Re‐challenging chemotherapy after pembrolizumab in platinum‐refractory urothelial carcinoma

Abstract

To assess the real-world clinical benefit of re-challenging chemotherapy after pembrolizumab in patients with metastatic urothelial carcinoma (mUC), as there have been several reports suggesting that programmed cell death protein-1/ programmed death-ligand 1inhibitors can restore platinum sensitivity. Patients and MethodsOf 236 patients treated with pembrolizumab, we excluded 45 patients who did not experience progressive disease (PD) for pembrolizumab during the follow-up and 86 patients who discontinued pembrolizumab by the diagnosis of PD followed by the best supportive care. A total of 105 patients were identified for a logistic regression propensity score model to compare the survival outcomes between patients treated with continuing pembrolizumab (80) and re-challenging chemotherapy (25) after the diagnosis of PD for pembrolizumab. ResultsA median overall survival (OS) from PD for pembrolizumab was 11 months in 105 patients. Of 25 patients treated with rechallenging chemotherapy, platinum-including chemotherapy (gemcitabine and cisplatin; gemcitabine/cisplatin/paclitaxel [GCP]; methotrexate and vinblastine and adriamycin and cisplatin; and methotrexate and carboplatin and vinblastine MCAVI) was offered in 20 patients (80%). The objective response rate (ORR) for the first-line chemotherapy in the 105 patients was 30%, with a comparable ORR in 25 patients treated with re-challenging chemotherapy of 28%. GCP as a rechallenging regimen was offered in 12 of 25 (48%) patients. The ORR for the GCP regimen was 50%. Propensity score matching was performed using putative clinical factors, from which 34 patients were identified as pair-matched groups. The OS for patients treated with re-challenging chemotherapy was significantly longer than continuing pembrolizumab (a median of 13.9 and 5.8 months, respectively: P = 0.048). ConclusionRe-challenging chemotherapy including platinum agents after PD with pembrolizumab offers clinical benefits in patients with mUC.

Enfortumab vedotin versus platinum rechallenge in post‐platinum, post‐pembrolizumab advanced urothelial carcinoma: A multicenter propensity score‐matched study

“…Platinum rechallenge has been reported to be a potentially effective treatment for advanced UC 13–20 . For example, Gravis et al.…”

“…Platinum rechallenge has been reported to be a potentially effective treatment for advanced UC. [13][14][15][16][17][18][19][20] For example, Gravis et al reported unexpected responses to cisplatin rechallenge after ICIs in metastatic UC, which was refractory to platinum regimens. 13 They reported that 2 of 14 patients achieved partial responses and 10 of 14 achieved stable disease.…”

“…On the other hand, rechallenging platinum-based chemotherapy, or "platinum rechallenge," has been reported to be potentially effective for platinum-refractory advanced UC, especially after ICIs. [13][14][15][16][17][18][19][20] These studies have raised the possibility that the use of ICIs might restore platinum sensitivity in platinum-refractory advanced UC. Nevertheless, platinum rechallenge is not recognized as a standard of care for patients with advanced UC.…”

Concurrent palliative radiation with pembrolizumab for platinum-refractory urothelial carcinoma is associated with improved overall survival

“…Protocols for discontinuing pembrolizumab treatment and administering palliative radiation were not standardized among the institutes. Third-line treatment including chemotherapy could impact the prognosis [27] , [28] . However, we could not incorporate this concept in the present study.…”

Tertiary lymphoid structure and neutrophil–lymphocyte ratio coordinately predict outcome of pembrolizumab

“…Immune CPIs for mUC patients were approved by the FDA in 2017, 1 leading to a dramatic change in the treatment landscape. However, the majority of patients did not respond to CPIs 2 . In short, the results from the KEYNOTE‐045 trial after more than 2 years of follow‐up exhibited only a modest improvement in progression‐free survival rate (2.1 months, 95% CI: 2.0–2.2 months), ORR (21.1%, 95% CI: 16.4%–26.5%) and disease control rate (DCR: 38.5%, 95% CI: 32.7%–44.6%) in the CPI arm compared with those in the conventional chemotherapy arm 3 .…”