'Really Durable Benefit' Emerging With Bladder Cancer ImmunoTx

Some of the 'Most Mature Data in Modern Immunotherapy'

Nick Mulcahy

February 16, 2018

SAN FRANCISCO — Immunotherapy is showing "really durable benefit" in patients with bladder cancer, experts said here at the Genitourinary Cancers Symposium (GUCS) 2018. Some patients are living much longer through immunotherapy than through chemotherapy — which is demonstrated by the "tail" at the end of overall survival curves from clinical trials.

The latest data come from long-term results from the KEYNOTE 045 trial, which shows ongoing superiority for immunotherapy with pembrolizumab (Keytruda, Merck) in comparison with chemotherapy in the treatment of locally advanced and metastatic bladder cancer.

This trial was the basis for the approval last year of pembrolizumab for the second-line treatment of advanced bladder cancer, also known as urothelial cancer.

That 2017 approval was based on interim data from a median follow-up of 14 months, which showed that median overall survival was significantly longer with pembrolizumab vs investigator's choice of chemotherapy (10.3 v 7.3 months; P = .002).

Those results were published in the New England Journal of Medicine (NEJM).

Here at the GUCS 2018, lead study author Joaquim Bellmunt, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, reported data from a median of 27.7 months' follow-up. The median overall survival difference continued, with pembrolizumab once again showing significantly more benefit than chemotherapy (10.3 vs 7.3 months; P = .00017).

Bellmunt also noted that at a median follow-up of 24 months (a standard timepoint), 27% of patients in pembrolizumab arm were still alive, vs 14.3% in the chemotherapy arm.

"The 2-year survival rate is similar to what has been seen with other immune-sensitive cancers, such as melanoma," he said.

The discussant for this paper, Robert J. Jones, MD, PhD, of the University of Glasgow and Beatson West of Scotland Cancer Center, United Kingdom, put the results into a wider context.

"Why is this exciting?" asked Jones. Because "this is some of the most mature data we have in the modern era of immunotherapy," he answered.

Overall survival curves in metastatic cancer treatment trials inevitably go down with time, explained Jones: "There's a predictable decay."

But, in KEYNOTE-045, as has been seen in clinical trials of immunotherapy in melanoma, the overall survival curves show "a settling down at about the 20% mark," he explained, referring to the percentage of patients who live on thanks to treatment.

In these Kaplan-Meier curves, there is a steady drop in the percentage of patients who are still alive over time. The curve eventually flattens out and stabilizes as the durable benefit emerges (the term "tail" refers to straightening that is seen at the bottom of the curve).

The holy grail here is that we might be able to achieve this really durable benefit — albeit with a subgroup of patients. Dr Robert Jones

"This is the paradigm shift...with immunotherapy. The holy grail here is that we might be able to achieve this really durable benefit — albeit with a subgroup of patients with urothelial cancer," he said.

Jones illustrated the point by showing Kaplan-Meier curves from the pivotal ipilimumab (Yervoy, Bristol-Myers Squibb) trial in melanoma, in which there was a long-lasting survival tail for a little less than 20% of the study population, starting at about 20 months.

About the KEYNOTE 045 trial, he said: "The data we are seeing today are in keeping with the possibility that we might be seeing a similar long-term tail...of survival of patients with urothelial cancer."

Elizabeth Plimack, MD, a urologic oncologist at Fox Chase Cancer Center in Philadelphia, Pennsylvania, who is a KEYNOTE 045 investigator, is a believer in the effect.

At GUCS 2018, she tweeted: "...looks like there's a real tail on the [survival] curve for pembrolizumab post-platinum in metastatic bladder cancer, especially for the 20% who respond."

Further Details

Bellmunt offered more of the latest information on the durability of the effects of pembrolizumab in KEYNOTE 045.

The median duration of response has not been reached for pembrolizumab (it is 4.4 months for chemotherapy). "At least more than 50% of patients [who respond] have maintained their response," he observed.

A greater proportion of responses lasted ≥12 months with pembrolizumab vs chemotherapy (68% vs 35%).

The objective response rate continues to be greater with pembrolizumab than with chemotherapy (21% vs 11%), he added.

In comparison with patients who received chemotherapy, fewer patients who received pembrolizumab experienced a treatment-related adverse event of any grade (62.0% vs 90.6%), and fewer experienced adverse events of grade 3 or higher (16.5% vs 50.2%). The toxicity profile remained the same as that reported in the 2017 NEJM article, said Bellmunt.

On the basis of findings from the phase 2 KEYNOTE-052 trial, pembrolizumab was approved as a frontline therapy for patients with urothelial carcinoma.

Dr Bellmunt is a paid consultant to Merck, who sponsored the trial, and has financial ties to multiple other drug companies. Dr Jones has financial ties with multiple pharmaceutical companies.

Genitourinary Cancers Symposium (GUCS) 2018. Abstract 410, presented February 9, 2018.

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