|Year : 2021 | Volume
| Issue : 3 | Page : 291-292
Role of atezolizumab therapy combined with platinum-based chemotherapy in untreated metastatic urothelial carcinoma – The new landscapes (IMvigor130 trial)
Department of Urology, AIIMS, Bhubaneswar, Odisha, India
|Date of Submission||20-Oct-2020|
|Date of Decision||25-Jan-2021|
|Date of Acceptance||12-Mar-2021|
|Date of Web Publication||1-Jul-2021|
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Misra A. Role of atezolizumab therapy combined with platinum-based chemotherapy in untreated metastatic urothelial carcinoma – The new landscapes (IMvigor130 trial). Indian J Urol 2021;37:291-2
|How to cite this URL:|
Misra A. Role of atezolizumab therapy combined with platinum-based chemotherapy in untreated metastatic urothelial carcinoma – The new landscapes (IMvigor130 trial). Indian J Urol [serial online] 2021 [cited 2021 Jul 31];37:291-2. Available from: https://www.indianjurol.com/text.asp?2021/37/3/291/320416
| Summary|| |
The IMvigor130 trial investigated the role of atezolizumab and chemotherapy as the first-line treatment for metastatic urothelial carcinoma. The trial consisted of three arms [Table 1]. Randomization was stratified by PD-L1 immune cell expression status (IC0 [<1%] vs. IC1 [≥1% and <5%] vs. IC2/3 [≥5%]), Bajorin risk factor score (comprising Karnofsky performance status and presence of visceral metastasis), and the choice of chemotherapy (cisplatin vs. carboplatin). The tumor was evaluated for PD-L1 expression on the tumor-infiltrating immune cells using the SP142 PD-L1 immunohistochemical assay. The co-primary endpoints were progression-free survival (as per RECIST version 1.1) and overall survival (Group A vs. Group C) and (Group B vs. Group C) (hierarchical). The type I error (0.025; one-sided) was split between the co-primary endpoints. The median follow-up for survival was 11.8 months. The tumor was assessed at the baseline and every 9 weeks thereafter (every 12 weeks after 54 weeks of treatment) until disease progression, toxicity, and other factors resulted in study termination.
The median duration of progression-free survival was 8.2 months in Group A and 6.3 months in Group C (P = 0·007). In the subgroup analysis, a larger effect size was seen in those with higher PD-L1 expression and those receiving cisplatin. At the interim analysis, the median overall survival was 16 months in Group A and 13.4 months in Group C (P = 0·027). There was a near doubling of the complete response. Even with low PD-L1 expression, a favorable effect was seen with atezolizumab therapy. The adverse effect profile was similar to the chemotherapy group. In conclusion, atezolizumab combination therapy may have a role in the first-line treatment of metastatic urothelial carcinoma.
| Comments|| |
Cisplatin-based chemotherapy has been the standard for metastatic urothelial carcinoma and the median survival in this group of patients is approximately 15 months. There have been no substantial improvements in the efficacy and around half of the patients are ineligible for cisplatin-based regimen. These patients are prescribed an inferior carboplatin based regimen . Atezolizumab is a monoclonal antibody that binds PD-L1, which is overexpressed in the immune cells, blocking its checkpoint function, thus unleashing the immune system to attack the cancer cells. A combination of chemotherapy and immunotherapy may have an advantage due to immunomodulation and the absence of cross-resistance.
The standout points of this multicentric, randomized controlled trial were the increase of almost 2 months in the progression-free survival (final analysis, significant) and 3 months in the overall survival (interim analysis) with the combination therapy. The atezolizumab-chemotherapy combination arm showed a doubling of the complete response rate. While comparing the median overall survival between Group A and Group C, in the first interim analysis, the upper limit of HR was one, indicating no significant association. Although no statistical testing was performed between Groups B and C, the monotherapy arm (Group B) showed an increase of more than 2 months in the median overall survival. There were no specific adverse effects of atezolizumab, indicating a role in patients who are unable to tolerate chemotherapy. Factors beyond PD-L1 expression may have a role in achieving benefit from immune checkpoint blockade.
The trial was initially designed to study atezolizumab in cisplatin-ineligible patients receiving carboplatin but later was amended to add a monotherapy arm (Group B) and expand the eligibility criteria (by including both cisplatin-eligible and cisplatin-ineligible patients). However, the disadvantage of this change in the protocol was that the criteria for determining the platinum therapy (cisplatin vs. carboplatin) were left at the investigator's judgment to have an extensive and comparable population base. As a result, around 40% of patients who were cisplatin eligible ended up receiving inferior carboplatin, which may have impacted the results. Similarly, 11% of patients who were cisplatin ineligible ended up receiving it. Moreover, eligibility is a dynamic variable and may not remain the same throughout the patient workup and treatment. There may also be a conflict of interest in that many of the authors were directly or indirectly employed by the sponsoring pharmaceutical company.
In patients with metastatic urothelial carcinoma, the subset which received the subsequent therapy is relatively small, which underscores the advantage of first-line combination chemotherapy. However, this benefit needs balancing with the cost of atezolizumab, which is available in India as a 20-ml vial containing 1200 mg and costs around one lakh rupees per vial. This trial is the first and the largest to test primary ICI in patients with metastatic urothelial carcinoma, the other being KEYNOTE-361, which tested pembrolizumab and failed to show any significant benefit. Drugs such as durvalumab and tremelimumab studied in the DANUBE trial also did not show any advantage. This indicates that there may be certain other factors besides PD-L1 expression which may determine the response. Although atezolizumab has shown some potential as the first-line treatment of metastatic urothelial carcinoma, further long-term data are awaited to ascertain its role in prolonging the overall survival.
Financial support and sponsorship: Nil.
Conflicts of interest: There are no conflicts of interest.
| References|| |
Galsky MD, Arija JÁ, Bamias A, Davis ID, de Santis M, Kikuchi E, et al
. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): A multicentre, randomised, placebo-controlled Phase 3 trial. Lancet 2020;395:1547-57.
von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, et al
. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 2005;23:4602-8.
Bamias A, Tzannis K, Harshman LC, Crabb SJ, Wong YN, Kumar Pal S, et al
. Impact of contemporary patterns of chemotherapy utilization on survival in patients with advanced cancer of the urinary tract: A Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC). Ann Oncol 2018;29:361-9.
Hato SV, Khong A, de Vries IJ, Lesterhuis WJ. Molecular pathways: The immunogenic effects of platinum-based chemotherapeutics. Clin Cancer Res 2014;20:2831-7.
Vander Velde N, Guerin A, Ionescu-Ittu R, Shi S, Wu EQ, Lin SW, et al
. Comparative effectiveness of non-cisplatin first-line therapies for metastatic urothelial carcinoma: Phase 2 IMvigor210 Study Versus US Patients Treated in the Veterans Health Administration. Eur Urol Oncol 2019;2:12-20.