Treatment with atezolizumab plus chemotherapy extended progression-free survival by 1.9 months vs chemotherapy alone in patients with metastatic urothelial cancer, according to the early results of the IMvigor130 trial, which were presented at the European Society for Medical Oncology (ESMO) Congress 2019.¹ The combination did not significantly extend overall survival at this early time point.

“IMvigor met the co-primary endpoint of progression-free survival in metastatic urothelial cancer for the combination of atezolizumab plus chemotherapy vs chemotherapy alone. The interim analysis showed a clinically meaningful [but not statistically significant] improvement in overall survival vs chemotherapy in patients selected for PD-L1 [programmed cell death ligand 1] expression,” said lead author Enrique Grande, MD, PhD, Head of the Medical Oncology Service and Clinical Research at the MD Anderson Cancer Centre, Madrid. “These results support the use of atezolizu-mab plus chemotherapy as a new option in patients with metastatic urothelial cancer,” he stated.

It is interesting to note … that patients overexpressing PD-L1 may benefit more from single-agent atezolizumab vs standard chemotherapy.

— Enrique Grande, MD, PhD

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Other experts were more cautionary in their appraisal of these study results. Press conference moderator Ignacio Duran, MD, of the Hospital Universitario Marques de Valdecilla-IDIVAL, Santander, Spain, said that the data look promising, but longer follow-up is needed. “We knew this combination worked in other tumor types, and we had a lot of hope. This is the first important signal that adding immunotherapy to chemotherapy might work better in a number of patients. Nevertheless, we need longer follow-up to confirm these striking findings,” Dr. Duran said.

“The complete responses were around twice as likely with the combination as with chemotherapy or immunotherapy alone. We are now eager to see if patients receiving the combination live longer with a similar quality of life as those receiving chemotherapy or immunotherapy alone or sequentially. The interim analysis of overall survival seems to be promising, but data are immature. Overall survival data are needed to consider the combination of chemotherapy and immunotherapy as a new standard of care,” Dr. Duran stated.

Ignacio Duran, MD

Cisplatin chemotherapy has been the standard of care for metastatic urothelial carcinoma for 30 years, but up to 50% of patients are ineligible for platinum treatment. “Our only achievement over this time is better selection for cisplatin. Patients who are eligible for cisplatin have a better prognosis. The median overall survival for eligible patients is 15 months, whereas it is 9 months for ineligible patients,” Dr. Grande told listeners.

Atezolizumab is currently approved by the U.S. Food and Drug Administration for the front-line treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy regardless of PD-L1 status. The PD-L1 inhibitor is also indicated for the treatment of patients with locally advanced or metastatic urothelial cancer whose disease progressed during or after platinum-based chemotherapy, or within 12 months of receiving a platinum-containing chemotherapy, either before or after surgery.

IMvigor is the largest trial of immunotherapy in metastatic urothelial cancer. It also is the first trial to study the combination of immunotherapy (already approved for platinum-ineligible patients) plus chemotherapy in both platinum-eligible and -ineligible patients.

IMvigor130 Details and Key Findings

IMvigor130 randomly assigned 1,213 patients with metastatic urothelial cancer in a 1:1:1 ratio to treatment with atezolizumab plus platinum-based chemotherapy (arm A); atezolizumab alone (arm B); or placebo plus platinum-based chemotherapy (arm C). Patients were stratified for PD-L1 expression and investigator’s choice of chemotherapy.

The study had two primary endpoints: progression-free survival (arm A vs arm C) and overall survival (arm B vs arm C). At a median follow-up of 11.8 months, the median progression-free survival was 8.2 months in arm A and 6.3 months in arm C—a modest yet statistically significant improvement of almost 2 months (P = .007).

An interim analysis of survival showed a median overall survival of 16 months in arm B with atezolizumab alone vs 13.4 months in arm A (the combination) and arm C (chemotherapy alone). The P value did not cross the prespecified boundary for statistical significance.

Of study participants, 24% had high PD-L1 expression (IC 2/3), and this group had an improvement in overall survival if they received single-agent atezolizumab compared with chemotherapy/placebo: median overall survival of 17.8 months for chemotherapy/placebo vs not evaluable for atezolizumab. In the subgroup with low PD-L1 expression (IC 0/1), the median overall survival was 13.5 months with single-agent atezolizumab vs 12.9 months with chemotherapy/placebo.

“It is interesting to note, and probably practice-changing, that patients overexpressing PD-L1 may benefit more from single-agent atezolizumab vs standard chemotherapy. Other patients benefit from the combination. The data are promising, and this approach may allow patients to be spared chemotherapy,” Dr. Grande said.

The objective response rates in arms A, B, and C were 47%, 23%, and 44%, respectively. The complete response rates were 13%, 6%, and 7%, respectively. Adverse events leading to treatment discontinuation were reported in 34%, 6%, and 34% of arms A, B, and C, respectively. ■

DISCLOSURE: IMvigor130 was funded by F. Hoffmann–La Roche. Dr. Grande reported financial relationships with Pfizer, Ipsen, Bristol-Myers Squibb, Eisai, Roche, Adacap, EUSA Pharma, Pierre Fabre, Lexicon, Celgene, and AstraZeneca. Dr. Duran reported institutional financial relationships with Astra-Zeneca and Roche; served as an advisor/board member for Roche, BMS, MSD, Pharmacyclycs, Jansen, Ipsen, and Novartis; has received honoraria from Roche, BMS, MSD, Jansen, Ipsen, Novartis, and Astellas; and has received travel/accommodation expenses from Ipsen and Astra-Zeneca.

REFERENCE

1. Grande E, Galsky M, Arranz-Arija JA, et al: IMvigor130: Efficacy and safety from a phase 3 study of atezolizumab as monotherapy or combined with platinum-based chemotherapy versus placebo and platinum-based chemotherapy in previously untreated advanced or metastatic urothelial carcinoma. 2019 ESMO Congress. Abstract LBA14_PR. Presented September 30, 2019.