Elsevier

The Lancet Oncology

Volume 22, Issue 7, July 2021, Pages 931-945
The Lancet Oncology

Articles
Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial

https://doi.org/10.1016/S1470-2045(21)00152-2Get rights and content

Summary

Background

PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma.

Methods

KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov, number NCT02853305.

Findings

Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group.

Interpretation

The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma.

Funding

Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Introduction

Platinum-based chemotherapy has formed the basis of standard-of-care systemic treatment for advanced urothelial carcinoma for more than 40 years.1, 2 In the past 5 years, PD-1 and PD-L1 inhibitors, such as atezolizumab, avelumab, nivolumab, and pembrolizumab, have become established treatments in the post-platinum disease setting, and, most recently, avelumab was recommended as maintenance therapy for the subgroup of patients who benefit from first-line platinum-based chemotherapy.3, 4, 5, 6, 7

There is increasing evidence to support the combination of immune checkpoint inhibitors with chemotherapy to treat cancer; for example, metastatic non-small-cell lung cancer is treated with pembrolizumab plus platinum-based chemotherapy as a standard of care.8, 9 Until 2020, there had been a paucity of data on combination treatment in patients with previously untreated, advanced urothelial carcinoma. IMvigor130 is a randomised, phase 3 trial comparing atezolizumab with or without platinum-based chemotherapy versus chemotherapy in patients with previously untreated, advanced urothelial carcinoma. The trial results showed a significant improvement in investigator-assessed progression-free survival with atezolizumab plus chemotherapy versus chemotherapy alone (hazard ratio [HR] 0·82; 95% CI 0·70–0·96), but has not yet shown a significant benefit in overall survival (interim analysis HR 0·83 [95% CI 0·69–1·00]; final analysis pending).10

Pembrolizumab and atezolizumab have both been approved by the US Food and Drug Administration and the European Medicines Agency for use as monotherapy in the first-line setting for cisplatin-ineligible patients with PD-L1-positive urothelial tumours, and—in the USA and Canada—for patients ineligible for any platinum-containing regimen irrespective of PD-L1 positivity, based on single-arm phase 2 studies.11, 12, 13, 14 At a minimum follow-up of 2 years, 52 (47%) of 110 cisplatin-ineligible patients with urothelial carcinoma and a PD-L1 combined positive score (CPS) of at least 10 in the KEYNOTE-052 study achieved an overall response to pembrolizumab, and median overall survival in these patients was 18·5 months (95% CI 12·2–28·5).15 Randomised clinical trials that include a comparison of first-line, single-agent PD-L1 inhibitors (atezolizumab and durvalumab) to standard chemotherapy in patients with PD-L1-positive disease have not yet demonstrated a significant survival benefit for immune checkpoint inhibitor monotherapy over chemotherapy.10, 16

Research in context

Evidence before this study

We searched PubMed on Sept 29, 2020, with no date or language restrictions, using the search strings: “PD-1 OR PD-L1 OR pembrolizumab OR MK-3475 OR nivolumab OR BMS-936558 OR MPDL3280A OR atezolizumab OR BMS-936559 OR MEDI4736 OR durvalumab OR avelumab AND urothelial cancer” OR “PD-1 OR PD-L1 OR pembrolizumab OR MK-3475 OR nivolumab OR BMS-936558 OR MPDL3280A OR atezolizumab OR BMS-936559 OR MEDI4736 OR durvalumab OR avelumab AND bladder cancer”. We identified reports of six phase 2 or 3 clinical studies describing results of PD-1 and PD-L1 inhibitors (including atezolizumab, durvalumab, nivolumab, and pembrolizumab) for patients with metastatic urothelial carcinoma that has progressed on a previous line of chemotherapy. Additionally, we identified two phase 3 studies in untreated, advanced urothelial carcinoma: one study investigated first-line anti-PD-L1 antibody atezolizumab alone or combined with chemotherapy versus chemotherapy, and one investigated first-line anti-PD-L1 antibody durvalumab alone or in combination with the anti-CTLA-4 antibody tremelimumab versus chemotherapy. We also found one phase 3 switch maintenance study of anti-PD-L1 antibody avelumab versus best supportive care as maintenance therapy for patients who achieve at least stable disease to first-line chemotherapy. Finally, we identified two phase 2 studies, of atezolizumab monotherapy and pembrolizumab monotherapy, in cisplatin-ineligible patients with untreated, advanced urothelial carcinoma.

Added value of this study

To our knowledge, this is the first randomised phase 3 study to report final overall survival data for the combination of chemotherapy and an immune checkpoint inhibitor as a first-line treatment for advanced urothelial carcinoma. The addition of pembrolizumab to first-line chemotherapy did not significantly prolong progression-free survival or overall survival versus chemotherapy alone in the total population. Overall survival with pembrolizumab monotherapy was not formally statistically tested due to the trial design; however, it did not appear different from chemotherapy. Pembrolizumab was associated with durable responses and lower rates of any-grade and grade 3 or worse adverse events of any cause versus chemotherapy. Outcomes with pembrolizumab in patients with PD-L1 CPS of at least 10 were in line with those observed for the total population, suggesting that PD-L1 CPS could not select for clinical benefit. Exploratory analyses suggested that some patients might benefit from pembrolizumab as a first-line treatment option, although selection criteria for these patients remain unclear.

Implications of all the available evidence

The final analysis of the KEYNOTE-361 study suggests that the addition of pembrolizumab to first-line platinum-based chemotherapy does not confer survival benefits for patients with advanced urothelial carcinoma. This trial adds to the growing body of evidence showing that the combination of immune checkpoint inhibitors and chemotherapy is not associated with superior survival in this disease setting. Based on our primary findings, platinum-based chemotherapy remains the current first-line standard of care for patients able to receive it, with avelumab maintenance therapy for those who achieve a clinical benefit.

KEYNOTE-361 is a randomised, phase 3 study investigating the efficacy of pembrolizumab plus platinum-based chemotherapy versus platinum-based chemotherapy for patients with previously untreated, advanced urothelial carcinoma. Furthermore, the trial investigated outcomes with pembrolizumab monotherapy versus platinum-based chemotherapy in patients with PD-L1 CPS of at least 10 and in all treated patients irrespective of CPS.

Section snippets

Study design and patients

The KEYNOTE-361 trial was a randomised, open-label, phase 3 trial done at 201 medical centres in 21 countries (appendix pp 2–8). Patients were recruited through hospitals and clinics. Eligible patients for enrolment had to be aged at least 18 years and have a histologically or cytologically confirmed diagnosis of locally advanced, unresectable or metastatic urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra, and no previous systemic treatment for advanced disease. Urothelial

Results

1360 patients were screened for this study, of whom 349 (26%) patients did not meet trial eligibility criteria and one patient withdrew from the trial. Between Oct 19, 2016 and June 29, 2018, 1010 patients (intention-to-treat population) were randomly allocated to receive pembrolizumab plus platinum-based chemotherapy (351 [35%]), pembrolizumab monotherapy (307 [30%]), or platinum-based chemotherapy (352 [35%]; figure 1). All 1010 patients were assessed for the dual primary endpoints of the

Discussion

The KEYNOTE-361 trial did not meet the primary endpoints of superior progression-free survival and overall survival with first-line pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced urothelial carcinoma. Prespecified analyses indicated that neither PD-L1 CPS of at least 10 nor physician's choice of platinum chemotherapy seemed to be associated with improved benefit from the addition of pembrolizumab to chemotherapy. No new or unexpected safety signals were

Data sharing

Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA is committed to providing qualified scientific researchers access to anonymised data and clinical study reports from the company's clinical trials for the purpose of conducting legitimate scientific research. Merck Sharp and Dohme is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with

Declaration of interests

TP reports honoraria and research funding from Merck Sharp and Dohme (a subsidiary of Merck, Kenilworth, NJ, USA), AstraZeneca, and Roche; honoraria from BMS, Seattle Genetics, Ipsen, Merck Sharp and Dohme, Novartis, and Pfizer; fees for a consultant or advisory role for AstraZeneca, BMS, Exelexis, Incyte, Ipsen, Merck Sharp and Dohme, Novartis, Pfizer, and Seattle Genetics; and travel expenses and accommodations from AstraZeneca and Roche. TC reports research funding from Merck Sharp and

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The KEYNOTE-361 investigators are listed in the appendix (pp 2–8)

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