Metastatic bladder cancer: Atezolizumab prolongs PFS in first-line therapy when added to chemotherapy

The PD-L1 inhibitor atezolizumab, when added to chemotherapy, prolonged the progression-free survival of untreated patients with metastatic bladder cancer from 6.3 to 8.2 months compared to chemotherapy.

Overall survival data are not yet mature

The PD-L1 inhibitor atezolizumab, when added to chemotherapy, prolonged the progression-free survival of untreated patients with metastatic bladder cancer from 6.3 to 8.2 months compared to chemotherapy. This was the finding of the IMvigor130 Phase 3 study presented by Enrique Grande, MD Anderson Cancer Center, Madrid (Spain), at the ESMO 2019 Congress in Barcelona, Spain.

For more than 30 years, cisplatin-based chemotherapy has been standard in first-line treatment of metastatic bladder cancer. However, about 50% of patients are not suitable for cisplatin therapy and are treated with less effective carboplatin-based regimens. PD-L1 and PD1 inhibitors are expected to provide new therapeutic options for this disease.

In the international multicenter randomized phase-3 study IMvigor 130, the efficacy and tolerability of platinum-based chemotherapy without and with atezolizumab, as well as atezolizumab monotherapy in the treatment of untreated metastatic bladder cancer, were compared in a partially blinded way. A total of 1,213 patients were enrolled in the study and treated as follows:

Coprimary endpoints of the study are progression-free survival (PFS) and overall survival of combination therapy (arm A) versus chemotherapy alone (arm C) and overall survival (OS) of atezolizumab monotherapy (arm B) versus chemotherapy alone (arm C).

Combination therapy prolongs PFS

Treatment with atezolizumab plus chemotherapy extended the PFS from 6.3 to 8.2 months compared to chemotherapy alone, which corresponds to a risk reduction of 18% (hazard ratio 0.82, p = 0.007). The OS at interim analysis was 16.0 months in arm A versus 13.4 months in arm C (HR 0.83) and 15.7 months in arm B versus 13.1 months in arm C (HR 1.02). However, patients with stronger PD-L1 expression responded better to atezolizumab, here the OS is not yet reached in atezolizumab treatment, and it was 17.8 months under chemotherapy (HR 0.68).

Objective response rates (ORR) were 47% for combination therapy, 23% for atezolizumab monotherapy and 44% for chemotherapy with a complete response of 13%, 6%, and 7%, respectively. Ignacio Durán, Hospital Universitario Marques de Valdecilla-IDIVAL, Santander (Spain), described this result during an ESMO press conference, as remarkable because the rate of complete response to the combination was almost twice as high as that of chemotherapy alone.

Adverse effects were more common in chemotherapy-containing treatment than in atezolizumab monotherapy.

Grande concluded from these results that atezolizumab plus platinum/gemcitabine could be an important new treatment option for non-pretreated patients with metastatic bladder cancer.

No change in clinical practice yet

Thomas Powles, Director of the Barts Cancer Center, London was the discussant of the study at the Presidential Symposium at the ESMO Congress. He pointed out that this is the first positive study in this setting and that it underlines the activity of atezolizumab in bladder cancer. The additional administration of atezolizumab has significantly prolonged the PFS, but the data on OS are not yet mature. However, they seem to point in the right direction. "Interestingly, the biomarker (PD-L1 expression) has no significance for the effect of the combination. The biomarker does not seem to work in combination with chemotherapy,” Powles explained.

Regarding the question of whether these study results will change clinical practice, Powler said that it would be necessary to wait for the overall survival results. In his opinion, however, a positive effect on the OS is conceivable.

In the monotherapy arm, atezolizumab prolonged the OS with an HR of 0.68 in patients with strong PD-L1 expression. All patients with high PD-L1 expression were treated with atezolizumab monotherapy in this arm, and the PD-L1 negative patients received platinum/gemcitabine. It was remarkable for Powles that in the atezolizumab arm side effects of grade 3-4 occurred at 16%, in the chemotherapy arm at 82%. However, data on the cisplatin subgroup are not yet available. In his view, however, these findings support the use of atezolizumab in patients with PD-L1 expression who are not suitable for platinum (except currently cisplatin patients).

Grande E, et al. IMvigor130: Efficacy and safety from a phase III study of atezolizumab as monotherapy or combined with platinum-based chemotherapy (PBC) vs placebo + PBC in previously untreated locally advanced or metastatic urothelial carcinoma. ESMO 2019 Annual Meeting, 27 September to 1 October 2019, Barcelona, LBA14_PR.