Efficacy Short-Lived Despite Early Responses With Frontline Avelumab in Metastatic Urothelial Carcinoma

Kilian M. Gust, MD

Although responses were observed with induction avelumab (Bavencio) prior to standard of care (SOC) gemcitabine/carboplatin, clinically meaningful efficacy was not sustained, showing this agent is not an adequate frontline treatment option for patients with metastatic urothelial carcinoma (mUC), according to early findings from a phase 2 study.¹

In total, 85 patients who were treatment-naïve and ineligible for cisplatin-based chemotherapy were randomized to 1:1 to 2 cycles of induction avelumab followed by 6 cycles of avelumab plus gemcitabine/carboplatin followed by avelumab maintenance therapy (n = 42) or SOC gemcitabine/carboplatin alone (n = 43). The overall response rates were 57.1% (24/42) in the avelumab arm and 53.5% (23/43) in SOC arm (P = .73). Specifically, 45.2% and 11.9% of patients in the avelumab arm experienced partial and complete responses, respectively, compared with 44.2% and 9.3% in the SOC arm.^1,2

However, the upfront effect was short-lived. The median PFS was 6.9 months (95% CI, 2.2-8.4) in the avelumab arm versus 7.4 months (95% CI, 5.8-9.7) in the SOC arm (P = .1356). Further, the median OS benefit was 10.5 months (95% CI, 6.9-not reached) versus 13.2 months (95% CI, 12.5-18.4; P = .2642), respectively.^1,2

“The sequence of short-term checkpoint inhibition followed by combination of avelumab and gemcitabine/carboplatin followed by avelumab maintenance therapy seems to be a quite reasonable approach in this hard to treat treatment population,” said invited discussant Kilian M. Gust, MD, during a presentation reviewing the data at the 2020 ESMO Virtual Congress. “[However,] this data shows that in the first 6 weeks of therapy approximately one-fourth of patients progress on avelumab monotherapy, which leads to a clinically relevant worsening of survival. While these 2 treatments seem to perform quite similar afterwards, the combination cannot make up for the opportunity of an early response to therapy.” Gust is head of uro-oncology in the Department of Urology at the Medical University of Vienna, in Austria.

Of note, higher rates of disease progression and death were observed in the avelumab arm. Thirteen patients (31%) progressed or died prior to the first response assessment, and 6 of the deaths occurred in the first month. Only 4 patients progressed or died in the SOC arm.¹ In terms of safety, treatment related adverse-events grade 3 or higher were reported in 71% and 65% of patients, respectively.

The hypothesis for the phase 2 study of avelumab was based on retrospective data which showed that in a small cohort of patients (n = 14), treatment with an immune checkpoint inhibitor (ICI) prior to chemotherapy elicited a 64% response rate to chemotherapy. In patients who received chemotherapy following failure of first-line platinum-based chemotherapy followed by an ICI (n = 14), the response rate was 21%.³ This reverse sequencing suggested a maintained response to chemotherapy with despite prior exposure to immune therapy.

Avelumab retains its position as the preferred regimen for patients who are cisplatin ineligible as maintenance therapy following gemcitabine and carboplatin. On June 30, 2020, the FDA approved the agent as maintenance treatment for patients with locally advanced or mUC that has not progressed with first-line platinum-based chemotherapy. The approval added to the 2017 indication in mUC for patients who have disease progression during or following platinum-containing chemotherapy, or experience disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.⁴

Hurdles Remain in ICI Frontline Sequencing

Benefit has been observed with upfront ICI therapy in data from patients with high PD-L1 expression. Both atezolizumab (Tecentriq) and pembrolizumab (Keytruda) have conditional approvals for patients whose tumors express PD-L1 based on results of their specified companion diagnostic, or who are not eligible for platinum-containing chemotherapy regardless of PD-L1 expression. These indications were based on unplanned assessments of atezolizumab and pembrolizumab as monotherapy in IMvigor130 (NCT02807636) and KEYNOTE-361 (NCT02853305), respectively.⁵

However, the data have left more to be desired from frontline ICIs as monotherapy and in combination for unstratified patient populations.

For example, Gust pointed to data from the phase 3 IMvigor130 trial, which randomized patients to atezolizumab with or without platinum chemotherapy versus chemotherapy alone. The interim OS was not statistically significant at 15.7 months for patients treated with the ICI alone (n = 360) versus 13.1 months with chemotherapy alone (n = 359; HR, 1.02; 95% CI, 0.83-1.24).⁵

Results from the same trial demonstrated the potential role for ICIs in frontline therapy as combination therapy with chemotherapy. At median follow-up of 11.8 months, median PFS was 8.2 months in the atezolizumab/chemotherapy arm and 6.3 months in the chemotherapy alone arm (HR, 0.82; 95% CI, 0.70-0.96; P = .007). In interim analysis, the median OS was 16.0 months with the combination versus 13.4 months with chemotherapy alone (HR, 0.83; 95% CI 0.69-1.00; P = .027). Objective response rates were notably higher in the combination and chemotherapy alone arms (47% and 44%, respectively) compared with 23% in the atezolizumab alone arm.⁵

Despite the statistically significant benefit, the improvement in PFS and OS was 1.9 months and 2.6 months, respectively. “[The early response data with avelumab are] are similar to what is seen in other trials, such as IMvigor130. [There is a] statistically significant improvement in PFS [IMvigor130] but is it clinically relevant?” Gust said.

Additionally, Merck, the developer of pembrolizumab, announced that data from the final analysis of the KEYNOTE-361 trial did not meet prespecified primary endpoints of OS or PFS. A reported improvement in OS and PFS in the pembrolizumab plus cisplatin or carboplatin plus gemcitabine arm did not reach statistical significance compared to chemotherapy alone.⁶

^References

1. ^{Valderrama BP. Phase II multicenter, randomized study to evaluate efficacy and safety of avelumab with gemcitabine/carboplatin (CG) vs CG alone in patients with unresectable or metastatic urothelial carcinoma (mUC) who are ineligible to receive cisplatin-based therapy. Abstract presented at: 2020 European Society for Clinical Oncology Virtual Congress.; September 18-21, 2020; virtual. LBA27. https://cslide.ctimeetingtech.com/esmo2020/attendee/confcal_1/session​}
2. ^{Gust KM. What’s the future of IO in urothelial carcinoma? How to combine or sequence the old and the new? Discussion presented at: 2020 European Society for Clinical Oncology Virtual Congress.; September 18-21, 2020; virtual. Presentation ID 5007. https://cslide.ctimeetingtech.com/esmo2020/attendee/confcal_1/session​}
3. ^{Szabados B, van Dijk N, Tang YZ, et al. Response rate to chemotherapy after immune checkpoint inhibition in metastatic urothelial cancer. Eur Urol. 2018;73(2):149-152. doi:10.1016/j.eururo.2017.08.022}
4. ^{FDA approves avelumab for urothelial carcinoma maintenance treatment. News release. FDA. Updated July 1, 2020. Accessed September 18, 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-avelumab-urothelial-carcinoma-maintenance-treatment​}
5. ^{Galsky M, Arranz JÁA, Bamias A, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395(10236):1547-1557. doi:10.1016/S0140-6736(20)30230-0}
6. ^{Merck provides update on phase 3 KEYNOTE-361 trial evaluating Keytruda (pembrolizumab) as monotherapy and in combination with chemotherapy in patients with advanced or metastatic urothelial carcinoma. News release. Merck. June 9, 2020. https://www.merck.com/news/merck-provides-update-on-phase-3-keynote-361-trial-evaluating-keytruda-pembrolizumab-as-monotherapy-and-in-combination-with-chemotherapy-in-patients-with-advanced-or-metastatic-urothelial-carc/​}