2021 Top Story in Bladder Cancer: Adjuvant Nivolumab vs Placebo in Muscle-Invasive Urothelial Carcinoma
In patients with high-risk muscle-invasive urothelial carcinoma (MIUC) who had undergone radical surgery and those with a PD-L1 expression level of ≥1%, adjuvant nivolumab improved disease-free survival (DFS).
The CHECKMATE274 phase III trial comparing adjuvant nivolumab with placebo for high-risk MIUC met the coprimary end points of statistically significant improvements in DFS with nivolumab in all-comers (HR 0.70) and the PD-L1+ (HR 0.55) populations.1,2 The median DFS in the intention-to-treat (ITT) population was 20.8 months with nivolumab and 10.8 months with placebo. These data are practice-changing and led to the US FDA approval of adjuvant nivolumab on August 20, 2021, in patients with urothelial carcinoma who are at a high risk of recurrence following radical resection regardless of prior treatment with neoadjuvant chemotherapy, nodal involvement, or PD-L1 status. To recall the eligibility criteria, patients must have had radical surgery (R0, with negative surgical margins) within 120 days before randomization, with or without neoadjuvant cisplatin-based chemotherapy. Patients must have had pathological evidence of urothelial carcinoma (primary site in the bladder, ureter, or renal pelvis) with a high risk of recurrence (pathological stage pT3, pT4a, or pN+ and patient not eligible for or declined adjuvant cisplatin-based combination chemotherapy for patients who had not received neoadjuvant cisplatin-based chemotherapy and pathological stage of ypT2 to ypT4a or ypN+ for patients who received neoadjuvant cisplatin). Eligible patients had to be disease-free by physical examination and imaging and exhibit an Eastern Cooperative Oncology Group performance status score 0-1.
The hazard ratios (HRs) for multiple secondary end points also were statistically significantly improved, including nonurothelial tract recurrence-free survival (ITT 0.72, PD-L1+ 0.55) and metastasis-free survival (ITT 0.75, PD-L1+ 0.61), and there was no decline in the quality of life. One would certainly like to see the survival data, which have not been presented. Improved DFS is a reasonable intermediate end point highly likely to translate to an improved overall survival (OS). Indeed, in the perioperative chemotherapy setting, DFS is associated with survival on an individual patient level. However, the magnitude of DFS increment at the trial level that translates to an improved OS is unclear. However, the secondary end points were not formally powered for. Nevertheless, at a minimum, trends for improved OS are desirable, and these data are eagerly awaited.
When examining the peri-operative chemotherapy setting of well-conducted phase III trials that reported both DFS and OS, the following phase III trials provide insights regarding the trial-level association of DFS and OS in the setting of peri-operative chemotherapy: (1) the International Collaboration of Trialists trial (accruing only muscle-invasive bladder cancer [MIBC]) evaluating neoadjuvant CMV3 reported the HR for OS = 0.84 and DFS = 0.82 (both significant), and (2) the POUT trial4 (only upper tract urothelial carcinoma, closed at interim analysis for meeting DFS primary end point threshold) evaluating adjuvant Gemcitabine-Platinum reported HR for DFS = 0.51 (P = significant) and HR for OS = 0.72 (P = NS), and (3) EORTC309945 (only bladder cancer, closed early for poor accrual) evaluated adjuvant GC/MVAC/ddMVAC and showed HR for DFS = 0.54 (P = significant) and HR for OS = 0.78 (P = NS). Adjuvant cisplatin-based chemotherapy is considered a standard for high-risk muscle invasive bladder and upper tract urothelial carcinoma (UTUC) based on the aforementioned POUT trial4 and meta-analyses of adjuvant trials of bladder cancer (in those who have not received neoadjuvant cisplatin-based combination chemotherapy). A DFS benefit in an immune checkpoint inhibitor setting is probably more likely to translate to an improved OS (compared with the chemotherapy setting where benefits tend to be brief).
The data supporting adjuvant nivolumab may increase the impetus to adopt neoadjuvant chemotherapy more thoroughly for all patients with cisplatin-eligible MIUC, given the added value provided by adjuvant nivolumab in these patients with ≥ypT2 or node+ disease at the time of radical surgery.1 The caveat is that in the case of UTUC, the baseline determination of pathologic muscle-invasion is challenging with the frequent employment of the presence of high-grade urothelial carcinoma with a mass lesion accepted as a surrogate for muscle-invasion. Thus, the POUT paradigm of adjuvant chemotherapy following optimal pathologic stage assessment at the time of upfront radical surgery is attractive to avoid over-treating nonmuscle-invasive patients with neoadjuvant chemotherapy. However, there is a risk of rendering many patients ineligible for cisplatin following nephroureterectomy, which inevitably leads to loss of renal function (while there was not a statistically significant interaction of benefit with the type of platinum, the benefit in the carboplatin-gemcitabine subgroup appeared less robust).
One may hypothesize that delayed immune checkpoint inhibitor therapy at progression may confer similar OS compared with adjuvant immune checkpoint inhibitor therapy. There is a continuously increasing complexity of therapy for progression following immune checkpoint inhibitor therapy with the arrival of enfortumab vedotin, sacituzumab govitecan, and erdafitinib, which may also improve OS.6 Conversely, although delayed immune checkpoint inhibitor therapy at progression may confer benefit, abundant data demonstrate that a fraction of patients is unfit for systemic therapy at disease progression, leading to a steady attrition of patients who receive successive lines of systemic therapy. It is important to evaluate the positive adjuvant nivolumab data in the context of the negative data for adjuvant atezolizumab from the IMvigor010 trial,7 where the primary end point of DFS was not met in the ITT population (HR 0.89 [95% CI 0·74–1·08]; P = 0.24). The median DFS was 19.4 months in the atezolizumab arm and 16.6 months in the observation arm. Although the relatively high-median DFS in the control arm has been proposed as a reason for the disappointing results of iMvigor010, the median merely represents a single snapshot in time, while the HR captures the overall benefit accounting for time. Whether there is a differential impact of adjuvant PD1 compared with that of PD-L inhibition is unclear. Interestingly, the median DFS of 19.4 months with adjuvant atezolizumab is somewhat similar to the median DFS of 20.8 months seen with adjuvant nivolumab (with the caveat of comparison across trials). The impact of lack of placebo in IMvigor010 is unclear. Early discontinuation due to patient withdrawal occurred in 35 of the 403 patients in the control arm compared with 15 of the 406 patients in the atezolizumab arm. Furthermore, no treatment benefit was observed with atezolizumab for the secondary end point of OS or for DFS in the PD-L1 high-expressing population. Interestingly, post-operative minimal residual disease (MRD) using tumor-informed circulating tumor (ct)-DNA (Natera) appeared to enrich for patients likely to benefit from adjuvant atezolizumab. However, the use of MRD to select patients for adjuvant nivolumab requires validation. The IMvigor011 is a phase III randomized, placebo-controlled, double-blind trial designed to evaluate adjuvant atezolizumab compared with placebo in patients with high-risk MIBC who are ctDNA positive for MRD following radical cystectomy.
Finally, data from the AMBASSADOR trial8 evaluating adjuvant pembrolizumab compared with observation with coprimary endpoints of DFS and OS in the ITT population are eagerly awaited. Notably, AMBASSADOR closed early after accruing 95% of the target enrollment following the FDA approval of adjuvant nivolumab (as it would be impossible to have a control untreated arm in the context of nivolumab approved as adjuvant therapy). Nevertheless, data from AMBASSADOR are maturing and hopefully will yield useful results. One important phase III trial, PROOF-302,9 is evaluating adjuvant infigratinib compared with placebo for high-risk MIUC with somatic FGFR3 activating mutations. Moreover, several phase III trials are evaluating neoadjuvant chemotherapy combined with immune checkpoint inhibitor therapy for cisplatin-eligible patients. In addition, immune checkpoint inhibitor(s) alone or combined with enfortumab vedotin are also being evaluated in neoadjuvant phase III trials in cisplatin-ineligible patients with MIBC.10 All of these trials will probably further alter the therapeutic landscape of perioperative therapy of MIUC and hopefully improve outcomes and cure more patients with MIUC.
Additional Info
- Bajorin DF, Witjes JF, Gschwend JE, et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med. 2021;384(22):2102-2114.
- Bajorin DF. ASCO GU 2021: Adjuvant Nivolumab for Advanced Urothelial Carcinoma Shows Benefits. PracticeUpdate. Accessed November 12, 2021.
- Griffiths G, Hall R, Sylvester R, et al. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011;29(16):2171-2177.
- Birtle AJ, Chester JD, Jones RJ, et al. Results of POUT: A phase III randomised trial of perioperative chemotherapy versus surveillance in upper tract urothelial cancer (UTUC). 2020. Clinicaltrials.gov. Accessed November 12, 2021.
- 5. Sternberg CN, Skoneczna I, Kerst JM, et al. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. Lancet Oncol. 2015;16(1):76 - 86.
- Rhea LP, Aragon-Ching JB. Advances and Controversies With Checkpoint Inhibitors in Bladder Cancer. Clin Med Insights Oncol. 2021;15:11795549211044963
- Bellmunt J, Hussain M, Gschwend JE, et al. IMvigor010 Study Group. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(4):525-537.
- Apolo AB. Testing MK-3475 (Pembrolizumab) After Surgery for Localized Muscle-Invasive Bladder Cancer and Locally Advanced Urothelial Cancer (AMBASSADOR). NCT03244384. Clinicaltrials.gov.
- Andresen C. Study of Oral Infigratinib for the Adjuvant Treatment of Subjects With Invasive Urothelial Carcinoma With Susceptible FGFR3 Genetic Alterations. NCT04197986. Clinicaltrials.gov.
- Carret AS, Narayanan S. A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer (EV-103). NCT03288545. Clinicaltrials.gov
Disclosure statements are available on the authors' profiles: