After decades of dormancy, the therapeutic landscape of locally advanced/metastatic urothelial cancer underwent a paradigm shift—with multiple regulatory approvals of immune checkpoint inhibitors as second-line treatment—leading to changes in guideline-recommended management of patients in this setting.
Thomas Powles, MD, MBBS
In 2020, the role of immune checkpoint inhibitors (ICIs) in urothelial cancer expanded beyond second-line treatment of patients with locally advanced/ metastatic disease. Based on data from the phase 3 JAVELIN Bladder 100 trial (NCT02603432), the FDA granted approval to the PD-L1 inhibitor avelumab (Bavencio) as maintenance therapy for patients with locally advanced or metastatic urothelial cancer who did not progress on first-line platinum chemotherapy.1
“Avelumab first-line maintenance in patients whose disease has not progressed with platinum-based induction chemotherapy represents a new standard first-line treatment for advanced urothelial cancer,” Thomas Powles, MD, MBBS, said during a presentation at the 2020 American Society of Clinical Oncology Virtual Scientific Program.2
After decades of dormancy, the therapeutic landscape of locally advanced/metastatic urothelial cancer underwent a paradigm shift—with multiple regulatory approvals of ICIs as second-line treatment—leading to changes in guideline-recommended management of patients in this setting.3 Per the National Comprehensive Cancer Network guidelines, pembrolizumab (Keytruda), atezolizumab (Tecentriq), nivolumab (Opdivo), durvalumab (Imfinzi), and avelumab are suitable systemic therapy options for patients who already received or who are ineligible for platinum-based chemotherapy based on durable responses and acceptable toxicity profiles.
However, outcomes in patients with disease that relapses following platinum-based chemotherapy, the mainstay of frontline therapy, are poor. Disease progression within approximately 9 months of treatment occurs in most patients treated with a combination platinum-based chemotherapy regimen.4 Therefore, therapies that improve outcomes in locally advanced/metastatic urothelial carcinoma, including in patients who have already received platinum, continue to be an area of clinical focus.
“Although most patient s with advanced [urothelial carcinoma] have disease control or indeed a response to first-line platinum-based chemotherapy, progression-free survival and overall survival are short, and this is because resistance to this disease occurs quickly,” said Powles, a professor of genitourinary oncology, group lead for Solid Tumour Research, and director of the Barts Cancer Center in London, United Kingdom.4 “After first-line chemotherapy, only a minority of patients get second-line treatment.”
JAVELIN Bladder 100 Data The JAVELIN Bladder 100 trial evaluated the potential for ICI therapy with avelumab as maintenance in patients with unresectable locally advanced or metastatic urothelial carcinoma who did not have disease progression on first-line chemotherapy.
The investigators’ rationale for introducing maintenance immunotherapy in this setting was the result of prolonged survival data observed in other solid tumors. In addition, urothelial carcinomas express high levels of PD-L1, harbor DNA repair mutations, and have a high tumor mutational burden, all of which have been associated with response to ICI therapy in other tumor types.
Similarly, data have shown that initial chemotherapy can enhance the effects of subsequent ICI therapy via immune priming and depletion of immunosuppression5 and that chemotherapy and ICIs are not cross-resistant, providing an earlier avenue for use of this clinically active treatment in urothelial carcinoma.6
In total, 700 patients were randomized 1:1 to receive best supportive care with or without maintenance avelumab. The primary end point was overall survival (OS), and progression-free survival (PFS) and safety were secondary end points. Baseline characteristics of the avelumab and the best supportive care arms were well balanced in the overall population, with 55% of patients in both arms having visceral metastasis; 54% and 48%, respectively, having positive PD-L1 status; and 52% and 59% having received gemcitabine and cisplatin as first-line therapy. The majority of patients, at 72% in each arm, had either a partial or complete response to frontline chemotherapy.2
The data showed that the addition of maintenance avelumab to best supportive care significantly prolonged OS compared with best supportive care alone, with medians of 21.4 months versus 14.3 months (HR, 0.69; 95% CI, 0.56-0.86; P < .001). The corresponding 1-year OS rates were 71.3% and 58.4%, respectively. Avelumab was also shown to prolong survival in the subset of patients with PD-L1–positive tumors, with a median OS that was not evaluable versus 17.1 months in the best supportive care arm (HR, 0.56; 95% CI, 0.40-0.79; P < .001). The 1-year OS rates were 79.1% and 60.4%, respectively.
The median PFS was also extended in the overall population, at 3.7 months versus 2.0 months for the experimental and control arms, respectively (HR, 0.62; 95% CI, 0.52-0.75; P<.001). The PD-L1–positive cohort showed similar PFS benefit, with corresponding medians of 5.7 months and 2.1 months (HR, 0.56; 95% CI, 0.43-0.73; P<.001).
As expected, higher incidence of adverse events occurred with avelumab than in the control group, with grade 3 or higher events reported in 47.4% and 25.2% of patients, respectively. No new safety signals for avelumab were identified.
Following these data, updated analyses of the trial presented at the European Society for Medical Oncology Virtual Congress 2020 suggested that patients benefit from the addition of avelumab to best supportive care regardless of PD-L1 expression or other baseline characteristics, such as ECOG performance status or response to frontline chemotherapy. These results taken together led the investigators to conclude that avelumab may be used in patients as maintenance therapy, regardless of PD-L1 expression status, and that further investigations may be necessary to reveal prognostic tumor biomarkers.7,8
The PD-1 inhibitor pembrolizumab is another ICI that has been investigated as switch maintenance therapy following platinum combinations based on the same rationale that motivated the JAVELIN Bladder 100 trial. According to the GU14-182 trial [NCT02500121] authors, led by Matthew Galsky, MD, switch maintenance is defined as “the initiation of immune checkpoint blockade immediately after cessation of firstline platinum-based chemotherapy.”
“With regard to switch maintenance approaches…it’s important to step back and think about what we are trying to achieve in this setting,” Galsky, director of genitourinary medical oncology and professor of urology, medicine and medical oncology at The Tisch Cancer Institute at Icahn School of Medicine at Mount Sinai in New York, said in an interview with Targeted Therapies in Oncology. “One of the potential benefits of immune checkpoint blockade as a switch maintenance strategy as opposed to other things that have been explored in this setting, [including] non–cross-resistant chemotherapies, is that you are hoping to allow patients to have their responses maintained or improved but at the same time give them a break from the toxicity of chemotherapy. The more we add in terms of adverse effect burden in that setting, [the more] we start to diminish what we are trying to achieve.”
In the double-blind phase 2 trial, 108 patients with metastatic urothelial carcinoma achieving at least stable disease on first-line cisplatin- or carboplatin-based combination chemotherapy regimens were randomized 1:1 to intravenous pembrolizumab at 200 mg once every 3 weeks (n=55) as switch maintenance versus placebo (n=53) for up to 24 months. Patients with disease progression could cross over to pembrolizumab. The primary end point was PFS, with OS and treatment outcomes per PD-L1 combined positive score as the secondary end points.9
The median PFS was significantly longer with maintenance pembrolizumab versus placebo, at 5.4 months versus 3.0 months, respectively (HR, 0.65; log-rank P=.04). Pembrolizumab maintenance yielded an objective response rate of 23% compared with 10% in the placebo group. The median OS with pembrolizumab was 22.0 months versus 18.7 months with placebo (HR, 0.91; 95% CI, 0.52-1.59). Interestingly, PD-L1 expression levels did not seem to have an impact on PFS or OS between arms.
“Theoretical advantages to a sequential, compared with a concurrent, combination approach, include the lack of concomitant administration of immune suppressive chemotherapy and corticosteroid antiemetic prophylaxis,” wrote Galsky and colleagues. “Ultimately, the outcomes of the several pending randomized trials will together shape the near-term landscape of first-line treatment of metastatic urothelial cancer, a disease state characterized by a paucity of advances in decades.”
Galsky and colleagues noted that data for ongoing trials, including the IMvigor130 trial [NCT02807636] comparing atezolizumab as monotherapy or in combination with platinum-based chemotherapy versus placebo in previously untreated locally advanced or metastatic urothelial carcinoma may help clarify the utility of advancing ICI therapy earlier in the treatment line.
With the approval of avelumab maintenance therapy, the role and timing of immune checkpoint blockade in metastatic urothelial carcinoma treatment continue to be refined. Data from trials investigating pembrolizumab switch, or sequential, maintenance and atezolizumab as first-line monotherapy or concurrent with platinum chemotherapy will likely further clarify the optimal sequencing of monotherapy and combination regimens of ICIs in locally advanced or metastatic disease. Positive data from these trials could likely result in opportunities for their use as first-line treatments and in patients who may be ineligible for, refuse, or are unable to tolerate platinum regimens.
1. FDA approves avelumab for urothelial carcinoma maintenance treatment. FDA. Updated July 1, 2020. Accessed November 4, 2020. https:// bit.ly/2IwgpfN
2. Powles P, Park SH, Voog E, et al. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. J Clin Oncol. 2020;38(suppl 18):LBA1. doi:10.1200/JCO.2020.38.18_suppl.LBA1
3. NCCN. Clinical Practice Guidelines in Oncology. Bladder cancer, version 6.2020. Accessed November 12, 2020. https://bit.ly/2IxHHlC
4. Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med. 2020;383(13):1218-1230. doi:10.1056/NEJMoa2002788
5. Hato SV, Khong A, de Vries IJM, Lesterhuis WJ. Molecular pathways: the immunogenic effects of platinum-based chemotherapeutics. Clin Cancer Res. 2014;20(11):2831-2837. doi:10.1158/1078-0432.CCR-13-3141
6. Galsky MD, Chowdhury S, Bellmunt J, et al. Treatment patterns and outcomes in “real world” patients (pts) with metastatic urothelial cancer (UC). J Clin Oncol. 2020;31(suppl 15):4525. doi:10.1200/jco.2013.31.15_ suppl.4525