This issue of Literature Express shares a multi-center, real-world study from Chinese patient data to investigate the use of antibody-drug conjugate (ADC) RC48 in patients with metastatic urothelial carcinoma. RC48 is an antibody-drug combination against HER2 that has been approved in China for patients with HER-2-positive metastatic bladder cancer. The study retrospectively collected data from 103 patients with metastatic urothelial carcinoma treated with RC48. The results showed that RC48 had an objective response rate of 50.5%, a disease control rate of 79.6%, a median progression-free survival of 6 months, and fewer serious treatment-related adverse events. Therefore, RC48 is effective and safe in clinical application in patients with metastatic bladder cancer. In addition, studies have also found that patients with metastatic urothelial carcinoma can benefit from RC48 treatment, regardless of the patient's physical condition or impaired kidney function. What is the specific content of the study? Let's take a look with the editor.
Background:
Urothelial carcinoma (UC) is a common malignancy in the urinary system, and its metastatic form (mUC) is usually incurable and has a poor prognosis, with a median overall survival of about 15 months. Although cisplatin-based chemotherapy is the first-line treatment for mUC, many patients are not candidates for this type of therapy for a variety of reasons. Immune checkpoint inhibitors (ICIs) offer a new treatment option for patients with advanced UC, however, only a small number of patients benefit from them.
Antibody-drug conjugates (ADCs) such as enfortumab vedotin (EV) and sacituzumab govitecan (SG) have shown good efficacy and safety in mUC treatment, but are not yet available in China. RC48-ADC is a novel anti-HER2 ADC that conjugates monomethyl auristatin E (MMAE) to an antibody via a linker and has been approved in China for the treatment of patients with mUC who are HER2-positive and have failed at least one platinum-based chemotherapy.
This study aims to evaluate the efficacy and safety of RC48-ADC in a real-world population of mUC patients, particularly in patients who are older, have renal insufficiency, have poor performance status, or have medical comorbidities. The study will provide clinical practice with data on the use of RC48-ADC in a broader patient population, helping to further understand how it behaves under different clinical conditions.
Research Methods:
The study included 103 patients with mUC who received primary treatment for RC48 at 12 centers in China between July 2021 and August 2023, and the inclusion criteria included histologically confirmed UC, presence of distant metastases, at least one response assessment, and good baseline hematological, hepatic, and cardiac function. RC48 is administered intravenously at a dose of 2.0 mg/kg once every two weeks and treatment is continued until disease progression, intolerable toxicity, death, or other causes. Demographic data, ECOG performance status, imaging features, laboratory test results, pathological data, HER2 expression levels, treatment strategies, and treatment-related adverse events (TRAEs) were collected. HER2 expression was assessed by immunohistochemistry (IHC), following ASCO/CAP guidelines.
The primary endpoints of the study were progression-free survival (PFS) and overall survival (OS), with secondary endpoints including assessment of objective response rate (ORR), disease control rate (DCR), and TRAEs. PFS is defined as the time from treatment initiation to disease progression or death from any cause, and OS is the time from treatment initiation to death from any cause. Tumor response was assessed according to RECIST 1.1 criteria and TRAEs were assessed according to CTCAE 5.0 criteria.
Findings:
Baseline characteristics
The male-to-female ratio is 2.1:1. The median age was 68 years (35-93 years). Twenty-five (24.3%) patients aged 75 years and older were associated with 11.7% and 3.9% of patients aged 80 years and older, respectively. ECOG performance status ≥ 2 in 34% of patients. Creatinine clearance (CCr) < 30 mL/min in 9.7% of cases. Primary lesions of the upper urinary tract (renal pelvis/ureter) accounted for 48.5%. Metastases included lymph nodes (64.1%), lungs (22.3%), bones (23.3%), and liver (17.5%). HER2 expression was IHC 0, 1+, 2+, 3+, and unknown in 12 (11.7%), 16 (15.5%), 48 (46.6%), 9 (8.7%), and 18 (17.5%) patients, respectively. Twenty-nine (28.2%) patients received RC48 alone; 73 (70.9%) patients were treated with RC48 in combination with immune checkpoint inhibitors (ICIs); One patient was treated with RC48 in combination with chemotherapy. Forty (38.8%) patients received RC48 as first-line therapy because they were unsuitable for platinum-based chemotherapy or refused chemotherapy, while 41 (39.8%) and 22 (21.4%) patients received RC48 as second- and third-line or higher-line therapy, respectively.
Efficacy Results:
- The overall objective response rate (ORR) was 50.5%.
- For patients who received primary therapy with RC48 as first-line therapy, the ORR was 57.5%.
- In patients younger than 70 years, 70 years and older, 80 years and older, and 90 years and older, the ORR was 45.7% (32/70), 60.6% (20/33), 75% (9/12), and 100% (4/4), respectively.
- In patients with ECOG performance status 0-1 and ≥2, the ORR was 51.5% (35/68) and 48.6% (17/35), respectively.
- For patients with impaired renal function, the ORR was 55.0% (22/40), 49.1% (26/53), and 40.0% (4/10) among patients with CCr ≥ 60 mL/min, 30-60 mL/min, and < 30 mL/min, respectively.
[Figure 1. Subgroup analysis of objective response rate (ORR) in key subgroups】
- The median follow-up was 9.0 months (2-46 months). By the time of the final follow-up, 31 patients (30.1%) had died. Median OS (overall survival) was not reached, and median PFS (progression-free survival) was 6.0 months (3.9-8.1 months).
- There was no statistically significant comparison of progression-free survival (PFS) in the subgroup of patients treated with RC48, with patients with HER2 2+/3+ appearing to have longer PFS than patients with HER2 0 or 1+ (P = 0.054).
l Safety Results:
- The overall safety profile of RC48 in patients with mUC was good.
- A total of 101 patients (98.1%) experienced any grade of treatment-related toxicity. The most commonly reported treatment-related adverse events (TRAEs) included peripheral sensory neuropathy (53.4%), alopecia (42.7%), fatigue (38.8%), anorexia (35.9%), weight loss (35.9%), and anemia (30.1%). Eighteen patients (17.5%) experienced grade 3-4 TRAEs.
- The incidence of grade 2 TRAEs was 33.3%, 50%, 60%, 81.1%, and 40% in patients aged 80 years and older, 90 years of age and older, with an ECOG performance status of ≥2, creatinine clearance (CCr) of 30 to 60 mL/min, and CCr < 30 mL/min, respectively. The incidence of grade 3-4 TRAEs was 12.5%, 0%, 22.9%, 25.9%, and 20%, respectively.
- The incidence of grade 3-4 TRAEs was 20.3% in the combination group and 17.2% in the monotherapy group, with no significant difference between the two groups (P = .727). Most neuropathy is grade 1-2, grade 3 accounts for 2.9%, and there are no grade 4 TRAEs. TRAEs resulted in treatment discontinuation in 16 patients (15.5%). There were no deaths due to TRAEs during RC48 treatment.
conclusion
This study is currently the largest retrospective multicenter study of the use of RC48 in real-world patients. In a previous combined analysis of RC48-C005 and C009 studies, 107 patients with HER2-positive locally advanced or metastatic UC were treated with RC48 after more than first-line systemic chemotherapy failure, with ORR, median PFS, and median OS of 50.5%, 5.9 months, and 14.2 months, respectively. In a real-world study, Chen et al. reported 36 patients with mUC treated with RC48; Their median PFS was 5.4 months, and the ORR and disease control rate (DCR) were 38.9% and 69.4%, respectively. In another real-world study, 40 patients received RC48 monotherapy or in combination with ICIs, with ORR and median PFS of 63.2% and 8.2 months, respectively. The efficacy of RC48 in our study was consistent with previous studies.
Bladder cancer usually affects patients between the ages of 70 and 80. Older patients with advanced bladder cancer often face age-related changes in overall health and often have multiple comorbidities. It has been reported that only 42% of patients over the age of 65 complete first-line chemotherapy. ICIs are fairly safe in older patients, but first- and second-line ORRs are only 28% and 18% respectively. There are few reports on the efficacy and safety of ADC drugs in older patients. In the TROPHY-U-01 study (SG), 53% of patients were over 65 years of age and 26% were over 75 years of age; The ORR was 23.3% for patients aged 65 years and older, and safety did not change with age. In the C-005 study (RC48), there was no significant difference in ORR between patients aged 65 years and older and those younger than 65 years, but no further analysis of safety was performed in older patients. In this study, subgroup analyses showed no significant correlation between age and efficacy, and older patients did not show more TRAEs. Therefore, RC48 has good efficacy and safety in elderly patients.
Renal function is an important factor influencing the treatment strategy of patients with mUC. Even in UC patients over 70 years of age, 40% cannot receive cisplatin chemotherapy due to renal insufficiency. In the UNITE study (EV), 11.8% of patients had impaired renal function (eGFR < 30 mL/min), and subgroup analysis showed no significant correlation between renal function and efficacy in EVs. Chen et al. reported that 5 patients with an eGFR < 30 mL/min achieved a durable response and stable renal function after treatment with RC48. In our study, no significant correlation between ORR and renal function was found, and no additional TRAEs were observed. Therefore, RC48 is both effective and safe in patients with impaired renal function.
ADCs are primarily approved for use in patients with mUC after failure of chemotherapy and immunotherapy. The standard of first-line treatment for metastatic urothelial carcinoma has been challenged, and the combination of pembrolizumab and EV has rapidly emerged as a practice option to transform from traditional cisplatin chemotherapy.
Summary: This multicenter retrospective study showed good efficacy and safety of RC48 in patients with mUC, consistent with previous data. In addition, our studies have shown that RC48 remains excellent in efficacy and tolerability in patients with poor general condition (e.g., older patients, poor ECOG PS, impaired renal function).
[References]
Chen J, et al. RC48-Antibody-Drug Conjugate in Metastatic Urothelial Carcinoma: A Multicenter Real-World Study in China. Clin Genitourin Cancer. 2024 Jun; 22(3):102093.
Disclaimer: This material is supported by AstraZeneca and is intended for healthcare professionals only
Approval number: CN-137743 Valid 2024-9-24