroesophageal cancer.
- Durability: In the dose-exploration cohort, the median duration of response was 8.3 months, with a median duration of disease control of 9.2 months.
- Pharmacodynamics: Complete inhibition of tumor SDMA (a marker for PRMT5 activity) was observed at doses of 400 to 480 mg and higher. Greater SDMA reduction in serum was associated with better disease control.
- Biomarkers: ctDNA analysis showed that 83% of patients with stable disease had more than 50% ctDNA reduction, suggesting disease stabilization may be the result of AMG 193’s antitumor activity rather than indolent disease.
- Mechanism of Action: Transcriptomic analysis of paired biopsies revealed significant impact on cell-cycle arrest, attenuation of DNA damage response, and increased alternative splicing events (primarily driven by higher levels of intron retention).
The 1,200 mg once-daily dose is being further evaluated in dose-expansion cohorts. AMG 193 is currently being studied as monotherapy for multiple indications and in combination with standard-of-care therapies for NSCLC and pancreatic cancer.
Ipilimumab/Nivolumab in Non–Clear Cell Renal Cancer
Ipilimumab plus nivolumab significantly improved the 12-month overall survival rate vs standard-of-care therapies in patients with non–clear cell renal cell carcinoma (RCC), meeting the primary endpoint of the phase II SUNNIFORECAST trial.3 At a median follow-up of 24.3 months, the 12-month overall survival rate was 78.3% with doublet immunotherapy and 68.3% with standard agents (P = .029) in the study of 309 patients.
Of note, expression of PD-L1 was important for benefit. The hazard ratio (HR) for overall survival favored the combination arm among patients with a PD-L1 combined positive score (CPS) of at least 1% (HR = 0.56; P = .008) but did not favor this arm among patients with a CPS of less than 1% (HR = 1.33; P = .257).
Lothar Bergmann, MD
“This is the first prospective randomized trial to compare dual checkpoint inhibitor combination therapy with the actual standard of care in non–clear cell RCC,” said Lothar Bergmann, MD, of the JW Goethe University in Frankfurt. “The randomized SUNNIFORECAST trial underlines a relevant clinical benefit of the combination [of ipilimumab and nivolumab] in non–clear cell RCC and may be a new standard in these entities.”
SUNNIFORECAST enrolled patients with metastatic or locally advanced non–clear cell RCC who had not received prior systemic therapy and did not have active central nervous system metastases. They were randomly assigned to receive standard-of-care agents or nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for four cycles followed by nivolumab at 240 mg every 2 weeks or 480 mg every 4 weeks. Most patients in the control arm received a single-agent tyrosine kinase inhibitor, and 17% also received an immunotherapeutic.
The primary endpoint was overall survival rate at 12 months, which if at least 15% would be considered clinically relevant; this was met by the study. At other time points, 6 and 18 months, there were nonsignificant trends favoring nivolumab plus ipilimumab. Median overall survival was 33.2 months and 25.2 months, respectively (P = .163).
Median progression-free survival was approximately 5.5 months in each arm, but objective response rates favored the doublet: 32.8%, with 8.0% complete responses, vs 19.6%, with 1.6% complete responses (P = .001). The higher response rates were observed in patients with papillary, nonpapillary, and chromophobe histologies, Dr. Bergmann noted.
First-Line T-DXd Combinations in HER2-Positive Gastric Cancers
Yelena Y. Janjigian, MD
First-line combinations with the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd) showed efficacy in HER2-positive esophageal, gastric, and gastroesophageal junction (GEJ) cancers in updated results from the phase I/II DESTINY-Gastric03 study, presented at the ESMO Congress by Yelena Y. Janjigian, MD, of Memorial Sloan Kettering Cancer Center, New York.4 Although the study evaluated six different combinations, findings for efficacy and toxicity have led investigators to select a reduced-dose triplet regimen for further evaluation.
DESTINY-Gastric03 evaluated T-DXd alone or in combination with fluoropyrimidine, with or without pembrolizumab. In part 1 of the study, T-DXd plus fluoropyrimidine chemotherapy demonstrated tolerable safety and activity in previously untreated patients. In part 2, a total of 229 patients with unresectable, locally advanced, or metastatic, HER2-positive esophageal, gastric, or GEJ cancer were assigned to one of six treatment groups, which elicited a variety of responses (in parentheses):
- Cohort 1: T-DXd monotherapy at 6.4 mg/kg (49%)
- Cohort 2: T-DXd at 6.4 mg/kg and fluoropyrimidine at the full dose of 1,000 mg/m2 (78%)
- Cohort 3: T-DXd at 6.4 mg/kg, fluoropyrimidine at the full dose of 1,000 mg/m2, and pembrolizumab (58%)
- Cohort 4: T-DXd at 6.4 mg/kg and pembrolizumab (63%)
- Cohort 5: T-DXd at a reduced dose of 5.4 mg/kg, fluoropyrimidine at a reduced dose of 750 mg/m2, and pembrolizumab (59%)
- Cohort 6: The standard-of-care regimen of trastuzumab, fluoropyrimidine, and cisplatin/oxaliplatin (76%).
The highest objective response rate (78%), the study’s primary endpoint, was reported in cohort 2 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. This group also had the longest median progression-free survival, 20 months; median overall survival was 23 months. In the absence of a checkpoint inhibitor, PD-L1 expression was not found to be associated with magnitude of benefit. Toxicities in this cohort included grade ≥ 3 adverse events in 76%. Drug-related interstitial lung disease (ILD) developed in 12% of this cohort, but all were grade 1 or 2.
In cohort 3, where patients were treated with full doses of both T-DXd and fluoropyrimidine plus pembrolizumab, PD-L1 expression was found to be associated with magnitude of benefit. The response rate in patients with CPS ≥ 1 was 70%, but it was 39% in those with a CPS < 1. Median progression-free survival was 14 months vs 6 months, respectively, and median overall survival was 23 months and 16 months.
However, more toxicities were reported in this cohort, with grade ≥ 3 events observed in 91% of patients. Drug-related ILD was seen in 19%, including grade ≥ 3 in 7%, and four patients (9%) experienced treatment-related deaths. Due to these safety findings, Dr. Janjigian commented: “The triplet arm is being explored at lower doses, and so far, it’s well tolerated.” Grade ≥ 3 adverse events in this cohort were seen in 34%, with no treatment-related deaths and no incidence of ILD. The progression-free and overall survival data for this cohort were immature and not reported at the meeting.
“Based on all of these data, there are several studies now planned to evaluate the combination of T-DXd with fluoropyrimidine and immunotherapies in HER2-positive, CPS-positive tumors,” Dr. Janjigian said.
DISCLOSURE: Dr. Drakaki has served as a consultant or advisor to AstraZeneca, Merck, Exelixis, EMD Serono, AVEO, Seagen, Eli Lilly, Silverback Therapeutics, Roche, Genentech, Infinity, Presisca, and Nektar Therapeutics. Dr. Sacher has received institutional research funding from and served as a clinical trial principal investigator for AstraZeneca, Amgen, Genentech, Merck, Lilly, Pfizer, BMS, Spectrum, GSK, Iovance, CRISPR Therapeutics, BridgeBio, HotSpot Therapeutics, and AdaptImmune; has served on an advisory committee (with no personal fees) for Genentech, Amgen, and Merck; and has been reimbursed for travel expenses for clinical trial investigator meetings from Amgen, Merck, and Genentech-Roche. Dr. Bergmann reported no conflicts of interest. Dr. Janjigian owns stock in Inspirna; has received honoraria from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Master Clinician Alliance, Michael J. Hennessy Associates, Merck, Research to Practice, PeerView Institute, AbbVie, AmerisourceBergen, AskGene Pharma, Arcus Biosciences, Basilea Pharmaceutical, Bayer, Clinical Care Options, Eli Lilly, Geneos Therapeutics, GlaxoSmithKline, Guardant Health, HMP Education, Imedex, Imugene, Inspirna, Lynx Health, Merck Serono, Mersana, Paradigm Medical Communications, Pfizer, Seagen, Silverback Therapeutics, Zymeworks, Eisai, Sanofi Genzyme, Ed Med Resources (OncInfo), H.C. Wainwright & Co., Physicians’ Education Resource, LLC, Boehringer Ingelheim, eChinaHealth, Suzhou Liangyihui Network Technology, Talem Healt, TotalCME, and WebMD; served as a consultant or advisor to Pfizer, Merck, Bristol-Myers Squibb, Merck Serono, Daiichi Sankyo, Bayer, Imugene, AstraZeneca, Eli Lilly, Zymeworks, Basilea Pharmaceutical, Michael J. Hennessy Associates, Paradigm Medical Communications, Seagen, AmerisourceBergen, Arcus Biosciences, Geneos Therapeutics, GlaxoSmithKline, Imedex, Lynx Health, Silverback Therapeutics, Mersana Therapeutics, Research to Practice, AskGene Pharma, AbbVie, Astellas Pharma, Guardant Health, Jazz Pharmaceuticals, Clinical Care Options, GlaxoSmithKline, HMP Education, Inspirna, PeerView Institute, Eisai, Sanofi Genzyme, Ed Med Resources (OncLive), H.C. Wainwright & Co., Physicians’ Education Resource, LLC, Boehringer Ingelheim, and WebMD; and has received institutional research funding from Bayer, Bristol-Myers Squibb, Merck, Eli Lilly, NCI, Department of Defense, Cycle for Survival, Fred’s Team, Genentech/Roche, AstraZeneca, Arcus Biosciences, Transcenta, Inspirna, Stand Up To Cancer, and Astellas Pharma.
REFERENCES
1. Drakaki A, Powles TB, Wang Y, et al: Circulating tumor DNA clearance with neoadjuvant durvalumab + tremelimumab + enfortumab vedotin for cisplatin-ineligible muscle-invasive bladder cancer from the safety run-in cohort of the phase III VOLGA trial. ESMO Congress 2024. Abstract 1970MO. Presented September 15, 2024.
2. Sacher AG, Villalona-Calero M, O’Neil BH, et al: Phase I dose escalation and initial dose expansion results of AMG 193: A MTA-cooperative PRMT5 inhibitor, in patients with MTAP-deleted solid tumors. ESMO Congress 2024. Abstract 604O. Presented September 16, 2024.
3. Bergmann L, Ahrens M, Albiges L, et al: Prospective randomised phase II trial of ipilimumab/nivolumab versus standard of care in non-clear cell renal cell cancer: Results of the SUNNIFORECAST trial. ESMO Congress 2024. Abstract LBA75. Presented September 13, 2024.
4. Janjigian YY, Van Laarhoven HW, Rha SY, et al: Trastuzumab deruxtecan monotherapy and combinations in patients with advanced/metastatic HER2-positive esophageal, gastric or gastroesophageal junction adenocarcinoma: DESTINY-Gastric03. ESMO Congress 2024. Abstract 1401O. Presented September 14, 2024.
