Expert Point of View: Peter C. Enzinger, MD


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Peter C. Enzinger, MD

Peter C. Enzinger, MD

Gulam A. Manji, MD, PhD

Gulam A. Manji, MD, PhD

Not so FAST? The study discussant Peter C. Enzinger, MD, Director of the Center for Esophageal and Gastric Cancer at Dana-Farber/Brigham and Women’s Cancer Center, Boston, viewed the findings of the FAST trial as promising but voiced several considerations, as did Gulam A. Manji, MD, PhD, Assistant Professor of Medicine at NewYork-Presbyterian/Columbia University Medical Center, New York, in an interview with The ASCO Post.

“The FAST trial has promising initial results, but additional data and some tinkering are required before moving to phase III,” Dr. Enzinger suggested. “I agree this looks promising, but it definitely needs to be repeated,” said Dr. Manji, who noted that population differences have been observed with gastric cancer.

Dr. Enzinger noted that the 7.7-month improvement in survival in CLDN18.2 high expressers compares favorably with that seen in the ToGA trial, where high expressers of HER2 had a 5.2-month improvement in overall survival.1 “But before we declare victory, let’s not forget rilotumumab,” he cautioned. Significant improvements were seen in MET-high patients—but the phase III RILOMET-1 and RILOMET-2 trials,2,3 “unfortunately, were completely negative,” pointed out Dr. Enzinger.

Both specialists were impressed with the outcomes in the high CLDN18.2 expressers but wondered how patients with relatively low levels of CLDN18.2 expression fared. Dr. Manji also wondered about response rates for the high expressers, which were not reported.

Underperformance of Control Arm

Both Drs. Enzinger and Manji pointed out that the FAST control arm seemed to underperform, compared with the comparable EOX arm in the REAL-2 study,4 where median overall survival was 11.2 months vs 8.2 months in the FAST trial; similarly, the response rate was 25%, compared with 47.9% in the REAL-2 study.

“Why did the control arm not measure up? Does it even matter? Should we worry that EOX is not necessarily the best backbone?” Dr. Enzinger questioned, noting that highly emetogenic epirubicin could potentially be contributing to the nausea and vomiting, the primary toxicities of this regimen.

Dr. Manji also wondered why there was a relatively modest improvement in progression-free survival compared with the benefit seen for overall survival, but he pointed out that such discrepancies are common with checkpoint inhibitors.

Looking Ahead

Putting the limitations of the study aside, Dr. Manji concluded, “The thing that excited me is that this is a biomarker-driven study, and that’s fantastic. The investigators were able to enroll almost 50% of the patients they screened, and that’s great. What is so impressive is that for patients with ≥ 70% positive cells, overall survival went from 9 months to 16.7 months.”

Looking ahead, he added, “If IMAB362 showed efficacy in phase III trials, this opens up lots of possibilities. You have a population of patients who can receive trastuzumab [Herceptin], and you have the immunotherapy population, and then this…. What if we could combine them?” ■

Disclosure: Drs. Enzinger and Manji reported no potential conflicts of interest.

References

1. Bang YJ, Van Cutsem E, Feyereislova A, et al: Trastzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA). Lancet 376:687-697, 2010.

2. Cunningham D, Tebbutt NC, Davidenko I, et al: Phase III, randomized, double-blind, multicenter, placebo-controlled trial of rilotumumab plus epirubicin, cisplatin and capecitabine as first-line therapy in patients with advanced MET-positive gastric or gastroesophageal junction cancer: ­RILOMET-1 study. 2015 ASCO Annual Meeting. Abstract 4000. Presented May 31, 2015.

3. Doi T, Kang Y-K, Muro K, et al: A phase 3, multicenter, randomized, double-blind, placebo-controlled study of rilotumumab in combination with cisplatin and capecitabine as first-line therapy for Asian patients with advanced MET-positive gastric or gastroesophageal junction adenocarcinoma: The RILOMET-2 trial. 2015 Gastrointestinal Cancers Symposium. Abstract TPS226.

4. Cunningham D, Starling N, Rao S, et al: Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 358:36-46, 2008.


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