Atezolizumab/Chemotherapy Trends Toward Improved OS in Urothelial Carcinoma

Enrique Grande, MD

First-line atezolizumab (Tecentriq) plus platinum-based chemotherapy and gemcitabine trended toward improved overall survival (OS) compared with placebo plus chemotherapy in patients with locally advanced or metastatic urothelial carcinoma, according to final OS data from arms A and C of the phase 3 IMvigor130 trial (NCT02807636) that were presented at the 2023 Gastrointestinal Cancers Symposium.

At a median follow-up of 13.4 months, 336 (75%) OS events occurred with atezolizumab plus platinum and gemcitabine and 310 (78%) occurred with placebo plus platinum and gemcitabine (HR, 0.85; 95% CI, 0.73-1.00) with a 1-sided P value of .023, which did not cross the prespecified efficacy boundary of 0.021. Moreover, the median OS was 16.1 months (95% CI, 14.2-18.8) with the atezolizumab combination compared with 13.4 months (95% CI, 12.0-15.3) with the placebo combination.¹

“Platinum-based chemotherapy and immunotherapy are considered standards of care for the upfront treatment of [patients with] metastatic urothelial carcinoma,” Enrique Grande, MD, of MD Anderson Cancer Center Madrid in Spain, said in a presentation of the data. “We have a huge biological background in which we can see the synergy between these 2 agents that potentiates immunomodulation.”

Previously, interim analyses of IMvigor130 demonstrated anumerical OS improvement with the atezolizumab combination vs the placebo combination, although the pre-specified significance threshold was not crossed.²

IMvigor130 enrolled platinum-eligible patients with locally advanced or metastatic urothelial cancer and an ECOG performance status of 0 to 2 who had received no prior systemic therapy for metastatic disease.¹

Enrolled patients were randomized 1:1:1 to 1 of 3 arms. Arm A received atezolizumab plus platinum and gemcitabine, Arm B received atezolizumab monotherapy, and Arm C received placebo plus platinum and gemcitabine

The co-primary efficacy end points were investigator-assessed progression-free survival (PFS) and OS in the intent-to-treat (ITT) populations of Arms A and C, as well as OS in the ITT populations of Arms B and C and in patients with at least 5% PD-L1 expression. Secondary efficacy end points included investigator-assessed overall response rate (ORR) and duration of response (DOR), as well as investigator-assessed PFS in Arms B and C. Safety was also evaluated. An exploratory subgroup analysis investigated outcomes by type of platinum-based chemotherapy and PD-L1 status.

At a median survival follow-up of 14.8 months in Arm A and 12.3 months in Arm C, 98% (n = 444/451) and 99% (n = 394/400) of patients, respectively, had received treatment. Of the 18% (n = 83) and 13% (n = 52) of patients in Arms A and C, respectively, who remained on study at the data cutoff, 7% (n = 33) and 3% (n = 13), respectively, were alive on treatment and 11% (n = 50) and 10% (n = 39), respectively, were alive in survival follow-up.

In total, 81% (n = 367) and 87% (n = 347) of patients in Arms A and C, respectively, discontinued the study. In Arm A, patients discontinued because of death (73%; n = 327), patient withdrawal (6%; n = 27), loss to follow-up (3%; n = 12), and symptomatic deterioration (<1%; n = 1). In Arm C, patients discontinued because of death (75%; n = 298), patient withdrawal (10%; n = 39), loss to follow-up (2%; n = 9), and protocol deviation (<1%; n = 1).

The 24-month OS rates were 38% (95% CI, 33%-42%) and 32% (95% CI, 28%-37%) in Arms A and C, respectively. The 36-month OS rates were 26% (95% CI, 22%-30%) and 22% (95% CI, 17%-26%) in arms A and C, respectively.

A total of 33% (n = 151) of patients in Arm A and 47% (n = 189) of those in Arm C were treated with at least 1 subsequent non-protocol therapy. In Arm A, 28% (n = 125), 8% (n = 38), and 2% (n = 9) of patients received chemotherapy, immunotherapy, or an antibody-drug conjugate (ADC), respectively. In Arm C, 31% (n = 125), 25% (n = 98), and 1% (n = 5) of patients received chemotherapy, immunotherapy, or an ADC, respectively.

“There is a trend toward improvement in survival for patients receiving cisplatin and not a trend in patients receiving carboplatin,” Grande noted. In patients who received cisplatin, the median OS was 21.5 months (95% CI, 17.2-25.4) in Arm A (n = 137) and 13.4 months (95% CI, 11.7-18.4) in Arm C (n = 136), with 93 (68%) and 103 (76%) OS events in Arms A and C, respectively (HR, 0.76; 95% CI, 0.57-1.01). In patients who received carboplatin, the median OS was 14.3 months (95% CI, 12.0-16.5) in Arm A (n = 314) and 13.4 months (95% CI, 10.8-15.6) in Arm C (n = 264), with 243 (77%) and 207 (78%) OS events in Arms A and C, respectively (HR, 0.89; 95% CI, 0.74-1.08).

In patients with less than 5% PD-L1 expression who received cisplatin, the median OS was 19.5 months (95% CI, 14.9-23.5) in Arm A (n = 102) and 12.7 months (95% CI, 11.2-17.0) in Arm C (n = 102), with 75 (74%) and 82 (80%) OS events in Arms A and C, respectively (HR, 0.75; 95% CI, 0.55-1.03). In patients with at least 5% PD-L1 expression, the median OS was 60.2 months (95% CI, 18.5-not evaluable [NE]) in Arm A (n = 35) and 27.9 months (95% CI, 12.8-NE) in Arm C (n = 34), with 18 (51%) and 21 (62%) OS events in Arms A and C, respectively (HR, 0.74; 95% CI, 0.39-1.38).

In patients with less than 5% PD-L1 expression who received carboplatin, the median OS was 13.9 months (95% CI, 11.9-16.1) in Arm A (n = 241) and 13.4 months (95% CI, 10.8-15.6) in Arm C (n = 207), with 194 (80%) and 164 (79%) OS events in Arms A and C, respectively (HR, 0.93; 95% CI, 0.75-1.15). In patients with over 5% PD-L1 expression, the median OS was 16.6 months (95% CI, 9.4-28.6) in Arm A (n = 73) and 14.0 months (95% CI, 8.9-19.9) in Arm C (n = 57), with 49 (67%) and 43 (75%) OS events in Arms A and C, respectively (HR, 0.78; 95% CI, 0.51-1.18).

Across the entire study population, the ORR was 48.1% (n = 215; 95% CI, 43.4%-52.8%) in Arm A vs 44.8% (n = 178; 95% CI, 39.9%-49.9%) in Arm C. In Arm A, 14%, 34%, 29%, and 12% of patients achieved best responses of complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), respectively. In Arm C, 8%, 37%, 34%, and 13% of patients achieved best responses of CR, PR, SD, and PD, respectively. Additionally, 18% of patients in Arm A who received cisplatin achieved a CR, with a median DOR of 13.2 months (95% CI, 10.3-24.3), which was longer than that observed in the other subgroups.

The disease control rate in the ITT population was 64.9% (95% CI, 60.3%-63.9%) in Arm A and 60.2% (95% CI, 55.2%-65.1%) in Arm C.

The median DOR was 9.1 months (95% CI, 8.0-10.6) in Arm A and 8.2 months (95% CI, 6.3-8.6) in Arm C.

Of the 454 patients in Arm A and 389 patients in Arm C included in the safety analysis, grade 3 or 4 adverse effects (AEs) were seen in 84% (n = 382) and 85% (n = 330) of patients, respectively, and treatment-related AEs (TRAEs) of grades 3 or 4 were seen in 81% (n = 370) and 80% (n = 312) of patients, respectively.

No new grade 5 TRAEs have occurred in either arm. A total of 2% (n = 9) and 1% (n = 4) of patients in Arms A and C, respectively, had grade 5 TRAEs.

In Arm A, AEs of special interest of grade 3 or 4 or grade 5 were observed in 9% (n = 41) and 1% (n = 4) of patients, respectively. In Arm C, AEs of special interest of grade 3 or 4 or grade 5 were observed in 4% (n = 17) and less than 1% (n = 1) of patients, respectively. Treatment-related serious AEs occurred in 32% (n = 145) and 26% (n = 101) of patients in Arms A and C, respectively.

In total, 36% (n = 165) and 34% (n = 132) of patients in Arms A and C, respectively, had AEs leading to withdrawal from any treatment. In Arm A, 13% (n = 61) of patients had AEs leading to atezolizumab withdrawal and 81% (n = 370) had AEs leading to dose modification or interruption. In Arm C, 8% (n = 31) had AEs leading to placebo withdrawal and 78% (n = 303) had AEs leading to dose modification or interruption.

“Consistent with prior exploratory analyses, improved OS with atezolizumab plus chemotherapy appeared greater relative to the ITT population when atezolizumab was combined with cisplatin rather than with carboplatin. Further mechanistic investigations are warranted,” Grande concluded.

Editor’s Note: This study is sponsored by F. Hoffman-La Roche, Ltd.

References

1. Galsky MD, Arija JAA, De Santis M, et al. Atezolizumab (atezo) + platinum/gemcitabine (plt/gem) vs placebo + plt/gem for first-line (1L) treatment (tx) of locally advanced or metastatic urothelial carcinoma (mUC): final OS from the randomized phase 3 IMvigor130 study. J Clin Oncol. 2023;41(suppl 6):LBA440. doi:10.1200/JCO.2023.41.6_suppl.LBA440
2. Galsky MD, Arija JAA, Bamias A, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomized, placebo-controlled phase 3 trial. Lancet. 2020;395(10236):1547-1557. doi:10.1016/S0140-6736(20)30230-0