Exploratory IMvigor130 Data Support Single-agent Atezolizumab in Select Patients With Urothelial Carcinoma

Aristotelis Bamias, MD

Despite failing to significantly improve survival vs chemotherapy in the first-line treatment of patients with locally advanced or metastatic urothelial carcinoma, atezolizumab (Tecentriq) monotherapy may provide clinical benefit and should still be considered for those who are cisplatin ineligible and have high PD-L1 expression, according to Aristotelis Bamias, MD.

Data from the final overall survival (OS) analysis of the phase 3 IMvigor130 trial (NCT02807636) were presented at the 2023 ASCO Genitourinary Cancers Symposium.¹

In the intention-to-treat population, those who received single-agent atezolizumab (arm B; n = 360) experienced a median OS of 15.2 months (95% CI, 13.1-17.7) compared with 13.3 months (95% CI, 11.9-15.6) in those who received chemotherapy (arm C; n = 359). Exploratory subgroup analyses showed that atezolizumab monotherapy (n = 88) resulted in a median OS of 27.5 months (95% CI, 17.7-49.4) in patients who were cisplatin ineligible and had a high PD-L1 status (IC2/3) vs 16.7 months (95% CI, 10.0-26.1) with chemotherapy (n = 85). No new safety signals were observed, and atezolizumab was deemed to be more tolerable than chemotherapy.

This final analysis is consistent with previously reported findings from IMvigor130.² Following a consultation with the FDA regarding data from IMvigor130, the FDA voluntarily withdrew atezolizumab monotherapy from the US market for its first-line indication in metastatic urothelial carcinoma on November 29, 2022, as the trial did not meet its co-primary end point.³

“This study will [go down] in history as a negative study,” said Bamias, who is study author and an associate professor of medicine at the Medical School, University of Athens, in Athens, Greece. “...still, our results support the current European label, and in general, the administration of atezolizumab as a first-line therapy in cisplatin-ineligible patients whose tumors highly express PD-L1.”

In an interview with OncLive^®, Bamias discussed the efficacy and safety data from the final OS analysis of the IMvigor130 trial and emphasized the clinical implications of this research in metastatic urothelial cancer.

OncLive^®: Could you provide some background on the IMvigor130 trial of atezolizumab monotherapy in metastatic urothelial cancer?What should be known about the study design and patient population enrolled?

Bamias: Treatment with immune checkpoint inhibitors is the standard of care in metastatic urothelial cancer for patients who [do not respond to] chemotherapy. Like other similar studies, IMvigor130 [investigated] whether there is a role for atezolizumab, or immunotherapy in general, as a first-line treatment [both] alone or in combination with chemotherapy.

IMvigor130 had a complex statistical design. Patients were randomized to receive either atezolizumab plus chemotherapy [arm A], atezolizumab alone [arm B], or chemotherapy alone [arm C]. The analysis [used] a hierarchical approach. First, progression-free survival between arms A [and C] was [evaluated]. This [first co-primary] end point was met, with a significant prolongation of PFS [observed in arm A]. Then, the OS between these 2 arms [was] tested. Unfortunately, this second co-primary end point was not met.

Therefore, any comparison of atezolizumab and chemotherapy monotherapies would be exploratory, and not a formal analysis. [At the meeting,] I presented the OS comparison between arms B and arms C, both in the intention-to-treat population as well as [according to] PD-L1 status.

[The study enrolled] a typical metastatic urothelial carcinoma population. Important characteristics [were] evenly balanced between the 3 arms, especially [regarding] ECOG performance status and the site of metastasis. [The population] was as close as a clinical trial can get to [reflecting the population seen in] everyday practice.

What efficacy data were reported in the final survival analysis of arms B and C of IMvigor130?

The 2 previous interim OS analyses [of IMvigor130] suggested a prolongation of OS with atezolizumab vs chemotherapy in patients whose tumors highly expressed PD-L1. In essence, this final OS analysis confirmed these previous findings.

In the overall population, there was no [statistically significant] difference in OS [between arms B and C]. The median OS [in the] atezolizumab [arm] was 15.2 months vs 13.3 months in the chemotherapy arm. When we looked at [OS benefit according to] PD-L1 expression, we found that there was no difference [with atezolizumab] when the tumor did not express PD-L1 or had low expression of PD-L1. However, the [data] suggested that there was prolongation of OS for patients who had high PD-L1 expression in their humors and received atezolizumab as compared with chemotherapy.

Then, we [increased our] focus on the cisplatin-ineligible population. This is an important population because we do not have [many] satisfying [treatment options] for these patients. In the United States, [the use of atezolizumab as frontline treatment] has been recently voluntarily withdrawn, but it is still a recommendation in the National Comprehensive Cancer Network [NCCN] guidelines. Therefore, this is a population of interest. We found that the prolongation of OS [with atezolizumab] was more pronounced in cisplatin-ineligible patients.

What was reported in terms of safety?

We did not observe any new signals with this additional follow-up. Atezolizumab is better tolerated than chemotherapy in these patients. It is important to mention that only 9% of patients receiving atezolizumab had to permanently interrupt or stop treatment because of toxicities, as opposed to [34%] of patients on chemotherapy.

There were some AEs of special interest, which are toxicities caused by immunotherapy. The most frequent AEs were rash, hepatitis, thyroid dysfunction and pneumonitis. [The incidence of] serious, grade 3 and 4 AEs [of special interest] was only 10% [in arm B].

Although the final analysis did show a numerical OS improvement with atezolizumab over chemotherapy, the benefit was not statistically significant. What should be taken away from this with regard to immunotherapy in this disease?

The statistical design and analysis were complex. These boundaries were set by the [trial’s] sponsor, and the regulatory authorities. There was a [positive signal] for OS improvement, but that was not statistically significant according to the study design.

Nevertheless, I think we learned a lot [from this research]. In the context of similar trials, we learned that immunotherapy probably does not work better [when] simultaneously [administered] with chemotherapy. Of course, these results now must be viewed in the context of the current standard of care for metastatic urothelial cancer. In most patients, [this is] chemotherapy, followed by avelumab [Bavencio] maintenance in non-progressors.

What other future avenues exist for the investigation of immunotherapy in this disease?

Most [current] trials [evaluating] immunotherapy in urothelial cancer are testing these agents in earlier stages of disease. [These agents are under evaluation] in patients with muscle-invasive bladder cancer [MIBC] without metastasis, and in those without MIBC [who have an] increased risk of needing cystectomy for superficial bladder cancer.

This is an area which could be revolutionized by immunotherapy, but we must be cautious and wait for these results. We’ll have to wait for [many] years to see whether these agents [are] as effective and safe [in earlier disease stages as they are] in metastatic disease.

What do these findings mean for clinical practice?

In general, the IMvigor130 study, as well as from other similar studies, confirm the efficacy of immunotherapy. In the past 5 to 10 years, we have [had] a waterfall of developments in systemic therapy [for patients with] urothelial cancer. That was not obvious for 20 or more years. We now have a powerful tool to use in this disease. Also, research is now moving toward combining this immunotherapy with other targeted therapies. [Both physicians and] patients are very excited to eventually hear these results.

What other data were you most excited to see presented at the meeting?

Results from the prostate cancer trials have attracted attention. The novel agents in prostate cancer show promise. [When] combined, [they] produce longer survival but also better quality of life. We shouldn’t forget that prostate cancer is a chronic disease. Many people will not die of their cancer, but they will need treatment for that cancer. Certainly, these novel therapies are more patient friendly.

Disclosure: Dr. Bamias disclosed honoraria from Astellas Pharma; Bristol-Myers Squibb; Debiopharm Group; MSD; Sanofi; consulting or advisory role for AstraZeneca; Bristol-Myers Squibb; Ferring; Ipsen; MSD; Pfizer; Roche; and research funding from AstraZeneca (Inst); Bristol-Myers Squibb (Inst); Ipsen (Inst); Pfizer (Inst); Roche (Inst).

References

1. Bamias A, Davis ID, Galsky MD, et al. Final overall survival (OS) analysis of atezolizumab (atezo) monotherapy vs chemotherapy (chemo) in untreated locally advanced or metastatic urothelial carcinoma (mUC) from the phase 3 IMvigor130 study. J Clin Oncol. 2023;41(suppl 6):LBA441. doi:10.1200/JCO.2023.41.6_suppl.LBA441
2. 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. Ann Oncol. 2019;30(suppl 5):V888-V889. doi:10.1093/annonc/mdz394.07
3. Roche provides update on Tecentriq US indication for previously untreated metastatic bladder cancer. News release. Roche. November 29, 2022. Accessed May 4, 2023. https://assets.cwp.roche.com/