First-line immune-combination therapies in mUC

Two trials, KEYNOTE-361 and DANUBE, explored the efficacy of first-line treatment of patients with metastatic urothelial cancer (mUC) with an immune checkpoint inhibitor combined with either chemotherapy or a second immune checkpoint inhibitor. None of the studies met its endpoint.

The current first-line treatment for mUC is platinum-based chemotherapy or best supportive care in case of platinum-ineligibility. Recently, monotherapy with pembrolizumab and atezolizumab were approved for patients with PD-L1 positive disease [1,2].

In the open-label, phase 3 KEYNOTE-361 study, 1,010 patients with unresectable or mUC and who had no prior systemic therapy for advanced disease were 1:1:1 randomised to receive pembrolizumab (200 mg every 3 weeks up to 35 cycles), pembrolizumab plus chemotherapy (gemcitabine plus cisplatin or carboplatin) or chemotherapy [3]. Median progression-free survival (PFS) was 8.3 months in the pembrolizumab plus chemotherapy arm versus 7.1 months in the chemotherapy arm (HR 0.87; P=0.0033, not statistically significant according to prespecified boundaries). Median overall survival (OS) was 17.0 months in the pembrolizumab plus chemotherapy arm versus 14.3 months in the chemotherapy arm (HR 0.86; P=0.0407, not statistically significant according to prespecified boundaries). Formal statistical testing was not performed for pembrolizumab versus chemotherapy due to prespecified statistical design. However, pembrolizumab did not appear superior to chemotherapy.

In DANUBE, 1,032 patients with unresectable or mUC and no prior systemic therapy for advanced disease were 1:1:1 randomised to durvalumab (1,500 mg every 4 weeks), durvalumab plus tremelimumab (75 mg every 4 weeks up to 4 doses), or chemotherapy (gemcitabine plus cisplatin or carboplatin up to 6 cycles) until disease progression or unacceptable toxicity [4]. Median OS was not significantly different between durvalumab and chemotherapy among patients with high PD-L1 expression (14.4 months vs 12.1 months; HR 0.89; P=0.3039). OS rates at 24 months were 36% and 29% in the durvalumab and chemotherapy arm, respectively. OS rates at 24 months were 39% and 29% in the durvalumab plus tremelimumab arm and chemotherapy arm, respectively. No statistically significant difference in median OS was found either between durvalumab plus tremelimumab versus chemotherapy in the ITT population (HR 0.85; P=0.075). Both experimental arms had lower grade 3 and 4 toxicity than chemotherapy.

Primary results of the IMvigor130 trial, a phase 3 trial of atezolizumab plus platinum-based chemotherapy versus placebo plus platinum-based chemotherapy in previously untreated patients with locally advanced or mUC, were recently published [5]. In short, atezolizumab significantly increased median PFS from 6.3 to 8.2 months (HR 0.82; P=0.007). Final analysis of OS is pending. Atezolizumab plus chemotherapy was well tolerated. In this study, patient-reported outcomes were also measured, using EORTC QLQ-C3, during treatment (day 1 of every cycle), at treatment discontinuation, and every 3 months during follow-up [6]. Completion rates were 86% at baseline and >70% until week 66 in both arms. Patients in both arms similarly reported nominal changes (either maintaining pre-treatment levels or improvements) in most symptoms, functions, and quality of life domains, suggesting positive impact of treatment overall. So, addition of atezolizumab to chemotherapy resulted in improved PFS without compromising patients’ quality of life.

1. Balar AV, et al. Lancet Oncol 2017;18:1483-1492.
2. Balar AV, et al. Lancet 2017;389:67-76.
3. Alva A, et al. Pembrolizumab (P) combined with chemotherapy (C) vs C alone as first-line (1L) therapy for advanced urothelial carcinoma (UC): KEYNOTE-361. ESMO 2020 Virtual Meeting, abstract LBA23.
4. Powels T, et al. A phase III, randomized, open-label study of first-line durvalumab (D) with or without tremelimumab (T) vs standard of care chemotherapy in patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE). ESMO 2020 Virtual Meeting, abstract 697O
5. Galsky MD, et al. Lancet 2020;395:1547-1557.
6. Bamias A, et al. Patient-reported outcomes (PROs) from IMvigor130: A global, randomised, partially blinded phase III study of atezolizumab (atezo) + platinum-based chemotherapy (PBC) vs placebo (PBO) + PBC in previously untreated locally advanced or metastatic urothelial carcinoma (mUC). ESMO 2020 Virtual Meeting, abstract 698O.

Posted on 25 November, 20204 September, 2023