Therapy For Advanced Urothelial Carcinoma Research Articles

Efficacy of avelumab maintenance therapy for advanced urothelial carcinoma with histologic subtype and divergent differentiation: a multicenter retrospective study conducted by the Uro-Oncology Group in Kyushu.

The subtype of urothelial carcinoma (SUC) has been known to possess morphological diversity for histologic subtype or divergent differentiation. However, the efficacy of avelumab against SUC remains unclear. Therefore, the effect of the treatment as well as the survival results of avelumab monotherapy were evaluated as a first-line therapeutic maintenance in patients with advanced SUC. A retrospective analysis was conducted on consecutive patients from the Uro-Oncology Group in Kyushu study population with advanced lower and upper urinary tract cancer who underwent avelumab maintenance therapy without progression after first-line platinum-based chemotherapy. Patients with pure urothelial carcinoma (PUC) and SUC were comparatively analyzed based on objective response rate (ORR), disease control rate, progression-free survival (PFS), and overall survival (OS). Out of 49 recorded patients, 38 and 11 had PUC and SUC, respectively. The most common subtype element was glandular differentiation (n=5), followed by squamous differentiation (n=3), micropapillary (n=1), and plasmacytoid subtypes (n=1). The SUC and PUC groups had comparable ORR (0% vs. 2.6%, P>0.99) and disease control rates (54.5% vs. 44.7%, P=0.73). These patient groups also showed no significant difference in PFS (median 3.9 vs. 3.1 months, P=0.33) or OS (median 16.7 vs. 22.1 months, P=0.47). The response of SUC and PUC to avelumab was comparable in patients with advanced lower and upper urinary tract cancer, indicating that avelumab maintenance therapy is also effective for SUC.

Treatment Patterns and Attrition With Lines of Therapy for Advanced Urothelial Carcinoma in the US

The treatment paradigm for advanced urothelial carcinoma (aUC) has undergone substantial transformation due to the introduction of effective, novel therapeutic agents. However, outcomes remain poor, and little is known about current treatment approaches and attrition rates for patients with aUC. To delineate evolving treatment patterns and attrition rates in patients with aUC using a US-based patient-level sample. This retrospective cohort study used patient-level data from the nationwide deidentified electronic health record database Flatiron Health, originating from approximately 280 oncology clinics across the US. Patients included in the analysis received treatment for metastatic or local aUC at a participating site from January 1, 2011, to January 31, 2023. Patients receiving treatment for 2 or more different types of cancer or participating in clinical trials were excluded from the analysis. Frequencies and percentages were used to summarize the (1) treatment received in each line (cisplatin-based regimens, carboplatin-based regimens, programmed cell death 1 and/or programmed cell death ligand 1 [PD-1/PD-L1] inhibitors, single-agent nonplatinum chemotherapy, enfortumab vedotin, erdafitinib, sacituzumab govitecan, or others) and (2) attrition of patients with each line of therapy, defined as the percentage of patients not progressing to the next line. Of the 12 157 patients within the dataset, 7260 met the eligibility criteria and were included in the analysis (5364 [73.9%] men; median age at the start of first-line treatment, 73 [IQR, 66-80] years). All patients commenced first-line treatment; of these, only 2714 (37.4%) progressed to receive second-line treatment, and 857 (11.8%) advanced to third-line treatment. The primary regimens used as first-line treatment contained carboplatin (2241 [30.9%]), followed by PD-1/PD-L1 inhibitors (2174 [29.9%]). The PD-1/PD-L1 inhibitors emerged as the predominant choice in the second- and third-line (1412 of 2714 [52.0%] and 258 of 857 [30.1%], respectively) treatments. From 2019 onward, novel therapeutic agents were increasingly used in second- and third-line treatments, including enfortumab vedotin (219 of 2714 [8.1%] and 159 of 857 [18.6%], respectively), erdafitinib (39 of 2714 [1.4%] and 28 of 857 [3.3%], respectively), and sacituzumab govitecan (14 of 2714 [0.5%] and 34 of 857 [4.0%], respectively). The findings of this cohort study suggest that approximately two-thirds of patients with aUC did not receive second-line treatment. Most first-line treatments do not include cisplatin-based regimens and instead incorporate carboplatin- or PD-1/PD-L1 inhibitor-based therapies. These data warrant the provision of more effective and tolerable first-line treatments for patients with aUC.

Change in the Neutrophil-to-Eosinophil Ratio After Avelumab Maintenance for Advanced Urothelial Carcinoma: The UROKYU Study.

The association between clinical outcomes and posttreatment changes in the neutrophil-to-lymphocyte ratio (NLR) and neutrophil-to-eosinophil ratio (NER) in patients receiving avelumab maintenance therapy for advanced urothelial carcinoma (UC) is unclear. We retrospectively analyzed data from advanced UC patients who received avelumab and had not progressed with first-line platinum-based chemotherapy. The association between the changes in NLR and NER from pretreatment to week 6 of avelumab treatment and therapeutic efficacy was evaluated. Thirty-two patients were enrolled in this study (male, n=25; female, n=7; median age, 71 years). At six weeks, 19 patients (59.4%) had a decreased NLR and 18 patients (56.3%) had a decreased NER. When the change in NER from pretreatment to six weeks was compared, there was a significant decrease in responders (without progressive disease) (p=0.008); however, there was no significant decrease in non-responders (progressive disease) (p=0.855). The NLR showed no significant change in either group (p=0.099, 0.358). When patients were compared according to the change in the NLR at six weeks, progression-free survival (PFS) and overall survival (OS) did not differ between the decreased NLR and increased NLR groups (p=0.116, 0.256). When patients were compared according to the change in the NER, the decreased and increased groups showed significant differences in PFS and OS (p<0.001, 0.030). In the present real-world study, the responders showed a significantly decreased NER at six weeks. This was associated with improved PFS and OS in patients with advanced UC.

EE369 Cost-Effectiveness Analysis of Pembrolizumab as a Second-Line Therapy for Advanced Urothelial Carcinoma in the United States

EE369 Cost-Effectiveness Analysis of Pembrolizumab as a Second-Line Therapy for Advanced Urothelial Carcinoma in the United States

Efficacy of immune checkpoint inhibitor therapy for advanced urothelial carcinoma in real-life clinical practice: results of a multicentric, retrospective study

Clinical trials revealed significant antitumor activity for immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma (mUC). Due to their strict eligibility criteria, clinical trials include selected patient cohorts, and thus do not necessarily represent real-world population outcomes. In this multicentric, retrospective study, we investigated real-world data to assess the effectiveness of pembrolizumab and atezolizumab and to evaluate the prognostic value of routinely available clinicopathological and laboratory parameters. Clinical and follow-up data from mUC patients who received ICIs (01/2017-12/2021) were evaluated. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and duration of response (DOR) were used as endpoints. Patients’ (n = 210, n = 76 atezolizumab and 134 pembrolizumab) median OS and PFS were 13.6 and 5.9 months, respectively. Impaired ECOG-PS, the presence of visceral, liver or bone metastases, and hemoglobin levels were independently associated with poor OS and DCR. Furthermore, Bellmunt risk factors and the enhanced Bellmunt-CRP score were shown to be prognostic for OS, PFS and DCR. In conclusion, ICIs are effective treatments for a broad range of mUC patients. Our results confirmed the prognostic value of numerous risk factors and showed that Bellmunt risk scores can further be improved when adding CRP to the model.

Administration of Enfortumab Vedotin after Immune-Checkpoint Inhibitor and the Prognosis in Japanese Metastatic Urothelial Carcinoma: A Large Database Study on Enfortumab Vedotin in Metastatic Urothelial Carcinoma.

Enfortumab vedotin shows promise as a targeted therapy for advanced urothelial carcinoma, particularly in patients who have previously received platinum-based chemotherapy and an immune-checkpoint inhibitor. The EV-301 phase III trial demonstrated significantly improved overall survival and response rates compared to standard chemotherapy. However, more data, especially from larger real-world studies, are needed to further assess its effectiveness in Japanese patients. A total of 6007 urothelial cancer patients inducted with pembrolizumab as a second-line treatment were analyzed. Among them, 563 patients received enfortumab vedotin after pembrolizumab, while 443 patients received docetaxel or paclitaxel after pembrolizumab, and all were included in the study for efficacy as a life prolonging agent. The enfortumab vedotin group showed a longer overall survival than the paclitaxel/docetaxel group (p = 0.013, HR: 0.71). In multivariate analysis, enfortumab vedotin induction was the independent risk factor for overall survival (p = 0.013, HR: 0.70). There were no significant differences in cancer-specific survival. Enfortumab vedotin prolonged the overall survival for Japanese advanced or metastatic urothelial carcinoma patients compared to paclitaxel or docetaxel after pembrolizumab treatment.

Avelumab First-line Maintenance Therapy for Advanced Urothelial Carcinoma: Comprehensive Clinical Subgroup Analyses from the JAVELIN Bladder 100 Phase 3 Trial

BackgroundIn the phase 3 JAVELIN Bladder 100 trial, avelumab first-line (1L) maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (aUC) who were progression-free following 1L platinum-based chemotherapy, leading to regulatory approval in various countries. ObjectiveTo analyze clinically relevant subgroups from JAVELIN Bladder 100. Design, setting, and participantsPatients with unresectable locally advanced or metastatic UC without progression on 1L gemcitabine + cisplatin or carboplatin were randomized to receive avelumab + BSC (n = 350) or BSC alone (n = 350). Median follow-up was >19 mo in both arms (data cutoff October 21, 2019). This trial is registered on ClinicalTrials.gov as NCT02603432. Outcome measurements and statistical analysisOS (primary endpoint) and PFS were analyzed in protocol-specified and post hoc subgroups using the Kaplan-Meier method and Cox proportional hazards models. Results and limitationsHazard ratios (HRs) for OS with avelumab + BSC versus BSC alone were <1.0 across all subgroups examined, including patients treated with 1L cisplatin + gemcitabine (HR 0.69, 95% confidence interval [CI] 0.50–0.93) or carboplatin + gemcitabine (HR 0.64, 95% CI 0.46–0.90), patients with PD-L1+ tumors treated with carboplatin + gemcitabine (HR 0.67, 95% CI 0.39–1.14), and patients whose best response to chemotherapy was a complete response (HR 0.80, 95% CI 0.46–1.37), partial response (HR 0.62, 95% CI 0.46–0.84), or stable disease (HR 0.70, 95% CI 0.46–1.06). Observations were similar for PFS. Limitations include the smaller size and post hoc evaluation without multiplicity adjustment for some subgroups. ConclusionsAnalyses of OS and PFS in clinically relevant subgroups were consistent with results for the overall population, further supporting avelumab 1L maintenance as standard-of-care treatment for patients with aUC who are progression-free following 1L platinum-based chemotherapy. Patient summaryIn the JAVELIN Bladder 100 study, maintenance treatment with avelumab helped many different groups of people with advanced cancer of the urinary tract to live longer.

Phase Ib study of anti-PD-L1 monoclonal antibody socazolimab in combination with nab-paclitaxel as first-line therapy for advanced urothelial carcinoma.

4563 Background: PD-1/PD-L1 immune checkpoint inhibitors (ICIs)0have demonstrated activity in the postplatinum and platinum-ineligible settings for advanced urothelial carcinoma (aUC). As only around 30% of patients with aUC can tolerate platinum standard treatment, first-line ICIs combined with non-platinum drugs have certain research value. Therefore we assessed the safety and efficacy of anti-PD-L1 monoclonal antibody Socazolimab in combination with nab-paclitaxel as first line therapy in aUC (NCT04603846). Methods: This is a multi-center,single-arm, phase Ib study which enrolled aUC patients with treatment-naive or first recurrence more than 6 months after the end of adjuvant chemotherapy in China. Eligible patients received Socazolimab (5mg/kg) and nab-paclitaxel (260mg/m2) every 3 weeks. Primary endpoint was to investigate the safety and tolerability of nab-paclitaxel in combination with Socazolimab. Second endpoints were the objective response rate (ORR) and progression-free survival (PFS). Results: 20 patients were enrolled, including 5 renal pelvis urothelial carcinoma, 8 bladder urothelial carcinoma, and 7 ureteral carcinoma. The median age was 69 years. As of January 14, 2022, the median follow-up time was 5.49 months. Median number of treatment cycles was 6.5 cycles. No patients had dose limiting toxicity. Among the 17 patients who had received at least one tumor assessment, 8 patients achieved partial responses. ORR was 52.94% (95% CI, 27.81-77.02). DCR was 88.24% (95% CI, 63.56-98.54). Median PFS was 8.18 months (95% CI, 5.32-13.60). Adverse reactions related to the study drug were mainly Grade 1-2. Common adverse reactions included rash (6/20,30%), increased alanine aminotransferase (6/20, 30%), increased γ-glutamyltransferase (4/20, 20%),sinus bradycardia (4/20, 20%), increased aspartate aminotransferase (4/20, 20%),pruritus (3/20, 15%). Grade 3 or higher treatment-related adverse events occurred in 4 (20%) patients, mainly Grade 3 increases in alanine aminotransferase (2/20, 10%). No confirmed treatment-related deaths occurred, and no treatment-related deaths occurred, and no new safety signals were observed. Conclusions: Socazolimab combined with nab-paclitaxel as first-line treatment was effective and well-tolerated in Chinese patients with advanced urothelial carcinoma, warranting phase II trials. Clinical trial information: NCT04603846.

Immunotherapy maintenance therapy for advanced urothelial carcinoma (aUC): a comprehensive review.

Immunotherapy has revolutionized the systemic treatment of solid tumors, including advanced urothelial carcinoma (aUC), providing durable responses with a favorable safety profile. Multiple immune checkpoint inhibitor agents have been approved in monotherapy in second-line setting, and for a selected group of chemo-naïve cisplatin-ineligible patients with high PD-L1 expression. Despite the incorporation of immunotherapy to the systemic treatment landscape of aUC, platinum-based chemotherapy remains the standard of care in frontline setting for vast majority of patients. Urothelial carcinoma is a chemosensitive disease with response rates of up to 50% to frontline chemotherapy. However, the response to chemotherapy is short lasting with vast majority of patients experiencing disease progression and death within months. In this context, maintenance therapy constitutes an attractive therapeutic strategy to maximize the time to treatment failure. Different cytotoxic and targeted agents have been investigated as maintenance therapy for aUC but have not shown an impact on survival. Avelumab has become the first and only drug to improve overall survival as maintenance therapy after frontline platinum-based therapy in aUC patients and the first drug to be approved in this setting. This article will review the rational for maintenance therapy, the different drugs investigated as maintenance therapy for aUC, and the impact of avelumab maintenance therapy as a new standard of care in the management of aUC.

Favorable Response of Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma with Only Small Lesions to not be Considered Measurable by RECIST.

Pembrolizumab is currently considered the standard second-line treatment for advanced urothelial carcinoma (UC). This study aimed to investigate the efficacy and safety of pembrolizumab in patients with advanced UC in real-world data, which is not well-reported. The study included 97 patients with advanced UC whose lesions were classified according to the Response Evaluation Criteria in Solid Tumors (RECIST). The median age was 73 years. Nineteen patients (20%) with performance status (PS) 2-4 were included. The percentages of liver, lung, bone, and lymph node metastasis were 18%, 27%, 19%, and 76%, respectively. The efficacy, safety, and risk factors for prognosis were evaluated for patients with and without measurable lesions. The best response was complete response in nine patients (9%) and partial response in 16 patients (17%). The median progression-free survival and overall survival were 3.7 months (95% confidence interval [CI]: 2.8-4.7) and 11.8 months (95% CI: 6.7-17.0), respectively. Twenty-one (22%) patients had no measurable lesions per RECIST. In univariate and multivariate analysis, PS 2-4 and lesions by RECIST were identified as factors associated with short overall survival (OS). The median OS of 18.3 months in patients without lesions by RECIST was significantly longer than the median OS of 6.7 months in patients with lesions by RECIST (p = .012). We demonstrated that good PS 0-1 and no measurable lesions, especially small lesions, by RECIST were favorable prognostic factors in patients with advanced UC treated by pembrolizumab.

738 Intratumoral administration of alum-tethered engineered inflammatory cytokines safely elicits potent local and systemic immunity

738 Intratumoral administration of alum-tethered engineered inflammatory cytokines safely elicits potent local and systemic immunity

Blood Cell Count Biomarkers Predicting Efficacy of Pembrolizumab as Second-line Therapy for Advanced Urothelial Carcinoma.

To investigate the blood markers for predicting pembrolizumab efficacy in advanced urothelial carcinoma (UC). This study included 91 advanced UC patients. The relationship between prognosis and markers from peripheral blood cell counts, including the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), and systemic inflammation response index (SIRI=monocytes × neutrophils/lymphocytes), was evaluated. Multivariate analysis indicated that pretreatment NLR and the 1-month-change NLR were both significantly associated with overall survival (OS) after pembrolizumab initiation. When the patients were divided into four groups according to calculated cutoffs using Cox proportional hazard model, the pretreatment NLR <2.9 and 1-month change NLR <+43% groups had a significantly better OS than the pretreatment NLR ≥2.9 and 1-month-change NLR ≥+43% groups. NLR, MLR, PLR and SIRI before pembrolizumab and 1-month-change NLR in advanced UC correlated with OS after pembrolizumab treatment.

Association between prior radical surgery (RS) and outcomes with immune checkpoint inhibitor (ICI) therapy for advanced urothelial carcinoma (aUC).

444 Background: It is unclear whether prior RS of primary tumor is associated with response and outcomes with ICI in aUC. We hypothesized that such response and outcomes would not differ based on prior RS. Methods: We performed a retrospective cohort study including patients (pts) with aUC who received ICI. We compared overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) between pts with vs without RS [cystectomy or (nephro)-ureterectomy]. Analysis was stratified based on ICI therapy line (first-line vs salvage). A separate comparison between pts with prior RS or radiation (RT) only or none was also pursued. ORR was compared between groups using logistic regression, as well OS and PFS using cox regression analysis; a multivariable model was built adjusting for calculated Bellmunt score. P&lt;0.05 was significant. Results: We identified 984 pts from 24 institutions; 682, 704 and 673 were included in OS, PFS and ORR analyses, respectively; 54% of pts had prior RS with median age 68 at ICI initiation with RS vs 71 without RS with similar proportion of men (73-74%) and ever smokers (70-71%). The RS group had higher proportion (%) of white pts (77% vs 71%), lower % of pts with Hb&lt;10g/dL at ICI initiation (23% vs 32%) but not significantly higher % of liver metastasis at ICI initiation (23% vs 17%). Bellmunt score with vs without RS was 16% vs 11%, 50% vs 48%, 27% vs 37%, 7% vs 4% for 0, 1, 2, and 3, respectively. ORR and PFS were not significantly different between groups, while prior RS was associated with longer OS (unadjusted HR 0.8, p=0.03). However, after adjustment for Bellmunt score, this association was not significant (table). Upon stratification based on treatment line, OS was longer with prior RS (0.7, p=0.03) for those treated with salvage ICI but this was not significant after adjusting for Bellmunt score. ORR, PFS and OS were not significantly different between pts receiving prior RT only vs RS vs none. Conclusions: Prior RS was not significantly associated with longer OS in pts with aUC receiving ICI after adjusting for Bellmunt score. Further work is needed to interrogate tumor-host immune interactions and identify biomarkers that can be prognostic and/or predictive of ICI response. [Table: see text]

Post-hoc analysis of long-term outcomes in patients with CR, PR, or SD to pembrolizumab (pembro) or platinum-based chemotherapy (chemo) as 1L therapy for advanced urothelial carcinoma (UC) in KEYNOTE-361.

435 Background: The phase III KEYNOTE-361 study compared efficacy and safety of 1L pembro + chemo or pembro vs chemo in pts with advanced UC. The trial did not meet its primary endpoints of PFS or OS superiority for pembro + chemo vs chemo; formal testing for OS for pembro vs chemo was not performed. We present a post hoc landmark analysis to examine the durability of CR/PR/SD and long-term survival in pts with CR, PR, or SD to pembro vs chemo at week 9 in KEYNOTE-361 (NCT02853305). Methods: Landmark analyses of OS by CR/PR/SD at 9 weeks after randomization in the ITT population were performed. Pts were included if they had a best response of CR/PR/SD per RECIST v1.1 by blinded independent central review at the landmark date of week 9 (first imaging assessment per study protocol). Duration of CR/PR/SD and OS were estimated by the Kaplan-Meier method. No formal comparisons were performed. Results: 307 pts were randomized to receive pembro and 352 pts to receive chemo in the KEYNOTE-361 study. As of Apr 29, 2020, the median (range) time from randomization to data cutoff was 32.5 (22.0-42.4) mo for the pembo arm and 31.4 (22.1-41.6) mo for the chemo arm. In the landmark analysis, fewer pts had CR/PR/SD at week 9 with pembro (n=137 [45%]) than with chemo (n=253 [72%]). Median (range) duration of response for pembro vs chemo was 18.7 (4.4+-35.4+) vs 12.3 (0.0+-29.7+) mo for pts with CR, and 35.0 (1.1-36.1+) vs 6.1 (0.0+-36.3+) mo for pts with PR. Median (range) duration of SD was 4.8 mo (0.0-38.2+) with pembro and 4.6 mo (0.0-16.1+) with chemo. Median OS (95% CI) for pembro vs chemo was not reached (NR) (25.5-NR) vs NR (19.1-NR) for pts with CR; NR (NR-NR) vs 14.8 mo (12.1-21.0) for pts with PR; and 18.5 mo (13.8-28.8) vs 11.1 mo (8.1-14.6) for pts with SD, respectively. Long-term OS rates were higher with pembro vs chemo across all groups (CR/PR/SD) at week 9 (Table). Conclusions: In this post hoc landmark analysis, chemo was associated with more initial responses than pembro, whereas pembro was associated with longer median duration of CR and PR, and generally longer median OS than chemo. Among pts who achieved CR/PR/SD at week 9, the relative OS benefit for pembro vs chemo increased over time. Clinical trial information: NCT02853305. [Table: see text]

Impact of subsequent therapy on survival in KEYNOTE-361: Pembrolizumab (pembro) plus chemotherapy (chemo) or pembro alone versus chemo as first-line therapy for advanced urothelial carcinoma (UC).

439 Background: The phase III KEYNOTE-361 study examined the efficacy and safety of 1L pembro + chemo or pembro alone vs chemo for pts with advanced UC. The PFS and OS benefit of pembro + chemo vs chemo did not reach statistical significance; no further formal tesing was done. We present an exploratory analysis of OS by subsequent therapy in KEYNOTE-361 (NCT02853305) to assess how 1L and 2L therapy selection affected survival outcomes; no formal comparisons were conducted. Methods: OS was estimated for pts by whether they received subsequent therapy, and by whether subsequent therapy included an anti–PD-(L)1 agent. Results: 351 pts were randomized to pembro + chemo, 307 pts to pembro, and 352 pts to chemo. As of Apr 29, 2020, the median (range) time from randomization to data cutoff was 31.7 (22.0-42.3) mo. 124/351 pts (35%) in the pembro + chemo arm, 126/307 pts (41%) in the pembro arm, and 215/352 pts (61%) in the chemo arm received any subsequent therapy. Similar rates of subsequent therapy (pembro + chemo: 32%; pembro: 43%; chemo: 59%) were observed for pts who experienced progressive disease (PD) by blinded independent central review (BICR). A higher rate of pts (169/352 [48%]) in the chemo arm received subsequent anti–PD-(L)1 therapy than in either the pembro + chemo arm (23/351 [7%]) or pembro arm (14/307 [5%]). Due to the small pt numbers, pts in the pembro + chemo or pembro arms who received subsequent anti−PD-(L)1 were not considered further. This analysis included all pts who received 2L therapy (465/1010 pts [46%]); the rate of 2L therapy was similar in pts with PD by BICR (274/615 [45%]). Chemo agents alone or in combination, specifically carboplatin, cisplatin, docetaxel, doxorubicin, gemcitabine, and paclitaxel, were the most commonly received subsequent therapies for pts who did not receive anti–PD-(L)1 in 2L. Pts who received 1L chemo followed by subsequent anti–PD-(L)1 had longer mOS (19.1 mo [95% CI 16.2-22.2]) than pts with 1L pembro followed by 2L therapy not including an anti−PD-(L)1 agent (16.0 mo [95% CI 11.8-19.2]) (Table). Conclusions: In this exploratory analysis, favorable survival outcomes were observed for pts who received 1L chemo followed by anti–PD-(L)1 compared with pts who received 1L pembro followed by 2L therapy not including an anti–PD-(L)1 agent. These data underline the continued importance of immunotherapy as 2L therapy for advanced UC. Clinical trial information: NCT02853305 . Research Sponsor: Merck &amp; Co., Inc[Table: see text]

Analysis of PFS2 by subsequent therapy in KEYNOTE-361: Pembrolizumab (pembro) plus chemotherapy (chemo) or pembro alone versus chemo as 1L therapy for advanced urothelial carcinoma (UC).

448 Background: 1L pembro + chemo did not show statistically superior PFS and OS vs chemo for pts with advanced UC in the phase III KEYNOTE-361 study; OS for pembro vs chemo was not formally tested. We analyzed PFS2 (time from randomization to progressive disease [PD] on first subsequent therapy, or death from any cause, whichever occurs first) by study treatment and subsequent therapy in KEYNOTE-361 (NCT02853305) to determine the effects, if any, of therapy sequence on PFS2. Methods: PFS2 was estimated for pts in each treatment arm, who received any subsequent therapy including any anti–PD-(L)1, any therapy other than anti–PD-(L)1, or no therapy. These were exploratory analyses; no formal comparisons were done. Results: 1010 pts were randomized: 351 pts to receive pembro + chemo, 307 to pembro, and 352 to chemo. As of Apr 29, 2020, the median (range) time from randomization to data cutoff was 31.7 (22.0-42.3) mo. Subsequent therapy was received by 124/351 (35%), 126/307 (41%), and 215/352 (61%) pts in the pembro + chemo, pembro, and chemo arms, respectively. Subsequent anti–PD-(L)1 therapy was received by 169/352 (48%) pts in the chemo arm vs 23/351 (7%) in the pembro + chemo arm and 14/307 (5%) in the pembro arm. Of pts in the pembro arm who received subsequent therapy, &gt;90% received 2L cisplatin-based or carboplatin-based treatment. Median (m) PFS2 (95% CI) for all pts by treatment arm was 14.1 mo (12.6-16.2) with pembro + chemo, 10.9 mo (9.5-12.9) with pembro, and 10.4 mo (9.8-11.2) with chemo. Across treatment arms, pts in the pembro + chemo arm had the longest mPFS2 with any subsequent therapy (14.5 mo [95% CI 13.1-16.6]) (Table). Pts in the pembro arm who received no subsequent therapy had a longer mPFS2 (12.9 mo [95% CI 8.1-17.9]) vs pts in the chemo arm who received no subsequent therapy (9.4 mo [95% CI 7.6-10.6]). Finally, pts treated with 1L pembro in the trial followed by 2L therapy other than anti−PD-(L)1 had comparable mPFS2 (10.2 mo [95% CI 8.6-12.1]) to pts treated with 1L chemo in the trial followed by 2L anti−PD-(L)1 (11.1 mo [95% CI 10.2-12.9]). Conclusions: In this exploratory analysis, treatment sequence of chemo followed by anti−PD-(L)1 upon PD vs anti–PD-(L)1 followed by chemo upon PD did not appear to impact mPFS2. Among pts who did not receive 2L therapy, 1L pembro appeared to be associated with longer mPFS2 than chemo, potentially driven by long-term responders to pembro. Clinical trial information: NCT02853305 . [Table: see text]

Association between sites of metastases (mets) and outcomes with immune checkpoint inhibitor (ICI) therapy for advanced urothelial carcinoma (aUC).

445 Background: Different metastatic sites have variable prognostic implications in aUC. However, details on response and outcomes with ICI for particular mets is still unknown. We hypothesized that bone and liver mets would have poor response and outcomes with ICIs. Methods: We performed a retrospective cohort study in patients (pts) with aUC who received ICI. We compared overall response rate (ORR) and overall survival (OS) between pts with different mets at ICI initiation. We developed 4 different models: 1) lymph node (LN) only vs other; 2) visceral mets (bone, lung, liver) vs other; 3) bone + liver mets vs bone without liver vs liver without bone vs neither and 4) 6 factor model: a. LN +/- soft tissue/locoregional recurrence b. lung +/- (a) c. bone +/- (b) d. liver +/- (c) e. central nervous system (CNS) +/- (d) and f. other. ORR and OS were compared among groups using multivariable (adjusting for ECOG PS and hemoglobin&lt;10g/dl) logistic regression and cox regression, respectively. Results: We identified 984 pts (24 institutions); 703 and 696 were included in OS and ORR analyses, respectively. Median age at ICI start was 71 (range 32-93), 77% white race, 74% men, 67% ever smokers, 72% pure UC, 18% upper tract UC, 55% extirpative surgery. Prevalence of LN, lung, bone and liver mets at ICI start was 74%, 32%, 27% and 21%, respectively. LN-only mets had significantly higher ORR (44% vs 22%, OR 2.6, p&lt;0.05) and longer mOS (22 vs 8 months, HR 0.5, p&lt;0.05) vs other mets. Visceral mets had significantly lower ORR (21% vs 35%, OR 0.5, p&lt;0.05) and shorter mOS (7 vs 17 months, HR 1.8, p&lt;0.05) vs non-visceral mets. Pts with bone and liver mets had significantly lower ORR and shorter OS vs those with bone or liver mets, which both had significantly lower ORR and shorter OS vs those with neither and with LN +/- local recurrence (Table). Conclusions: In the context of ICI treatment, bone, liver, lung or CNS mets were associated with lower ORR and/or shorter OS, and bone and liver mets were particularly associated with low ORR and short OS. LN-only mets were associated with higher ORR and longer OS. Further work is needed to interrogate site-specific tumor-host immune interactions and identify biomarkers. Research Sponsor: None[Table: see text]

LBA23 Pembrolizumab (P) combined with chemotherapy (C) vs C alone as first-line (1L) therapy for advanced urothelial carcinoma (UC): KEYNOTE-361

LBA23 Pembrolizumab (P) combined with chemotherapy (C) vs C alone as first-line (1L) therapy for advanced urothelial carcinoma (UC): KEYNOTE-361

The cost effectiveness of pembrolizumab versus chemotherapy or atezolizumab as second-line therapy for advanced urothelial carcinoma in the United States

Aims: Pembrolizumab demonstrated significantly prolonged overall survival (OS) vs. chemotherapy in the Phase III KEYNOTE-045 trial, and is approved in the US for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who progressed after platinum-based chemotherapy. Using longer follow-up and individual patient-data from KEYNOTE-045, this study evaluates the cost-effectiveness of pembrolizumab vs. chemotherapy or atezolizumab from a US payer perspective.Materials and methods: A partitioned-survival model was developed over a 20-year time horizon. Progression-free survival (PFS) and OS for pembrolizumab and chemotherapy were extrapolated using a piecewise modelling approach, where patient-level data from KEYNOTE-045 were used for the initial period followed by parametric distributions. OS of atezolizumab was estimated by indirect treatment comparisons based on KEYNOTE-045 and IMvigor211. Different scenarios were explored in the absence of indirect comparisons on PFS and time-on-treatment (ToT) between pembrolizumab and atezolizumab. Drug acquisition/administration, disease management, adverse events, and terminal care costs were considered.Results: Compared with chemotherapy, pembrolizumab resulted in a mean gain of 1.33 life-years and 1.14 quality-adjusted life-years (QALYs) and an incremental cost of $106,299, yielding an incremental cost-effectiveness ratio of $93,481/QALY gained. Pembrolizumab dominated atezolizumab in extending patients’ life by 0.89 years and 0.76 QALYs, while reducing costs by $26,458. Key drivers of cost-effectiveness included survival extrapolation, OS hazard ratio of pembrolizumab vs. atezolizumab, and time horizon. Pembrolizumab had a 66% and 100% probability of being cost-effective vs. chemotherapy and atezolizumab, respectively, at a $100,000 willingness-to-pay threshold.Limitations and conclusions: Uncertainties remain with extrapolated PFS and OS for pembrolizumab, OS indirect comparison, and ToT for atezolizumab. Despite these limitations, the model used robust methods to estimate key clinical endpoints with patient-level data from longer follow-up of KEYNOTE-045. Pembrolizumab dominates atezolizumab and is very likely cost-effective vs. chemotherapy in 2 L mUC at a $100,000 willingness-to-pay threshold.

Validation of 3-factor clinical-genomic model to predict response to atezolizumab as first-line or post-platinum therapy for advanced urothelial carcinoma.

552 Background: Previously, we reported a 3-factor model including tumor mutation burden (TMB), peripheral blood neutrophil/lymphocyte ratio (NLR) and visceral metastasis status to predict tumor regression (c-statistic=0.90) when using ICIs for mUC regardless of line of therapy. We conducted an external validation of this model to determine its ability to predict response. Methods: We utilized data from a phase II trial, IMvigor210, which evaluated atezolizumab (atezo) for post-platinum pts or as first-line therapy for cisplatin-ineligible pts with mUC. Pts with TMB, NLR, visceral metastasis and RECIST1.1 response status available were evaluable. Tumor genomic analysis was performed using FoundationOne, which sequences 324 cancer-related genes. Multivariable regression studied the association of TMB (&lt;10 vs. ≥10 mutations/megabase), NLR (&lt;5 vs. ≥5) and visceral metastasis status (yes vs.no) with RECIST 1.1 response status (≥partial response [PR] vs no PR). Model discrimination performance was assessed using the concordance (c)-index. Results: A total of 234 pts were evaluable for analysis, of whom 185 (79%) were men. 164 (70.1%) pts received post-platinum therapy and 70 (29.9%) received first-line therapy with atezo. 60 pts exhibited RECIST 1.1 ≥PR. On multivariate analysis, all 3 factors were independently and significantly associated with ≥PR: TMB ≥10 mutations/megabase (HR -4.254, p=2.1 x 10−5), low NLR (HR=2.591, p=0.00958) and absence of visceral metastasis status (HR=4.105, p=4.04 x 10−5). The c-index of this 3-factor model to predict ≥PR was 0.77. Presence of all 3 favorable factors (TMBhigh, NLRlow, no visceral metastases) was associated with ≥PR in 15/21 pts (71.4%), while the absence of all 3 factors (TMBlow, NLRhigh, visceral metastases) was associated with ≥PR in 2/37 pts (5.4%). Conclusions: A 3-factor model combining readily available clinical and genomic variables including TMB, NLR and visceral metastasis status was validated to robustly predict RECIST 1.1 response in pts with mUC receiving atezo as first-line or post-platinum therapy. This model may improve the therapeutic index and cost efficacy of atezo.