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Efforts Continue to Optimize Immunotherapy in Gastric Cancer

Danielle Bucco
Published: Wednesday, Jan 10, 2018

David H. Ilson, MD, PhD
David H. Ilson, MD, PhD
The treatment of gastric cancer with immunotherapy continues to be an exciting area of investigation, particularly with the PD-1 inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo).

In the phase III ONO-4538-12 trial, treatment in the third-line or later setting with nivolumab reduced the risk of death by 37% compared with placebo for patients with advanced gastric or gastroesophageal junction (GEJ) cancer. Median overall survival (OS) was 5.32 months with nivolumab versus 4.14 months in the placebo arm (HR, 37%; HR, 0.63; P <.0001).1

Pembrolizumab was approved by the FDA in September 2017 for the treatment of patients with PD-L1–positive recurrent or advanced gastric or GEJ cancer who have received 2 or more lines of chemotherapy. This includes fluoropyrimidine- and platinum-containing chemotherapy, and, if appropriate, HER2/neu-targeted therapy.

However, exploring checkpoint inhbitors in earlier settings remains a challenge. In the phase III KEYNOTE-061 trial, pembrolizumab did not improve survival for PD-L1–positive patients with advanced gastric or GEJ adenocarcinoma in the second-line setting. The PD-1 inhibitor also failed to demonstrate a statistically significant improvement in progression-free survival (PFS).

In an interview during the 2017 OncLive® State of the Science SummitTM on Gastrointestinal Cancers, David H. Ilson, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed practice-changing trials, the optimal available therapies, and how immunotherapy fits into the future treatment paradigm for gastric cancer.*

OncLive: Please provide an overview of your presentation on gastric cancer.

Ilson: One of the most important and potentially practice-changing trials [this past year] was determining the optimal adjuvant therapy for resectable gastric cancer. 

In gastric cancer, perioperative chemotherapy with the regimen ECF [epirubicin, cisplatin, and 5-flourouracil] or ECX [epirubicin, cisplatin, and capecitabine] either administered intravenously or orally was the standard of care for more than 10 years. There was a trial presented at the 2017 ASCO Annual Meeting, which compared standard perioperative ECF or ECX chemotherapy with a regimen combining FLOT [fluorouracil, leucovorin, oxaliplatin, and docetaxel]. Investigators had pilot data for this regimen because we know that a taxane triplet is more active in metastatic disease than a chemotherapy doublet. 

Investigators did a head-to-head comparison of FLOT given every 2 weeks for 4 cycles before surgery and 4 cycles after surgery compared with standard perioperative ECF for 3 pre- and postoperative cycles. The primary endpoint was OS.

We saw preliminary data from the phase II part of the study that indicated that the FLOT regimen had a higher pathologic complete response rate than ECF. This study showed superiority for FLOT at all endpoints. It had a higher curative resection rate by 7% over ECF and it also had a higher complete remission rate of 7% to 8%. The primary endpoint of median OS was improved from 30 months to 50 months. That translated into a survival improvement of about 9% at 5 years. That is a significant benefit over ECF and with improvements in all the other endpoints, which indicates that it probably should be the new standard of care.

The problem is that not all patients can tolerate a 3-drug therapy. The subset analysis indicated that even patients over the age of 65 had benefits, but not all patients are going to be candidates for a taxane triplet regimen. However, this study does displace ECF and should be considered as the new standard of care for perioperative chemotherapy in gastric cancer. 

Tumors of the esophagus and GEJ need the addition of radiation concurrently with preoperative therapy to make sure there is a negative margin. There are some other large studies from the United Kingdom that gave chemotherapy alone, primarily esophagus and GEJ, that had curative resection rates of only about 60%. We know from the Dutch CROSS trial that when you give chemotherapy and radiation, the curative resection rate is around 90%. We may need to add concurrent radiation to chemotherapy in tumors of the esophagus and GEJ, but for more dismal gastric cancers, perioperative chemotherapy with FLOT should be considered the standard.




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