Adjuvant docetaxel shows benefit for gastric cancer

CHICAGO — The addition of docetaxel to S-1 after resection extended RFS for patients with stage III gastric, according to results of a phase 3 study conducted in Japan and presented at ASCO Annual Meeting.

Perspective from Christos Fountzilas, MD

Postoperative adjuvant chemotherapy with S-1, an oral fluoropyrimidine, is among the standard treatments for resected stage II/stage III gastric cancer in Asia. However, outcomes for stage III patients remain suboptimal.

“Everyone agrees advanced resectable gastric cancer needs adjuvant therapy, which is chemoradiation in North America,” Yasuhiro Kodera, MD, PhD, professor in the department of gastroenterological surgery at Nagoya University Graduate School of Medicine in Nagoya, Japan, said during his presentation. “But in Asia, the standard remains to be postoperative chemotherapy. This perhaps may be because of the relatively early rate of diagnosis, in which case tumor shrinkage is not always required, and also we preform D2 dissection, which we consider superior in terms of local control.”

Kodera and colleagues evaluated the addition of docetaxel to S-1 among 915 patients from 138 Japanese institutions.

After patients with stage III gastric cancer underwent R0 resection by D2 gastrectomy, researchers randomly assigned them to receive S-1 with (n = 456; 69% men; median age, 66 years) or without (n = 459; 72% men; median age, 66 years) docetaxel. Those in the combination group received 80 mg/kg to 120 mg/kg oral S-1 on days 1-14 followed by 1 week off. For the next six cycles, patients also received 40 mg/m² docetaxel on day 1 of each cycle, followed by four cycles of S-1 on days 1 to 28 every 42 days.

Patients in the control arm received eight cycles of 80 mg/kg to 120 mg/kg oral S-1 on days 1 to 28 every 42 days.

Three-year RFS served as the study’s primary endpoint. Secondary endpoints included OS, time to treatment failure and safety.

Researchers conducted a planned second interim analysis in April 2017 based on 216 events, conducted at a median follow-up of 12.5 months.

The intent-to-treat population included 459 patients in the S-1 arm and 454 in the combination arm.

Results showed significantly more patients in the combination arm achieved 3-year RFS (65.9% vs. 49.5%; HR = 0.63; 99% CI, 0.4-0.99). This benefit occurred for patients with stage IIIa, IIIb and IIIc disease.

Based on these data, the independent data and monitoring committee recommended ending the trial.

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OS data were premature at the time of the analysis.

Researchers observed suppression of hematogenous (5.3% vs. 9.8%), lymphatic (4.8% vs. 11.3%) and peritoneal (9.3% vs. 12.9%) recurrences in the combination arm compared with the S-1 control arm.

Grade 3 or worse leucopenia (22.6% vs. 2%), neutropenia (38.1% vs. 16.1%), febrile neutropenia (4.7% vs. 0.3%), anorexia (14.1% vs. 112.4%) and anemia (4.4% vs. 2.3%) occurred more frequently in the combination arm. However, researchers said the treatment was safe and manageable. One cause of treatment-related death occurred due to respiratory failure in the S-1 group.

“Postoperative S-1/docetaxel was superior to S-1 alone for stage III gastric cancer in the interim analysis,” Kodera said. “There also was a marked reduction in lymphatic and hematogenous recurrences. Addition of docetaxel to S-1 was effective with little safety concerns.” – by Alexandra Todak

Reference:

Kodera Y, et al. Abstract 4007. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.

Disclosures: Kodera reports honoraria from Ajinomoto, Asahi Kasei, Chugai Pharma, Covidien/Medtronic, Eli Lilly, Johnson & Johnson, Kaken Pharmaceutical; Merck, Olympus, Ono Pharmaceutical, Otsuka, Taiho Pharmaceutical, Takeda and Yakult Honsha, and research funding to institution from Abbott, AbbVie, Bristol-Myers Squibb Japan, Chugai Pharma, Covidien, CSL Behring, Daiichi Sankyo, EA Pharma, Japan Blood Products Organization, Kaken Pharmaceutical, Lilly Japan, Maruho, Merck, Novartis, Ono Pharmaceutical, Otsuka, Pfizer, Sanofi, Taiho Pharmaceutical, Takeda, Tsumura & Co and Yakult.

Perspective

Christos Fountzilas, MD

Kodera and colleagues present the results of JACCRO GC-07, a phase 3 study evaluating the efficacy of docetaxel and S-1 vs. S-1 alone in Japanese patients with stage III gastric cancer after D2 resection. The combination therapy significantly improved 3-year DFS.

This study confirms the efficacy of fluoropyrimidine-based therapy as adjuvant treatment for resected gastric cancer. In the ACTS-GC study (S-1 vs. surgery) the 3-year RFS was approximately 70% with S1 —compared with 50% in this trial —but almost half of the patients had stage II disease, so the patient population in this trial is at a much higher risk for relapse. Further, in the CLASSIC study, which evaluated capecitabine/oxaliplatin following resection for stage II/III gastric cancer and was conducted in China, Taiwan and South Korea, the 3-year DFS for the combination therapy was 75%. Interstudy comparisons are always risky, but taking into account the different patient population — mainly inclusion of stage II in CLASSIC study — the results appear similar. It will be interesting to see any future genomic analyses of this study evaluating the benefit of adjuvant therapy. Recently, the CLASSIC investigators published the results of a study evaluating a genomic signature using a real-time polymerase chain reaction assay; patients with epithelial signature benefited from adjuvant therapy while patients with immune signatures did not.

Is this study relevant in the U.S.? Apart from the fact that S-1 is not approved in the U.S., most patients in the U.S. are diagnosed at a more advanced stage compared with patients in Japan, and proximal gastric tumors predominate. The treatment is based on the MAGIC study and, most recently, the FLOT4 study, which utilize perioperative chemotherapy. Further, patients with gastroesophageal junction carcinomas tend to be treated with preoperative chemoradiotherapy.

Finally, novel treatment strategies are urgently needed. Studies evaluating immunotherapy in the adjuvant setting are underway and the results are eagerly waited.

References:

Bang YJ, et al. Lancet. 2012: doi: 10.1016/S0140-6736(11)61873-4.

Cheong JH, et al. Lancet Oncol. 2018;doi: 10.1016/S1470-2045(18)30108-6.

Sakuramoto S, et al. N Engl J Med. 2007;doi:10.1056/NEJMoa072252.

Christos Fountzilas, MD

Roswell Park Comprehensive Cancer Center

Disclosures: Fountzilas reports no relevant financial disclosures.