Combination therapy for advanced urothelial cancer: LEAP-011 trial

SUMMARY LEAP-0111 was a multicenter, double-blind, phase-3 randomized trial (RCT). Pembrolizumab 200 mg intravenously every three weeks along with either lenvatinib 20 mg or placebo orally once daily was randomly allocated (1:1) to 487 patients with advanced urothelial carcinoma (UC) who were not eligible for cisplatin-based treatment or any platinum-based chemotherapy. The coprimary endpoints goals were to assess progression-free survival (PFS) and overall survival (OS). Notable findings from the LEAP-011 trial include the following: the combination arm had a median PFS of 4.5 months, whereas the pembrolizumab arm had a median PFS of 4.0 months (hazard ratio HR = 0.90 95% confidence interval [CI 0.72–1.14]). For the combination arm, the median OS was 11.8 months, while for the pembrolizumab arm, it was 12.9 months (HR 1.14 95% CI 0.87–1.48). Around 51% of patients treated with lenvatinib with pembrolizumab experienced grade 3–5 adverse events, compared to 27% treated with placebo plus pembrolizumab. This trial was terminated earlier than anticipated because the benefit-to-risk ratio for first-line lenvatinib plus pembrolizumab was not deemed superior to pembrolizumab plus placebo as first-line treatment in patients with advanced UC. COMMENTS LEAP-0111 is a well-conducted prospective assessment of pembrolizumab with or without lenvatinib as first-line therapy for patients with advanced UC. Despite its early termination, it adds important information regarding alternative forms of treatment for advanced UC. The combination, i.e., pembrolizumab with lenvatinib, is chosen on the basis of the potential preclinical synergy of vascular endothelial growth factor inhibitors and checkpoint inhibitors and early data from KEYNOTE-146 (LEAP Program), a basket trial of lenvatinib and pembrolizumab in advanced solid tumors.2 The combination of lenvatinib plus pembrolizumab or triple therapy with lenvatinib plus pembrolizumab plus chemotherapy is expected to have better antitumor activity in specific tumor types compared to using either agent alone or the standard of care. This expectation is based on the promising results obtained from Study 111/KEYNOTE-146 and Study 116/KEYNOTE-524. The combination of pembrolizumab plus lenvatinib has been approved in the USA, Australia, and Canada for the treatment of advanced endometrial carcinoma that is not MSI-H or dMMR. This approval is based on interim results from study 111/KEYNOTE-146. The treatment is specifically for patients who have experienced disease progression after prior systemic therapy and are not eligible for curative surgery or radiotherapy. In tumor types where lenvatinib or pembrolizumab has already been authorized as a monotherapy, the combination may lead to enhanced effectiveness. As monotherapies, pembrolizumab and lenvatinib have well-established safety characteristics. The safety profile of the combination is in line with the safety profiles of each individual agent, and there have been no additional indications of safety concerns. Thus, it is anticipated that the pairing of lenvatinib with pembrolizumab will be well-tolerated in the LEAP program. The standard treatment for advanced or metastatic UTUC is a combination chemotherapy that includes cisplatin.3 Several chemotherapy regimens that include cisplatin have demonstrated effectiveness, with gemcitabine and cisplatin being the most commonly utilized. Cisplatin-based chemotherapy is commonly administered to individuals with an estimated glomerular filtration rate >45 mL/min. A significant percentage of individuals diagnosed with metastatic or advanced UC are not suitable candidates for cisplatin treatment. The investigators' efforts to discover medicines for this specific group of patients have resulted in the EORTC 30986 trial, which has confirmed that the combination of gemcitabine and carboplatin is a suitable initial treatment option. In the LEAP-011 trial, the criteria for "platinum ineligibility" were at the investigators' discretion, but this is not desirable. It is better to use the Galsky criteria to have more objective criteria. Galsky et al.4 generated eligibility criteria (popularly known as Galsky criteria) to be considered "Unfit" for cisplatin-based chemotherapy (at least one of the following) - WHO or Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≥2, Creatinine clearance ≤60 mL/min, Common Terminology Criteria for Adverse Events (CTCAE) v4 grade ≥2 audiometric hearing loss, CTCAE v4 grade ≥2 peripheral neuropathy, or New York Heart Association (NYHA) Class ≥III heart failure. Pembrolizumab shows prolonged OS for patients who are PD-L1 positive and not eligible/fit for platinum-based chemotherapy based on KEYNOTE-052 trial. Based on a recent EV-302 trial,5 treatment with enfortumab vedotin and pembrolizumab results in significantly better outcomes than chemotherapy in patients with untreated locally advanced or metastatic UTUC, with good safety profile. A large proportion of patients with metastatic or advanced UC belong to ECOG ≥2, but in this trial, only ECOG 0-2 patients were included, which does not replicate the real-world scenario. The high cost and adverse event rate may prompt the adoption of other options in the Indian population. In the future, new and more effective medications with greater tolerability may make it possible to do away with the need to evaluate patients with metastatic bladder cancer in different groups according to their suitability for cisplatin treatment. Financial support and sponsorship: Nil. Conflicts of interest: There are no conflicts of interest.