Association Between Sites of Metastasis and Outcomes With Immune Checkpoint Inhibitors in Advanced Urothelial Carcinoma

Makrakis, Dimitrios; Talukder, Rafee; Lin, Genevieve Ihsiu; Diamantopoulos, Leonidas; Dawsey, Scott J.; Gupta, Shilpa; Carril-Ajuria, Lucía; Castellano, Daniel; Kouchkovsky, Ivan de; Koshkin, Vadim S.; Park, Joseph J.; Alva, Ajjai; Bilen, Mehmet Asım; Stewart, Tyler F.; McKay, Rana R.; Tripathi, Nishita; Agarwal, Neeraj; Vather-Wu, Naomi; Zakharia, Yousef; Morales-Bárrera, Rafael; Devitt, Michael; Cortellini, Alessio; Maria, Fulgenzi Claudia Angela; Pinato, David J.; Nelson, Ariel Ann; Hoimes, Christopher J.; Gupta, Kavita; Gartrell, Benjamin A.; Sankin, Alex; Tripathi, Abhishek; Zakopoulou, Roubini; Bamias, Aristotelis; Murgić, Jure; Fröbe, Ana; Rodríguez‐Vida, Alejo; Drakaki, Alexandra; Liu, Sandy; Lu, Eric; Kumar, Vivek; Lorenzo, Giuseppe Di; Joshi, Monika; Isaacsson-Velho, Pedro; Buznego, Lucía Alonso; Durán, Ignacio; Moses, Marcus W.; Jang, Albert; Barata, Pedro; Sonpavde, Guru; Yu, Evan Y.; Montgomery, Robert B.; Grivas, Petros; Khaki, Ali Raza

doi:10.1016/j.clgc.2022.06.001

Cited by 13 publications

(10 citation statements)

References 38 publications

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“…ECOG-PS ≥ 2 and the presence of bone or liver metastases were significantly associated with worst OS and PFS, while smoking attitude was associated with longer OS, in accordance with previous studies focused on the use of immunotherapy in cancer patients [ 17 , 18 ]. These findings are consistent with a recent multicenter retrospective study that included 917 patients with mUC and treated with immune checkpoint inhibitors, which reported bone and liver metastases as strong predictors of worse oncologic outcome [ 19 ]. The ORR was 31% with 10% of CR.…”

Section: Discussionsupporting

confidence: 91%

Global real-world experiences with pembrolizumab in advanced urothelial carcinoma after platinum-based chemotherapy: the ARON-2 study

Massari,

Santoni,

Takeshita

et al. 2024

Cancer Immunol Immunother

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Background Immune checkpoint inhibitors have changed previous treatment paradigm of advanced urothelial carcinoma (UC). The ARON-2 study (NCT05290038) aimed to assess the real-world effectiveness of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy. Patients and Methods Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were retrospectively collected from 88 institutions in 23 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Cox proportional hazards models were adopted to explore the presence of prognostic factors. Results In total, 836 patients were included: 544 patients (65%) received pembrolizumab after progression to first-line platinum-based chemotherapy in the metastatic setting (cohort A) and 292 (35%) after recurring within < 12 months since the completion of adjuvant or neoadjuvant chemotherapy (cohort B). The median follow-up time was 15.3 months. The median OS and the ORR were 10.5 months and 31% in the overall study population, 9.1 months and 29% in cohort A and 14.6 months and 37% in cohort B. At multivariate analysis, ECOG-PS ≥ 2, bone metastases, liver metastases and pembrolizumab setting (cohort A vs B) proved to be significantly associated with worst OS and PFS. Stratified by the presence of 0, 1–2 or 3–4 prognostic factors, the median OS was 29.4, 12.5 and 4.1 months (p < 0.001), while the median PFS was 12.2, 6.4 and 2.8 months, respectively (p < 0.001). Conclusions Our study confirms that pembrolizumab is effective in the advanced UC real-world context, showing outcome differences between patients recurred or progressed after platinum-based chemotherapy.

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Section: Discussionsupporting

confidence: 91%

Global real-world experiences with pembrolizumab in advanced urothelial carcinoma after platinum-based chemotherapy: the ARON-2 study

Massari,

Santoni,

Takeshita

et al. 2024

Cancer Immunol Immunother

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“…In our study, poor response and survival outcome of bone and liver metastases was significant, while lymph nodes metastases correlated with higher ORR. These results are consistent with published data in the literature for patients treated with ICI 57–59. Makrakis et al showed lower response rates and shorter OS for bone and liver metastases on retrospective data from 917 mUC treated with ICI as first or ≥ second line, but higher ORR for lymph node-confined metastases 57.…”

Section: Discussionsupporting

confidence: 90%

Clinical variables associated with immune checkpoint inhibitor outcomes in patients with metastatic urothelial carcinoma: a multicentre retrospective cohort study

Labidi,

Meti,

Barua

et al. 2024

BMJ Open

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ObjectivesImmune checkpoint inhibitors (ICIs) are indicated for metastatic urothelial cancer (mUC), but predictive and prognostic factors are lacking. We investigated clinical variables associated with ICI outcomes.MethodsWe performed a multicentre retrospective cohort study of 135 patients who received ICI for mUC, 2016–2021, at three Canadian centres. Clinical characteristics, body mass index (BMI), metastatic sites, neutrophil-to-lymphocyte ratio (NLR), response and survival were abstracted from chart review.ResultsWe identified 135 patients and 62% had received ICI as a second-line or later treatment for mUC. A BMI ≥25 was significantly correlated to a higher overall response rate (ORR) (45.4% vs 16.3%, p value=0.020). Patients with BMI ≥30 experienced longer median overall survival (OS) of 24.8 vs 14.4 for 25≤BMI<30 and 8.5 months for BMI <25 (p value=0.012). The ORR was lower in the presence of bone metastases (16% vs 41%, p value=0.006) and liver metastases (16% vs 39%, p value=0.013). Metastatic lymph nodes were correlated with higher ORR (40% vs 20%, p value=0.032). The median OS for bone metastases was 7.3 versus 18 months (p value <0.001). Patients with liver metastases had a median OS of 8.6 versus 15 months (p value=0.006). No difference for lymph nodes metastases (13.5 vs 12.7 months, p value=0.175) was found. NLR ≥4 had worse OS (8.2 vs 17.7 months, p value=0.0001). In multivariate analysis, BMI ≥30, bone metastases, NLR ≥4, performance status ≥2 and line of ICI ≥2 were independent factors for OS.ConclusionsOur data identified BMI and bone metastases as novel clinical biomarkers that were independently associated with ICI outcomes in mUC. External and prospective validation are warranted.

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“…In our study, poor response and survival outcome of bone and liver metastasis was significant, while lymph nodes metastasis correlated with higher ORR. These results are consistent with published data in the literature for patients treated with ICI [57-59]. Makrakis et al showed lower response rates and shorter OS for bone and liver metastasis on retrospective data from 917 mUC treated with ICI as 1 st or ≥ 2 nd line, but higher ORR for lymph node confined metastasis [57].…”

Section: Discussionsupporting

confidence: 90%

Clinical variables associated with immune checkpoint inhibitor outcomes in patients with metastatic urothelial carcinoma

Labidi,

Meti,

Barua

et al. 2023

Preprint

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BackgroundAnti-PD-1/L1 immune checkpoint inhibitors (ICI) are indicated for metastatic urothelial cancer (mUC), however, only a minority of patients will derive therapeutic benefit. Strong predictive and prognostic factors are lacking. We investigated if clinical variables were associated with ICI outcomes in mUC.MethodsWe performed a multi-center retrospective cohort study of patients with mUC who received anti-PD-1/L1 ICI for metastatic disease between 2016-2021 at 3 Canadian cancer centres. Clinical characteristics, including demographics, BMI, metastatic sites, neutrophil-to-lymphocyte ratio (NLR), objective response, and survival were abstracted from chart review. ICI treatment response was determined by investigator assessment of clinical and radiologic parameters. Fisher’s exact test was used to assess differences in response rates between groups. Log rank and Cox regression models were used to assess overall survival (OS).ResultsWe identified 135 patients with mUC who received anti-PD1/L1 ICI. A BMI ≥ 25 was significantly correlated to a higher overall response rate (ORR) to ICI (45.4% vs 16.3%, P = 0.020). After a median follow-up of 14.5 months, patients with BMI ≥ 30 experienced significant longer median OS 24.8 months vs. 14.4 months for 25 ≤ BMI < 30 and 8.5 months for BMI < 25 (P = 0.012). The ORR was significantly less in the presence of bone metastasis 16% vs 41% P = 0.006, and liver metastasis 16% vs 39% P = 0.013. Conversely, the presence of metastatic lymph nodes was significantly correlated with higher ORR 40% vs 20% P = 0.032. The median OS for patients with bone metastasis was 7.3 months vs 18 months in the absence of bone metastasis (P < 0.001). Patients with liver metastasis had a median OS of 8.6 months compared to 15 months for those without liver metastasis (P = 0.006). For lung metastasis, median OS was 8.7 months compared to 17.3 months (P = 0.004). No statistical difference was shown in OS for lymph nodes metastasis, with a median of 13.5 months vs 12.7 months (P = 0.175). Patients with NLR ≥ 4 had a significant worse OS (8.2 months vs 17.7 months P = 0.0001). In multivariate analysis, BMI ≥ 30, bone metastasis and NLR ≥ 4 were independent prognosis factor for OS.ConclusionsOur data identified BMI and bone metastasis as novel, independent, clinical biomarkers that were strongly and independently associated with ICI response and survival in mUC. External validation of these data in a larger study and investigations into the mechanisms behind these findings are warranted.

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Association Between Sites of Metastasis and Outcomes With Immune Checkpoint Inhibitors in Advanced Urothelial Carcinoma

Cited by 13 publications

References 38 publications

Global real-world experiences with pembrolizumab in advanced urothelial carcinoma after platinum-based chemotherapy: the ARON-2 study

Global real-world experiences with pembrolizumab in advanced urothelial carcinoma after platinum-based chemotherapy: the ARON-2 study

Clinical variables associated with immune checkpoint inhibitor outcomes in patients with metastatic urothelial carcinoma: a multicentre retrospective cohort study

Clinical variables associated with immune checkpoint inhibitor outcomes in patients with metastatic urothelial carcinoma

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