Survival Is Not Improved by Adding Tecentriq to Chemo for Metastatic Bladder Cancer

Adding Tecentriq (atezolizumab) to platinum-based chemotherapy and gemcitabine did not improve survival for patients with previously untreated locally advanced or metastatic (disease that has spread to other parts of the body) bladder cancer, according to results from the phase 3 IMvigor 130 clinical trial.

These results, which were reported at the 2023 Genitourinary Cancer Symposium, also showed a potential increase in benefit with Tecentriq in patients with high PD-L1 expression (the protein on cancer cells that Tecentriq targets), particularly in those who were cisplatin ineligible.

The results showed that the average overall survival (time from treatment until death of any cause) was 15.2 months in the Tecentriq group (360 patients), compared with 13.3 months in the chemotherapy-only group (359 patients). The survival difference between these two groups was not significant enough to deduce that Tecentriq added benefit.

The 12- and 24-month overall survival rates with Tecentriq were 57.9% and 34.5%, compared with 54.6% and 32.3% with chemotherapy, respectively.

“Data from this final (overall survival) analysis of the IMvigor130 study of first-line (Tecentriq) in mUC were generally consistent with the findings from the first and second interim (overall survival) analyses.

Exploratory efficacy data suggest a clinical benefit with Tecentriq monotherapy (given as the only drug) as first-line treatment for cisplatin-ineligible patients with PD-L1 IC2/3 metastatic urothelial cancer” study co-author Dr. Aristotelis Bamias, of the National and Kapodistrian University of Athens in Greece, said in a presentation of the data.

The trial enrolled patients with platinum-eligible, locally advanced or metastatic urothelial cancer who had not received prior systemic therapy in the metastatic setting. To be eligible, patients had to have an ECOG status of 0-2, meaning that there were little, if any, interruptions to their daily functioning due to their disease.

Patients were split up into three groups and randomly assigned to receive Tecentriq plus platinum and gemcitabine (arm A); Tecentriq alone (arm B); or placebo plus platinum-based chemotherapy and gemcitabine (arm C).

The main goals of the trial were investigator-assessed progression-free survival (time from treatment until disease worsens) and overall survival for arm A vs arm C in the entire study population and overall survival for arm B vs arm C in the intention to treat population (ITT) and PD-L1 IC2/3 population.

Per the design of the trial, progression-free survival benefit had to be met for arm A vs arm C in the population before overall survival could be formally tested in arm A vs arm C (ITT), arm B vs arm C (ITT), and arm B vs arm C (PD-L1 IC2/3), respectively. Prior findings from the primary analysis showed a significant improvement in progression-free survival with Tecentriq/chemotherapy vs placebo/chemotherapy.

However, because the first and second interim overall survival analyses proved negative, the comparison of Tecentriq and chemotherapy was exploratory only. Findings from the final overall survival analysis for arms A and C were presented by Dr. Enrique Grande, of MD Anderson Cancer Center Madrid in Spain, during the meeting.

Secondary study goals included investigator-assessed objective response rate (percentage of patients whose disease shrunk or disappeared from treatment), duration of response (the time the disease responds to a treatment without growth or spread) and progression-free survival for arm B vs arm C. Safety and outcomes in the cisplatin-ineligible population were also evaluated.

Forty-nine months had passed from the last patient randomly assigned to data cutoff. At this time, 19% (67 patients) of patients remained on study in the Tecentriq monotherapy arm compared with 14% (49 patients) in the chemotherapy arm. Most study discontinuations in the Tecentriq and chemotherapy arms were due to death, at 73% (264 patients) and 74% (265 patients), respectively.

Median survival follow-up was 13.4 months (14 months in arm B and 12.0 months in arm C).

Additional survival data showed an advantage with Tecentriq in patients with higher PD-L1 expression. Average overall survival was 27.5 months with Tecentriq (88 patients) vs 16.7 months with chemotherapy (85 patients) in patients with PD-L1 IC2/3, though again this difference in survival was not statistically significant.

Patients with PD-L1 IC0/1 had median overall survival of 13.5 months with Tecenriq (272 patients) vs 12.9 months with chemotherapy (274 patients) — again, not statistically significant.

Taken further, investigators showed more pronounced benefit with Tecentriq in cisplatin-ineligible patients with PD-L1 IC2/3 expression. Here, median overall survival was 18.6 months with Tecentriq (50 patients) vs 10.0 months with chemotherapy (43 patients). Cisplatin-ineligible patients with PD-L1 IC0/1 expression had median overall survival of 11.2 months with Tecentriq (140 patients) vs 11.8 months with chemotherapy (140 patients).

Response data were also assessed in the entire and cisplatin-ineligible PD-L1 IC2/3 populations. In the former population, the response rate was 24.2% with Tecentriq vs 44.4% with chemotherapy. The median duration of response was 29.6 months and 8.1 months with placebo plus chemotherapy, and the disease control rates were 38% and 59%, respectively.

In the cisplatin-ineligible PD-L1 IC2/3 population, the objective response rate was 40.0% with Tecentriq vs 32.6% with chemotherapy, which was not a significant difference. The median duration of response was not evaluable with Tecentriq vs 6.2 months with chemotherapy; disease control rates were not available in this population.

Subsequent non-protocol therapy analysis showed that approximately half of patients in the Tecentriq and chemotherapy arms received at least one additional treatment, respectively, including chemotherapy (162, 45% vs 114 patient, 32%), immunotherapy (13 patients, 4% vs 88 patients, 25%) or treatment with the antibody-drug conjugate Padcev (enfortumab vedotin-ejfv; seven patients, 2% vs five patients, 1%).

Regarding safety, no new signals were reported with additional follow-up. Treatment-related side effects and side effects leading to discontinuation were less common with Tecentriq vs chemotherapy, at 61% (217 patients) and 9% (31 patients) with Tecentriq vs 96% (372 patients) and 34% (132 patients) with chemotherapy.

Serious side effects and serious treatment-related side effects occurred in 46% (163 patients) and 12% (44 patients) of patients in the Tecentriq arm vs 50% (196 patients) and 26% (101 patients) in the chemotherapy arm. Notably, no new treatment-related deaths were recorded in either arm since the first interim overall survival analysis.

“Overall, the tolerability profile of (Tecentriq) monotherapy was favorable relative to that of placebo plus chemotherapy,” Bamias said. “The benefit-risk ratio of (Tecentriq) vs chemotherapy support (Tecentriq) as first-line treatment for cisplatin-ineligible patients with PD-L1 IC2/3 mUC,” Bamias concluded.

However, in November 2022, (Tecentriq) was voluntarily withdrawn from the US market for its first-line indication in metastatic urothelial carcinoma.

Discussant Dr. Andrea B. Apolo, of the National Institutes of Health, added, “Chemotherapy plus checkpoint (inhibitor) combinations have different efficacy in a variety of solid tumors. The combination of chemotherapy plus a checkpoint inhibitor did not work with (Tecentriq) and with Keytruda (pembrolizumab) in metastatic urothelial carcinoma. The chemotherapy used in the chemotherapy plus checkpoint (inhibitor) combinations may make a difference––cisplatin may be a better choice, but additional data from other trials are pending.

“Hierarchical studies limit the statistical testing of subsequent study arms if the first question asks are negative, so this important to consider when designing these large trials. Checkpoint inhibitor monotherapy is no longer an FDA approved standard-of-care option for the first-line treatment of platinum-eligible patients. There are ongoing trials assessing the efficacy of ADCs plus checkpoint inhibitors vs chemotherapy in the metastatic and neoadjuvant settings.”

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