The first-line combination of atezolizumab (Tecentriq) and chemotherapy led to an improvement in median progression-free survival compared with placebo/chemotherapy in patients with locally advanced or metastatic urothelial carcinoma.
Enrique Grande, MD
The first-line combination of atezolizumab (Tecentriq) and chemotherapy led to a 1.9-month improvement in median progression-free survival (PFS) compared with placebo/chemotherapy in patients with locally advanced or metastatic urothelial carcinoma, but it did not show a statistically significant improvement in overall survival (OS), according to results of the phase III IMvigor130 trial presented at the 2019 ESMO Congress.
At a median follow-up of 11.8 months, the final median PFS was 8.2 months with atezolizumab plus chemotherapy compared with 6.3 months with chemotherapy plus placebo, leading to an 18% reduction in the risk of disease progression or death (HR, 0.82; 95% CI, 0.70-0.96; one-sided P = .007).
However, at the interim analysis, the median OS was 16.0 months and 13.4 months with atezolizumab/chemotherapy and placebo/chemotherapy, respectively (HR, 0.83; 95% CI, 0.69-1.00; one-sided P = .027), which was clinically meaningful, but did not cross the prespecified interim efficacy boundary for significance.
“The IMvigor130 trial met the co-primary endpoint of PFS in those patients with metastatic bladder cancer who received the combination of atezolizumab plus chemotherapy versus chemotherapy,” said lead study author Enrique Grande, MD, head of the Medical Oncology Service, head of Clinical Research of the MD Anderson Foundation Spain, MD Anderson Cancer Centre Madrid, Spain, in a press conference during the meeting.
“At this interim analysis, we observed a clinically meaningful improvement in OS for the combination arm versus chemotherapy,” he added. “There was an OS benefit in the atezolizumab monotherapy arm in patients expressing PD-L1. The results of the IMvigor130 trial support the use of atezolizumab plus chemotherapy as an important new treatment option for patients with metastatic urothelial carcinoma.”
Atezolizumab is currently approved by the FDA for the frontline treatment of patients with locally advanced or metastatic urothelial cancer who are ineligible for cisplatin-containing chemotherapy and whose tumors express PD-L1, or those who are not eligible for any platinum-based 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.
IMvigor130 is the first trial to evaluate the combination of immunotherapy and chemotherapy in patients with metastatic urothelial cancer who are eligible and ineligible for chemotherapy.
In the international phase III IMvigor130 trial, investigators randomized 1213 patients 1:1:1 to receive atezolizumab plus platinum-based therapy and gemcitabine (arm A; n = 451), atezolizumab monotherapy (arm B; n = 362), or placebo plus platinum-based therapy and gemcitabine (arm C; n = 400). Grande noted that the first 129 patients were randomized 2:1 to arm A and arm C as per the initial trial design, and arm B enrolled patients later.
To be eligible for enrollment, patients with locally advanced or metastatic urothelial cancer could not have received prior systemic therapy in the metastatic setting, must have had an ECOG performance status ≤2, and have been eligible for platinum-based therapy in the first-line setting.
Patients were stratified by PD-L1 IC status (IC0 vs IC1 vs IC2/3); Bajorin risk factor score, including Karnofsky performance score <80% versus ≥80% and the presence of visceral metastases; and investigator’s choice of chemotherapy, which included gemcitabine/carboplatin or gemcitabine/cisplatin.
The co-primary endpoints were investigator-assessed PFS and OS in arm A versus arm C, and OS in arm B versus arm C with a hierarchical approach. Key secondary endpoints included investigator-assessed overall response rate (ORR) and duration of response, PFS and OS in arm B versus arm C in the PD-L1 IC2/3 subgroup, and safety.
Results showed that, in the intent-to-treat population, the median OS with atezolizumab monotherapy was 15.7 months and was 13.1 months for chemotherapy/placebo (HR, 1.02; 95% CI, 0.83-1.24).
Data also showed that when stratified by PD-L1 expression status, patients with PD-L1—positive tumors (IC2/3) had an improvement in OS when treated with single-agent atezolizumab compared with chemotherapy/placebo (HR, 0.68; 95% CI, 0.43-1.08). Specifically, the median OS with the PD-L1 inhibitor was not estimated and was 17.8 months with chemotherapy. However, this was not formally tested, Grande added.
“Very interestingly, and probably practice-changing, it seems that patients who overexpress PD-L1 may experience an OS benefit with atezolizumab as a single agent versus standard chemotherapy,” said Grande. “[While] it is not statistically significant at this time, it is very promising and probably clinically meaningful in this setting; these results may allow patients to not receive chemotherapy.”
In the PD-L1 IC0/1 subgroup, the median OS was 13.5 months with single-agent atezolizumab versus 12.9 months with chemotherapy/placebo (HR, 1.07; 95% CI, 0.86-1.33).
The ORRs in arms A, B, and C were 47%, 23%, and 44%, respectively, and the complete response rates were 13%, 6%, and 7%.
Regarding safety, Grande said that the immunotherapy/chemotherapy combination was well tolerated and each agent’s profile was consistent with what has been previously reported. Adverse events that led to treatment withdrawal occurred in 34% of the patients on arm A, 6% of those on arm B, and 34% of patients on arm C.
OS data will continue to be followed, concluded Grande, who added that the longer follow-up is necessary for those data to mature and biomarker work is also ongoing.
“IMvigor130 comes to answer a question that has been around for several years: whether or not the addition of immunotherapy to chemotherapy could improve outcomes in patients with metastatic urothelial cancer,” commented Ignacio Durán, MD, PhD, Department of Medical Oncology at the Hospital Universitario Marques de Valdecilla-IDIVAL, in Santander, Spain, during the press conference.
“What Grande presented is the first signal, which suggests that probably adding immunotherapy to chemotherapy might work better than chemotherapy alone in several patients,” he said. “It’s a very important signal that probably needs a little bit of maturity, but we're seeing a very powerful benefit in terms of PFS and a trend in OS that we [hope] to confirm over time.”
Grande E, Galsky MD, Arranz Arija JA, et al. IMvigor130: a phase III study of atezolizumab with or without platinum-based chemotherapy in previously untreated metastatic urothelial carcinoma. Presented at: 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract LBA14.