Abstract
Introduction
Lenvatinib (Len) plus everolimus (Eve) is an approved therapy for metastatic renal cell carcinoma (mRCC) after first‐line vascular endothelial growth factor receptor‐tyrosine kinase inhibitors (VEGFR‐TKIs), but limited data exist on the efficacy of Len ± Eve after progression on immune checkpoint inhibitors (ICIs) and VEGFR‐TKIs.
Methods
We retrospectively reviewed the records of patients with mRCC at our institution who were treated with Len ± Eve after ICI and VEGFR‐TKI. A blinded radiologist assessed objective response as defined by RECIST version 1.1. Descriptive statistics and the Kaplan‐Meier method were used.
Results
Fifty‐five patients were included in the analysis. Of these patients, 81.8% had clear‐cell histology (ccRCC), and 76.4% had International Metastatic RCC Database Consortium intermediate‐risk disease. Median number of prior therapies was four (range, 2–10); all patients had prior ICIs and VEGFR‐TKIs, and 80% were previously treated with ICI and at least two VEGFR‐TKIs, including cabozantinib. One patient (1.8%) achieved a complete response, and 11 patients (20.0%) achieved a partial response, for an overall response rate (ORR) of 21.8%; 35 patients (63.6%) achieved stable disease. In all patients, median progression‐free survival (PFS) was 6.2 months (95% confidence interval [CI], 4.8–9.4) and median overall survival (OS) was 12.1 months (95% CI, 8.8–16.0). In patients with ccRCC, ORR was 24.4%, PFS was 7.1 months (95% CI, 5.0–10.5), and OS was 11.7 months (95% CI, 7.9–16.1). 50.9% of patients required dose reductions and 7.3% discontinued treatment because of toxicity.
Conclusion
Len ± Eve demonstrated meaningful clinical activity and tolerability in heavily pretreated patients with mRCC after disease progression with prior ICIs and VEGFR‐TKIs.
Implications for Practice
As the therapeutic landscape for patients with metastatic renal cell carcinoma continues to evolve, this single‐center, retrospective review highlights the real‐world efficacy of lenvatinib with or without everolimus in heavily pretreated patients. This article supports the use of lenvatinib with or without everolimus as a viable salvage strategy for patients whose disease progresses after treatment with immune checkpoint inhibitors and vascular endothelial growth factor receptor‐tyrosine kinase inhibitor therapies, including cabozantinib.
Keywords: Renal cell carcinoma, Lenvatinib, Lenvatinib plus everolimus, Immune checkpoint inhibitors, Cabozantinib
Short abstract
This article reports on the efficacy and safety of lenvatinib alone or in combination with everolimus in patients with clear‐cell and non–clear‐cell metastatic renal cell carcinoma who previously received immune checkpoint inhibitor and VEGFR‐TKI therapies.
Introduction
Over the past decade, the number of therapies for patients with metastatic renal cell carcinoma (mRCC) has expanded and overall survival (OS) has substantially improved [1, 2, 3, 4]. However, most patients eventually succumb to their disease, and the 5‐year survival rate has remained low (13.0%) in the general U.S. population, according to data from the Surveillance, Epidemiology, and End Results program [5]. The current treatment approach to mRCC involves immune checkpoint inhibitors (ICIs), vascular endothelial growth factor receptor‐tyrosine kinase inhibitors (VEGFR‐TKIs), and mammalian target of rapamycin (mTOR) inhibitors [6]. Although ICIs have emerged as the preferred cornerstone for frontline treatment of mRCC, VEGFR‐TKIs remain essential for patients who develop progressive disease [7]. Lenvatinib is a multitarget tyrosine kinase inhibitor, with activity against VEGFR, fibroblast growth factor receptors (FGFR), platelet derived growth factor receptor (PDGFR), RET, and KIT that has demonstrated activity in mRCC in early‐phase clinical trials [8, 9, 10, 11]. Everolimus is an mTOR inhibitor that has also demonstrated antitumor effects in mRCC [12]. The efficacy and safety of lenvatinib in combination with everolimus was first established in a phase Ib clinical trial that showed a disease control rate of over 80% in 20 patients [13].
In 2016, the U.S. Food and Drug Administration (FDA) approved lenvatinib in combination with everolimus for patients with mRCC who received at least one prior VEGFR‐TKI. This approval was based on the results of a randomized, phase II, open‐label trial that showed improved investigator assessed progression‐free survival (PFS) with lenvatinib plus everolimus compared with everolimus alone (14.6 vs. 5.5 months, hazard ratio [HR] 0.40; 95% confidence interval [CI], 0.24–0.68), improved OS (25.5 vs. 15.4 months, HR 0.51; 95% CI, 0.30–0.88), and higher overall response rate (ORR, 43% vs. 6%) in 153 patients with clear‐cell mRCC (ccRCC) who had progressive disease after prior anti‐angiogenic therapy. The combination arm had higher rates of grade ≥ 3 adverse events compared with everolimus alone (71% vs. 50%), the most common of which included diarrhea, fatigue, and hypertension. All patients had received one prior VEGFR‐TKI, but only five patients (3%) were previously treated with an ICI and no patients were reported to have received cabozantinib [14]. Despite the increasing use of ICIs in the frontline setting for mRCC, the activity of lenvatinib alone or in combination with everolimus after ICIs and VEGFR‐TKIs, and its use beyond second‐line treatment, has not been reported. Furthermore, there are very limited data on the efficacy of lenvatinib with or without everolimus in patients with non–clear‐cell mRCC (nccRCC) [15]. In this study, we report on the efficacy and safety of lenvatinib alone or in combination with everolimus in patients with ccRCC and nccRCC who previously received ICI and VEGFR‐TKI therapies.
Materials and Methods
We conducted a single‐center, retrospective review of consecutive patients with mRCC who were treated with lenvatinib alone or in combination with everolimus from November 2016 through February 2020 at The University of Texas, MD Anderson Cancer Center (MDACC). The MDACC Institutional Review Board approved this study under protocol PA16‐0736, and baseline demographic and clinical data were collected by individual chart review from the institution's electronic medical record system. Age, gender, Eastern Cooperative Oncology Group (ECOG) performance status, International Metastatic RCC Database Consortium (IMDC) risk score at the start of therapy, nephrectomy status, histological subtype, sites of disease, prior systemic therapies, and time on all prior lines of systemic therapy were recorded. During lenvatinib with or without everolimus therapy, patients were managed per best practice at MDACC, and charts were reviewed with attention to the starting dose of therapy, dose reductions or discontinuations, and accompanying toxicities assessed according to the Common Terminology Criteria for Adverse Events version 5. A board‐certified radiologist (T.K.B.) blinded to patient history and clinical data assessed radiographic tumor response to lenvatinib with or without everolimus using RECIST, version 1.1.
Patient characteristics were summarized using median (range) for continuous variables and frequency (%) for categorical variables. PFS was defined as the time interval between the date of first dose and the date of disease progression or death from any cause, whichever occurred first. Patients who were alive without disease progression were censored at the time of last follow‐up. OS was defined as the time interval between the date of first dose and the date of death due to any cause. Patients who were alive were censored at the last follow‐up. The Kaplan‐Meier method was applied to estimate time‐to‐event outcomes.
Results
Forty‐two patients (76.4%) received lenvatinib plus everolimus and 13 patients (23.6%) received lenvatinib alone. Baseline characteristics for all 55 patients are listed in Table 1. IMDC risk score calculated upon beginning lenvatinib with or without everolimus was favorable in 10.9% of patients, intermediate in 76.4% of patients, and poor in 12.7% of patients. Forty‐five patients had ccRCC, and 10 patients had variant, nccRCC. Eight patients had sarcomatoid dedifferentiation in their tumors. Most patients had three or more sites of metastatic disease upon beginning lenvatinib with or without everolimus (96.4%). The median number of prior therapies was four (range, 2–10); 40% of patients received lenvatinib with or without everolimus as fourth‐line treatment of mRCC, 20% as fifth‐line treatment, 16.4% as sixth‐line treatment, and 16.4% as seventh‐line or later. All patients had received an ICI prior to receiving lenvatinib with or without everolimus, 96.4% received sunitinib, pazopanib, or axitinib, and 83.6% received cabozantinib. In sum, 80% of patients received an ICI and two or more VEGFR‐TKIs, including cabozantinib, prior to beginning lenvatinib with or without everolimus.
Table 1.
Baseline patient and disease characteristics
| Variable | Value |
|---|---|
| Median age at Len ± Eve start, yr (range) | 62 (34–87) |
| Gender n (%) | |
| Male | 39 (70.9) |
| Female | 16 (29.1) |
| ECOG performance status at Len ± Eve start, n (%) | |
| 0 | 15 (27.3) |
| 1 | 23 (41.8) |
| 2 | 16 (29.1) |
| 3 | 1 (1.8) |
| IMDC risk score at Len ± Eve start, n (%) | |
| Favorable | 6 (10.9) |
| Intermediate | 42 (76.4) |
| Poor | 7 (12.7) |
| Stage at initial diagnosis of RCC, n (%) | |
| Stage I–III | 33 (60.0) |
| Stage IV | 22 (40.0) |
| Nephrectomy status, n (%) | |
| Status post nephrectomy | 47 (85.5) |
| Primary in situ | 8 (14.5) |
| Median time since dx of mRCC to Len ± Eve start, mo. (range) | 45.7 (7.9–151.6) |
| Histology, n (%) | |
| Clear‐cell | 45 (81.8) |
| Papillary type 1 | 1 (1.8) |
| Papillary type 2 | 1 (1.8) |
| Chromophobe | 4 (7.3) |
| Translocation | 1 (1.8) |
| Unclassified | 3 (5.5) |
| Sarcomatoid dedifferentiation, n (%) | |
| Yes | 8 (14.5) |
| No | 47 (85.5) |
| Sites of metastatic disease at Len ± Eve start, n (%) | |
| Lung | 46 (83.6) |
| Lymph node(s) | 43 (78.2) |
| Bone | 38 (69.1) |
| Liver | 24 (43.6) |
| Brain | 12 (21.8) |
| Other | 26 (47.3) |
| Three or more sites of metastatic disease, n (%) | 53 (96.4) |
| Prior local therapy for metastases, n (%) | |
| Surgery | 13 (23.6) |
| Radiation therapy | 33 (60.0) |
| Line of therapy for Len ± Eve, n (%) | |
| 3L | 4 (7.3) |
| 4L | 22 (40.0) |
| 5L | 11 (20.0) |
| 6L | 9 (16.4) |
| ≥7L | 9 (16.4) |
| Median number of prior lines of therapy, n (range) | 4 (2–10) |
| Prior treatments before Len ± Eve start, n (%) | |
| ICI | 55 (100) |
| ICI monotherapy | 38 (69.1) |
| ICI + ICI combination therapy | 5 (9.1) |
| ICI + TKI combination therapy | 6 (10.9) |
| Other ICI combination therapy | 11 (20) |
| VEGFR‐TKI | 55 (100) |
| Sunitinib | 16 (29.1) |
| Pazopanib | 32 (58.2) |
| Axitinib | 17 (30.1) |
| Cabozantinib | 46 (83.6) |
| Prior ICI and ≥2 TKIs, including cabozantinib | 44 (80.0) |
| Prior ICI and ≥3 TKIs, including cabozantinib | 12 (21.8) |
| TKI + medication other than ICI | 3 (5.5) |
| Bevacizumab | 8 (14.5) |
| Everolimus | 9 (16.4) |
| Interleukin–2 | 6 (10.1) |
| Chemotherapy | 2 (3.6) |
Abbreviations: 3L, third‐line; 4L, fourth‐line; 5L, fifth‐line; 6L, sixth‐line; 7L, seventh‐line; dx, diagnosis; ECOG, Eastern Cooperative Oncology Group; Eve, everolimus; ICI, immune checkpoint inhibitor; IMDC, International Metastatic RCC Database Consortium; Len, lenvatinib; mRCC, metastatic renal cell carcinoma; RCC, renal cell carcinoma; VEGFR‐TKI, vascular endothelial growth factor receptor‐tyrosine kinase inhibitor.
At the time of analysis, 48 patients had experienced disease progression or death, and the median PFS was 6.2 months (95% CI, 4.8–9.4) for all patients. Median PFS was 7.1 months (95% CI, 5.0–10.5) in patients with ccRCC and 3.2 months (95% CI, 3.1–NA) in patients with nccRCC (Table 2). At the time of analysis, 44 patients had died, and the median OS from initiation of lenvatinib with or without everolimus was 12.1 months (95% CI, 8.8–16.0) for all patients. Median OS was 11.7 months (95% CI, 7.9–16.1) for patients with ccRCC and 12.5 months (95% CI, 4.3–NA) for patients with nccRCC. The Kaplan‐Meier curves of PFS and OS for all patients are shown in Figure 1, and the Kaplan‐Meier curves of PFS and OS for ccRCC and nccRCC are shown in supplemental online Figure 1. Confirmed ORR was 21.8% across all patients with one complete response (CR, Table 2, Fig. 2). Computed tomography images of the patient who achieved a CR are shown in supplemental online Figure 2. Patients with ccRCC had an ORR of 24.4% and patients with nccRCC had an ORR of 10.0%. A formal statistical comparison of response rates by histology was not performed due to small sample size. In patients who had received ICIs and cabozantinib prior to treatment with lenvatinib with or without everolimus (n = 46), the ORR was 15.2% (n = 7, Fig. 2), and 67.4% of patients (n = 31) achieved stable disease (SD).
Table 2.
Efficacy of lenvatinib ± everolimus in patients with metastatic renal cell carcinoma
| Variable | All patients n = 55 | Clear‐cell RCC n = 45 | Non–clear‐cell RCC n = 10 |
|---|---|---|---|
| Median PFS, mo | 6.2 | 7.1 | 3.8 |
| Median OS, mo | 12.1 | 11.7 | 12.5 |
| ORR, n (%) | 12 (21.8) | 11 (24.4) | 1 (10) |
| CR | 1 (1.8) | 1 (2.2) | 0 (0) |
| PR | 11 (20.0) | 10 (22.2) | 1 (10) |
| SD | 35 (63.6) | 28 (62.2) | 7 (70) |
| PD a | 7 (12.7) | 5 (11.1) | 2 (20) |
| NE | 1 (1.8) | 1 (2.2) | 0 (0) |
PD defined by RECIST version 1.1 or clinical disease progression prior to restaging.
Abbreviations: CR, complete response; NE, not evaluable; OS, overall survival; ORR, overall response rate; PD, progressive disease; PFS, progression‐free survival; PR, partial response; RCC, renal cell carcinoma; SD, stable disease.
Figure 1.
(A) Progression‐free survival and (B) overall survival among all patients.
Abbreviations: CI, confidence interval; OS, overall survival; PFS, progression‐free survival
Figure 2.
Waterfall plot of confirmed overall response. Best % change = best radiographic response of target lesion per RECIST version 1.1, as measured by a board‐certified radiologist specializing in genitourinary cancers. The dotted lines at −30% and +20% correspond to classification of best overall response. A best % change >20% corresponds to progressive disease, between 20% and −30% corresponds to stable disease, <−30% corresponds to a partial response, and −100% corresponds to complete response. Abbreviation: cabo, cabozantinib.
Of the 13 patients treated with lenvatinib alone, 9 patients had previously received everolimus, and 1 patient had previously received temsirolimus, so they were not retreated with everolimus. The other three patients were treated with lenvatinib alone due to concern for tolerability of the combination. The vast majority of the patients started with lenvatinib 18 mg daily (74.5%) plus everolimus 5 mg daily (72.7%). Patients who were initially treated with a reduced dose of lenvatinib and/or everolimus are shown in Table 3. Of the patients, 50.9% required dose reduction of lenvatinib, and 16.7% of patients required dose reduction of everolimus. 7.3% of patients discontinued treatment due to proteinuria and fatigue (two patients each). The most frequent grade 3 adverse events (Table 4) of interest were proteinuria (18.2%), diarrhea (9.1%), and fatigue (9.1%). No grade 4 or 5 adverse events were attributed to lenvatinib or everolimus. The most frequent grade 1–2 adverse events of interest were fatigue (67.3%), nausea (38.2%), decreased appetite (36.4%), hypertension (34.5%), decreased weight (23.6%), and diarrhea (21.8%).
Table 3.
Dosing information for patients who received lenvatinib alone or in combination with everolimus
| Dosing information | n (%) |
|---|---|
| Therapy received | |
| Lenvatinib + everolimus | 42 (76.4) |
| Lenvatinib alone a | 13 (23.6) |
| Starting dose of lenvatinib | |
| 18 mg daily | 41 (74.5) |
| 14 mg daily | 12 (21.8) |
| 10 mg daily | 1 (1.8) |
| 8 mg daily | 1 (1.8) |
| Starting dose of everolimus | |
| 0 mg daily | 13 (23.6) |
| 5 mg daily | 40 (72.7) |
| 5 mg QOD | 1 (1.8) |
| 10 mg QOD | 1 (1.8) |
| Dose reduction | |
| Yes | 28 (50.9) |
| No | 27 (49.1) |
| Lenvatinib dose reduction | |
| Yes | 28 (50.9) |
| No | 27 (49.1) |
| Everolimus dose reduction | |
| Yes | 7 (16.7) |
| No | 35 (83.3) |
| Reason for treatment discontinuation | |
| Progressive disease | 35 (63.6) |
| Toxicity | 4 (7.3) |
| Death | 2 (3.6) |
| N/A | 14 (25.5) |
| Treatment after lenvatinib | |
| Yes | 11 (20) |
| No | 33 (60) |
| N/A | 11 (20) |
Nine of 13 patients had previously received everolimus, so they were treated with lenvatinib alone.
Abbreviations: N/A, not available; QOD, every other day.
Table 4.
Select adverse events attributed to lenvatinib ± everolimus using the National Cancer Institute Common Terminology Criteria for Adverse Events
| Adverse event, n (%) | Grade 1–2 | Grade 3 |
|---|---|---|
| Proteinuria | 3 (5.4) | 10 (18.2) |
| Diarrhea | 12 (21.8) | 5 (9.1) |
| Fatigue | 37 (67.3) | 5 (9.1) |
| Hypertension | 19 (34.5) | 2 (3.6) |
| Hand‐foot syndrome | 3 (5.4) | 2 (3.6) |
| Decreased appetite | 20 (36.4) | 1 (1.8) |
| Decreased weight | 13 (23.6) | 1 (1.8) |
| Nausea | 21 (38.2) | 0 (0) |
| Hypothyroidism | 10 (18.2) | 0 (0) |
| Mucositis | 9 (16.4) | 0 (0) |
| Electrolyte disturbance | 3 (5.4) | 0 (0) |
| AST or ALT elevation | 3 (5.4) | 0 (0) |
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Discussion
The therapeutic landscape for patients with mRCC has significantly changed over the past 5 years [16]. Contemporary, second‐line, or later therapies were approved based on clinical trials that evaluated efficacy and safety after progression on first‐line VEGFR‐TKIs [7]. The majority of patients today receive ICIs with or without VEGFR‐TKIs as first‐line therapy, and the efficacy of lenvatinib plus everolimus after ICIs or cabozantinib is unknown. In this single‐center retrospective analysis, lenvatinib with or without everolimus demonstrated promising efficacy and tolerability in heavily pretreated patients, most of whom had progressive disease after ICIs and two or more VEGFR‐TKIs, including cabozantinib. The eight patients with sarcomatoid dedifferentiation appeared to experience limited clinical benefit with lenvatinib plus everolimus (Fig. 2). This histology portends a poor prognosis, and prior retrospective studies have established that patients with sarcomatoid mRCC do not substantially benefit from VEGFR‐TKI therapies [17]. This finding is hypothesis‐generating and warrants further investigation in a larger cohort of patients with sarcomatoid dedifferentiation.
Limited trial data exist on the efficacy of VEGFR‐TKIs or cabozantinib after progression on ICIs. In three real‐world studies, second‐line VEGFR‐TKIs, including cabozantinib, had similar or improved efficacy after disease progression on ICIs, compared with the post‐VEGFR‐TKI setting [18, 19, 20]. Cabozantinib is a multitarget TKI that inhibits VEGFR1‐3, MET, AXL, RET, ROS1, TYRO3, MER, KIT, and FLT3 and is approved in the first‐line and subsequent‐line settings for mRCC based on results from the CABOSUN and METEOR trials, respectively [21, 22, 23, 24]. Since cabozantinib inhibits a wider spectrum of angiogenesis‐related tyrosine kinases, some clinical investigators hypothesize that VEGFR‐TKIs will have limited efficacy after disease progression on cabozantinib; however, there are no real‐world data available to support or refute this hypothesis. In our cohort, 46 patients had previously received cabozantinib, yet lenvatinib with or without everolimus produced a clinical benefit rate (CR + partial response + SD) of 82.6% in these patients. Lenvatinib is a multitarget TKI that targets FGFR1–4, in addition to VEGFR1–3, RET, KIT, and PDGFRα [8, 9]. It is approved in combination with everolimus, an mTOR inhibitor with known activity against mRCC [12]. Based on the activity of lenvatinib plus everolimus after disease progression on cabozantinib, we hypothesize that targeting the FGFR/MAPK and mTOR pathways remain relevant in patients who develop cabozantinib resistance. Our findings suggest that clinicians should consider lenvatinib plus everolimus in patients who develop progressive disease after ICIs and VEGFR‐TKIs, including cabozantinib.
Approximately half the patients with mRCC will not receive any subsequent lines of treatment after disease progression, and the efficacy of VEGFR‐TKIs declines in the later‐line setting [25, 26]. The optimal sequence of therapies for patients with mRCC is unknown due to the rapid pace of therapy development. The efficacy of lenvatinib plus everolimus in our heavily pretreated cohort supports the earlier administration of this regimen, and the CLEAR trial confirmed the activity of lenvatinib in combination with pembrolizumab or everolimus for treatment‐naïve mRCC. CLEAR was a three‐arm, randomized, phase III clinical trial that compared lenvatinib plus pembrolizumab or everolimus versus sunitinib as first‐line treatment in patients with mRCC [3]. In the CLEAR trial, lenvatinib plus pembrolizumab significantly improved median PFS (23.9 vs. 9.2 months; HR 0.39; 95% CI, 0.32–0.49), median OS (HR 0.66; 95% CI, 0.49–0.88), and resulted in a higher ORR (71.0% vs. 36.1%) compared with sunitinib. Lenvatinib plus everolimus significantly improved median PFS (14.7 vs. 9.2 months; HR 0.65; 95% CI, 0.53–0.80) and resulted in a higher ORR (53.5% vs. 36.1%) compared with sunitinib, but the combination did not provide an OS benefit (HR 1.15; 95% CI, 0.88–1.50). The randomized phase III CheckMate 9ER trial showed that nivolumab plus cabozantinib significantly improved median PFS (16.6 vs. 8.3 months; HR 0.51; 95% CI, 0.41–0.64), median OS (HR 0.60; 98.89% CI, 0.40–0.89), and resulted in a higher ORR (55.7% vs. 27.1%) compared with sunitinib, and the combination of nivolumab plus cabozantinib is now approved by the U.S. FDA [4]. Accordingly, there are now multiple phase III clinical trials that show improved median PFS and median OS with anti‐programmed cell death 1 monoclonal antibodies in combination with ipilimumab or VEGFR‐TKIs in the frontline setting for mRCC [2, 3, 4, 27]. For patients who develop progressive disease, VEGFR‐TKIs remain an essential cornerstone of subsequent‐line treatment, but the optimal sequence of these therapies is not known. A clinical trial comparing lenvatinib plus everolimus versus cabozantinib after first‐line ICI‐based regimens would shed light on the clinical efficacy and safety of these two regimens as salvage therapies. In this context, our findings are valuable for clinicians selecting a subsequent‐line therapy after progression on ICIs and cabozantinib, including the CheckMate 9ER regimen.
In the three‐arm, randomized, phase II, registration trial (Study 205), 51 patients with mRCC received lenvatinib plus everolimus [14]. Besides a case series of seven patients, there are no real‐world data on the efficacy or safety of lenvatinib plus everolimus for patients with ccRCC or nccRCC [28]. Our cohort included 42 patients who received lenvatinib plus everolimus and 13 patients who received lenvatinib alone, making it one of the largest real‐world experiences using lenvatinib for ccRCC and nccRCC. In our experience, the regimen was well tolerated but required close supervision to adequately manage toxicities in patients with heavily pretreated disease. 50.9% of patients required a dose reduction, yet only 7.3% of patients had treatment discontinued due to toxicity and no patient experienced a grade 4 or 5 adverse event. The most frequent grade 3 adverse event in our study was proteinuria (18.2%), similar to what was reported with lenvatinib alone in Study 205 (19%) but higher than reported with lenvatinib plus pembrolizumab (7.7%) or lenvatinib plus everolimus (8.2%) in CLEAR, presumably because patients in CLEAR were treatment‐naïve. Our rates of grade 3 hypertension (3.6% vs. 14% vs. 22.5%) and diarrhea (9.1% vs. 20% vs. 11.5%) were lower than reported with lenvatinib plus everolimus in Study 205 or CLEAR, respectively. Furthermore, health‐related quality of life (HRQOL) data from an open‐label, randomized, phase II trial comparing the efficacy and safety of two different starting doses of lenvatinib (18 mg vs. 14 mg) in combination with everolimus 5 mg for patients with mRCC following one prior VEGFR‐TKI has been reported [29]. The authors concluded that patients who started with lenvatinib 18 mg plus everolimus had better HRQOL and longer time to deterioration than those who received the lenvatinib 14 mg starting dose. Additionally, the CLEAR trial provides further information on the toxicity of lenvatinib plus everolimus in patients with treatment‐naïve mRCC [3].
Our study is limited by being a single‐center, retrospective study at a high‐volume academic medical center in the U.S. Our efficacy findings are thus prone to selection bias, and our safety findings are limited by clinician documentation. The strengths of our study include independent radiographic review to determine ORR and PFS and a relatively large sample size compared with previous reports.
Conclusion
Lenvatinib with or without everolimus had encouraging late‐line efficacy in heavily pretreated patients with mRCC, including many with disease progression after ICIs and cabozantinib. The combination was well tolerated but requires close supervision to adequately manage toxicities. As the first‐line treatment landscape and sequencing of therapies for mRCC continues to evolve, this single‐center experience provides insight into the real‐world efficacy of lenvatinib with or without everolimus, and clinicians should consider this regimen for patients whose disease progresses after treatment with immune checkpoint inhibitors and VEGFR‐TKI therapies, including cabozantinib.
Author Contributions
Conception/design: Andrew J. Wiele, Andrew W. Hahn, Jeremy A. Ross, Pavlos Msaouel, Nizar M. Tannir
Provision of study material or patients: Eric Jonasch, Amishi Y. Shah, Matthew T. Campbell, Pavlos Msaouel, Nizar M. Tannir
Collection and/or assembly of data: Andrew J. Wiele, Tharakeswara K. Bathala, Andrew W. Hahn, Munevver Duran, Jeremy A. Ross
Data analysis and interpretation: Andrew J. Wiele, Tharakeswara K. Bathala, Andrew W. Hahn, Lianchun Xiao, Pavlos Msaouel, Nizar M. Tannir
Manuscript writing: Andrew J. Wiele, Andrew W. Hahn, Munevver Duran, Jeremy A. Ross, Amishi Y. Shah, Matthew T. Campbell, Pavlos Msaouel, Nizar M. Tannir
Final approval of manuscript: Andrew J. Wiele, Tharakeswara K. Bathala, Andrew W. Hahn, Lianchun Xiao, Munevver Duran, Jeremy A. Ross, Eric Jonasch, Amishi Y. Shah, Matthew T. Campbell, Pavlos Msaouel, Nizar M. Tannir
Disclosures
Eric Jonasch: Exelixis, Merck, Pfizer, Eisai, Novartis, Roche (C/A, H), Exelixis, Merck, Pfizer (RF); Amishi Y. Shah: Bristol‐Myers Squibb, Exelixis, Pfizer, Roche, Eisai (C/A, H), Bristol‐Myers Squibb, EMD Serono (RF); Matthew T. Campbell: Exelixis, Pfizer, EMD Serono, Eisai, AstraZeneca, Seattle Genetics (C/A, H), Exelixis, Pfizer, EMD Serono, Apricity Health, Janssen (RF); Pavlos Msaouel: Bristol‐Myers Squibb, Mirati, Pfizer, Exelixis, Axiom Healthcare Strategies (C/A, H), Bristol‐Myers Squibb, Mirati, Takeda, Gateway for Cancer Research (RF), Exelixis, Pfizer (other—nonbranded educational programs); Nizar M. Tannir: Bristol‐Myers Squibb, Pfizer, Exelixis, Nektar Therapeutics, Eisai, Eli Lilly & Co., Novartis, Ono Pharmaceutical, Oncorena, Ipsen, Surface Oncology, Neoleukin Therapeutics (C/A, H), Bristol‐Myers Squibb, Pfizer, Exelixis, Nektar Therapeutics, Eisai, Eli Lilly & Co., Calithera Bioscience, Mirati Therapeutics, Arrowhead Pharmaceuticals, Takeda, Epizyme (RF). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
Supporting information
See http://www.TheOncologist.com for supplemental material available online.
Figure S1 Progression‐free survival and overall survival among patients with clear cell and non‐clear cell mRCC. CI, Confidence Interval. ccRCC, metastatic clear‐cell renal cell carcinoma. nccRCC, metastatic non‐clear cell renal cell carcinoma.
Figure S2. Axial computed tomography images demonstrating the patient's pancreatic and soft tissue metastases (A) at the time of progression on prior therapy and (B) complete response after 1 year of lenvatinib therapy.
Acknowledgments
The authors acknowledge the patients and caregivers who participated and contributed to this study. This study was approved by the Internal Review Board/Ethics Committee of The University of Texas, MD Anderson Cancer Center. There was no writing assistance provided in the preparation of this manuscript. This work was supported in part by Cancer Center Support (Core) grant P30 CA016672 from the National Cancer Institute, National Institutes of Health, to The University of Texas MD Anderson Cancer Center. Pavlos Msaouel is supported by a Young Investigator Award from the Kidney Cancer Association, a Career Development Award from the American Society of Clinical Oncology, by a Concept Award from the U.S. Department of Defense, by a KCCure Research Award, and by the MD Anderson Khalifa Scholar award.
Disclosures of potential conflicts of interest may be found at the end of this article.
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Supplementary Materials
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Figure S1 Progression‐free survival and overall survival among patients with clear cell and non‐clear cell mRCC. CI, Confidence Interval. ccRCC, metastatic clear‐cell renal cell carcinoma. nccRCC, metastatic non‐clear cell renal cell carcinoma.
Figure S2. Axial computed tomography images demonstrating the patient's pancreatic and soft tissue metastases (A) at the time of progression on prior therapy and (B) complete response after 1 year of lenvatinib therapy.