Breaking Resistance in Gynaecological Clear Cell Carcinoma: Pembrolizumab plus Lenvatinib Achieves 40% Response Rate in LARA Trial

Highlights

• Objective response rate (ORR) reached 40% in patients with recurrent gynaecological clear cell carcinoma (CCGC).
• The combination therapy showed efficacy in both ovarian and endometrial clear cell subtypes.
• Responses were observed regardless of prior anti-angiogenic treatment or microsatellite stability status.
• The safety profile was consistent with known toxicities of the combination, primarily hypertension and liver enzyme elevations.

Background: The Clinical Challenge of Clear Cell Gynaecological Carcinoma

Clear cell gynaecological carcinomas (CCGCs), predominantly arising from the ovary or endometrium, represent a distinct clinico-pathological entity characterized by poor prognosis and relative resistance to standard platinum-based chemotherapy. While high-grade serous carcinomas often respond to traditional cytotoxic agents and PARP inhibitors, CCGCs frequently exhibit a more indolent but chemo-refractory course.

The molecular landscape of CCGC is unique, frequently involving ARID1A mutations, PIK3CA activations, and HNF1B over-expression. Furthermore, these tumors are known for their highly angiogenic microenvironment and specific immune evasion mechanisms. Despite the success of immune checkpoint inhibitors in mismatch repair-deficient (dMMR) endometrial cancers, the majority of CCGCs are proficient in mismatch repair (pMMR) or microsatellite stable (MSS), where single-agent immunotherapy has historically shown limited activity.

The rationale for combining pembrolizumab (a PD-1 inhibitor) with lenvatinib (a multi-kinase inhibitor targeting VEGFR, FGFR, and PDGFR) lies in the potential for lenvatinib to modulate the tumor microenvironment. By reducing VEGF-mediated immunosuppression and increasing tumor-infiltrating lymphocytes, lenvatinib may sensitize these resistant tumors to PD-1 blockade.

Study Design: The LARA Multicentre Phase 2 Trial

The LARA trial (NCT04699071) was a multicentre, single-arm, phase 2 study conducted across tertiary hospitals in Singapore and South Korea. The study aimed to evaluate the efficacy and safety of the pembrolizumab-lenvatinib combination in a cohort specifically enriched for clear cell histology.

Eligible participants were adults with histologically confirmed CCGC that had progressed after at least one line of platinum-based chemotherapy. Key inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 and no prior exposure to immune checkpoint inhibitors. Notably, patients with prior anti-angiogenic therapy were not excluded, providing a real-world perspective on treatment sequencing.

The intervention consisted of 200 mg intravenous pembrolizumab administered every three weeks, paired with 20 mg oral lenvatinib daily. Treatment continued for up to two years or until disease progression or unacceptable toxicity. The primary endpoint was the investigator-assessed objective response rate (ORR) within the first 24 weeks, according to RECIST version 1.1, analyzed by modified intention to treat.

Key Findings: Efficacy and Response Durability

Between March 2021 and October 2023, 27 patients received the study intervention. The cohort was predominantly Asian (Chinese, Korean, Malay, and Filipino) with a median age of 52 years. The majority (89%) had primary ovarian clear cell carcinoma, while 11% had endometrial clear cell carcinoma. Crucially, all tumors tested were pMMR or MSS.

The primary outcome analysis, conducted on 25 evaluable patients, revealed an ORR of 40% (95% CI 21-61) within the first 24 weeks. This included 10 patients with confirmed objective responses. At the data cutoff on March 19, 2025, with a median follow-up of 21 months, the data suggested that these responses were not only rapid but also durable.

Subgroup analyses provided further clinical insights. Responses were observed even in patients who had previously failed anti-angiogenic therapies (such as bevacizumab), suggesting that the dual mechanism of lenvatinib and pembrolizumab overcomes previous pathways of resistance. The disease control rate and progression-free survival metrics further underscored the clinical utility of this regimen in a population with limited secondary treatment options.

Safety and Tolerability Profile

The safety profile of the combination was consistent with the established toxicities observed in other pembrolizumab-lenvatinib trials, such as KEYNOTE-775. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 14 (52%) of 27 patients.

The most frequent high-grade adverse event was hypertension, affecting 22% of the cohort. Other notable Grade 3-4 events included decreased platelet counts (7%) and elevations in liver enzymes, specifically aspartate aminotransferase (AST) and alanine aminotransferase (ALT) at 7% each. Serious adverse events (SAEs) were reported in 19% of patients, with immune-related hepatitis and thrombocytopenia being the most common reasons for hospitalization or intensive monitoring.

Despite the frequency of adverse events, there were no treatment-related deaths. Dose interruptions and reductions for lenvatinib were common, reflecting the need for proactive toxicity management in this patient population. Clinicians must be vigilant in monitoring blood pressure and hepatic function to ensure treatment continuity and mitigate the risks of severe immune-mediated reactions.

Expert Commentary and Clinical Implications

The results of the LARA trial are particularly significant for several reasons. First, CCGC is an orphan disease within the gynaecological oncology sphere, often excluded or under-represented in larger basket trials. By focusing specifically on this histology, LARA provides high-quality evidence for a niche but difficult-to-treat patient group.

Second, the 40% ORR in an entirely pMMR/MSS cohort is remarkable. In most gynaecological cancers, MSS status is a biomarker for poor response to PD-1 monotherapy, where response rates typically hover around 10-15%. The synergy between lenvatinib’s anti-angiogenic properties and pembrolizumab’s immune activation appears to bypass the traditional requirements for high mutational burden or mismatch repair deficiency.

Mechanistically, clear cell carcinomas are characterized by high levels of VEGF expression. Lenvatinib’s potent inhibition of VEGFR1-3 likely plays a dual role: directly inhibiting tumor angiogenesis and remodeling the immune microenvironment to be more ‘inflamed,’ thereby facilitating pembrolizumab’s efficacy. This ‘normalization’ of the vasculature allows for better infiltration of cytotoxic T-cells into the tumor core.

However, limitations must be acknowledged. As a single-arm, phase 2 trial with a small sample size (n=27), the findings require validation in larger, randomized controlled trials. The Asian-predominant population also raises questions about generalizability, although the molecular drivers of CCGC are relatively consistent across ethnicities. Future research should focus on identifying predictive biomarkers beyond MMR status to better select patients who will derive the most benefit from this potentially toxic combination.

Conclusion

The LARA trial establishes pembrolizumab plus lenvatinib as a highly active combination for patients with recurrent gynaecological clear cell carcinoma. With an objective response rate of 40% and a manageable safety profile, this regimen offers a potent alternative to second-line chemotherapy. These results represent a significant step forward in personalized medicine for CCGC and provide a strong foundation for future phase 3 investigations to potentially shift the standard of care.

Funding and ClinicalTrials.gov

This study was funded by the National Medical Research Council (Singapore), the Pangestu Family Foundation Gynaecological Cancer Research Fund, and MSD. The trial is registered at ClinicalTrials.gov under the identifier NCT04699071.

References

1. Ngoi NYL, Lee JY, Lim D, et al. Pembrolizumab plus lenvatinib in recurrent gynaecological clear cell carcinoma (LARA): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2026;27(2):201-211. doi: 10.1016/S1470-2045(25)00662-X.
2. Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. N Engl J Med. 2022;386(5):437-448.
3. Miller RE, Leary A, Scott CL, et al. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its influence on tumour type-agnostic decision-making. Ann Oncol. 2020;31(8):1032-1045.