Immune checkpoint inhibitors (ICI) have been developed in gastric adenocarcinomas and approved in first-line metastatic setting (in combination with chemotherapy) as well as in pretreated patients. Microsatellite instability-high (MSI-H) tumors are predicted to derive high benefit from ICI but data in gastric locations are limited. Here, we describe the case of a 68-year old patient with stage IV MSI-H gastric adenocarcinoma, referred to our center to receive immunotherapy after failure of standard of care (surgery with perioperative platin-based chemotherapy and paclitaxel plus ramucirumab at disease progression). The patient received one injection of durvalumab and tremelimumab and was hospitalized eighteen days after because of occlusive syndrome. The CT scan showed hyperprogression of the lymph nodes and hepatic lesions, compressing the gastric stump. He died few days later. Molecular analyses did not explain this outcome. To our knowledge, this is one of the first reported cases of hyperprogressive disease after combined ICI for a patient with MSI-H tumor. We review the potential causes and discuss the emerging literature regarding predictive factors of hyperprogression in the particular subset of MSI-H patients. If some data were available in retrospective studies, validation of strong predictive factors is needed to avoid such dramatic evolutions.
Background: Since 2000, the combination of three drugs and targeted drugs has further improved the survival of metastatic colorectal carcinoma(mCRC), while the incidence of side effects of triple regimens over grade 3 are much higher than double regimens. Since adjusting the dosage of drugs can't avoid serious toxicity, here we present a new methode of optimizing the scheme by adjusting the time and mode of administration.Methods: TROT is a prospective, open-label, multicentric phase II randomized trial in which unresectable and previously untreated mCRC patients are randomized to receive first-line XELOX followed by XELIRI after disease progression AE bevacizumab(arm A) or these two schemes alternatively use AE bevacizumab of every 2 cycles until disease progression(arm B). The primary endpoint is to compare the efficacy of these two treatment strategies in terms of time to failure of strategy (TFS) and secondary objectives were ORR、DCR、OS and safety. The curative effect will evaluate in every 2 cycles.Results: 66 patients were enrolled.6 patients were lost to follow or fall off. The analysis of curative effect has been evaluated in 31 patients in the arm A and 29 patients in the arm B.ORR was 27.6% in the first-line and 11.5% in the second-line in the arm A vs 67.7% in the arm B (P < 0.001).The DCR was 89.7% in the first-line and 57.7% in the second-line in the arm A vs 100% in the in the arm B (P < 0.001). ETS was 64.5% and DpR was 46% in the arm B. Median TFS was 12.9 months in arm A vs 12.0 months in arm B (P ¼0.735,HR 1.103). Median OS was 20.4 months in arm A vs 18.8 months in arm B (P¼0.712,HR 0.887).Grade !3 AEs occurred in 10 patients (32%)in arm B vs 21 patients (72.4%)in arm A(P<0.001). No treatment-related death was reported. There were significantly lower AEs than current triplet regimens.Conclusions: XELOX/XELIRI alternate regimen AE bevacizumab,compared with first-line XELOX followed by XELIRI after disease progression AE bevacizumab,can improve the effect of tumour shrinkage and significantly reduce treatment-related side effects in mCRC patients with widespread metastasis,and this alternate regimen may become an alternative for patients who can't tolerate the three-drug combination regimen.
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