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Phase III Trial Suggests Tecentriq Survival Benefit in Bladder Cancer Subgroup

Update: The Ventana's PD-L1 (SP142) Assay was classified as a complementary diagnostic for atezolizumab when the drug was granted accelerated approval from the US Food and Drug Administration in 2016. It has since become a companion diagnostic for the drug in urothelial and other cancers.

BARCELONA – Initial findings from a Phase III trial suggest that combination treatment with chemotherapy and the anti-PD-L1 immune checkpoint drug atezolizumab (Genentech's Tecentriq) may benefit patients with untreated, metastatic forms of urothelial carcinoma, while atezolizumab monotherapy may help those with increased PD-L1 levels in their tumors.

For the IMvigor130 trial, investigators began by randomizing 129 individuals with locally advanced or metastatic disease at a two-to-one ratio to receive either combination atezolizumab-chemotherapy or chemotherapy with placebo, respectively, explained Enrique Grande, head of medical oncology at the MD Anderson Cancer Center Madrid, who presented at the European Society for Medical Oncology Congress here this week.

Eventually, though, the protocol was tweaked to include a third arm — atezolizumab monotherapy — and the remaining metastatic UC (mUC) patients were randomized equally to each. Based on data for 1,213 mUC patients, the trial met its primary endpoint of enhanced progression-free survival, Grande said.

In 451 mUC patients treated with atezolizumab and chemotherapy, the team saw disease progression in 334 patients after an average follow-up time of 11.8 months, while 326 of 400 chemotherapy plus placebo patients progressed. That translated into an average progression-free survival time of 8.2 months in the immunotherapy-chemo combination arm compared to 6.3 months in the chemotherapy arm.

An interim analysis of overall survival, one of the trial's secondary endpoints, hinted that the immunotherapy plus chemotherapy arm might have a slightly lower risk of death compared to the placebo-chemotherapy group, Grande reported, though the difference between these treatment arms was not significant at that time point.

At data cutoff, 235 of the 451 — or 52 percent — of the combination-treated mUC patients had died, as had 57 percent of patients receiving the placebo with chemotherapy. Based on these data, the team estimated an average overall survival time of 16 months with the immunotherapy-chemotherapy combination versus 13.4 months with chemotherapy, though a final analysis of overall survival will not be done until there are additional deaths.

After stratifying their survival analysis based on tumor PD-L1 expression, however, the investigators saw early clues that the atezolizumab monotherapy might outpace chemotherapy-placebo in the subset of patients with PD-L1-high tumors.

Survival dropped 49 percent in the 85 PD-L1-high patients receiving chemotherapy compared to 38 percent of those on atezolizumab alone after 11.8 months of average follow up, though it remains to be seen whether that apparent survival advantage will persist.

In contrast, the overall survival rates were similar between the PD-L1-low patients treated with atezolizumab monotherapy or with chemotherapy and placebo, Grande said.

"It seems that patients over-expressing PD-L1 may benefit more, in terms of overall survival, with atezolizumab as a single agent over standard chemotherapy," Grande told reporters during a press briefing on Monday. "The hazard ratio for overall survival in this patient population was 0.68 — not statistically significant at this time, but very promising and probably clinically meaningful in this setting."

If that finding does hold in the longer term, he explained, clinicians might have an immunotherapy treatment option that allows a subset of mUC patients to forego chemotherapy, which was associated with higher rates of treatment withdrawal alone or in combination than the atezolizumab monotherapy.

"We have been treating our patients with bladder cancer with cisplatin-based chemotherapy since the 80s, with no major improvements at all in efficacy," Grande said. "During the last three or four decades, the only thing we could achieve was to select patients according to their eligibility to receive cisplatin or not."

For the mUC patients who are eligible to receive the cisplatin-based combination, he noted that the survival rates on average have been around 15 months, adding that those treated with non-cisplatin chemotherapy typically fare even worse.

The IMvigor130 trial included patients treated with either cisplatin plus gemcitabine, or carboplatin plus gemcitabine chemotherapy, depending on their eligibility and their clinicians' choice.

"Those patients that are eligible to receive cisplatin have a better prognosis than those patients that are not," Grande said, noting that the both the US Food and Drug Administration and the European Medicines Agency revised labeling for atezolizumab and pembrolizumab (Keytruda from Merck) last year to include locally advanced or metastatic patients who are not eligible for cisplatin-based treatment.

In 2016, the FDA granted accelerated approval to atezolizumab for the treatment of metastatic urothelial carcinoma cases that advanced on or after chemotherapy, and approved Ventana's PD-L1 (SP142) Assay as a complementary diagnostic for the drug.

Ignacio Duran, with the Hospital Universitario Marques de Valdecilla, who was not involved in IMvigor130, noted that the potential overall survival benefit for mUC patients with enhanced PD-L1 expression in their tumors is "a very important signal that needs, probably, a little bit more maturity."

In addition to that trend in the checkpoint immunotherapy alone arm, Duran told reporters, results from the trial suggest that atezolizumab in combination with chemotherapy provided a "very powerful" progression-free survival benefit.

Commenting on the IMvigor130 results during a presentation at ESMO, Thomas Powles, a genitourinary oncology research at the Queen Mary University of London's Barts Cancer Institute and director of the Barts Cancer Centre, said that overall survival is "trending in the right direction" despite being immature.

Powles also noted that the PD-L1 biomarker did not appear to be as informative in the immunotherapy plus chemotherapy combination arm of the trial as it appeared to be in the monotherapy arm.