Immunotherapies are becoming increasingly important in the treatment armamentarium of a variety of malignancies. Immune checkpoint inhibitors are the most representative drugs receiving regulatory approval over the past few years. In a recent study published in Clinical Cancer Research, we demonstrated that these agents are being developed faster than other prior anticancer therapies. All checkpoint inhibitors received priority review, being granted with at least one Food and Drug Administration expedited program. Hence, some of them are getting marketing approval after preliminary trials. The model continues to rely on phase I trials, designed with traditional models for dose definition, although a substantial number of patients are treated during the dose expansion cohorts. We demonstrated that efficacy and safety are reasonably predicted from the dose-finding portion of phase I trials with these agents, assuring a low treatment-related mortality for patients throughout the development process. In this article, we further discuss and summarize these findings and update some recent approval information for immune checkpoint inhibitors.

Hundreds of trials are being conducted to evaluate combination of newer targeted drugs as well as immunotherapy. Our aim was to compare efficacy and safety of combination versus single non-cytotoxic anticancer agents. We searched PubMed (01/01/2001 to 03/06/2018) (and, for immunotherapy, ASCO and ESMO abstracts (2016 through March 2018)) for randomized clinical trials that compared a single non-cytotoxic agent (targeted, hormonal, or immunotherapy) versus a combination with another non-cytotoxic partner. Efficacy and safety endpoints were evaluated in a meta-analysis using a linear mixed-effects model (guidelines per PRISMA Report).We included 95 randomized comparisons (single vs. combination non-cytotoxic therapies) (59.4%, phase II; 41.6%, phase III trials) (29,175 patients (solid tumors)). Combinations most frequently included a hormonal agent and a targeted small molecule (23%). Compared to single non-cytotoxic agents, adding another non-cytotoxic drug increased response rate (odds ratio [OR]=1.61, 95%CI 1.40-1.84)and prolonged progression-free survival (hazard ratio [HR]=0.75, 95%CI 0.69-0.81)and overall survival (HR=0.87, 95%CI 0.81-0.94) (all p<0.001), which was most pronounced for the association between immunotherapy combinations and longer survival. Combinations also significantlyincreased the risk of high-grade toxicities (OR=2.42, 95%CI 1.98-2.97) (most notably for immunotherapy and small molecule inhibitors) and mortality at least possibly therapy related (OR: 1.33, 95%CI 1.15-1.53) (both p<0.001) (absolute mortality = 0.90% (single agent) versus 1.31% (combinations)) compared to single agents. In conclusion, combinations of non-cytotoxic drugs versus monotherapy in randomized cancer clinical trials attenuated safety, but increased efficacy, with the balance tilting in favor of combination therapy, based on the prolongation in survival.

Background

The purpose of this study was to determine the prevalence of MET amplification and mutation among GU malignancies and its association with clinical factors and responses to c-MET inhibitors.

Patients and methods

Patients with GU malignancies referred to our Phase I Clinical Trials Program were evaluated for MET mutation and amplification and outcomes using protocols with c-MET inhibitors.

Results

MET amplification was found in 7 of 97 (7.2%) patients (4/27 renal [all clear cell], 1/18 urothelial, and 2/12 adrenocortical carcinoma), with MET mutation/variant in 3 of 54 (5.6%) (2/20 renal cell carcinoma [RCC] [1 clear cell and 1 papillary] and 1/16 prostate cancer). No demographic characteristics were associated with specific MET abnormalities, but patients who tested positive for mutation or amplification had more metastatic sites (median, 4 vs. 3 for wild type MET). Median overall survival after phase I consultation was 6.1 and 11.5 months for patients with and without a MET alteration, respectively (hazard ratio, 2.8; 95% confidence interval, 1.1 to 6.9; P = .034). Twenty-nine (25%) patients were treated according to a c-MET inhibitor protocol. Six (21%) had a partial response (prostate and RCC) and 10 (34%) had stable disease as best response. Median time to tumor progression was 2.3 months (range, 0.4-19.7) for all treated patients with no responses in patients with a MET abnormality or single-agent c-MET inhibitor treatment.

Conclusion

MET genetic abnormalities occur in diverse GU malignancies and are associated with a worse prognosis in a phase I setting. Efficacy of c-MET inhibitors was more pronounced in patients without MET abnormalities and when combined with other targets/drugs.

We sought to investigate the demographics and tumor-associated features in patients with gastroesophageal (GE) malignancies referred to our Phase I Program who had formalin-fixed, paraffin-embedded tissue from archival or new biopsies tested for MET mutation and/or amplification. MET amplification was found in 5 of 76 (6.6%) patients (3/34 [8.8%] esophageal, 2/26 [7.7%] gastric and none in 22 gastroesophageal junction cancers). The only MET mutation detected in 3 of 41 (7.3%) patients was N375S. No demographic and histologic characteristics were associated with specific MET abnormalities. Median overall survival was 3 and 5 months for patients with and without a MET alteration, respectively (hazard ratio [HR] = 2.1; 95% CI, 0.8 to 5.5; P=.14). Sixteen of 81 (20%) patients were enrolled in a c-MET inhibitor trial. Best responses were stable disease in 3 patients (19%), including a patient with esophageal adenocarcinoma that remained on the trial for 9.9 months (wild-type for MET abnormality). All tumors with MET abnormality (n=3) progressed on a c-MET inhibitor in fewer than 2 months. In conclusion, MET abnormalities can be found in a small group of patients with GE adenocarcinoma and further studies are necessary to better characterize the prognostic and predictive impact of MET alterations.