David H. Ilson, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center, discusses the utility of zolbetuximab in claudin-positive gastric cancers.

The claudin-directed antibody zolbetuximab is an interesting drug on the horizon that is now under investigation in an ongoing phase III trial, says Ilson. Claudin is a gap junction protein that is often overexpressed in 70% of gastric cancers, according to Ilson. Provocative phase II data was observed with zolbetuximab when it was combined with chemotherapy in claudin-positive cancers. This approach resulted in a significant survival benefit, particularly in patients with high expression of the protein.

Two randomized trials of zolbetuximab in advanced gastric and gastroesophageal junction (GEJ) cancers are ongoing, adds Ilson. One trial called the ILUSTRO trial, which is evaluating FOLFOX with or without zolbetuximab in patients with high claudin expression. The other trial, SPOTLIGHT, is examining capecitabine and oxaliplatin with or without zolbetuximab in patients with claudin 18.2-positive HER2-negative, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma, concludes Ilson.

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David H. Ilson, MD, PhD, discusses the utility of zolbetuximab in claudin-positive gastric cancers.

Dr. Ilson on the Utility of Zolbetuximab in Claudin-Positive Gastric Cancers

David H. Ilson, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses TKI combinations under investigation in gastric cancer.

The addition of ramucirumab (Cyramza), an anti-VEGF therapy, to second-line chemotherapy with paclitaxel improves outcomes, explains Ilson. A recent publication showed no benefit when ramucirumab was added to chemotherapy in the frontline setting. Other TKIs that target the VEGF pathway, such as regorafenib (Stivarga) and apatinib, are being investigated.

Apatinib was approved in China based on a survival benefit versus best supportive care, says Ilson. The phase III trial conducted in the West, on the other hand, was a negative trial, meaning apatinib will likely not move forward in development, according to Ilson.

Regorafenib remains the subject of ongoing randomized trials compared with best supportive care in patients with refractory gastric cancer. Some preliminary data for the combination of TKIs and checkpoint inhibitors indicate there may be a role for these combinations, concludes Ilson.

David H. Ilson, MD, PhD, discusses TKI combinations under investigation in gastric cancer.

Dr. Ilson on Investigative TKI Combinations in Gastric Cancer

David H. Ilson, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the use of chemotherapy in advanced gastric cancer.

Novel agents have been evaluated in gastric cancer, says Ilson. However, chemotherapy remains a frontline standard of care in the advanced setting. Typically, regimens such as FOLFOX, which consist of a fluoropyrimidine and a platinum-based agent, are given, says Ilson.

Past research efforts have suggested that the addition of taxane chemotherapy to docetaxel, cisplatin, and 5-fluorouracil might improve patient outcomes. However, data from a large Japanese trial showed that the addition of docetaxel to fluoropyrimidine and platinum did not result in better outcomes. As such, fluoropyrimidine and platinum-based chemotherapy continues to be the standard of care, concludes Ilson.

Dr. Ilson on Chemotherapy in Advanced Gastric Cancer

David H. Ilson, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses remaining challenges with immunotherapy in gastric cancer.

A key remaining challenge in gastric cancer is the need for more effective biomarkers to select which patients will benefit most from immunotherapy, says Ilson, as only a small subset of patients with the disease will benefit from this approach.

It is known that patients with microsatellite instablity—high (MSI-H) tumors will typically experience a high degree of benefit from checkpoint inhibitors, but that is not always the case, says Ilson. Some patients with MSI-H tumors will not respond to immunotherapy, and in some cases, a small percentage of patients will experience hyper-progression. When this happens, the patient's tumor will grow even more quickly once exposed to these agents, explains Ilson. 

Currently, MSI and PD-L1 are the only 2 biomarkers that are available in the space, although CPS scores have also been looked at, says Ilson. For example, patients with CPS scores that are 10% or higher might achieve a greater benefit from immunotherapeutics than those whose scores are just 1%, says Ilson. The hunt for more effective biomarkers is not the only thing that will propel the field forward, he adds.

To do that, investigators must examine other avenues to overcome immune suppression. Other targets and newer drugs are also needed, concludes Ilson.

David H. Ilson, MD, PhD, discusses remaining challenges with immunotherapy in gastric cancer.

Dr. Ilson Discusses Challenges with Immunotherapy in Gastric Cancer

David H. Ilson, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses a trial from Germany comparing standard perioperative ECF/ECX chemotherapy with a regimen combining 5-FU (5-fluorouracil) with oxaliplatin and docetaxel.

This trial, presented at the 2017 ASCO Annual Meeting, involved a head-to-head comparison of perioperative docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) for every 2 weeks for 4 cycles before surgery, and 4 cycles after surgery to standard perioperative ECF for typically 3 pre- and 3 postoperative cycles. Pilot data for the regimen were based on the knowledge that taxing triplets are more active in metastatic disease versus a chemotherapy doublet.

The primary endpoint of the study was overall survival (OS), and preliminary data from phase II revealed overall superiority compared with ECF. The FLOT regimen had a higher pathologic complete response rate and curative resection rate of approximately 7%. A 7% to 8% improvement in complete remission rates was also reported.

This new regimen suggests a new standard of care for perioperative chemotherapy in gastric cancer, Ilson concludes.

Dr. Ilson Discusses the Optimal Adjuvant Therapy for Resectable Gastric Cancer

David H. Ilson, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the conclusions of the RTOG 0436 trial, a phase III trial of cisplatin, paclitaxel, and radiation with or without cetuximab in the non-operative treatment of esophageal cancer.

Ilson says results of the study showed that in the non-operative management of esophageal cancer, adding cetuximab to concurrent chemotherapy in radiation does not improve overall survival. It also does not improve the rate of endoscopic complete response, regardless of whether the patients had adenocarcinoma or squamous cancers. The study also showed that good performance status and a smaller tumor size correlates with better outcomes.

The outcome of this study is identical to other reported recent series in the non-operative management of esophageal cancer. Ilson says this supports the use of a regimen of paclitaxel and cisplatin in this subset of patients.

David H. Ilson, MD, PhD

Articles

Dr. Ilson on the Utility of Zolbetuximab in Claudin-Positive Gastric Cancers

Dr. Ilson on Investigative TKI Combinations in Gastric Cancer

Dr. Ilson on Chemotherapy in Advanced Gastric Cancer

Dr. Ilson Discusses Challenges with Immunotherapy in Gastric Cancer

Dr. Ilson Discusses the Optimal Adjuvant Therapy for Resectable Gastric Cancer

Dr. Ilson Discusses the Findings of the RTOG 0436 Trial