Immunotherapy-based regimens as evolving strategies for management of metastatic urothelial carcinoma

Immunotherapy-chemotherapy combinations, immunotherapy doublets, and combinations of immunotherapy with novel targeted agents are emerging as strategies for management of metastatic urothelial carcinoma (mUC) in view of the limitations with chemotherapy and single-agent immunotherapy, said an expert at the Uro-Oncology Asia 2020 conference. 

“There is a need to develop combination regimens for management of mUC. Chemotherapy has reached a peak of activity of 15 months for cisplatin-eligible patients and 9 months for cisplatin-ineligible patients. While responses to anti–PD-1/PD-L1 therapy are rapid and sustained, only about 16–24 percent of patients respond to treatment,” said Dr Enrique Grande of MD Anderson Cancer Center Madrid, Spain.

“A number of agents that can potentially be used in combination are being investigated. Immunotherapy-chemotherapy combinations, immunotherapy doublets, and combinations of immunotherapy with novel targeted agents are emerging as key strategies of combining immunotherapeutic agents in management of mUC,” he suggested.

IMvigor130: Atezolizumab + chemo as first-line treatment

In the phase III IMvigor 130 trial, for example, the PD-1 inhibitor atezolizumab, given in combination with platinum-based chemotherapy (PBC), showed superior progression-free survival (PFS) compared with PBC alone in first-line treatment of patients with locally advanced or mUC. [Grande E, et al, ESMO 2019, abstract LBA14_PR]

“IMvigor130 is the first trial on first-line treatment of mUC that evaluated an immunotherapy-chemotherapy combination,” said Grande.

After a median follow-up of 11.8 months, combination therapy with atezolizumab plus PBC (arm A) demonstrated a statistically significant improvement in investigator-assessed PFS vs PBC alone (arm C) (median, 8.2 months vs 6.3 months; hazard ratio [HR], 0.82; 95 percent [CI], 0.7 to 0.96; p=0.007).

While a positive trend in overall survival (OS) was observed in arm A compared with arm C (median, 16.0 months vs 13.4 months; 95 percent CI, 0.69 to 1.00; p=0.027), the difference did not cross the prespecified interim efficacy boundary (ie, p=0.007).

Among patients with ECOG performance status (ECOG PS) of 0/1 and Bajorin risk factor score of 0/1, combination therapy was associated with numerical improvements in OS (ECOG PS 0: median, 22.0 months vs 18.2 months; HR, 0.83; 95 percent CI, 0.60 to 1.15) (ECOG OS 1: median, 14.2 months vs 10.8 months; HR, 0.78; 95 percent CI, 0.60 to 1.01) (Bajorin risk factor score 0: median, 24.5 months vs 18.2 months; HR, 0.79; 95 percent CI, 0.57 to 1.11) (Bajorin risk factor score 1: median, 15.8 months vs 12.6 months; HR, 0.80; 95 percent CI, 0.60 to 1.08) that did not reach statistical significance. “[These results show that] patients with a poor prognosis may be not the best candidates to receive immunotherapy combinations,” commented Grande.

In addition, the use of cisplatin, as compared with carboplatin, was associated with significantly improved OS among patients in arm A vs arm C (cisplatin: median, 21.7 months vs 13.4 months; HR, 0.66; 95 percent CI, 0.47 to 0.94) (carboplatin: median, 14.2 months vs 13.4 months; HR, 0.91; 95 percent CI, 0.74 to 1.14). “Maybe [this is because] cisplatin is more immunogenic than carboplatin, or because those patients [who were on cisplatin] had better prognosis,” suggested Grande.

A similar improvement in OS was demonstrated with atezolizumab monotherapy (arm B) vs chemotherapy alone among patients with PD-L1 IC 2/3 (median, not estimable vs 17.8 months; HR, 0.68; 95 percent CI, 0.43 to 1.08), but not in those with PD-L1 IC 0/1 (median, 13.5 months vs 12.9 months; HR, 1.07; 95 percent CI, 0.86 to 1.33). “This is practice-changing, from my point of view. Patients with high PD-L1 expression should receive immunotherapy, such as atezolizumab as a single agent, instead of any PBC as the first-line treatment,” said Grande.

“In terms of objective response rate [ORR], there was no difference between arm A and arm C [47 percent vs 44 percent], and the duration of response [DoR] was similar in both arms [median, 8.5 months vs 7.6 months],” he noted.

IMvigor130 enrolled 1,213 patients with locally advanced or mUC who had received no prior systemic therapy, regardless of eligibility for PBC. Patients were randomized (1:1:1) to receive atezolizumab plus PBC (gemcitabine plus cisplatin/carboplatin) (arm A; n=447), atezolizumab alone (arm B; n=369), or placebo plus platinum-based chemotherapy (PBC) (arm C; n=397). Gemcitabine 1,000 mg/m² intravenously (IV) was given on day (D) 1 and D8, carboplatin was given at AUC 4.5 IV, while cisplatin 70 mg/m² IV was administered on D1. Atezolizumab 1,200 mg IV was administered on D1 of each 3-week cycle.

Patient cohorts were relatively well-balanced. Of note, 52 percent of patients eligible for cisplatin (according to the Galsky criteria) received carboplatin as chemotherapy. “There was deviation from standard practice in some physicians, which could potentially impact survival of these patients,” commented Grande.

The safety profile of the combination therapy was consistent with the known safety profiles of the individual agents. Treatment-related adverse events (TRAEs) occurred in 34 percent of patients in both arms A and C.

“Two ongoing phase III trials, KEYNOTE-361 and NILE, are assessing the efficacy and safety of immunotherapy-chemotherapy combinations involving pembrolizumab as well as durvalumab and durvalumab plus tremelimumab vs chemotherapy alone as first-line therapy,” said Grande. [NCT02853305, NCT03682068]

Immunotherapy doublets

The efficacy and safety of immunotherapy doublets were assessed in the phase I/II CheckMate-032 trial, which compared nivolumab plus ipilimumab vs nivolumab alone in previously treated mUC patients. Patients in the trial were treated with nivolumab 3 mg/kg monotherapy Q2W (NIVO3), nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q3W for four doses followed by nivolumab monotherapy 3 mg/kg Q2W (NIVO3+IPI1), or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q3W for four doses followed by nivolumab monotherapy 3 mg/kg Q2W (NIVO1+IPI3). [J Clin Oncol 2019;37:1608-1616] “We see more responses [ORR, 38 percent for NIVO1+IPI3 vs 26.9 percent for NIVO3+IPI1 vs 25.6 percent for NIVO3] and longer OS in patients receiving doublet vs single-agent immunotherapy [median, 15.3 months for NIVO1+IPI3 vs 7.4 months for NIVO3+IPI1 vs 9.9 months for NIVO3],” pointed out Grande. [J Clin Oncol 2019;37:1608-1616]

The phase III CheckMate-901 and DANUBE trials, which evaluate nivolumab plus ipilimumab vs nivolumab plus PBC vs PBC alone, and durvalumab alone vs durvalumab plus tremelimumab vs PBC, respectively, are ongoing in patients with previously untreated, unresectable or mUC. [Galsky MD, et al, ASCO 2019, abstract TPS539; Powles T, et al, ASCO 2019, abstract TPS4574]

Combining immunotherapy with novel targeted agents

The combination of enfortumab vedotin, an antibody-drug conjugate targeting Nectin-4, with pembrolizumab has demonstrated encouraging activity, with an ORR of 71 percent in first-line treatment of cisplatin-ineligible advanced/mUC patients in the EV-103 study. The safety profile was favourable. [Holmes CJ, et al, ESMO 2019, abstract 901O]

“It seems that this combination is the most promising in this field,” pointed out Grande. “The combination works by inducing immunogenic cell death and may enhance anti-tumour activity.” [Alley SC, et al, ACCR 2019, abstract 221]

The ongoing phase III EV-302 study is evaluating enfortumab vedotin in combination with pembrolizumab with or without chemotherapy vs chemotherapy alone in 1,095 patients with previously untreated, locally advanced or mUC. “This is something we need to take into consideration in the control arm [of this study], as most likely [in practice] the standard [treatment with] chemotherapy will be followed by enfortumab vedotin plus pembrolizumab,” commented Grande.

In the BISCAY trial, an open-label, randomized, biomarker-directed, multi-arm study in mUC, a higher ORR was demonstrated with durvalumab plus olaparib (35.7 percent) compared with AZD4547 plus durvalumab (28.6 percent), vistusertib plus durvalumab (24.1 percent), durvalumab alone (27.6 percent) or AZD4547 alone (20.0 percent).

Meanwhile, the MORPHEUS-mUC trial is an umbrella study that will evaluate atezolizumab in combination with different agents (including enfortumab vedotin, niraparib, the anti-CD47 agent Hu5F9-G4, the anti-CD38 agent isatuximab, linagliptin, and tocilizumab) vs atezolizumab alone in patients with platinum-refractory mUC. [NCT04223856; NCT03869190]

Importance of biomarkers

“Tumour biomarkers should also be taken into consideration in first-line treatment of patients with mUC,” said Grande. To date, six consensus muscle-invasive bladder cancer molecular classes have been identified, with each associated with different prognoses. “[For example,] tumours with stroma-rich, basal/squamous and neuroendocrine-like features will most likely respond to immunotherapy, but confirmatory results from clinical trials are needed,” Grande suggested. [Eur Urol 2019;pii:S0302-2838(19)30695-5]