Benefit-risk ratio of lenvatinib plus pembrolizumab not positive in bladder cancer subset
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SAN FRANCISCO — Lenvatinib plus pembrolizumab did not demonstrate a positive benefit-risk ratio compared with pembrolizumab and placebo as first-line therapy for certain patients with advanced urothelial carcinoma, study results showed.
The findings, presented at ASCO Genitourinary Cancers Symposium, showed no new safety signals with the lenvatinib-pembrolizumab combination and — with pembrolizumab monotherapy — antitumor activity similar to that observed in prior studies of patients ineligible for cisplatin or any platinum-based chemotherapy.
“First-line pembrolizumab remains a standard of care in the United States for patients with who are ineligible for any platinum-based chemotherapy regardless of PD-L1 status and, in Europe, for patients who are cisplatin-ineligible and have tumors that express PD-L1 with a [combined positive score] of 10 or greater,” Yohann Loriot, MD, PhD, oncologist in the department of cancer medicine at Institut Gustave Roussy in Villejuif, France, said during a presentation.
In the phase 1b/phase 2 KEYNOTE-146 trial, the anti-PD-1 antibody pembrolizumab (Keytruda, Merck) demonstrated antitumor activity and acceptable safety in combination with the multiple receptor tyrosine kinase inhibitor lenvatinib (Lenvima, Eisai). The randomized, multicenter phase 3 LEAP-011 trial evaluated first-line pembrolizumab with or without lenvatinib among 487 cisplatin-ineligible adults with locally advanced/unresectable or metastatic urothelial carcinoma who had a tumor PD-L1 combined positive score of 10 or greater or were ineligible for platinum-based chemotherapy.
Researchers randomly assigned patients to 200 mg IV pembrolizumab every 3 weeks for as many as 35 cycles with 20 mg oral lenvatinib (n = 245) or placebo (n = 242). The groups had similar baseline characteristics with regard to median age (74 years vs. 73 years), percentage of patients with an ECOG performance status of 2 (80% vs. 80.2%).
PFS per RECIST version 1.1 and OS served as primary endpoints. Objective response rate served as a key secondary endpoint.
An independent data monitoring committee assessed safety data at 3-month intervals and, based on the data presented at the symposium, recommended the investigators stop enrollment.
Median follow-up was 5.9 months in the pembrolizumab-lenvatinib group and 7 months for the pembrolizumab-placebo group.
Results showed median PFS according to blinded independent central review of 4.5 months (95% CI, 4-6) with pembrolizumab-lenvatinib and 4 months (95% CI, 2.7-5.4) with pembrolizumab-placebo (HR, 0.9; 95% CI, 0.72-1.14). The addition of lenvatinib resulted in median OS of 11.8 months (95% CI, 9.1-15.1) compared with 12.9 months (95% CI, 9.8-17.8) for those who received pembrolizumab and placebo (HR = 1.14; 95% CI, 0.87-1.48).
The combination-therapy group had a lower median duration of response (12.8 months vs. 19.3 months) and a numerically higher ORR (33.1% vs. 28.9%).
A safety assessment of 483 treated patients showed the pembrolizumab-lenvatinib group had a higher rate of any-grade (87.6% vs. 69%) and grade 3 or higher (51% vs. 27.3) treatment-related adverse events. Six patients in the combination-therapy group and one patient in the pembrolizumab-placebo group died of a treatment-related adverse event.
The most common treatment-related adverse events in the combination therapy group included proteinuria (37.8% vs. 18.6% with pembrolizumab and placebo), hypothyroidism (36.5% vs. 7%) and hypertension (34.9% vs. 7%). Clinically significant events related to lenvatinib included hypertension (41.9%), proteinuria (41.5%) and hypothyroidism (36.9%).
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Debra Wong, MD
Individuals with advanced urothelial carcinoma who are unable to receive platinum-based chemotherapy are often frail and have other comorbidities. Efforts to improve outcomes in this challenging patient population are ongoing.
LEAP-011 sought to enhance the antitumor effects of standard first-line pembrolizumab by adding the multitarget tyrosine kinase inhibitor lenvatinib, which acts on VEGF and FGF receptors, KIT and RET. The pembrolizumab/lenvatinib combination has known efficacy in other solid tumors, including endometrial cancer and renal cell carcinoma, and showed promising activity in patients with previously treated urothelial carcinoma in KEYNOTE-146. The results of LEAP-011 were, thus, highly anticipated.
Dr. Loriot and colleagues are commended on conducting this important study that mostly comprised patients with a lower performance status and visceral metastases, which are poor prognostic indicators. Interestingly, there was no meaningful synergy between pembrolizumab and lenvatinib, with the data suggesting inferior survival with the combination. Although antitumor effects with lenvatinib might have been expected due to FGFR targeting (it would be insightful to know what percentage of patients had tumors harboring FGFR alterations), this was not the case, highlighting that there are key differences in the biology and tumor microenvironment of urothelial carcinoma compared with lenvatinib-sensitive cancers that may be more VEGF-driven. The efficacy of pembrolizumab in LEAP-011 is reassuringly consistent with previous results and, ultimately, this study strengthens the evidence for pembrolizumab monotherapy as a standard of care for patients with advanced urothelial carcinoma who are ineligible for platinum-based chemotherapy.
The future of lenvatinib in advanced urothelial carcinoma is uncertain, and ongoing and new trials of other agents (eg, enfortumab vedotin, PARP inhibition in patients with HRR alterations) with anti-PD-1/PD-L1 therapy will clarify whether non-chemotherapy/immunotherapy combinations that are both potent and well-tolerated find their place in the treatment arsenal for this patient population with a high unmet need.
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Loriot Y, et al. Abstract 432. Presented at: ASCO Genitourinary Cancers Symposium; Feb. 17-19, 2022; San Francisco.
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