An early study of combination therapy targeting two key pathways involved in solid tumor progression suggested the approach has merit, demonstrating safety and showing signs of efficacy in patients with both advanced or metastatic non small-cell lung cancer (NSCLC) and in those with advanced gastro-esophageal cancer and some activity in bladder cancer as well.
In the non-randomized, phase Ia/b JDVF trial, no unexpected safety findings were observed during the 21-day treatment cycle in the study's initial safety phase with ramucirumab (Cyramza), a vascular epithelial growth factor receptor-2 (VEGFR-2) inhibitor, plus pembrolizumab (Keytruda), the immune checkpoint inhibitor, in either of the three cohorts treated, Roy Herbst, MD, Yale School of Medicine, New Haven, Connecticut, and colleagues reported in The Lancet Oncology.
And, in a subsequent expansion phase, objective responses were seen in 7% of patients with gastric or gastro-esophageal junction adenocarcinomas; 30% of NSCLC patients, and in 13% of urothelial cancer patients, investigators added. All patients received the dual pathway inhibition strategy as second to fourth-line therapy. "The idea is that when you block VEGF, you can enhance dendritic cell presentation of new antigens so theoretically we can enhance the immune response that way," Herbst explained to MedPage Today.
"And while this is an early study, the data in lung and gastric cancer especially look quite promising and hopefully this combination or similar combinations [will be explored] to better enhance immune targeting," he added.
The multicohort, non-randomized, open-label trial involved a total of 92 previously treated patients with advanced or metastatic cancer: 41 with gastric or gastro-esophageal junction adenocarcinoma; 27 with NSCLC, and 24 with urothelial carcinoma.
All patients with the exception of those with gastric or gastro-esophageal junction adenocarcinoma received standard-dose intravenous (IV) pembrolizumab at 200 mg, every 3 weeks, given concurrently with IV ramucirumab at a dose of 10 mg/kg on day 1 of a 21-day cycle. Patients with gastric or gastro-esophageal junction adenocarcinoma received IV ramucirumab at a dose of 8 mg/kg on days 1 and 8. Results from the 21-day treatment cycle evaluating the safety of the combination showed that 24% of the overall cohort developed one or more grade 3 or worse treatment-related adverse events (AEs) -- a rate that was actually similar to rates seen with either drug alone, suggesting that toxicity was not synergistic enhanced.
The most frequent AE was hypertension at 7% followed by colitis at 5%; one patient died of a complication deemed related to the study drug. At median follow-up of 32.8 months (interquartile range 28.1-33.6), 93% of the gastric or gastro-esophageal junction adenocarcinoma group had experienced disease progression and 80% of them had died. For the NSCLC group, 63% of patients had disease progression and 56% of them had died, while for patients with urothelial carcinoma, 88% of patients had disease progression, of whom 75% had died.
Patients with programmed ligand 1 (PD-L1) gastric or gastro-esophageal junction tumors had "numerically higher" antitumor activity outcomes compared with those with PD-L1-negative tumors, as Herbst and colleagues pointed out. For example, the median overall survival was 12.6 months (95% CI 4.7-20.3) in those with PD-L1-positive tumors compared with 5.2 months (95% CI 1.3-8.6), although the difference between the 2 groups was not statistically significant.
Responses seen in the NSCLC cohort, on the other hand, occurred regardless of the patients' PD-L1 status, with a median duration of response not reached by study endpoint. In contrast, the only objective responses observed in the urothelial carcinoma cohort were seen in patients who were positive for PD-L1. However, the group also noted the small sample size in the expansion phase as a limitation to the study.
Herbst said this approach is likely going to be tumor-specific as the results in bladder cancer are not that exciting at the moment.
"In the future, I think we will also need to define biomarker and specific subsets where this works best," he said. However, as Herbst also pointed out, a lot of NSCLC patients are already getting pembrolizumab on its own despite the fact that treatment works well in only about one out of 10 patients, although about one out of 5 patients respond to pembrolizumab monotherapy. "If this combination can improve this response, it would be huge," Herbst said.
Currently, the National Institutes of Health Lung Master Protocol trial has an arm that includes this particular combination so that it is now being more formally and prospectively studied.
Commenting on the findings, editorialists Samuel Klempner, MD, of the Massachusetts General Hospital Cancer Center in Boston, and Zev Wainberg, MD, University of California Los Angeles, called the study well designed and clinically relevant as ramucirumab has already been well studied in different combinations for each tumor type explored in the JDVF trial.
They also felt progression-free survival (PFS) results were "encouraging" given results from previous trials of PD-1 and PD-L1 inhibitors. For example, one study in PD-L1-positive patients with gastric or gastro-esophageal junction adenocarcinomas showed PFS of 2.0 months compared with 4.6 months (95% CI 2.3-8.5 months) in the current JDVF study.
The editorialists also pointed out that several ongoing trials are likely to help define which patients will benefit the most from targeting VEGF plus immune checkpoints. "Overall, it was unclear if the combination of pembrolizumab and ramucirumab was clinically additive or synergistic, although the combination seemed to be safe," Klempner and Wainberg cautioned.
"But as we move toward precision immunotherapy, it is increasingly relevant to understand the patient molecular phenotype, especially in combination studies," they noted.
The study was funded by Eli Lilly and Company and Merck and Co.
Herbst has received honoraria for consulting from Abbvie Pharmaceuticals, ARMO Biosciences, AstraZeneca, Biodesix, Bristol-Myers Squibb (BMS), Eli Lilly, EMD Serrano, Genentech/Roche, Genmab, Halozyme, Heat Biologics, Infinity Pharmaceuticals, Loxo Oncology, Merck, Nektar, Neon Therapeutics, NextCure, Novartis, Pfizer, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, Symphogen, Tesaro, and Tocagen. He also declared having received honoraria for research support from AstraZeneca, Eli Lilly, and Merck; and is a member of the board of directors (non-executive/independent) for Junshi Pharmaceuticals.
Klempner has received honoraria from Foundation Medicine, consultant or advisory fees from Astellas, Eli Lilly, Foundation Medicine, and Boston Biomedical, and holds stock or equity in TP Therapeutics.
Wainberg has received honoraria for consulting from Merck, Bristol-Myers Squibb, Eli Lilly, EMD Serono, and Bayer, as well as research funding from Genentech/Roche, Eli Lilly, Five Prime, AbbVie, BMS, and Novartis.
Tumour vessel normalization and immune checkpoint
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