Discussion
death, toxicity, cancer, PDAC, TTP, tumour
PROLIFERATION, CANCER, TTP, TUMOUR
In the present clinical trial, the efficacy evaluation was conducted in 148 patients of the FAS population, and the median OS was 11.3 months in the GV1001 group and 7.5 months in the control group, with a significant difference (Our study was conducted to confirm the clinical implication of serum eotaxin levels, suggested as predictive markers for improved survival in patients with PDAC who received GV1001 treatment according to the previous subgroup analysis of the TeloVac study [Our study substantiated the relationship between serum eotaxin level and the efficacy of GV1001 treatment in a prospective randomised study. However, not all patients with high serum eotaxin levels presented a favourable response to GV1001. To determine potential biomarkers to predict the response to GV1001 treatment, we conducted a correlative study with serum protein array before treatment. The correlative study suggested MMP-2 and Catenin-alpha1 as potential serological protein markers to predict response to the GV1001 based on patients’ survival. Pretreatment serum levels of MMP-2 and Catenin-alpha1 were significantly related to survivals of the GV1001 group. The activity of MMPs is critical for cancer cells to invade through extracellular matrices. PDAC is characterised by a strong tumour microenvironment and contains many proteases consisting of MMPs [Alteration of T-cell proliferation could be another predictive marker for GV1001. GV1001 can penetrate cell membranes and is endogenously processed by proteasome-mediated degradation followed by Major Histocompatibility Complex mediated surface expression of telomere peptide fragments [In analysing survival data, the most widely used estimation methods of the survival function are the Kaplan–Meier estimation and Cox’s proportional hazard estimation. The log-rank test and Gehan’s generalised Wilcoxon test are often used to test for equality of the survival functions between the treatment and control groups. The outcomes of these estimations and tests are valid only if censoring is random, which is also called the uninformative censoring or independent censoring condition. Random censoring means that the time to censoring is not associated with the time to death. However, informative or dependent censoring can occur when participants are lost to follow-up due to reasons related to the study, such as drug toxicity, patient preference, or inadequate response [This study has some limitations. First, the treatment regimen in the control group was gemcitabine/capecitabine rather than gemcitabine/nab-paclitaxel, which is the current standard gemcitabine-based chemotherapy for PDAC, because of regulatory difficulties in nab-paclitaxel use at the time of initiation of the current clinical trial in Korea. Moreover, there is no evidence that serum eotaxin levels function as a predictive marker to GV1001 efficacy even when used in combination with therapies other than gemcitabine/capecitabine. Further clinical trials to verify the effect of GV1001 using standard chemotherapy as control should be considered. To overcome this limitation, we plan to evaluate the effect of GV1001 in combination with current standard chemotherapy, FOLFORINOX, or a gemcitabine/nab-paclitaxel regimen in a large-scale randomised controlled Phase III clinical trial. The second issue relates to the statistical method used in the survival function estimation under dependent censoring. As mentioned earlier in the main part of the paper, we could not exclude the possibility of dependent censoring, and following the SAP, we used the copula-graphic estimator method in estimating the survival function instead of the Kaplan–Meier method, which is the widely used standard estimation method that is valid only under random censoring situation. The external statisticians verified the specific estimation method used in the paper [In conclusion, GV1001 with GemCap treatment significantly extends the OS and TTP compared to GemCap in patients with advanced PDAC having high serum eotaxin levels, and specific safety-related issues have not been found. Therefore, GV1001 should be considered as one of the options in patients with advanced PDAC having high serum eotaxin levels.