BACKGROUND-Patients with advanced urothelial carcinoma that progresses after platinumbased chemotherapy have a poor prognosis and limited treatment options.
Summary
Background
First-line chemotherapy for patients with cisplatin-ineligible locally-advanced or metastatic urothelial carcinoma (mUC) is associated with short response duration, poor survival, and high toxicity. This multicenter, 2-cohort phase 2 study evaluated atezolizumab (anti–programmed death-ligand 1 [PD-L1]) as treatment for mUC in this setting, as well as in later lines.
Methods
In a cohort of previously untreated patients who were cisplatin ineligible, atezolizumab was given 1200 mg every 3 weeks until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria In Solid Tumors v1.1 (central review), evaluated in pre-specified subgroups based on PD-L1 expression and in all patients. Secondary endpoints included response duration, progression-free survival, overall survival, and safety. Exploratory analyses included biomarker correlates of response and survival. This study is registered with ClinicalTrials.gov, number NCT02108652.
Findings
Of 119 patients who received atezolizumab in the first-line setting, 83 (70%) had baseline renal impairment, and 24 (20%) had Eastern Cooperative Oncology Group performance status 2. At 17·2 months’ median follow-up, the objective response rate was 23% (95% CI 16–31), the complete response rate was 9%, and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months. Median overall survival was 15·9 months. Tumour mutation load was associated with response. Treatment-related adverse events ≥10% were fatigue, diarrhoea, and pruritus. One treatment-related death (sepsis) occurred. Nine patients (8%) had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients.
Interpretation
Atezolizumab demonstrated encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated mUC.
Funding
F. Hoffmann-La Roche Ltd./Genentech, Inc., a member of the Roche Group.
Summary
Somatic mutations of ERBB2 (HER2) and
ERBB3 (HER3) are found in a wide range of cancers.
Preclinical modelling suggests that a subset lead to constitutive HER2
activation, but most remain biologically uncharacterized. We sought to
prospectively define the biologic and therapeutic significance of known
oncogenic HER2 and HER3 mutations and variants of unknown biological
significance by conducting a multi-histology, genomically selected,
‘basket’ study utilizing the pan-HER kinase inhibitor neratinib
(SUMMIT; Clinicaltrials.gov NCT01953926). Efficacy in HER2-mutant cancers varied
as a function of both tumour type and mutant allele to a degree not predicted by
preclinical models, with the greatest activity seen in breast, cervical and
biliary cancers and with tumours harbouring kinase domain missense mutations.
This study demonstrates how a molecularly driven clinical trial can be used to
further refine our biological understanding of both characterized and novel
genomic alterations with potential broad applicability for advancing the
paradigm of genome-driven oncology.
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