Platinum rechallenge in the era of immune checkpoint inhibitor in locally advanced/metastatic urothelial carcinoma: Multicenter retrospective study

초록

Background In locally advanced/metastatic urothelial carcinoma (UC) which progressed after platinum-based chemotherapy (P), treatment with 2nd-line immune checkpoint inhibitor (ICI) is considered. If disease progresses thereafter, there is no domestically approved drug with proven OS benefit in Korea, despite the development of new drugs. Therefore, P rechallenge is common in clinical practice, in spite of little evidence. This study aimed to evaluate efficacy of P rechallenge, and to explore clinical/genetic biomarkers predicting the efficacy of P rechallenge in locally advanced/metastatic UC. Methods A total of 66 patients who rechallenged P for locally advanced/metastatic UC from Jan 2017 to Mar 2023 in 3 tertiary referral hospitals was included. Clinical data were retrospectively evaluated. Next generation sequencing was performed for 43 available patients. Results Gemcitabine-based regimens (GP, GCb; [G]; n=28), MVAC-based regimens (MVAC/Cb, ddMVAC; [M]; n=35) and other P (n=3) were administered for P rechallenge; ORR, median PFS and OS were 40.9%, 4.5 and 8.7 months. In patients who received [G] for both 1st-line-P and P-rechallenge (n=24), whose ORR (70.8%) and median TTP (7 months) were favorable to 1st-line P, ORR of P rechallenge was 66.7%. On the other hand, in patients who received 1st-line [G] and rechallenged P with [M] (n=35), whose ORR (45.7%) and mTTP (0.5 months) were relatively poor with 1st-line P, ORR of P rechallenge was 22.9%. Median OS of P rechallenge were significantly longer in patients who received ICI between 1st-line-P and P-rechallenge than those who did not receive (12.4 vs 6.5 months, p=.004). In multivariate analysis, poor response to 1st-line P, visceral metastasis and no alterations in DNA damage repair (DDR) genes were significant prognostic factors for poorer OS after P rechallenge. Conclusions This study demonstrated favorable efficacy of P rechallenge in era of ICI in locally advanced/metastatic UC, providing a basis for treatment decision after P and ICI failure. P rechallenge showed fair efficacy even in poorly responded patients from 1st-line P. DDR gene alterations and ICI use before P rechallenge may be associated with improved survival after P rechallenge.