S-1 might have potential, PEP02 may not

David H. Ilson, MD, PhD, a medical oncologist with Memorial Sloan-Kettering Cancer Center’s Gastrointestinal Oncology Service and a HemOnc Today editorial board member, said there was little groundbreaking research pertaining to esophageal or gastric cancer presented at this year’s Gastrointestinal Cancers symposium in San Francisco, but results from two studies caught his attention.

In the first study, David Cunningham, MD, consultant medical oncologist and head of the gastrointestinal unit at The Royal Marsden Hospital in the UK, presented phase 2 results from the PEP02 trial. PEP02 is a liposomal irinotecan; researchers previously observed tumor response in 25% of patients in a phase 1 study.

In the study, patients with locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma who had failed at least one prior chemotherapy were assigned to 120 mg/m² PEP02, 300 mg/m² irinotecan or 75 mg/m² docetaxel every 3 weeks.

In the analysis population, there were 41 patients in the PEP02 arm, 43 in the irinotecan arm and 40 in the docetaxel arm.

In the intent-to-treat population, 13.6% of the PEP02 arm had a confirmed response compared with 6.8% for irinotecan and 15.9% in the docetaxel group. Disease control for both PEP02 and irinotecan was 61.4% vs. 54.6% for docetaxel. Cunningham added that PFS and OS were similar among the three groups.

“PEP02 had a similar safety profile to irinotecan, but less neurotoxicity and nail changes than docetaxel,” he said.

Ilson said the conclusions weren’t dramatic because the response rates seemed to favor both PEP02 and docetaxel arms compared with irinotecan. Similarly, toxicities were similar in the PEP02 and docetaxel arms.

“However, at the end result, there were no differences in PFS and OS between the three arms,” he said. “I don’t think the trial establishes liposome-encapsulated irinotecan as a viable new treatment option. The new agent did not improve survival, and did not improve outcomes compared with agents that are already available. It’s not clear where this drug is going to go because we already have comparable alternatives.”

Docetaxel and S-1

Ilson had a slightly more positive opinion on the potential for the oral fluoropyrimidine S-1 based on the results from the START trial comparing first-line therapy with S-1 and docetaxel with S-1 alone. Researchers conducted the prospective, randomized phase 3 trial in Japan and Korea to determine whether the combination could extend OS for patients with advanced gastric cancer.

Patients in the combination arm (n=314) were assigned to 40 mg/m2 IV docetaxel on day 1 along with twice daily 40 mg/m2 S-1 followed by 7 days rest. Patients in the control arm (n=314) were assigned to 28 days of S-1 followed by 14 days rest.

Yeul Hong Kim, MD, PhD, with the Korea University College of Medicine in Seoul, South Korea presented the results. He said the trial was designed to have 90% power to detect an improvement in OS from 300 to 400 days, but the combination only improved median survival to 390 vs. 344 in the control arm (HR=0.88).

Time to progression was superior in the experimental group, 160 days vs. 126 days (HR=0.74). Response rate was 30.3% in the study arm and 18.4% in the control arm.

Multiple lines of therapy

Kim suggested that high usage of extended lines of therapy after disease progression on intitial therapy — he said it was common in Japan and Korea for physicians to assign patients to as many as four lines of chemotherapy — may have affected study results.

Ilson said that the combination arm did not show a survival benefit and, unlike the combination of S-1 and cisplatin, did not appear to be clearly superior to S-1 alone.

However, Ilson said it is often difficult to see a survival benefit in Asian studies because so many patients go on to second- or third-line treatment.

“The trial does establish a better response for S-1 and docetaxel and I think it does represent a potential first-line treatment option for patients who are not candidates for cisplatin,” he said.

Ilson added that it is still unclear whether S-1 will be approved in the US because other studies have shown that S-1 was not superior to conventional 5-FU combined with cisplatin. Further, reductions in toxicity associated with S-1 could be explained by scheduling and dosing issues in the control arms of those studies. – by Jason Harris

Disclosure: Dr. Ilson reports no relevant financial disclosures.