CHICAGO — A novel antibody added to standard chemotherapy extends survival in patients with advanced gastric cancer, according to findings from the phase 2 randomized FAST study.
The first-in-class agent, IMAB362 (Ganymed Pharmaceuticals AG), targets claudin-18 splice variant 2 (CLDN18.2), a tight junction protein that is expressed by a number of cancers, including gastric and gastroesophageal junction adenocarcinoma.
Median overall survival was significantly longer in patients who received IMAB362 than in those who did not (13.2 vs 8.4 months). For patients with the highest levels of CLDN18.2, median overall survival was even longer (16.7 vs 9.0 months).
The study was presented here at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting.
"As claudin 18.2 is abundant in gastric tumors, we estimate that half of all patients with advanced gastric cancer may be candidates for this new treatment," said lead study author Salah-Eddin Al-Batran, MD, a medical oncologist and director of the Institute of Clinical Cancer Research at Nordwest Hospital in Frankfurt, Germany.
"IMAB362 significantly improved overall survival and progression-free survival," said Dr Al-Batran. "IMAB362 plus epirubicin, oxaliplatin, and capecitabine is feasible and was well tolerated."
Results from this study provide a "strong rationale for a confirmatory phase 3 trial," he noted.
Use in Other Cancers?
IMAB362 is a chimeric monoclonal antibody that mediates specific killing of CLDN18.2-positive cancer cells by activating immune effector mechanisms. It has already demonstrated single-agent activity, safety, and tolerability in patients with pretreated gastric cancer
CLDN18.2 is found in a variety of tumors. It is broadly expressed in about 70% to 90% of biliary duct, pancreatic, gastric, and mucinous ovarian cancers, and in about 10% of non-small-cell lung cancers.
It is not expressed in any healthy tissue expect for stomach mucosa, Dr Al-Batran explained.
"Claudin 18.2 is expressed in approximately 50% of cancers, suggesting that this treatment could apply to many patients," said ASCO spokesperson Smitha Krishnamurthi, MD, from University Hospitals in Cleveland.
Improvement in All End Points
The FAST trial involved 161 patients with advanced or recurrent gastric or gastroesophageal junction cancer with CLDN18.2 expression of at least 2+ in at least 40% tumor cells and an ECOG performance status of 0 or 1. None of the patients were eligible for trastuzumab.
All patients received first-line epirubicin 50 mg/m² and oxaliplatin 130 mg/m² on day 1, and capecitabine 625 mg/m² twice daily on days 1 to 21. In addition, 77 patients were randomized to received a loading dose of IMAB362 800 mg/m², then IMAB362 600 mg/m² on day 1. The other 84 patients served as the control group.
The study also involved an exploratory group of 85 patients who received the same first-line chemotherapy regimen plus high-dose IMAB362 (1000 mg/m²). Those results were not presented.
Median progression-free survival was worse in the control group than in the IMAB362 group (4.8 vs 7.9 months; hazard ratio [HR], 0.47; P = .0001). The same was true for median overall survival (8.4 vs 13.2 months; HR, 0.51; P = .0001).
In the subset of patients with very high CLDN18.2 expression (intensity of at least 2+ in at least 70% tumor cells), efficacy was more pronounced. Median progression-free survival was worse for the 59 patients in the control group than for the 57 in the IMAB62 group (5.6 vs 7.2 months; HR, 0.36; P = .005). Again, the same was true for median overall survival (9.0 vs 16.7 months; HR, 0.45; P < .0005).
Objective response rates also favored IMAB62 plus chemotherapy over chemotherapy alone (25% vs 39%).
Complete responses were achieved by more patients in the IMAB62 group than in the control group (3 vs 8), as were partial responses (18 vs 22).
Adverse effects were mostly manageable, said Dr Al-Batran, and the addition of IMAB362 did not significantly increase grade 3/4 events.
The most common IMAB362-related adverse events were vomiting, neutropenia, and anemia. Grade 3/4 neutropenia was higher in the IMAB362 group than in the control group (32.5% vs 21.4%), as were grade 1/2 vomiting (55.8% vs 34.5%) and grade 3/4 vomiting (10.4% vs 3.6%).
Tinkering Needed
This study shows promising improvement in survival with minimal increases in toxicity, said Peter Enzinger, MD, from the Dana-Farber Cancer Institute in Boston.
However, even though the initial FAST results are promising, additional data and some "tinkering" are needed before moving on to phase 3, he explained.
The inclusion criteria for a phase 3 study are also an issue. "And why not include an arm of negative patients to confirm that the mechanism of action is related," Dr Enzinger said.
In addition, because epirubicin is highly emetogenic, whether it is the "the best partner" for IMAB362 needs to be assessed, because nausea and vomiting appear to be the primary toxicity. "Why not FOLFOX or FOLFIRI?" he asked.
Overall, the study showed good survival and low toxicity, but there are some considerations to make before moving to phase 3, Dr Enzinger concluded.
This study received funding from Ganymed Pharmaceuticals AG. Dr Al-Batran reports financial relationships with Merck, Roche, Celgene, Lilly, Nordic Bioscience, Novartis, Vifor Pharma, Medac, and Hospira. Some of his coauthors report relationships with industry, as detailed in the abstract. Dr Krishnamurthi reports receiving research funding from Nektar and Taiho Pharmaceutical. Dr Enzinger reports relationships with Amgen, Pfizer, Merck, Sirtex Medical, and Five Prime Therapeutics.
American Society of Clinical Oncology (ASCO) 2016 Annual Meeting: Abstract LBA 4001. Presented June 6, 2016.
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου