Association of disease progression pattern during third-line chemotherapy with nivolumab with poor prognosis in advanced gastric cancer: A multicenter retrospective study in Japan.
Authors: Kadowaki Shigenori , Aoki Masahiko , Suzuki Takeshi , Takahashi Naoki , Shirasu Hiromichi , Ando Takayuki , Yamamoto Yoshiyuki , Kawakami Kentaro , Kito Yosuke , Matsumoto Toshihiko , Shimozaki Keitaro , Miyazaki Yasuhiro , Yamaguchi Toshifumi , Akiyoshi Kohei , Baba Eishi , Makiyama Akitaka , Nakashima Koji , Sugimoto Naotoshi , Nagashima Kengo , Boku Narikazu 
Published: January 2022

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Background: An acceleration of tumor growth during immunotherapy, (hyperprogressive disease [HPD]: defined as >2 times increase in tumor growth rates during nivolumab compared with prior chemotherapy, Champiat S, 2017) has been reported. We reviewed the prevalence and clinical outcomes of HPD in AGC patients treated with nivolumab, and reported that there were no differences either in progression-free survival (PFS) or overall survival (OS) between patients with HPD and those with PD other than HPD (Suzuki T, ASCO Gastrointestinal Cancers Symposium 2020). Then, we hypothesized that PD in unmeasurable lesion (ascites representing peritoneal metastasis) and appearance of new lesions, which are not included in definition of HPD, might have influenced the prognosis of AGC. Methods: The subjects of this retrospective study were 245 AGC patients with measurable disease who received nivolumab after failure of >2 chemotherapy regimens, and their responses were assessed at least 3 times (during prior therapy, before and after nivolumab) in 24 institutions. We explored the impact on prognosis of HPD, new lesion, increase of ascites in AGC patients receiving nivolumab 3 mg/kg or 240 mg/body intravenously every 2 weeks. We divided patients to 4 group according to new lesions at different organ/increase of ascites: Group (G) 1 (-/-), G 2 (+/-), G 3 (-/+), G 4 (+/+). Results: One hundred forty-seven patients (60%) showed PD, and their PFS and OS were 1.5 months(M) and 4.8 M, while those of 41 patients (16.7%) with HPD were 1.4 M and 5.0 M. Fifty-three patients showed appearance of new lesions at different organ and 58 patients showed increase of ascites (31 patients showed both). Survival outcomes of the 4 groups are shown in the Table. Patients with appearance of new lesions at different organ showed shorter prognosis compared with patients without it (median OS: G 2+4 vs G 1+3, 3.3 M vs 7.1 M; hazard ratio [HR], 1.8 [95% CI: 1.2–2.7]; p = 0.003). Also, patients with increase of ascites showed shorter prognosis compared to patients with stable/decrease of ascites (median OS: G 3+4 vs G 1+2, 3.0 M vs 7.8 M; HR, 2.6 [95% CI: 1.8–3.8]; p < 0.001). More of patients with increase of ascites could not receive subsequent chemotherapy after disease progression than others (G 1+2 vs G 3+4, 51.7% [46/89] vs 75.9% [44/58]; p = 0.03). Large tumor size, number of prior lines of chemotherapy, and high neutrophil-to-lymphocyte ratio at baseline were associated with G 4. Conclusions: Appearance of new lesions at different organ and increase of ascites, not HPD, were disease progression pattern associated with poor prognosis in AGC patients receiving nivolumab.[Table: see text]