Neoadjuvant lenvatinib and pembrolizumab for metastatic clear cell renal cell carcinoma: A potential opportunity for complete pathologic and radiographic response

Abstract

A 70-year-old man with a 9.1 cm infiltrative right renal mass involving the inferior vena cava (IVC), with retroperitoneal lymphadenopathy and pulmonary nodules, received 27 months of lenvatinib and 6 months of pembrolizumab after biopsy confirmed metastatic clear cell renal cell carcinoma (ccRCC). Restaging imaging demonstrated a reduction of the renal mass to 3.6 cm, resolution of IVC thrombus, lymphadenopathy, and pulmonary metastases. He underwent right robotic cytoreductive radical nephrectomy. Final pathology was ypT0Nx. To our knowledge, this is the first reported case of complete pathologic and radiographic response of metastatic ccRCC predominantly on lenvatinib, with brief duration of pembrolizumab.

1. Introduction

Renal cell carcinoma (RCC) is the sixth most common neoplasm among males in the United States. Of these, 10% of patients have metastatic disease upon diagnosis.¹ Additionally, 4-10% of RCC cases will have venous invasion, including renal vein and inferior vena cava (IVC) tumor thrombus.² Metastatic RCC portends an overall poor prognosis, with a median overall survival of 46 to 56 months on contemporary systemic therapy.¹

While long-term treatment-free survival remains rare for metastatic RCC patients, over the past decade, there has been considerable progress in finding effective systemic therapies in this setting. Given the limited response to conventional chemotherapy, interferon, and interleukin-2, recent first-line treatments rely on either dual immune checkpoint inhibitors (ICIs), or combinations of ICIs and tyrosine kinase inhibitors (TKIs), such as lenvatinib and pembrolizumab.3, 4, 5, 6, 7, 8, 9, 10, 11.

Herein, we report a case of complete pathologic and radiographic response confirmed on cytoreductive nephrectomy and imaging, after treatment with lenvatinib and pembrolizumab in a patient with locally advanced and metastatic clear cell RCC (ccRCC).

2. Case report

A 70-year-old man who initially presented with gross hematuria was found to have a large, 9.1 cm × 6.9 cm infiltrative right renal mass occupying most of the right kidney and obstructing the right renal pelvis, resulting in mild to moderate hydronephrosis on computed tomography (CT) scan. The mass also showed invasion of the right renal vein to its confluence with the inferior vena cava (IVC). An abnormally enlarged (1.5cm) lymph node was also identified between the right kidney and IVC, suggestive of local lymph node involvement (Fig. 1, Fig. 2). Multiple pulmonary nodules were also identified concerning for distant metastatic disease. A biopsy of the primary renal mass revealed ccRCC. No sarcomatoid, or rhabdoid features were identified. The patient had no history of prior cancers and was a non-smoker. He denied any history of other urologic symptoms, including flank pain, unintentional weight loss, and did not have a family history of RCC. The patient had one of six International Metastatic RCC Database Consortium (IMDC) risk factors; there was less than one year from time of diagnosis to systemic therapy indicating the need for prompt treatment given biologically aggressive disease. This classified the patient as intermediate risk, supporting the use of first line systemic therapy such as lenvatinib and pembrolizumab, with a median survival of 22.5 months.

Fig. 1.

Axial views of initial CT scan demonstrating a large, infiltrative right renal mass (A and B) associated regional lymphadenopathy (C) and invasion of right renal vein at the confluence of the IVC.

Fig. 2.

Coronal views of initial CT scan demonstrating a large, infiltrative right renal mass (A) with associated right renal vein invasion at the confluence of the IVC (B).

Due to the metastatic nature of the disease, the patient elected to proceed with neoadjuvant systemic therapy with lenvatinib and pembrolizumab from June 2023 to January 2024. Notable adverse effects included mucositis, hand-foot syndrome, fatigue, decreased appetite, and severe diarrhea due to colitis, which led to discontinuation of pembrolizumab. He then continued lenvatinib alone.

He was subsequently referred for a cytoreductive nephrectomy after the medical oncologist determined that the patient had an excellent response to systemic therapy. A CT of the chest, abdomen, and pelvis with and without intravenous contrast in April of 2025 demonstrated a significant reduction in size of the right renal mass to 3.6 cm × 3 cm x 2.6 cm. There was no evidence of IVC or renal vein involvement, hydronephrosis, retroperitoneal lymphadenopathy, or pulmonary metastatic disease (Fig. 3). The bone scan was negative for osseous lesions. Additional positron emission tomography (PET)-CT was ordered; this confirmed the absence of local extension, any pulmonary metastases, or other distant metastases. His kidney function was within normal limits, with a serum creatinine of 1.1 and an estimated glomerular filtration rate (eGFR) of 68.

Fig. 3.

Axial views of preoperative CT scan demonstrate a reduction in size of right renal mass (A) as well as resolution of right renal vein invasion (B) after lenvatinib and pembrolizumab.

The patient underwent robotic-assisted right radical nephrectomy in October of 2025. Lenvatinib was held 7 days before the procedure. Intraoperative ultrasound confirmed no renal vein thrombus. There was no evidence of retroperitoneal lymphadenopathy on direct visualization. The estimated blood loss was 50 mL. There were no intraoperative complications, and the patient had an unremarkable post-operative course.

Final pathology revealed a 3.1 cm right renal mass composed almost entirely of hyalinized fibrosis, florid lymphohistocytic inflammation, and focal calcification (Fig. 4). There was no evidence of residual viable tumor. Final pathologic stage was ypT0NX.

Fig. 4.

(A) Gross image of exophytic renal mass, (B) low-power image of mass showing predominant areas of hyalinization (H&E stain, 2× magnification), (C) higher power image showing foci with necrosis, cholesterol clefts, histiocytes, and lymphocytes with hyalinization (H&E stain, 10× magnification).

He restarted lenvatinib four weeks after surgery. On the four-month follow-up visit, the patient continues to do well with his surveillance PET imaging, demonstrating no evidence of locally recurrent or metastatic disease. Currently, there are no established guidelines for optimal duration of immunotherapy following cytoreductive nephrectomy. The patient will continue lenvatinib only, with surveillance imaging and laboratory work every 3-6 months in accordance with current guidelines until there is disease progression, unacceptable toxicity, or shared decision to discontinue treatment.

3. Discussion

RCC is a common malignancy, the 14th most common cancer, accounting for 155,700 deaths worldwide in 2022.¹² The most common histological subtype is ccRCC, contributing to 75-80% of all RCC cases.¹ Discoveries in the pathogenesis of RCC, such as the inactivation of the von-Hippel-Lindau (VHL) genes and subsequent overexpression of vascular endothelial growth factor receptors (VEGFR) have revolutionized treatment options for metastatic RCC.¹³ However, despite the evolution of first-line therapies over the past 20 years, complete response remains elusive.

The discovery of TKIs with the ability to inhibit VEGFR and other angiogenic or tumor growth-promoting receptors, such as sunitinib, demonstrated longer progression-free survival (PFS), objective response rate (ORR), and better quality of life compared to interferon-alpha, the prior standard of care for metastatic RCC.³

mTOR inhibitors, such as temsirolimus and everolimus, were also found to have better treatment outcomes than patients receiving interferon-alpha or placebo.^4,5 However, subsequent clinical trials demonstrated that they had shorter durability and inferior efficacy compared to TKIs.^6,14 Additionally, in 2015, Motzer et al. demonstrated nivolumab, an ICI, had better overall survival (OS) with fewer grade 3 or 4 treatment-related adverse events than everolimus in patients with advanced RCC.⁷

Clinical trials in the past decade have demonstrated that current first-line therapies, including dual ICI and ICI/TKI combination therapies increase OS and PFS compared to sunitinib alone.8, 9, 10, 11^,15 Combination of lenvatinib, a TKI with VEGFR and Fibroblast Growth Factor Receptor inhibition providing antiangiogenic effects in tumor cells, and pembrolizumab, an anti-programmed death-1 (PD-1) monoclonal antibody ICI, has shown increased overall and progression-free survival compared to sunitinib across IMDC groups.¹⁵ Lenvatinib and pembrolizumab are generally used for the treatment of adult patients who do not require immunosuppression or have uncontrolled cardiovascular disease.¹⁵ Most patients on therapy will have adverse events, the most common side effects being diarrhea, hypertension, hypothyroidism, decreased appetite, fatigue, and nausea.¹⁵ In the CLEAR trial, 78.4% of patients had adverse events of any grade that led to interruption of lenvatinib, pembrolizumab, or both, with 37.2% of patients discontinuing either or both therapies due to adverse events.¹⁵

In the CLEAR trial, median PFS for patients randomized to lenvatinib and pembrolizumab was 23.9 months when compared to sunitinib alone at 9.2 months (hazard ratio for disease progression or death, 0.39; 95% CI, 0.32 to 0.49, p < 0.001). Additionally, OS was longer for lenvatinib plus pembrolizumab when compared to sunitinib (hazard ratio for death, 0.66, 95% CI 0.39 to 0.88; p = 0.005). Radiographic response for lenvatinib and pembrolizumab was also favorable, with 16.1% of patients demonstrating a complete response, 54.9% demonstrating a partial response, and 19.2% resulting in stable disease.¹⁵ While direct comparisons between first-line therapies have not been completed, these outcomes are remarkable compared with other trials comparing current therapies to sunitinib.8, 9, 10, 11.

Long-term follow up of CLEAR trial patients has demonstrated sustained oncologic benefits with lenvatinib and pembrolizumab continuing to have longer PFS and OS compared to sunitinib after an additional 7 months.¹⁶ Favorable outcomes for metastatic RCC have also been demonstrated outside the setting of clinical trials.¹⁷ Both studies reported cases of complete radiographic response per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) protocol, occurring in 18.3% of patients on extended CLEAR trial follow up, and 8% of patients in Stelmach et al.^16,17 However RECIST v1.1 protocol assesses only radiographic response and does not evaluate pathologic response.

From the literature, we came across two case reports where patients with advanced ccRCC were treated with lenvatinib and pembrolizumab with partial or complete radiographic and pathologic response. Radiographic resolution of lung metastases after nine weeks of therapy was reported in a 49-year-old male with metastatic ccRCC; however, a complete pathologic response in the primary tumor was not achieved (ypT3a).¹⁸ Secondly, a 61-year-old male who presented with metastatic RCC to the 4th rib and a level IIIc IVC thrombus underwent 6 months of lenvatinib and pembrolizumab. In this patient, only a radiographic partial response was achieved in the primary tumor and the caval thrombus, but when the nephrectomy and caval thrombectomy was performed, pathologically there were no viable tumor cells in the kidney or the caval thrombus.¹⁹

Our case raises important clinical and research implications. It supports a growing body of evidence suggesting that ICI/TKI therapy can achieve complete pathologic response in certain patient populations with metastatic RCC, possibly rendering cytoreductive surgical resection unnecessary for disease control, or potentially allowing nephron-sparing approaches in this setting. This may provide favorable outcomes to poor surgical candidates, although surgery remains valuable for confirmation of response. Currently, there is no consensus or guidelines for the treatment timeline of ICI/TKI combination therapies and cytoreductive nephrectomy. To fully optimize multimodal treatment for metastatic RCC, improved radiographic, molecular, or immunological biomarkers are needed to inform how to predict complete response of metastatic RCC on lenvatinib and pembrolizumab and optimize treatment plans to improve oncologic outcomes.

4. Conclusion

To our knowledge, this is the first reported case of metastatic RCC treated with lenvatinib and pembrolizumab that had complete radiographic resolution of lung metastases and renal vein/IVC thrombus on imaging, as well as complete pathologic response (ypT0NX) on cytoreductive nephrectomy. The patient subjectively feels well, and a recent PET-CT performed 4 months after surgery demonstrated no evidence of disease. We aim to highlight the remarkable response after systemic therapy in this specific instance of metastatic RCC. Studies of larger patient cohorts with longer interval follow-ups are necessary to confirm these findings.

CRediT authorship contribution statement

Eva Kiri Walker: Conceptualization, Data curation, Writing – original draft. Joon Yau Leong: Conceptualization, Data curation, Writing – original draft. Manju Aron: Data curation, Writing – review & editing. Monish Aron: Conceptualization, Data curation, Supervision, Writing – review & editing.

Declaration of competing interests

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Given their role as editorial board member, Manju Aron, MD had no involvement in the peer-review of this article and has no access to information regarding its peer-review. Full responsibility for the editorial process for this article was delegated to another journal editor. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.