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First-Line Combo Boosts PFS in Untreated Bladder Cancer

— 'Clinically meaningful' trend in OS with atezolizumab-chemotherapy

MedpageToday

BARCELONA -- An immunotherapy-chemotherapy combination for untreated metastatic urothelial carcinoma improved progression-free survival (PFS) versus chemotherapy and showed a "promising trend" in the endpoint of overall survival (OS), a large randomized trial found.

Median PFS improved from 6.3 months with platinum-gemcitabine chemotherapy to 8.2 months with the same chemotherapy plus atezolizumab (Tecentriq). An interim analysis of OS showed an improvement from 13.4 to 16.0 months with atezolizumab, but the difference did not meet prespecified parameters for statistical significance.

A comparison of single-agent atezolizumab and chemotherapy showed no significant difference between treatment groups in an interim OS analysis, Enrique Grande, MD, of MD Anderson Cancer Center in Madrid, reported here at the . However, patients whose tumors had high PD-L1 expression derived substantially more benefit from immunotherapy.

"At this interim analysis, clinically meaningful improvement in overall survival was observed with atezolizumab plus chemotherapy versus placebo and chemotherapy but did not cross the prespecified interim efficacy boundary," said Grande. "The observed overall survival treatment benefit of atezolizumab monotherapy versus chemotherapy was greater in PD-L1-selected patients than in the intention-to-treat population, although not formally tested."

"Results of the support atezolizumab plus platinum-gemcitabine chemotherapy as an important new treatment option for patients with untreated metastatic urothelial carcinoma," he added.

ESMO invited discussant Thomas Powles, MD, of Barts Cancer Hospital in London, who prefaced his comments about new strategies to treat metastatic bladder cancer by saying, "We've started from a very low bar."

Until recently, chemotherapy was the only option for metastatic bladder cancer and was associated with median OS of a year or less. "When that failed, we just gave more chemotherapy," said Powles.

Both atezolizumab and pembrolizumab have FDA and European Medicines Agency approval as second-line therapy, following first-line cisplatin chemotherapy and as first-line therapy for patients who are ineligible for cisplatin. IMvigor130 sought to move past consideration of platinum-sensitivity status by adding upfront immunotherapy to platinum-containing chemotherapy.

"Does this change practice?" Powles asked. "Well, there is a significant delay in PFS, but how meaningful is that? OS is trending in the right way but not significant yet. Response rates weren't very different from one another. As such, it's hard to argue that the two [therapies] are synergistic together."

With those caveats, Powles said the atezolizumab combination looked "very acceptable, and I'm really looking forward to the quality-of-life data in the future."

IMvigor130 involved 1,200 patients with newly diagnosed metastatic urothelial carcinoma, making it the largest such trial ever conducted, said Grande. Investigators in the multicenter, multinational trial randomized patients to one of three treatment arms:

  • Atezolizumab plus platinum (cisplatin or carboplatin)-gemcitabine chemotherapy
  • Atezolizumab monotherapy
  • Placebo plus platinum-gemcitabine chemotherapy

The trial had coprimary endpoints:

  • Investigator-assessed PFS and OS in the atezolizumab combination arm versus the chemotherapy-placebo arm
  • OS for the comparison of single-agent atezolizumab versus placebo-chemotherapy

The primary analysis showed that adding atezolizumab to chemotherapy reduced the PFS hazard by 18% versus chemotherapy and achieved statistical significance (P=0.007). The atezolizumab combination also reduced the survival hazard by 17%. The difference was associated with a P-value of 0.027, which did not meet prespecified statistical requirements significance. Nonetheless, the OS finding "is remarkable, considering that 20% of patients in the chemotherapy arm crossed over to immunotherapy at progression," said Grande.

The interim OS analysis of single-agent atezolizumab versus chemotherapy showed no difference between the groups (13.1 vs 15.7 months, HR 1.02, 95% CI 0.83-1.24). The immunotherapeutic agent performed better in patients with high PD-L1 (17.8 months vs not evaluable, HR 0.68), but that analysis was not formally tested in the trial, Grande noted.

As Powles pointed out, the objective response rates with atezolizumab-chemotherapy (47%) and chemotherapy-placebo (44%) were similar, as was median duration of response (8.2 vs 7.6 months). Atezolizumab monotherapy achieved fewer responses (23%), but they tended to be more durable. The median had yet to be reached, but the low end of the confidence intervals was 15.9 months.

Adverse events, treatment-related adverse events, grade 3/4 adverse events, and serious adverse events occurred in a similar proportion of patients treated with atezolizumab-chemotherapy or chemotherapy-placebo. Rates were substantially lower with single-agent atezolizumab.

  • author['full_name']

    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined 鶹ý in 2007.

Disclosures

The study was supported by Hoffmann-La Roche.

Grande disclosed relationships with Pfizer, Bristol-Myers Squibb, Ipsen, Roche, Eisai, EUSA Pharma, MSD, Sanofi Genzyme, Adacap, Novartis, Fabre, Lexicon, Celgene, Astellas, Janssen, Bayer, and Molecular Templates.

Primary Source

European Society for Medical Oncology

Grande E, et al "IMvigor130: A phase III study of atezolizumab with or without platinum-based chemotherapy in previously untreated metastatic urothelial carcinoma" ESMO 2019; Abstract LBA14_PR.