First-line pembrolizumab feasible for cisplatin-ineligible advanced urothelial cancer patients
medwireNews: Advanced urothelial carcinoma patients who are unsuitable for platinum-based chemotherapy could benefit from first-line pembrolizumab, suggest phase II results reported at the American Society of Clinical Oncology 2017 annual meeting in Chicago, Illinois, USA.
The KEYNOTE-052 trial findings demonstrate efficacy among 370 patients with metastatic disease who were ineligible for cisplatin because of ECOG performance status, heart failure, creatinine clearance rate, neuropathy, or hearing loss.
Best supportive care is a “reasonable option” for patients unable to tolerate cisplatin as alternative therapies have shown poorer outcomes with greater toxicity, the presenter said, although he noted that atezolizumab has showed anti-tumor activity in the IMvigor21 study of platinum-eligible urothelial carcinoma patients, with an objective response rate (ORR) of 23%.
An objective response to pembrolizumab 200 mg given every 3 weeks was achieved by 29% of the patients by the data cutoff in March 2017. After a median of 2.0 months of treatment, 7% of patients had a complete response and 22% a partial response, with an ongoing response in 67% patients – median duration of response has not yet been reached.
Notably, the ORR was retained in subgroup analysis for patients aged 85 years and older versus young individuals, and for patients with an ECOG performance status of 2 versus 0–1, Peter O’Donnell, from The University of Chicago Medical Center in Illinois, USA, told the meeting.
But “quite predictably”, patients with liver metastases had a poorer ORR than those without, while patients with lymph node metastases had a “somewhat higher” ORR than those with visceral disease, he remarked.
“[T]he results confirm that first-line pembrolizumab elicits clinically meaningful, durable antitumor activity in cisplatin-ineligible patients with advanced urothelial cancer,” the presenter said.
Analysis of programmed cell death ligand 1 (PD-L1) expression in a training set of patients indicated that the 30 participants with a combined positive score (CPS) of 10% or higher had an ORR of 37% versus 17% for the 66 patient with a CPS of below 10%. The corresponding values for the validation study groups were 51% of 80 patients and 23% of 185 patients.
The treatment-related side effects were as those previously described for pembrolizumab, with 66% of patients experiencing any grade of adverse event and 19% a grade 3–5 event, “suggesting tolerability of pembrolizumab,” O’Donnell said.
“Importantly, only 7% of patients discontinued treatment because of treatment-related adverse events,” he emphasized. “This is a rate that that would be approximately only one third of that traditionally described for gemcitabine–carboplatin.”
Analysis using an 18-gene, T-cell inflamed, gene expression profile (GEP) of pretreatment samples of 278 patients showed that those who responded to treatment had a significantly higher score than nonresponders. Indeed, all 18 genes were individually significantly associated with response, the presenter reported.
There was also significant agreement for the area under the receiver operating characteristic curve for overall response when it was plotted against both the PD-L1 CPS and against the GEP.
O’Donnell showed what happened when data for patients who did and did not respond to pembrolizumab were plotted in a graph for PD-L1 CPS score versus GEP score, including for 41 patients above the 10% CPS cutoff for PD–L1. Using a suggested GEP threshold of –0.318, the large majority of patients who responded had a GEP score above the cut point, as did an additional 31 of 81 responding patients who had a CPS score of less than 10%.
Thus, “an appreciable number of additional responders were captured using the T-cell inflamed GEP as compared with the PD-L1 [immunohistochemical] biomarker,” O’Donnell concluded.
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