Dr. Wei Yu
Department of Urology, Peking University First Hospital
The American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium 2023 (ASCO-GU 2023) kicked off on February 16th in San Francisco, USA. In the field of urothelial carcinoma (UC), significant progress has been made in research. Immunotherapy with immune checkpoint inhibitors (ICIs) in the first-line treatment for advanced UC, as reported in the final analysis of the IMvigor130 study, has provided more information on the population benefiting from immune therapy. Additionally, immunotherapy has expanded into early-stage treatment, with the updated 3-year follow-up data from the CheckMate 274 study showing a Disease-Free Survival (DFS) of up to 52.6 months in the PD-L1 > 1% subgroup. Furthermore, different targets such as Trop-2 and Nectin-4 in antibody-drug conjugates (ADCs) are being explored in various treatment modalities and are extending from later-line to first-line treatment.
Perioperative Treatment
The CheckMate 274 study represents the first phase III clinical trial with positive results for adjuvant immunotherapy in UC. This trial enrolled 709 high-risk patients with muscle-invasive urothelial carcinoma (MIUC) who underwent radical surgery and received either nivolumab (NVIO) or placebo (PBO) as adjuvant therapy for up to 1 year in a 1:1 randomization. Previously, data with a 20-month follow-up demonstrated significant improvements in the primary endpoints for both groups: a 30% reduction in disease risk in the ITT population (20.8 vs. 10.8 months, HR 0.70, P < 0.001) and a 45% reduction in disease risk in the PD-L1 ≥ 1% population (HR 0.55, P < 0.001) (Bajorin DF, NEJM 2021). The ASCO meeting now reports extended follow-up data with a median follow-up time of 36.1 months. In the ITT population, the median DFS was 22.0 months for the NVIO group and 10.9 months for the PBO group, representing a 29% reduction in disease risk (HR 0.71, 95% CI: 0.58-0.86). Among patients with PD-L1 > 1%, the NVIO group achieved a remarkable median DFS of 52.6 months, compared to 8.4 months in the PBO group, signifying a 48% reduction in disease risk (HR 0.52, 95% CI: 0.37-0.72). Subgroup analyses revealed DFS benefits across different age groups, genders, ECOG PS, prior platinum-based chemotherapy, and PD-L1 status. Secondary endpoints such as non-urinary tract recurrence-free survival (NUTRFS) and distant metastasis-free survival (DMFS) also favored the NVIO group. Treatment-related adverse events of grades 3-4 occurred in 18.2% and 7.2% of patients in the NVIO and PBO groups, respectively, consistent with the initial interim analysis.
In the context of bladder preservation treatment, the HCRN GU 16-257 study is a multicenter phase II trial that enrolled 76 patients with cT2-T4aN0M0 urothelial bladder cancer. After receiving 4 cycles of gemcitabine and cisplatin (GC) combination therapy, patients underwent clinical restaging based on urine cytology, bladder MRI/CT, cystoscopy, and bladder biopsy. Patients who achieved a complete clinical response (cCR), defined as having normal cytology and imaging (cT0/Ta), did not undergo bladder removal surgery. Instead, they received 8 cycles of nivolumab (q2wk) treatment and monitoring. Patients who did not achieve cCR were recommended to undergo bladder removal surgery. The primary endpoints of the study were cCR rate and 2-year survival outcomes.
In the data reported, 72 out of 76 patients underwent clinical restaging, and 33 out of 76 patients (43%) achieved cCR. Among them, one patient immediately underwent bladder removal surgery (ypTaN0M0). The 2-year survival rates for patients achieving cCR and those who did not achieve cCR were 100% and 75.8%, respectively. This study suggests that the preoperative treatment approach combining nivolumab with GC can result in a high cCR rate, allowing bladder preservation. Furthermore, patients who achieved cCR experienced a 2-year survival benefit.
In the context of neoadjuvant therapy, the multicenter phase I/II HCRN GU14-188 study enrolled 82 patients with T2-4aN0M0 urothelial carcinoma (UC), including a cisplatin-tolerant cohort (CE, n=42) and a cisplatin-intolerant cohort (CI, n=40). Both cohorts received 5 cycles of neoadjuvant therapy with atezolizumab (200 mg, q3wk) before surgery. Additionally, the CE cohort received neoadjuvant chemotherapy with 4 cycles (every 21 days) of gemcitabine (1000 mg/m2, d1/8) and cisplatin (70 mg/m2, d1, or 35 mg/m2, d1/8). The CI cohort received neoadjuvant chemotherapy with 3 cycles (every 28 days) of gemcitabine (1000 mg/m2, d1/8/15). The primary endpoint was the rate of pathologic muscle-invasive disease response (PaIR, ≤ypT1N0) assessed at surgery.
The study results showed that in the evaluable CE cohort patients, the PaIR rate was 54% (95%CI: 38-69), with 41% (95%CI: 27-57) achieving ypT0. The 18-month recurrence-free survival (RFS) rate for this cohort was 82% (95%CI: 66-91), and the 36-month overall survival (OS) rate was 78.9% (95%CI: 65-90). In the evaluable CI cohort patients, the PaIR rate was 53% (95%CI: 37-69), with 41% (95%CI: 27-57) achieving ypT0. The 18-month RFS rate for this cohort was 65.1% (95%CI: 48-78), and the 36-month OS rate was 65.7% (95%CI: 47-79). The most common grade ≥3 adverse events were anemia (28.3%), hypertension (28.3%), and neutropenia (22.2%), with blood cell count reduction being more common in the CE cohort. One patient in the CE cohort died due to postoperative sepsis. Grade ≥3 immune-related adverse events (irAEs) included elevated liver enzymes (3.7%), rash (2.5%), pneumonia (2.5%), and colitis (2.5%).
At the urothelial carcinoma conference, Professor Geynisman from the Fox Chase Cancer Center proposed the use of biomarkers in conjunction with clinical staging to guide subsequent treatment after neoadjuvant chemotherapy. In a single-arm phase II RETAIN study that he presented, 71 patients with urothelial carcinoma (UC) staged as cT2-T3N0M0 and who had completed MVAC neoadjuvant chemotherapy were enrolled. For patients who had undergone transurethral resection of the bladder (TURBt), urinary cytology, and clinical imaging with no evidence of disease (NED) after neoadjuvant chemotherapy, active surveillance (AS) was recommended if their pre-neoadjuvant chemotherapy TURBt specimens showed ≥1 mutations (such as ATM, ERCC2, FANCC, RB1, etc.).
The study results showed that the 2-year metastasis-free survival (MFS) rate in the intention-to-treat (ITT) population was 72% (lower 95% CI bound = 62%), which unfortunately did not meet the non-inferiority criteria (the pre-specified lower 95% CI bound non-inferiority threshold was >64%). There was no significant difference in the 2-year MFS rates between AS patients and other patients (65% vs. 76%; P=0.42). Despite 50% of AS patients avoiding bladder removal, 38% of them still experienced disease progression. This biomarker-based neoadjuvant AS strategy requires further refinement.
First-Line Treatment
The IMvigor130 study is a phase III clinical trial evaluating atezolizumab (Atezo) as monotherapy or in combination with platinum-based chemotherapy (cisplatin or carboplatin) for first-line treatment of locally advanced or metastatic bladder urothelial carcinoma. The trial consists of three treatment groups: A (Atezo + platinum), B (Atezo alone), and C (platinum alone). Previously reported data showed that in comparison to Group C, Group A had a significant improvement in progression-free survival (PFS) (8.2 vs. 6.3 months, HR 0.82, P=0.007), but overall survival (OS) did not show a significant improvement (16.0 vs. 13.4 months, HR 0.83, P=0.027) (Galsky, Lancet 2020). Group B, when compared to Group C, did not demonstrate a statistically significant difference in OS (15.2 vs. 13.1 months, HR 0.99) (Davis, AACR 2021). This report at the ASCO-GU conference presents the final analysis results for OS.
In the comparison of Group A to Group C: OS benefits for ITT patients remained statistically insignificant (16.1 vs. 13.4 months, HR 0.85, 95% CI: 0.73-1.00, P=0.023; did not reach the significance threshold of P=0.021). However, in the cisplatin subgroup (Atezo + cisplatin vs. cisplatin) patients, there was a more substantial OS benefit (HR 0.76), and PD-L1 IC0/1 (HR 0.75) and IC2/3 (HR 0.74) patients in the cisplatin group also showed improved OS. In the carboplatin subgroup, only PD-L1 IC2/3 patients (HR 0.78) demonstrated a better OS benefit.
Furthermore, in ITT and cisplatin or carboplatin subgroups, the overall response rates (ORR) and median duration of response (mDOR) were generally similar between Groups A and C. However, in the cisplatin subgroup, the mDOR was as long as 13.2 months (see the table below). The safety profile was similar to previous reports, with 9 cases (2%) of grade 5 treatment-related adverse events (TRAE) in Group A and 4 cases (1%) in Group C. Additionally, 41 cases (9%) in Group A and 17 cases (4%) in Group C experienced grade 3/4 adverse events of interest.
In Group B compared to Group C: In the overall ITT population, there was no significant improvement in overall survival (OS) (HR 0.98, 95% CI: 0.82-1.16). However, in the PD-L1 IC2/3 subgroup, Atezolizumab demonstrated a better OS benefit compared to chemotherapy (HR 0.70), although the overall response rate (ORR) was not high (24.2% vs. 44.4%). Particularly in patients who were both PD-L1 IC2/3 positive and cisplatin-intolerant, the risk of death was reduced by 44% (HR 0.56), and the ORR was also improved (40% vs. 32.6%). Patients who were PD-L1 IC0/1 positive and cisplatin-intolerant did not experience a benefit (HR 1.14).
In terms of safety, Group B and Group C had 57 cases (16%) and 312 cases (80%) with grade 3/4 treatment-related adverse events (TRAEs), respectively. There were 3 cases (1%) in Group B and 4 cases (1%) in Group C with grade 5 TRAEs. Additionally, 36 cases (10%) in Group B and 17 cases (4%) in Group C experienced grade 3/4 adverse events of interest.
These results indicate that Atezolizumab monotherapy in Group B may not provide a significant OS benefit in the overall ITT population compared to chemotherapy in Group C. However, in the subgroup of patients with PD-L1 IC2/3 expression, Atezolizumab appears to offer a more favorable OS benefit, especially in patients who are both PD-L1 IC2/3 positive and cisplatin-intolerant. The safety profiles of both groups are notable, with a higher incidence of grade 3/4 TRAEs in the chemotherapy group (Group C) compared to the Atezolizumab group (Group B).
Based on the updated data presented, it seems that Atezolizumab monotherapy is a suitable option for patients who are intolerant to platinum-based chemotherapy, especially those with high PD-L1 expression (IC2/3), as they experience more significant benefits. When Atezolizumab is used in combination with chemotherapy, cisplatin appears to be a preferred chemotherapy choice, and patients with different levels of PD-L1 expression can benefit from first-line treatment with Atezolizumab in combination with cisplatin.
For second-line treatment:
The TROPHY-U-01 study (NCT03547973) is a phase II clinical trial with multiple cohorts and an open-label design. Based on the positive results from cohort 1, the FDA has granted accelerated approval for the use of the Trop-2 ADC sacituzumab govitecan (SG) in advanced UC patients who have received prior platinum-based chemotherapy and immunotherapy. Several cohorts of this study were updated or disclosed for the first time at the ASCO-GU conference.
Cohort 1’s updated results are generally consistent with previous findings, with an ORR of 28%, a CBR of 38%, and median PFS and OS of 5.4 months and 10.9 months, respectively. Cohort 2 targeted patients who were platinum-intolerant and had failed immunotherapy (median prior lines of therapy: 2). SG monotherapy had an ORR of 32%, with a median PFS of 5.6 months and a median OS of 13.5 months. Cohort 3 focused on patients who had failed platinum-based therapy. The combination treatment of SG plus pembrolizumab had an ORR of 41%, with a median PFS of 5.3 months and a median OS of 12.7 months.
Additionally, Cohorts 6 (SG monotherapy or in combination with immunotherapy for first-line treatment in platinum-intolerant patients) and 5 (SG monotherapy or in combination with immunotherapy for first-line maintenance treatment in platinum-intolerant patients) are ongoing.
These results suggest that SG, both as monotherapy and in combination with immunotherapy, shows promise as a treatment option for patients who have failed prior therapies, including platinum-based chemotherapy and immunotherapy.
EV-103 is also a multi-cohort phase 1b/2 clinical trial. Previously, data from Cohort K were published in the Journal of Clinical Oncology (JCO), which investigated enfortumab vedotin (EV), a nectin-4 ADC, as monotherapy or in combination with pembrolizumab (EV+P) for patients with platinum-ineligible locally advanced or metastatic urothelial carcinoma (la/mUC). The results showed an objective response rate (ORR) of 64.5% for EV+P. In this update, patient-reported outcomes (PROs) data were presented. After 24 weeks of EV+P treatment, patients showed improvements in emotional functioning, pain, sleep disturbances, and other aspects compared to baseline. Particularly, there was a significant reduction in pain (-13.20). The Brief Pain Inventory-Short Form (BPI-SF) pain scores also indicated continuous improvement in the severity of the worst and average pain, pain interference, and pain severity, with a 2.08-point reduction in the worst pain score at week 21.
Reference
[1] Matt D. Galsky, et al.Extended follow-up results from the CheckMate 274 trial.J Clin Oncol 41, 2023 (suppl 6; abstr 443)
[2] Matt D. Galsky, et al.Co-primary endpoint analysis of HCRN GU 16-257: Phase 2 trial of gemcitabine, cisplatin, plus nivolumab with selective bladder sparing in patients with muscle-invasive bladder cancer (MIBC).J Clin Oncol 41, 2023 (suppl 6; abstr 447)
[3] Jason Brown, et al.HCRN GU14-188: Phase Ib/II study of neoadjuvant pembrolizumab and chemotherapy for T2-4aN0M0 urothelial cancer.J Clin Oncol 41, 2023 (suppl 6; abstr 448)
[4] aniel M. Geynisman,et al.A phase II trial of risk-enabled therapy after initiating neoadjuvant chemotherapy for bladder cancer (RETAIN).J Clin Oncol 41, 2023 (suppl 6; abstr 438)
[5] Matt D. Galsky, et al.Atezolizumab (atezo) + platinum/gemcitabine (plt/gem) vs placebo + plt/gem for first-line (1L) treatment (tx) of locally advanced or metastatic urothelial carcinoma (mUC): Final OS from the randomized Phase 3 IMvigor130 study.J Clin Oncol 41, 2023 (suppl 6; abstr LBA440)
[6] Final overall survival (OS) analysis of atezolizumab (atezo) monotherapy vs chemotherapy (chemo) in untreated locally advanced or metastatic urothelial carcinoma (mUC) from the Phase 3 IMvigor130 study.J Clin Oncol 41, 2023 (suppl 6; abstr LBA440)
[7] Scott T. Tagawa,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).J Clin Oncol 41, 2023 (suppl 6; abstr 526)
[8] Daniel P. Petrylak,et al.Primary analysis of TROPHY-U-01 cohort 2, a phase 2 study of sacituzumab govitecan (SG) in platinum (PT)-ineligible patients (pts) with metastatic urothelial cancer (mUC) that progressed after prior checkpoint inhibitor (CPI) therapy.J Clin Oncol 41, 2023 (suppl 6; abstr 520)
[9] Petros Grivas, et al.Primary analysis of TROPHY-U-01 cohort 3, a phase 2 study of sacituzumab govitecan (SG) in combination with pembrolizumab (Pembro) in patients (pts) with metastatic urothelial cancer (mUC) that progressed after platinum (PT)-based therapy.J Clin Oncol 41, 2023 (suppl 6; abstr 518)
[10] Matthew I. Milowsky, et al.Patient-reported outcomes (PROs) in cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC) treated with enfortumab vedotin (EV) alone or in combination with pembrolizumab (P) in the phase 1b/2 EV-103 Cohort K study.J Clin Oncol 41, 2023 (suppl 6; abstr 439)
