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Platinum-based therapy superior in study of upper GI tumors



A study that aimed to validate intratumoral ERCC1 levels as a predictive marker of platinum sensitivity in upper GI tumors failed to do so, but it did reach one firm conclusion: That platinum therapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) was superior in efficacy to a non–platinum-containing regimen of irinotecan and docetaxel (IT).

Approximately 200 untreated patients with unresectable advanced or metastatic HER2-negative adenocarcinoma of the esophagus, stomach or gastroesophageal junction were evaluated in the phase 2 study for mRNA expression of ERCC1 level and then randomized to either a platinum-containing or non–platinum-containing treatment arm with stratification for ERCC1 level (either low, with levels less than 1.7, or high, meaning 1.7 or more).

In retrospective studies of patients with gastric cancer, levels of gene expression of ERCC1 within the primary tumor have had a significant inverse relationship to response to platinum compounds and overall survival; low ERCC1 expression, in other words, has been associated with higher response rates and better survival. This inverse relationship of expression of the ERCC1 gene and platinum sensitivity has been demonstrated in colon cancer and other tumor types as well.

The problem is, approximately 86% of the patients in this phase 2, randomized study had ERCC1 values lower than 1.7 – many more than the investigators anticipated based on data from prior studies. (They expected a 50-50 distribution, roughly.) The predominance of low ERCC1 mRNA expression meant that evaluation of the ERCC1-high subgroup – and evaluation of interactive effects between ERCC1 expression and treatment type – was limited, said Syma Iqbal, MD, of the University of Southern California, Los Angeles, and coinvestigators.

“Unfortunately, this study did not validate or identify ERCC1 as a predictive marker of platinum sensitivity in upper GI tumors,” they wrote in the Journal of Clinical Oncology. However, “it did support the use of FOLFOX, a platinum-containing regimen, as a standard and superior frontline regimen, compared with the non–platinum-containing IT.”

Across all patients in the FOLFOX arm, the median progression-free survival (PFS) was significantly longer – 5.7 months versus 2.9 months in the IT arm (hazard ratio, 0.71; P = .02). The median overall survival was greater with FOLFOX as well, though this difference – 11.4 months versus 8.7 months – did not reach statistical significance. Similarly, in the ERCC1-low subgroup, the median PFS in patients receiving FOLFOX was statistically superior to IT – 5.9 months versus 2.8 months – and overall survival was better as well, though this latter difference was not statistically significant.

In the ERCC1-high subgroup, the median PFS was similar in the FOLFOX and IT arms (4.7 months vs. 5.3 months), the investigators noted. They plotted PFS within ERCC1 quartiles and found a consistent pattern of improved PFS in the FOLFOX versus IT arm, and “thus, little evidence of differential treatment effects on PFS across ERCC1 levels in this population.”

Regarding safety, the investigators noted, of 91 patients who completed protocol therapy in the FOLFOX arm and were analyzed for adverse events, 3 treatment-related deaths were reported and 9 additional patients experienced grade 4 adverse events. Of 98 patients assessed for adverse events in the IT arm, 3 treatment-related deaths were reported and 14 additional patients experienced grade 4 adverse events.

To be eligible for the study patients had to have a Zubrod performance status of 0-1 and been either treatment naive or have completed adjuvant therapy at least 180 days prior to enrollment.

The study was supported by the National Cancer Institute. Dr. Iqbal reported receiving honoraria from Celgene, Eisai, and F. Hoffmann–La Roche; serving a consulting or advisory role for F. Hoffmann–La Roche; serving on the speakers’ bureau for Celgene and Eisai; and receiving research funding from Bayer and Onyx.

SOURCE: Iqbal S et al. J Clin Oncol. 2019 Dec 9. doi: 10.1200/JCO.19.00925.

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