Phase III randomized, double‐blind study of paclitaxel with and without everolimus in patients with advanced gastric or esophagogastric junction carcinoma who have progressed after therapy with a fluoropyrimidine/platinum‐containing regimen (RADPAC)

The RADPAC trial evaluated paclitaxel with everolimus in patients with advanced gastroesophageal cancer (GEC) who have progressed after therapy with a fluoropyrimidine/platinum‐containing regimen. Patients were randomly assigned to receive paclitaxel (80 mg/m2) on day 1, 8 and 15 plus everolimus (10 mg daily, arm B) d1‐d28 or placebo (arm A), repeated every 28 days. Primary end point was overall survival (OS). Efficacy was assessed in the intention‐to‐treat population and safety in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT01248403. Between October 2011 and September 2015, 300 patients (median age: 62 years; median lines prior therapy: 2; 47.7% of patients had prior taxane therapy) were randomly assigned (arm A, 150, arm B, 150). In the intention to treat population, there was no significant difference in progression‐free survival (PFS; everolimus, 2.2 vs placebo, 2.07 months, HR 0.88, P = .3) or OS (everolimus, 6.1 vs placebo, 5.0 months, HR 0.93, P = .54). For patients with prior taxane use, everolimus improved PFS (everolimus, 2.7 vs placebo 1.8 months, HR 0.69, P = .03) and OS (everolimus, 5.8 vs placebo 3.9 months, HR 0.73, P = .07). Combination of paclitaxel and everolimus was associated with significantly more grade 3‐5 mucositis (13.3% vs 0.7%; P < .001). The addition of everolimus to paclitaxel did not improve outcomes in pretreated metastatic gastric/gastroesophageal junction (GEJ) cancer. Activity was seen in the taxane pretreated group. Additional biomarker studies are planned to look for subgroups that may have a benefit.


| INTRODUCTION
The incidence of gastroesophageal cancer ranges around 10 newly diagnosed patients/100000 inhabitants/year in the western hemisphere, and two thirds of patients present with inoperable or metastatic disease. 1,2 Overall 5-year relative survival rates are approximately 20% in most areas of the world.
Chemotherapy is the mainstay of treatment, however, responses are often short and median survival in advanced disease is between 8 and 11 months in non-Asian patients. After failure of standard firstline platinum and fluoropyrimidine-based combination therapy, nearly all patients continue to have disease progression after treatment.
Selected second-line chemotherapy regimens, including irinotecan and taxanes, have been investigated with small increments in survival. [3][4][5][6] Today, the monoclonal antibody VEGFR2 antagonist ramucirumab is the only approved targeted therapy in second-line due to an improvement in overall survival by 2.2 months in combination with Paclitaxel. 7 However, there remains a need for more effective new agents to improve the poor prognosis of patients with advanced gastroesophageal cancer patients in later treatment lines.
The PI3K-Akt-mTOR pathway plays a pivotal role in oncogenesis and progression and is activated in 30% to 60% of human gastric carcinomas. 8,9 Its dysregulation is also associated with chemotherapy What's new?
Patients with advanced gastroesophageal cancer who fail firstline chemotherapy regimens often suffer poor prognosis in later rounds of therapy. A promising therapeutic strategy for these patients entails targeting the PI3K-Akt-mTOR pathway with everolimus. Here, in a randomized, double-blind phase III study, the chemotherapeutic agent paclitaxel was tested with or without everolimus in patients with advanced gastroesophageal cancer. For most patients, everolimus had no significant impact on survival. Survival benefits were observed, however, for certain patient subgroups, namely patients previously treated with taxanes who might not be candidates for paclitaxel and ramucirumab combination therapy after failure of first-line platinum therapy. resistance 8 and decreased survival. [10][11][12] When the current trial was designed, clinical and laboratory evidence indicated a promising potential of targeting the PI3K-Akt-mTOR pathway for efficacious treatment of gastroesophageal cancer. However, in the meanwhile, the Phase III GRANITE trial failed to demonstrate a significant survival benefit of everolimus monotherapy over best supportive care (BSC) in patients with refractory advanced gastric cancer. 13 Paclitaxel was chosen as combination based on single-agent second-line trials. [14][15][16] The combination of everolimus and paclitaxel has been well tolerated in patients with breast cancer and several responses were observed in a heavily pretreated population. 17 Both everolimus and paclitaxel have demonstrated activity against gastric cancer in vitro and in vivo. 9,18 Together, these data provide a rationale for the use of paclitaxel and everolimus in the second-line setting in advanced gastroesophageal cancer.
The Phase III RADPAC trial reports on the efficacy and safety of paclitaxel with or without everolimus in patients with advanced or metastatic gastroesophageal carcinoma who experienced treatment failure after one or more lines of previous chemotherapy.

| METHODS
Our study was an investigator-initiated, prospective, randomized, double-blind, phase III study. It has been registered at ClinicalTrials. gov, identifier NCT2009-01809214. All participants gave written informed consent by the use of forms approved by the ethics committees of participating institutions.

| Patients
Patients were eligible if they had histologically confirmed adenocarcinoma of the stomach or GEJ and had documented disease progression during/after one, two or three prior chemotherapy regimens containing a fluoropyrimidine/Platinum and/or its precursors or derivatives for advanced disease. Additional inclusion criteria included Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2, and adequate organ and hematologic function.
Exclusion criteria included paclitaxel refractory disease, defined as a disease progression within 12 weeks or less of last administration of paclitaxel-based treatment in any treatment line. The appropriate ethics committees at each participating center approved the protocol and all amendments. The study was conducted in accordance with the protocol, the Declaration of Helsinki, and all applicable local regulations. An independent data monitoring committee performed annual safety reviews.

| Study design and assessment
Patients were centrally randomized in a 1:1 fashion to paclitaxel 80 mg/ m 2 on day 1, 8 and 15 and everolimus 10 mg daily d1-d28 or to paclitaxel 80 mg/m 2 on day 1, 8 and 15 and matching placebo daily d1-d28 using an interactive web-response system (IWRS) based on a sequence generated with permuted blocks stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 vs 2), prior taxane use (yes vs no) and treatment line (2 vs 3 or 4 line). The randomization schedule was generated using a validated randomization program and verified for accuracy using strict quality control procedures.
Randomization numbers were linked to the treatment groups, which were in turn linked to medication numbers. The independent data monitoring committee and all individuals involved in the study were blinded to treatment assignment.
Study treatment continued until progression, intolerable toxicity, or consent withdrawal. Further treatment after progression was at the investigator's discretion. The protocol provided guidelines for dose interruptions or reductions for adverse events (AEs). An initial dose reduction to 5 mg/day and a subsequent reduction to 5 mg every other day were permitted. Dose adjustment for certain drugs for specific toxicities were permitted at the investigator's discretion.

| Statistical analysis
All randomly assigned patients were assessed for efficacy following the intent-to-treat principle. Patients were analyzed per the treatment and stratum to which they were assigned on randomization.
Safety was assessed in all patients who received at least one dose of study drug.
The primary efficacy endpoint was overall survival (OS), measured from the date of enrolment into the study to the date of death of any cause. For patients dropping out of the study or lost to follow-up the survival date was censored at the last date known of the patient to be alive. Secondary efficacy end points included PFS, defined as the time from enrolment into the study to the first documented evidence of disease progression or death of any cause; overall response rate (ORR) defined as proportion of patients with complete or partial response and disease control rate (DCR), defined as proportion of patients with complete or partial response or stable disease for at least 12 weeks.
Secondary safety end points included the incidence and severity of adverse events AEs as determined by CTCAE version 4, the discontinuation rate, the dose adjustment rate and tolerability.
Between-arm comparisons of OS were performed using log-rank tests stratified by the three randomization stratifications factors at a twosided cumulative 5% significance level. OS analyses were repeated in several patient subgroups; no interaction test was performed. No   and due to investigators decision (6.0% vs 2.7%; Figure 1).

Baseline characteristics and disease characteristics (ITT population)
of all 300 randomized patients were generally well balanced between treatment groups, although minor differences were observed (Table 1).

| Safety
Seven and three patients in the everolimus and placebo arm did not receive study medication and were excluded from the safety analysis

| DISCUSSION
The randomized double-blind, placebo-controlled RADPAC trial did not demonstrate a significant survival benefit for the addition of everolimus to paclitaxel vs placebo plus paclitaxel in patients with EGC whose disease progressed after one or two lines of previous systemic chemotherapy. In the subgroup analysis, patients with liver involvement seemed to derive a particular benefit from the treatment with everolimus. Comparable findings have been observed in other trials with experimental second-and third-line treatments in GEC, such as the GRANITE-1 trial 13 and the recently presented ANGEL trial 21 with rivoceranib (apatinib) vs placebo in heavily pretreated GEC patients. Both, the GRANITE-1 trial and the ANGEL trial reported improved survival rates (HR 0.79 and 0.64, respectively) if either everolimus or rivoceranib was given instead of placebo, suggesting that for patients with liver involvement and anticipated higher tumor burden, the experimental treatment might be the more effective option. However, this has to be evaluated prospectively in future trials including liver only patients.
Notably, OS was numerically higher with everolimus (6.1 months vs 5.0 months) as was disease control rate (39% vs 30%). Although these trends may be a result of chance alone, comparable increase in activity with everolimus has been described in the GRANITE-1 trial. 13  with everolimus, were more often observed in the experimental arm respectively, leading to an increased rate of dose reduction of everolimus compared to placebo. As a consequence, treatment interruptions were more frequently reported for paclitaxel, as were treatment discontinuations in the combination arm due to toxicity.
Our trial had several limitations. First, the trial stopped recruitment prematurely due to a lower as expected recruitment rate, mainly because of the positive results of the Rainbow trial, establishing paclitaxel in combination with ramucirumab as the new second-line treatment standard in 2014. Furthermore, due to the limited number of taxane-pretreated patients, only a trend toward an improved efficacy with the combination could be observed, however evaluation of taxane re-challenge in combination with everolimus should be assessed in a larger patient population.
We also must state that the initially expected survival rates were overestimated. At the time the study was designed, most data for paclitaxel were derived from Asian trials, where median survival was around 7 months. However, in the western patients, median survivals proved to be lower with paclitaxel. For example, in the Rainbow trial, median survival was 7.4 months in the paclitaxel arm in the whole population. 7 However, in the western population, median survival was 5.9 only for paclitaxel. In addition, many patients had received prior docetaxel in our trial leading to a less favorable study population. However, this issue did not seem to have an impact on the overall results of the trial, as the overestimation of the survival assumptions was done for both arms.
In conclusion, our trial failed to show a significant improvement in efficacy and toxicity in patients with GEC, relative to treatment with paclitaxel alone. However, in taxane-refractory patients, mTOR inhibition in addition to paclitaxel chemotherapy might be a promising therapeutic strategy.