A Review of Selected Presentations From the ESMO Congress 2023 • October 20-24, 2023 • Madrid, Spain
The Double Antibody Drug Conjugate (DAD) Phase I Trial: Sacituzumab Govitecan (SG) Plus Enfortumab Vedotin (EV) as ≥ Second-Line Therapy for Metastatic Urothelial Carcinoma (mUC)
Metastatic urothelial cancer (mUC) continues to present treatment challenges.1 However, the addition of immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) has improved the outlook for patients with mUC. ADCs that have received approval in the United States for the treatment of mUC include sacituzumab govitecan (SG) and enfortumab vedotin (EV).2,3 In SG, an antibody that binds to Trop-2 is conjugated by a hydrolyzable linker to SN-38, the active metabolite of irinotecan.4 In EV, an antibody against nectin-4 is conjugated by a hydrolyzable linker to monomethyl auristatin E, a microtubule-disrupting agent.5 These 2 ADCs have different antibody-binding targets, different mechanisms of action, and different toxicity profiles, and they are typically used sequentially in the treatment of mUC.
The phase 1 Double Antibody Drug Conjugate (DAD) trial evaluated the safety and maximum tolerated dose (MTD) of SG plus EV in patients with treatment-resistant mUC.6 The investigator-initiated trial enrolled patients who had mUC that had progressed on platinum plus immunotherapy or who were ineligible to receive cisplatin. The patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and had received at least 1 prior line of therapy. The trial design was based on a Bayesian Optimal Interval strategy. SG and EV were administered on days 1 and 8 of each 21-day cycle. Dose levels of SG ranged from 6 to 10 mg/kg, and dose levels of EV ranged from 1.0 to 1.25 mg/kg. Patients were required to receive both drugs on day 1 of each cycle to be able to continue on the study therapy. The primary endpoint was to assess the feasibility of the double ADC combination on the basis of the MTD determined during cycle 1 of the trial.
The DAD trial enrolled 23 patients with a median age of 70 years (range, 41-88). Of these, 78% were male and 83% were white. The primary site of cancer was the bladder in 70% of the patients, upper tract in 26%, and urethra in 4%. Pure urothelial cell histology was noted in 70% of the patients. The number of prior lines of therapy was 3 to 5 in 48% of the patients, 2 in another 48%, and 1 in 4%. The most common metastatic sites included the lymph nodes (74%), bone (26%), and liver (26%). The study enrolled 9 patients at dose level 1 (SG at 8 mg/kg plus EV at 1.0 mg/kg), 8 patients at dose level 2 (SG at 8 mg/kg plus EV at 1.25 mg/kg), and 5 patients at dose level 3 (SG at 10 mg/kg plus EV at 1.25 mg/kg). Dose level 3 was determined to be the MTD. Dose-limiting toxicities observed in this cohort included febrile neutropenia, mucositis, and delay in treatment. Across all dose levels, the most common adverse events (AEs) observed with the double ADC therapy were diarrhea, anemia, and neutropenia. One patient died of pneumonitis, possibly as a consequence of EV therapy in the setting of other medical problems. Any degree of shrinkage of target lesions occurred in 20 patients (87%). The objective response rate (ORR) was 70%. After a median follow-up of 14.9 months, 3 patients had a complete response (CR) and 13 had a partial response (PR) (Table 1).
References
1. Rani B, Ignatz-Hoover JJ, Rana PS, Driscoll JJ. Current and emerging strategies to treat urothelial carcinoma. Cancers (Basel). 2023;15(19):4886.
2. Padcev (enfortumab vedotin) prescribing information. Seagen, Inc.; 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761137s007lbl.pdf. Accessed November 8, 2023.
3. Trodelvy (sacituzumab govitecan) prescribing information. Gilead Sciences, Inc.; 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/ 2023/761115s035lbl.pdf. Accessed November 8, 2023.
4. Tagawa ST, Balar AV, Petrylak DP, et al. Updated outcomes in TROPHY-U-01 cohort 1, a phase 2 study of sacituzumab govitecan (SG) in patients (pts) with metastatic urothelial cancer (mUC) that progressed after platinum (PT)-based chemotherapy and a checkpoint inhibitor (CPI) [ASCO GU abstract 526]. J Clin Oncol. 2023;41(6)(suppl).
5. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384(12):1125-1135.
6. McGregor BA, Sonpavde GP, Kwak L, et al. The double antibody drug conjugate (DAD) phase I trial: sacituzumab govitecan (SG) plus enfortumab vedotin (EV) as ≥ second-line therapy for metastatic urothelial carcinoma (mUC). Abstract 2360O. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain.
Efficacy of Paclitaxel With Tremelimumab +/- Durvalumab in Metastatic Urothelial Carcinoma After Progression on Platinum Chemotherapy and Anti-PD-(L)1
Therapeutic options for patients with mUC after progression on platinum plus immune checkpoint therapy are limited.1,2 Tremelimumab is an anti-cytotoxic T-lymphocyte–associated protein 4 (CTLA4) antibody with single-agent activity in patients who have mUC.3 The phase 1/2 ICRA trial evaluated tremelimumab in combination with paclitaxel and/or durvalumab in patients with previously treated mUC.4 The trial enrolled 20 patients in arm A, 12 in arm B, and 12 in arm C. Patients in arm A received paclitaxel at 70 mg/m2 plus 750 mg of tremelimumab; patients in arm B received paclitaxel at 70 mg/m2, 300 mg of tremelimumab, and 1500 mg of durvalumab; and patients in arm C received 750 mg of tremelimumab alone. The primary objective of the trial was the confirmed ORR according to RECIST 1.1 criteria.5
Across the 3 arms, most of the patients were male (75%-95%), and the median age ranged from 64 to 71 years (range, 56-78). Liver metastasis was observed in 20% of the patients in arm A, 0% in arm B, and 17% in arm C. Between 25% and 33% of the patients had received 3 or more prior lines of therapy. The 2 grade 3 treatment-related AEs observed during the run-in phase of the study were both blood transfusions for anemia. During the entire study, the most common immune-related AEs of any grade were rash and pruritus, hypothyroidism, and colitis. The most common chemotherapy-related AEs of any grade were nausea/fatigue, anemia, and neuropathy. The rates of grade 3/4 treatment-related AEs were 55% in arm A, 67% in arm B, and 33% in arm C. The rates of grade 3/4 immune-related AEs were 30% in arm A, 25% in arm B, and 33% in arm C.
The confirmed ORR was 26% in arm A (88% CI, 14%-37%), 8% in arm B (88% CI, 0.5%-33%), and 8% in arm C (88% CI, 0.5%-33%) (Table 2). A reduction in tumor size was observed in 50% of the patients in arm A, 67% of those in arm B, and 17% of those who received tremelimumab monotherapy (arm C). After a median follow-up of 9.5 months, the median overall survival (OS) was 16.0 months (95% CI, 4.4-27.5) in arm A, 13.9 months (95% CI, 9.5-18.3) in arm B, and 6.6 months (95% CI, 0.0-14.8) in arm C (P=.68). Median progression-free survival (PFS) was 5.7 months (95% CI, 4.0-7.3) in arm A, 6.5 months (95% CI, 3.7-9.4) in arm B, and 2.8 months (95% CI, 0.0-5.7) in arm C (P=.27).
References
1. Bellmunt J, de Wit R, Vaughn DJ, et al; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015-1026.
2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Bladder Cancer. v3.2023. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Updated May 25, 2023. Accessed November 8, 2023.
3. Sharma P, Sohn J, Shin SJ, et al. Efficacy and tolerability of tremelimumab in locally advanced or metastatic urothelial carcinoma patients who have failed first-line platinum-based chemotherapy. Clin Cancer Res. 2020;26(1):61-70.
4. Einerhand SMH, van Dorp J, de Feijter J, et al. ICRA: efficacy of paclitaxel with tremelimumab +/- durvalumab in metastatic urothelial carcinoma after progression on platinum chemotherapy and anti-PD-(L)1. Abstract LBA103. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain.
5. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.
EV-302/KEYNOTE-A39: Open-Label, Randomized Phase III Study of Enfortumab Vedotin in Combination With Pembrolizumab (EV+P) vs Chemotherapy (Chemo) in Previously Untreated Locally Advanced Metastatic Urothelial Carcinoma (la/mUC)
Among patients with mUC at diagnosis, the 5-year survival rate is only 8.3%.1 Targeted therapies are being investigated as alternatives to platinum compounds for the treatment of patients with locally advanced or metastatic urothelial carcinoma (la/mUC). EV is an ADC that binds to nectin-4 and delivers monomethyl auristatin E, causing apoptosis of the targeted cell.2 Pembrolizumab is an ICI that binds to programmed death 1 (PD-1).3 The combination of these 2 antibodies was approved for the treatment of patients with la/mUC who are ineligible for cisplatin therapy.
The international phase 3 EV-302/KEYNOTE-A39 trial evaluated EV plus pembrolizumab (EV+P) as first-line therapy in patients with la/mUC regardless of their cisplatin eligibility and level of programmed death ligand 1 (PD-L1) expression.4 Stratification factors included cisplatin eligibility, PD-L1 expression level, and liver metastasis. Investigators evenly randomized 886 patients to receive either 35 cycles of EV+P or a maximum of 6 cycles of chemotherapy consisting of cisplatin or carboplatin plus gemcitabine. The 2 primary endpoints were PFS by blinded independent review and OS. Baseline characteristics were well balanced between the 2 arms. Of the total number of patients, 77% were male and 68% were White. The median age was 69 years (range, 22-91). The primary tumor location was the lower tract in 69% to 76% of patients in the 2 arms. More than half (54%) of the patients were ineligible for cisplatin, and the majority (72%) had visceral metastasis.
Compared with chemotherapy, treatment with EV+P reduced the risk of disease progression or death by 55% (hazard ratio [HR], 0.45; P<.00001). The median PFS was 12.5 months (95% CI, 10.4-16.6) with EV+P vs 6.3 months (95% CI, 6.2-6.5) with chemotherapy (Figure 1). A clear PFS benefit was observed in prespecified subgroups based on age, sex, ECOG performance status, primary tumor site, liver metastasis, PD-L1 expression level, and cisplatin eligibility. After a median follow-up of 17.2 months, the dual-antibody combination also yielded a superior OS in comparison with chemotherapy (31.5 vs 16.1 months; HR, 0.47; P<.00001). An OS benefit was observed with EV+P vs chemotherapy in patients who were eligible for cisplatin therapy (HR, 0.53; 95% CI, 0.39-0.72) as well as in those who were not (HR, 0.43; 95% CI, 0.31-0.59). EV+P also yielded a superior OS benefit vs chemotherapy in patients with a high level of PD-L1 expression (HR, 0.49; 95% CI, 0.37-0.66) or a low level of PD-L1 expression (HR, 0.44; 95% CI, 0.31-0.61). In a blinded independent review, the CR rate was 29.1% with the dual-antibody combination vs 12.5% with chemotherapy, and the PR rate was 38.7% with the dual-antibody combination vs 32.0% with chemotherapy. The most common treatment-related AEs of grade 3 or higher in the EV+P arm were maculopapular rash (7.7%), anemia (4.8%), diarrhea (3.6%), and peripheral sensory neuropathy (3.6%). In the chemotherapy arm, the most common treatment-related AEs of at least grade 3 were hematologic, including anemia (31.4%), neutropenia (20.0%), and thrombocytopenia (19.4%). In each arm, 4 patients died of a treatment-related AE. These included asthenia, diarrhea, immune-mediated lung disease, and multiple organ dysfunction syndrome in the EV+P arm and febrile neutropenia, myocardial infarction, neutropenic sepsis, and sepsis in the chemotherapy arm. In the EV+P arm, the most common AEs of special interest of at least grade 3 were skin reactions (15.5%), peripheral neuropathy (6.8%), and hyperglycemia (6.1%).
References
1. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: bladder cancer. https://seer.cancer.gov/statfacts/html/urinb.html. Accessed November 8, 2023.
2. Padcev (enfortumab vedotin) prescribing information. Seagen, Inc.; 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761137s007lbl.pdf. Accessed November 8, 2023.
3. Keytruda (pembrolizumab) prescribing information. Merck & Co., Inc. 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s096lbl.pdf. Accessed November 8, 2023.
4. Powles T, Perez-Valderrama B, Gupta S, et al. EV-302/KEYNOTE-A39: open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (Chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Abstract LBA6. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain.
Nivolumab Plus Gemcitabine-Cisplatin Versus Gemcitabine-Cisplatin Alone for Previously Untreated Unresectable or Metastatic Urothelial Carcinoma: Results From the Phase III CheckMate 901 Trial
The mechanisms of action of targeted therapies are different from those of chemotherapy in the treatment of mUC.1-3 The international, open-label, phase 3 CheckMate 901 trial investigated nivolumab plus cisplatin/gemcitabine vs chemotherapy alone as first-line therapy in patients with unresectable or mUC.4 The trial enrolled 608 patients with treatment-naive unresectable or mUC involving the renal pelvis, ureter, urethra, or bladder. All patients were eligible for cisplatin therapy and had an ECOG performance status of 0 or 1. Stratification factors included level of tumor PD-L1 expression and liver metastasis. All patients received gemcitabine (1000 mg/m2) on days 1 and 8 plus cisplatin (70 mg/m2) on day 1 every 3 weeks for up to 6 cycles. Patients in the experimental arm also received nivolumab (360 mg) on day 1 of each cycle. After 6 cycles of therapy, patients in the nivolumab arm received nivolumab (480 mg) every 4 weeks until disease progression, unacceptable toxicity, or withdrawal, for up to 24 months. The primary endpoints were OS and PFS according to blinded independent review.
Baseline characteristics were well balanced between the 2 arms. Patients had a median age of 65 years (range, 32-86), and the majority were White (69%-74%). Most of the primary tumors were located in the bladder (72%-77%), and 64% of the patients in each arm had liver metastasis. The level of PD-L1 expression was less than 1% in 64% of the patients. The median follow-up was 33.6 months (range, 7.4-62.4). The median duration of study treatment was 7.4 months (range, 0.0-47.9) in the nivolumab combination arm vs 3.7 months (range, 0.0-14.2) in the chemotherapy arm. The proportion of patients who completed 6 cycles of therapy was 74% in the nivolumab combination arm vs 55% in the chemotherapy arm.
The CheckMate 901 trial met its primary endpoint, demonstrating superior OS with nivolumab plus chemotherapy vs chemotherapy alone (21.7 vs 18.9 months; HR, 0.78; 95% CI, 0.63-0.96; P=.0171) (Figure 2). A significant benefit with the nivolumab combination vs chemotherapy alone was observed among patients younger than 65 years, male patients, those with an ECOG performance status of 0, patients without liver metastasis, and those who were treatment-naive at baseline. The median PFS was 7.9 months (95% CI, 7.6-9.5) with nivolumab plus chemotherapy vs 7.6 months (95% CI, 6.1-7.8) with chemotherapy alone (HR, 0.72; 95% CI, 0.59-0.88; P=.0012). In most of the subgroups examined, median PFS was superior with nivolumab plus chemotherapy vs chemotherapy alone. In the nivolumab combination arm vs the chemotherapy arm, the CR rate was 21.7% vs 11.8% and the PR rate was 35.9% vs 31.3%, respectively. The median duration of response was longer with the addition of nivolumab to chemotherapy than with chemotherapy alone (9.5 vs 7.3 months). The rate of AEs of grade 3 or higher was 62% with the nivolumab combination vs 52% with chemotherapy alone. In the nivolumab combination arm, the most common AEs of grade 3 or higher were anemia (22%), neutropenia (19%), and decreased neutrophil count (14%). In the chemotherapy-only arm, the most common AEs of at least grade 3 were anemia (18%), neutropenia (15%), and decreased neutrophil count (11%).
References
1. Galsky MD, Arija JÁA, Bamias A, et al; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395(10236):1547-1557.
2. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384(12):1125-1135.
3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Bladder Cancer. v3.2023. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Updated May 25, 2023. Accessed November 8, 2023.
4. van der Heijden MS, Sonpavde GP, Powles T, et al. Nivolumab plus gemcitabine-cisplatin versus gemcitabine-cisplatin alone for previously untreated unresectable or metastatic urothelial carcinoma: results from the phase III CheckMate 901 trial. Abstract LBA7. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain.
Phase III THOR Study: Results of Erdafitinib vs Pembrolizumab in Pretreated Patients With Advanced or Metastatic Urothelial Cancer With Select Fibroblast Growth Factor Receptor Alterations (FGFRalt)
The fibroblast growth factor receptor (FGFR) is altered in approximately one-fifth of patients with advanced UC or mUC of the bladder.1-4 Erdafitinib is an orally administered selective tyrosine kinase inhibitor (TKI) of FGFR1-4 that is approved to treat advanced or mUC with FGFR alteration after progression on platinum-containing therapy.5 The open-label, international, phase 3 THOR study investigated the safety and efficacy of erdafitinib in previously treated patients with unresectable advanced or mUC.6-8 In cohort 1, a total of 200 patients were randomized to receive erdafitinib monotherapy vs the physician’s choice of chemotherapy.6,8 Results from cohort 1 showed a superior median OS (12.1 vs 7.8 months; P=.0050) and a superior median PFS (5.6 vs 2.7 months; P=.0002) with the TKI vs chemotherapy.
Cohort 2 of the THOR trial included 351 patients with unresectable or mUC who were evenly randomized into 2 arms.7 Enrolled patients had confirmed disease progression on 1 prior regimen, no prior exposure to anti–PD-L1 therapy, and 1 or 2 specified FGFR3 translocations or mutations. Stratification factors included region, performance status, and disease distribution. Patients in arm 1 received erdafitinib (8 mg, daily) with dose escalation up to 9 mg daily on the basis of pharmacodynamic data. Patients in arm 2 received pembrolizumab (200 mg, once every 3 weeks). The primary endpoint was OS. Baseline characteristics were well balanced between the 2 arms. Patients had a median age of 67.5 years (range, 31-87), and the majority were male (75%-81%). More than half of the patients (54%-63%) were White, and the primary tumor was in the upper tract in one-fourth of patients. Visceral metastasis was noted in 67% of patients in the erdafitinib arm and 76% of patients in the pembrolizumab arm. Approximately 90% of the patients had a PD-L1 combined positive score (CPS) of less than 10.
The trial failed to meet its primary endpoint, showing similar median OS with erdafitinib vs pembrolizumab (10.9 vs 11.1 months, respectively; HR, 1.18; 95% CI, 0.9-1.5; P=.18) (Figure 3). Median OS was also similar with erdafitinib vs pembrolizumab in subgroups based on age, sex, primary tumor location, FGFR or PD-L1 status, and other factors. The median PFS was 4.4 months with erdafitinib vs 2.7 months with pembrolizumab (HR, 0.88; 95% CI, 0.70-1.10; P=.26). In the erdafitinib arm, the ORR was 40%, including a CR rate of 6.3%. In the pembrolizumab arm, the ORR was 21.6%, including a CR rate of 4.5%. The median duration of response was 4.3 months with the TKI vs 14.4 months with the ICI. Safety outcomes were consistent with prior results in this patient setting.
References
1. Benjamin DJ, Hsu R. Treatment approaches for FGFR-altered urothelial carcinoma: targeted therapies and immunotherapy. Front Immunol. 2023;14:1258388.
2. di Martino E, Tomlinson DC, Williams SV, Knowles MA. A place for precision medicine in bladder cancer: targeting the FGFRs. Future Oncol. 2016;12(19):2243-2263.
3. Necchi A, Lo Vullo S, Raggi D, et al. Prognostic effect of FGFR mutations or gene fusions in patients with metastatic urothelial carcinoma receiving first-line platinum-based chemotherapy: results from a large, single-institution cohort. Eur Urol Focus. 2019;5(5):853-856.
4. Sfakianos JP, Cha EK, Iyer G, et al. Genomic characterization of upper tract urothelial carcinoma. Eur Urol. 2015;68(6):970-977.
5. Balversa (erdafitinib) prescribing information. Janssen Products; 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212018s000lbl.pdf. Accessed November 8, 2023.
6. Loriot Y, Matsubara N, Huddart RA, et al. Erdafitinib (erda) vs chemotherapy (chemo) in patients (pts) with advanced or metastatic urothelial cancer (mUC) with select FGFR alterations (FGFRalt): subgroups from the phase III THOR study. Abstract 2362MO. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain.
7. Siefker-Radtke AO, Matsubara N, Park SH, et al. Phase III THOR study: results of erdafitinib vs pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select fibroblast growth factor receptor alterations (FGFRalt). Abstract 2359O. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain.
8. Loriot Y, Matsubara N, Park SH, et al. Phase 3 THOR study: results of erdafitinib (erda) versus chemotherapy (chemo) in patients (pts) with advanced or metastatic urothelial cancer (mUC) with select fibroblast growth factor receptor alterations (FGFRalt) [ASCO abstract 4619]. J Clin Oncol. 2023;41(17)(suppl).
Erdafitinib (erda) vs Chemotherapy (chemo) in Patients (pts) With Advanced or Metastatic Urothelial Cancer (mUC) With Select FGFR Alterations (FGFRalt): Subgroups From the Phase III THOR Study
ICIs are used in both first- and second-line settings to treat mUC; however, treatment options are limited after progression.1 In cohort 1 of the phase 3 THOR study, researchers investigated erdafitinib vs the physician’s choice of chemotherapy in patients with mUC harboring FGFR alteration.2,3 Enrolled patients had unresectable or mUC, prior anti–PD-L1 therapy, and disease progression after 1 or 2 prior lines of therapy. Included patients had 1 or 2 specified alterations in the FGFR gene. Patients in the experimental arm received erdafitinib (8 mg, daily), with the dose increased to 9 mg on the basis of pharmacodynamic results. Patients in the control arm received the physician’s choice of chemotherapy. Stratification factors included region, performance status, and disease distribution. The primary endpoint was OS.
An earlier interim analysis of data from cohort 1 showed both a superior median OS (12.1 vs 7.8 months; HR, 0.64; 95% CI, 0.47-0.88; P=.005) (Figure 4) and a superior median PFS (5.6 vs 2.7 months; HR, 0.58; 95% CI, 0.44-0.78; P=.0002) with erdafitinib vs chemotherapy.3 To further elucidate the activity of erdafitinib in this patient setting, subgroup analysis was performed.2 The analysis showed a superior OS benefit with erdafitinib vs chemotherapy in most subgroups based on age, sex, FGFR alteration, and primary tumor location. Patients with a PD-L1 CPS of less than 10 experienced a benefit with erdafitinib vs chemotherapy; however, only 7 patients had a PD-L1 CPS of 10 or higher, and the analysis favored chemotherapy in these patients. Erdafitinib generally yielded a superior OS benefit in comparison with chemotherapy in subgroups based on the following: number of lines of prior treatment; prior exposure to platinum, docetaxel, or vinflunine; prior anti–PD-L1 therapy; and the presence of bone, liver, or lung metastasis, but not all of the OS comparisons reached statistical significance.
Observed toxicities were consistent with previously reported safety profiles for erdafitinib and chemotherapy. Approximately 46% of patients in each arm had treatment-related grade 3/4 AEs. Serious treatment-related AEs were more common in the chemotherapy arm (24.1% vs 13.3%), and treatment-related deaths were also more common in the chemotherapy arm (6 vs 1). AEs related to treatment with erdafitinib were generally well managed with dose modifications and supportive care. The most common AEs of any grade in the erdafitinib arm were hyperphosphatemia (78.5%), diarrhea (54.8%), and stomatitis (45.9%). The most common AEs of any grade in the chemotherapy arm were anemia (27.7%), alopecia (21.4%), and nausea (19.6%).
References
1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Bladder Cancer. v3.2023. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Updated May 25, 2023. Accessed November 8, 2023.
2. Loriot Y, Matsubara N, Huddart RA, et al. Erdafitinib (erda) vs chemotherapy (chemo) in patients (pts) with advanced or metastatic urothelial cancer (mUC) with select FGFR alterations (FGFRalt): subgroups from the phase III THOR study. Abstract 2362MO. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain.
3. Loriot Y, Matsubara N, Park SH, et al. Phase 3 THOR study: results of erdafitinib (erda) versus chemotherapy (chemo) in patients (pts) with advanced or metastatic urothelial cancer (mUC) with select fibroblast growth factor receptor alterations (FGFRalt) [ASCO abstract 4619]. J Clin Oncol. 2023;41(17)(suppl).
Real-World Efficacy and Treatment Patterns of Enfortumab Vedotin and Avelumab
EV is an ADCs indicated for the treatment of mUC in patients who have previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy, or who are ineligible for cisplatin and have received at least 1 prior line of therapy.1 Real-world outcomes with EV according to line of therapy and the effect of prior therapy have not been well documented. A retrospective study evaluated these parameters in patients with mUC identified in a United States–based nationwide database. Included patients had advanced, recurrent, or mUC in the upper or lower urinary tract and had received single-agent EV as therapy for their second or later line of therapy.2 Patients were treated after December 18, 2019, the accelerated approval date from the US Food and Drug Administration (FDA). Patients with no documentation of their first-line therapy were not included. Patients who had had no contact with the treating institution for 90 days from diagnosis were also excluded to ensure that patients who received care at the institution providing the data were selected.
Among 6566 patients with mUC, 431 had received EV from January 2020 to September 2022. EV demonstrated activity even when used as the fifth line of therapy. Among patients who received EV as the second, third, fourth, or fifth line of therapy, the median time to next treatment (TTNT) ranged from 4.1 to 6.2 months; the TTNT among patients with prior platinum exposure ranged from 3.4 to 11.0 months; and the TTNT among patients with prior exposure to a PD-1 or PD-L1 inhibitor ranged from 4.6 to 7.4 months. In this same set of patients, the median OS ranged from 7.2 to 11.0 months; the median OS among patients with prior platinum exposure ranged from 5.4 to 14 months; and the median OS among patients with prior exposure to a PD-1 or PD-L1 inhibitor ranged from 6.3 to 11.0 months (Table 3). The study showed that EV continued to provide efficacy among patients with mUC regardless of prior platinum or ICI therapy and when administered as late as the fifth line of therapy.
Avelumab is approved in the United States as maintenance therapy for patients who have locally advanced or mUC without disease progression following first-line platinum-based chemotherapy.3 A retrospective study assessed real-world outcomes in patients with locally advanced or mUC who received avelumab as maintenance therapy.4 The study included patients with locally advanced or mUC in a US database whose disease was diagnosed between January 2016 and March 2023. Patients who had completed first-line platinum-containing therapy after the date of approval of avelumab for this indication were considered eligible for avelumab as maintenance therapy. Among 3299 patients originally identified in the database, 1939 (59%) had received first-line systemic therapy, and 644 patients had received platinum-based chemotherapy as their first-line regimen. The median real-world OS was 13.6 months. After completing first-line therapy, 574 patients (89%) had no evidence of disease progression. Among these patients, 219 (38%) received first-line maintenance therapy, including 135 patients who received avelumab. Among these 135 patients, the median follow-up from the start of maintenance therapy was 8.9 months; 108 patients (80%) patients were still alive at 6 months, and 85 patients (63%) were alive at 12 months. The real-world median PFS from the start of avelumab maintenance therapy was 6.4 months, and the median time on therapy was 3.85 months.
References
1. Padcev (enfortumab vedotin) prescribing information. Seagen, Inc.; 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761137s007lbl.pdf. Accessed November 8, 2023.
2. Sayegh N, Jung Jo Y, Gebrael G, et al. Real-world effectiveness of single agent enfortumab vedotin (EV) in patients (pts) with locally advanced or metastatic urothelial carcinoma (mUC) based on line of therapy and impact of prior platinum (plat) chemotherapy (chemo) and PD-1/PD-L1 inhibitors (PD-1/PD-L1i). Abstract 2380P. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain.
3. Bavencio (avelumab) prescribing information. Merck KGaA. 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761049s009lbl.pdf. Accessed November 8, 2023.
4. Carson K, Mahmoudpour H, Ike C, et al. Avelumab first-line maintenance (1LM) for locally advanced or metastatic urothelial carcinoma (la/mUC): treatment (tx) patterns and real-world (rw) outcomes in the US. Abstract 2387P. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain.
Highlights in Metastatic Urothelial Carcinoma From the European Society for Medical Oncology Congress 2023: Commentary
Several presentations at the European Society for Medical Oncology (ESMO) Congress 2023, which was held in Madrid, Spain, this October, provided important insights into the management of metastatic urothelial carcinoma (mUC). Data were presented on a variety of antibody-drug conjugates (ADCs), including sacituzumab govitecan and enfortumab vedotin, as well as on the relative efficacy of single agents, such as erdafitinib vs pembrolizumab, and more.
Antibody-Drug Conjugates: Sacituzumab Govitecan Plus Enfortumab Vedotin
ADCs have revolutionized the treatment of UC. Sacituzumab govitecan and enfortumab vedotin are both approved for sequential use in the management of treatment-resistant UC.1,2 We frequently combine different chemotherapies, so why not explore combining ADCs?
In this investigator-initiated trial, patients with treatment-resistant mUC received a combination of sacituzumab govitecan and enfortumab vedotin.3 The primary endpoint was to assess feasibility and safety by determining the maximum tolerated dose on the basis of dose-limiting toxicities experienced during cycle 1 in a Bayesian Optimal Interval design. We found that the drugs can be safely combined. In fact, it was possible to administer both drugs at their maximum tolerated doses on days 1 and 8 of a 21-day cycle, although this approach was associated with cumulative toxicities in subsequent cycles. Importantly, no synergistic toxicities were observed. The recommended phase 2 dose would involve a lower dose of sacituzumab govitecan, at 8 mg/kg, with a full dose of enfortumab vedotin, administered on days 1 and 8 of a 21-day cycle. This combination resulted in a 70% objective response rate (ORR), with no significant toxicity signals observed, although it was administered with the support of granulocyte-colony stimulating factor (G-CSF). These are exciting data from the first trial to combine 2 ADCs in the treatment of any malignancy. We are hopeful that combining ADCs will have applications in UC as we look to do expansion cohorts of sacituzumab govitecan and enfortumab vedotin in treatment-resistant settings, as well as in combination with pembrolizumab in the treatment-naive setting (DAD-IO phase 1), looking to build upon the success of EV-302.4,5 Furthermore, the concept may extend to other diseases for which ADCs are approved, allowing us to explore combinations for the treatment of other diseases and enhance outcomes for our patients.
Cisplatin Eligibility
For years, patients with metastatic disease were classified as either cisplatin-eligible or cisplatin-ineligible, and our treatment decisions were based on that classification. The EV-302/KEYNOTE-A39 trial looked to break the mold, including patients with mUC who were cisplatin-eligible or -ineligible and randomizing them to the combination of enfortumab vedotin plus pembrolizumab or to chemotherapy alone.5 Pembrolizumab was administered for up to 2 years; enfortumab vedotin, an ADC, was administered indefinitely until unacceptable toxicity or progression. This trial is quite remarkable in that the risk of progression or death was reduced by 53% in the patients who received enfortumab vedotin plus pembrolizumab as opposed to platinum chemotherapy. Even more remarkable was the nearly doubled median overall survival (OS), which increased from 16.1 to an impressive 31.5 months. This result was independent of cisplatin eligibility and independent of programmed death ligand 1 expression. However, it came with a unique toxicity profile, including rash, hypoglycemia, and neuropathy. With a response rate approaching 70% and a complete response (CR) rate approaching 30%, the combination represents a new standard of care in the treatment of UC.
Enfortumab vedotin plus pembrolizumab is already approved in the United States by the US Food and Drug Administration (FDA) for cisplatin-ineligible patients on the basis of early phase 2 data.6 This trial represents a paradigm shift in our approach. As we consider frontline treatments, we may no longer need to factor in cisplatin eligibility; the combination of enfortumab vedotin plus pembrolizumab offers remarkable results, which is probably why this presentation received a standing ovation at ESMO.
Immunotherapy: Nivolumab
The phase 3 CheckMate 901 was also presented at ESMO.7 Several trials have looked to combine immunotherapy with platinum therapy in the frontline treatment of UC, with no clinically significant improvement in outcomes. However, in exploratory analyses, a potential benefit was noted in the patients treated with cisplatin. The CheckMate 901 trial constituted one arm of a larger study. Patients with previously untreated unresectable or mUC in this arm received gemcitabine/cisplatin with or without nivolumab and underwent chemotherapy for up to 6 cycles. Then, they proceeded to maintenance nivolumab if they showed a response. Notably, the ORR when we added nivolumab went up significantly from 43.1% to 57.6%, and the CR rate increased to 21.7%. When we looked specifically at CRs, the median CR duration was more than 37 months. No new toxicity signals appeared, even though quite a few patients in the gemcitabine/cisplatin-only group went on to receive maintenance nivolumab. These are exciting data. CheckMate 901 is the first trial to show improved outcomes with nivolumab plus gemcitabine/cisplatin vs gemcitabine/cisplatin alone, although the role of the combination will need to be defined with data from EV-302.5
FGFR Alterations: Erdafitinib
Erdafitinib has been FDA-approved on an accelerated basis for some time, on the basis of results of a single-arm phase 2 trial for patients with select fibroblast growth factor receptor (FGFR) mutations. The phase 3 THOR trial comparing erdafitinib with chemotherapy demonstrated a clear advantage of erdafitinib across all subgroups.8 THOR highlights the importance of considering erdafitinib as a treatment option for patients with FGFR mutations, with benefit seen across subgroups. At ESMO, we also saw data from another arm, which compared erdafitinib with pembrolizumab.9 Although the ORR was higher with erdafitinib than with pembrolizumab, the response rate with pembrolizumab approached what is seen in an FGFR unselected population. Moreover, these responses were quite durable. The durable responses to pembrolizumab sort of muddied the waters when the overall data were evaluated—and it just goes to show that we have so much to learn about treatments. Finding the right biomarker for immunotherapy is incredibly challenging, and it is very clear that FGFR mutations are not associated with less response to immunotherapy. Overall, immunotherapy should continue to play an important role in the management of UC, independently of FGFR mutations.
Real-World Setting
Enfortumab Vedotin
The introduction of maintenance therapy involving immunotherapy and ADCs indicates a significant evolution in the UC treatment landscape. At ESMO, we saw some nice real-world data presented on posters drawn from different databases. In my assessment, when we examine data on enfortumab vedotin in the real-world setting, we observe responses that are comparable with what we have seen overall.10 We may not have specific response data, but we do have valuable data regarding time to the next therapy and OS. Although this real-word evidence may not quite match the robustness of phase 3 trial data, it convincingly shows the activity of these drugs and emphasizes the importance of enfortumab vedotin in the management of UC.
Avelumab
At the same time, we saw real-world data on the use of maintenance avelumab. The data showed an early adoption of this approach in first-line maintenance for patients whose disease had not progressed.11 With the paradigm-shifting data recently presented at ESMO, it is evident that we now need to develop new real-world data, including understanding the adoption of the combination of enfortumab vedotin plus pembrolizumab in clinical practice and assessing its effect on future treatment strategies.
Immune Checkpoint Inhibitors
In the phase 2 ICRA trial, patients with mUC that was refractory to checkpoint blockade showed a response to paclitaxel plus the cytotoxic T-lymphocyte–associated antigen 4 inhibitor tremelimumab.12 Although a small trial, ICRA is thought-provoking and highlights the potential for novel therapeutic approaches in the ICI-refractory setting.
Future Outlooks
This was a remarkable ESMO meeting for bladder cancer. In the frontline setting, it has been decades since we have seen such progress. Not one trial was able to show an improvement over platinum-based doublet. And here we had 2 presentations, one right after the other, that both showed an improvement over platinum. One involved the addition of nivolumab to cisplatin, and the other compared enfortumab vedotin plus pembrolizumab with cisplatin or carboplatin–I think this is an exciting time. These studies truly signify a paradigm shift in our approach to bladder cancer, and I look forward to the next trial designs, which we hope will advance treatment for metastatic disease still further. Additionally, we aim to draw lessons from this disease in the metastatic setting and apply similar strategies in the perioperative setting to prevent more patients’ disease from progressing to that point.
Disclosures
Dr McGregor has received honoraria from Seagen, Gilead, Pfizer, BMS, Exelixis, and Eisai and has received funding from Seagen, Gilead, Exelixis, Pfizer, and BMS.
References
1. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384(12):1125-1135.
2. Tagawa ST, Balar AV, Petrylak DP, et al. Updated outcomes in TROPHY-U-01 cohort 1, a phase 2 study of sacituzumab govitecan (SG) in patients (pts) with metastatic urothelial carcinoma (mUC) that progressed after platinum (PT)-based chemotherapy and a checkpoint inhibitor (CPI) [ASCO GU abstract 526]. J Clin Oncol. 2023;(41)(6)(suppl).
3. McGregor BA, Sonpavde GP, Kwak L, et al. The double antibody drug conjugate (DAD) phase I trial: sacituzumab govitecan (SG) plus enfortumab vedotin (EV) as ≥ second-line therapy for metastatic urothelial carcinoma (mUC). Abstract 2360O. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain.
4. ClinicalTrials.gov. Sacituzumab govitecan plus EV in metastatic UC. https://clinicaltrials.gov/study/NCT04724018. Identifier: NCT04724018. Updated November 7, 2023. Accessed, November 7, 2023.
5. Powles T, Perez-Valderrama B, Gupta S, et al. EV-302/KEYNOTE-A39: open-label, randomized, phase 3 study of enfortumab vedotin in combination with pembrolizumab vs chemotherapy in previously untreated locally advanced or metastatic urothelial carcinoma. Abstract LBA6. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain.
6. Padcev (enfortumab vedotin) prescribing information. Astellas/Seagen; 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761137s007lbl.pdf. Accessed November 6, 2023.
7. van der Heijden M, Sonpavde G, Powles T, et al. Nivolumab plus gemcitabine-cisplatin versus gemcitabine-cisplatin alone for previously untreated unresectable or metastatic urothelial carcinoma: results from the phase 3 CheckMate 901 trial. Abstract LBA7. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain.
8. Loriot Y, Matsubara N, Huddart RA, et al. Erdafitinib (erda) vs chemotherapy (chemo) in patients (pts) with advanced or metastatic urothelial cancer (mUC) with select FGFR alterations (FGFRalt): subgroups from the phase III THOR study. Abstract 2362MO. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain.
9. Siefker-Radtke AO, Matsubara N, Park SH, et al. Phase III THOR study: results of erdafitinib (erda) vs pembrolizumab (pembro) in pretreated patients (pts) with advanced or metastatic urothelial cancer (muc) with select fibroblast growth factor receptor alterations (FGFRalt). Abstract 2359O. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain.
10. Sayegh N, Jung Jo Y, Gebrael G, et al. Real-world effectiveness of single agent enfortumab vedotin (EV) in patients (pts) with locally advanced or metastatic urothelial carcinoma (mUC) based on line of therapy and impact of prior platinum (plat) chemotherapy (chemo) and PD-1/PD-L1 inhibitors (PD-1/PD-L1i). Abstract 2380P. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain.
11. Carson K, Mahmoudpour H, Ike C, et al. Avelumab first-line maintenance (1LM) for locally advanced or metastatic urothelial carcinoma (la/mUC): treatment (tx) patterns and real-world (rw) outcomes in the US. Abstract 2387P. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain.
12. Einerhand SMH, van Dorp J, de Feijter J, et al. ICRA: efficacy of paclitaxel with tremelimumab +/- durvalumab in metastatic urothelial carcinoma after progression on platinum chemotherapy and anti-PD-(L)1. Abstract LBA103. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain.