Makito Miyake1, Takuto Shimizu2, Nobutaka Nishimura2, Keisuke Kiba3, Fumisato Maesaka4, Yuki Oda5, Akira Tachibana6, Mitsuru Tomizawa7, Chihiro Ohmori8, Yoshiaki Matsumura8, Kazuki Ichikawa9, Shinichiro Mizobuchi10, Takanosuke Yoshikawa11, Shunta Hori2, Yosuke Morizawa2, Daisuke Gotoh2, Yasushi Nakai2, Satoshi Anai2, Kazumasa Torimoto2, Katsuya Aoki2, Nobumichi Tanaka12, Kiyohide Fujimoto2. 1. Department of Urology, Nara Medical University, Kashihara, Nara, Japan. Electronic address: makitomiyake@yahoo.co.jp. 2. Department of Urology, Nara Medical University, Kashihara, Nara, Japan. 3. Department of Urology, Kindai University Nara Hospital, Ikoma, Nara, Japan. 4. Department of Urology, Nara City Hospital, Nara, Japan. 5. Department of Urology, Nara Prefecture Seiwa Medical Center, Nara, Japan. 6. Department of Urology, Osaka Kaisei Hospital, Yodogawa, Osaka, Japan. 7. Department of Urology, Yamatotakada Municipal Hospital, Yamatotakada, Nara, Japan. 8. Department of Urology, Nara Prefecture General Medical Center, Nara, Japan. 9. Department of Urology, Koseikai Takai Hospital, Tenri, Japan. 10. Department of Urology, Tane General Hospital, Osaka, Japan. 11. Department of Urology, Matsusaka Chuo General Hospital, Matsusaka, Mie, Japan. 12. Department of Urology, Nara Medical University, Kashihara, Nara, Japan; Department of Prostate Brachytherapy, Nara Medical University, Kashihara, Nara, Japan.
Abstract
INTRODUCTION: Response to pembrolizumab after first-line chemotherapy is vital to prolonged survival in advanced, unresectable, and/or metastatic urothelial carcinoma (aUC). However, there are sparse clinical data on host-tumor immune modification by first-line platinum-based chemotherapy. This study investigated the association between response to first-line gemcitabine plus cisplatin (GC) or carboplatin (GCarbo) chemotherapy and response to subsequent pembrolizumab treatment. PATIENTS AND METHODS: A multicenter-derived database registered 454 patients diagnosed with aUC between 2008 and 2020. Of these, 108 patients who received first-line GC or GCarbo followed by second-line or later pembrolizumab were eligible for investigation and were classified into 3 groups: 48 receiving full-dose GC, 21 receiving dose-reduced GC, and 39 receiving GCarbo. Overall survival (OS) was calculated using the Kaplan-Meier method and compared using the log-rank test. Possible factors associated with the response to pembrolizumab were evaluated using binary logistic regression methods. RESULTS: The rate of patients undergoing surgical removal of the primary organ was higher and creatinine clearance was lower in the dose-reduced GC and GCarbo groups than in the full-dose GC groups. Pembrolizumab responders had significantly better survival benefits than nonresponders. The rate of pembrolizumab responders was much higher in first-line chemotherapy responders than in first-line chemotherapy nonresponders. In contrast to the full-dose GC and GCarbo groups, the pembrolizumab responder rate was lower, and no association was observed between response to first-line chemotherapy and response to pembrolizumab in the dose-reduced GC group. CONCLUSION: Cisplatin and carboplatin may play an important role in the antitumor immune response, which could impact the outcome of subsequent pembrolizumab treatment. Given that the rate of response to pembrolizumab after dose-reduced GC chemotherapy was relatively low, this regimen is not recommended for cis-unfit patients with aUC. Further studies are required to understand the mechanisms responsible for the cross-reactivity of platinum and immune checkpoint inhibitors.
INTRODUCTION: Response to pembrolizumab after first-line chemotherapy is vital to prolonged survival in advanced, unresectable, and/or metastatic urothelial carcinoma (aUC). However, there are sparse clinical data on host-tumor immune modification by first-line platinum-based chemotherapy. This study investigated the association between response to first-line gemcitabine plus cisplatin (GC) or carboplatin (GCarbo) chemotherapy and response to subsequent pembrolizumab treatment. PATIENTS AND METHODS: A multicenter-derived database registered 454 patients diagnosed with aUC between 2008 and 2020. Of these, 108 patients who received first-line GC or GCarbo followed by second-line or later pembrolizumab were eligible for investigation and were classified into 3 groups: 48 receiving full-dose GC, 21 receiving dose-reduced GC, and 39 receiving GCarbo. Overall survival (OS) was calculated using the Kaplan-Meier method and compared using the log-rank test. Possible factors associated with the response to pembrolizumab were evaluated using binary logistic regression methods. RESULTS: The rate of patients undergoing surgical removal of the primary organ was higher and creatinine clearance was lower in the dose-reduced GC and GCarbo groups than in the full-dose GC groups. Pembrolizumab responders had significantly better survival benefits than nonresponders. The rate of pembrolizumab responders was much higher in first-line chemotherapy responders than in first-line chemotherapy nonresponders. In contrast to the full-dose GC and GCarbo groups, the pembrolizumab responder rate was lower, and no association was observed between response to first-line chemotherapy and response to pembrolizumab in the dose-reduced GC group. CONCLUSION: Cisplatin and carboplatin may play an important role in the antitumor immune response, which could impact the outcome of subsequent pembrolizumab treatment. Given that the rate of response to pembrolizumab after dose-reduced GC chemotherapy was relatively low, this regimen is not recommended for cis-unfit patients with aUC. Further studies are required to understand the mechanisms responsible for the cross-reactivity of platinum and immune checkpoint inhibitors.