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Real-world Clinical Effectiveness of Lenvatinib/Everolimus in a Heavily Pretreated Advanced/Metastatic Renal Cell Carcinoma Population in the US Community Oncology Setting

Open AccessPublished:May 15, 2021DOI:https://doi.org/10.1016/j.clgc.2021.05.002

      Abstract

      Introduction

      Few studies have evaluated real-world effectiveness of lenvatinib (Len)/everolimus (Eve) for advanced/metastatic renal cell carcinoma (a/mRCC). This study evaluated patient profiles and clinical outcomes of second- and subsequent-line (≥ 2L) Len/Eve for a/mRCC.

      Patients and Methods

      A longitudinal retrospective study examined adult patients initiating ≥ 2L Len/Eve for a/mRCC from May 13, 2016, to July 31, 2019. Len/Eve clinical trial participants or those treated for other primary tumors were excluded. Outcomes included objective response rate, duration of response, progression-free survival (PFS), time to treatment discontinuation, and overall survival. Time-to-event outcomes were estimated using Kaplan-Meier methods.

      Results

      Seventy-nine patients were assessed: the median age was 64.8 years, 78.5% were Caucasian, 73.4% were male, 78.5% had an Eastern Cooperative Oncology Group performance status score of 0/1, 29.1% received 2L/3L Len/Eve, and the median number of prior lines of therapy was 3 (range, 1-8). At initial diagnosis, 55.7% had stage IV disease, 65.8% had International Metastatic risk scores of intermediate/poor, 19.0% favorable, and 15.2% with missing score. Thirty-one (39.2%) patients received immuno-oncology–based regimens, and 50.6% received tyrosine kinase inhibitors directly before Len/Eve initiation. The median time to treatment discontinuation was 5.7 months (95% CI, 3.3-6.9). The physician-assessed objective response rate was 55.7% (1.6% complete response and 54.1% with some degree of tumor shrinkage). The median duration of response was 9.7 months (95% CI, 5.8-17.1). The median PFS was 6.1 months (95% CI, 4.4-9.0). The median PFS for patients receiving Len/Eve post–immuno-oncology was 6.4 months (95% CI, 4.1-10.8) and for post–tyrosine kinase inhibitor 5.7 months (95% CI, 4.1-10.5). Median overall survival was 14.8 months (95% CI, 10.2-23.9).

      Conclusion

      In this longitudinal retrospective study, Len/Eve showed real-world effectiveness in clinical practice in a heavily pretreated a/mRCC patient population.

      Keywords

      Abbreviations:

      : BMI (body mass index), ECOG (Eastern Cooperative Oncology Group), eCRF (electronic case report form), HER (electronic health record), HCRU (health care resource utilization), iKM (iKnowMed), IMDC (International Metastatic RCC Database Consortium), LADMF (Limited Access Death Master File), LOT (line of therapy), OS (overall survival), RCC (renal cell cancer), SSDI (Social Security Death Index), SSN (Social Security number)

      Introduction

      Renal cell carcinoma (RCC) is the most common type of kidney cancer, ranked the sixth and tenth most common malignancy in American males and females, respectively.
      • Siegel RL
      • Miller KD
      • Jemal A
      Cancer statistics, 2020.
      In the United States, the estimated number of diagnosed cases in 2018 was 65,340, and the estimated number of deaths was 14,970.
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      • Ruhban IA
      • Sonbol MB
      • Ho TH
      Trends in renal-cell carcinoma incidence and mortality in the United States in the last 2 decades: A SEER-based study.
      The most recent survival estimates for advanced/metastatic RCC (a/mRCC) are 82.3% at 18 months (KEYNOTE-426)
      • Rini BI
      • Plimack ER
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      Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.
      and 52% at 42 months (CheckMate-214).
      • Motzer RJ
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      • et al.
      Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial.
      The treatment landscape for a/mRCC has been evolving in recent years. The Food and Drug Administration (FDA) has approved immuno-oncology (IO)–based therapies and tyrosine kinase inhibitor (TKI)–based therapies for first-line treatment for a/mRCC. Second- and subsequent-line (≥ 2L) treatments approved include axitinib, cabozantinib, nivolumab, lenvatinib (Len)/everolimus (Eve), and everolimus monotherapy, among others.
      • Tannir NM
      • Pal SK
      • Atkins MB
      Second-line treatment landscape for renal cell carcinoma: A comprehensive review.
      In May 2016, the FDA approved Len/Eve for treatment of advanced RCC after 1 prior antiangiogenic therapy.

      FDA approves Lenvima (lenvatinib) for the treatment of patients with advanced renal cell carcinoma. Available at: https://www.drugs.com/newdrugs/fda-approves-lenvima-lenvatinib-patients-advanced-renal-cell-carcinoma-4382.html.

      The approval was based on a phase 2 randomized open-label trial that showed a median progression-free survival (PFS) of 14.6 months for the Len/Eve arm versus 5.5 months for the everolimus arm (hazard ratio, 0.40; 95% CI, 0.24-0.68) (ClinicalTrials.gov, NCT01136733).
      • Motzer RJ
      • Hutson TE
      • Glen H
      • et al.
      Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: A randomised, phase 2, open-label, multicentre trial.
      Clinical outcomes for patients with a/mRCC treated with ≥ 2L Len/Eve combination therapy have not been thoroughly evaluated in real-world settings. Prior research has mainly focused on TKIs for a/mRCC patients treated in the ≥ 2L.
      • Tannir NM
      • Pal SK
      • Atkins MB
      Second-line treatment landscape for renal cell carcinoma: A comprehensive review.
      ,
      • Shah AY
      • Kotecha RR
      • Lemke EA
      • et al.
      Outcomes of patients with metastatic clear-cell renal cell carcinoma treated with second-line VEGFR-TKI after first-line immune checkpoint inhibitors.
      • Campbell MT
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      • et al.
      Cabozantinib for the treatment of patients with metastatic non–clear cell renal cell carcinoma: A retrospective analysis.
      • Deuker M
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      Second-line tyrosine kinase inhibitor-therapy after immunotherapy-failure.
      A recent case report study by Hamieh et al
      • Hamieh L
      • Beck RL
      • Le VH
      • Hsieh JJ
      The efficacy of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma exhibiting primary resistance to front-line targeted therapy or immunotherapy.
      assessed the use of Len/Eve in patients with a/mRCC with primary resistance to first-line therapies in real-world settings and found that patients benefitted from subsequent Len/Eve combination therapy. However, this study only included 7 patients, and further research is warranted.
      Real-world data on Len/Eve use and associated clinical outcomes may help clinicians and patients choose the most appropriate treatment to optimize clinical outcomes. Therefore, we aimed to assess treatment patterns and clinical outcomes of patients treated with ≥ 2L Len/Eve for a/mRCC in a US community oncology setting.

      Patients and Methods

       Data Source

      Data from May 13, 2016, to January 31, 2020, were captured from the US Oncology Network (USON). USON includes 1200 affiliated physicians operating in over 470 sites of care across states and provides care for nearly 1 million patients newly diagnosed with cancer annually. Structured data were extracted directly from the EMR database, and unstructured data were extracted using electronic case report forms with supplemental vital status provided by the Social Security Administration's Limited Access Death Master File. All data were handled in compliance with HIPAA (Health Insurance Portability and Accountability Act) and the Health Information Technology for Economic and Clinical Health Act. The study protocol was granted an exemption and waiver of informed consent by the US Oncology institutional review board (IRB #20-004E).

       Study Design and Patient Population

      This was a retrospective observational study via chart review approach. The study cohort included adult patients (≥ 18 years) diagnosed with a/mRCC who initiated ≥ 2L Len/Eve between May 13, 2016, and July 31, 2019. Patients were followed longitudinally until January 31, 2020, or the last patient record. Patients enrolled in Len/Eve clinical trials or receiving treatment for other primary tumor types at any time during the index period were excluded because they had clinical scenarios that deviated from the population of interest.
      The index date was defined as the initiation of Len/Eve. The preindex period was the time from the initial a/mRCC diagnosis date until the index date (but not including the index date). The postindex period was the time from the index date until death, the last clinical visit, or the end-of-study date, whichever came first. During the postindex period, patients had variable follow-up durations because they were each followed longitudinally until the last patient record or the end of the study period.

       Patient Characteristics and Treatment Patterns

      Patient demographics, including patients’ age, sex, race, ethnicity, geographic region, and smoking status, were included. Clinical characteristics, International Metastatic RCC Database Consortium (IMDC) risk status, and treatment details were collected if available. Patients’ treatment sequences were considered based on the absolute order of regimens, which were based on start and stop dates. The reasons for treatment discontinuation or initiation were not considered for line of therapy (LOT) advancement. The treatment episode was determined within 28 days, meaning that if a patient had multiple regimens with overlapping start dates within 28 days, this was defined as a single combined LOT. If there was a gap greater than a certain time window (ie, ≥ 90 days), LOT was advanced even with the same drug. Canceled drug order and administration were not used to determine the LOT.

       Clinical and Statistical Endpoints

      All patients were followed from the index date until the end of the study period for outcomes. Endpoints included were (1) real-world best overall response (BOR) and objective response rate (ORR), (2) duration of response (DOR), (3) PFS, (4) time to treatment discontinuation (TTD), and (5) overall survival (OS). BOR was defined as the superior physician-assessed response from the following: complete response, partial response, stable disease, mixed response, progressive disease, or not evaluated. ORR was the proportion of patients who achieved a complete response or partial response (including a response not otherwise specified) based on physician assessments, as documented in patient charts. DOR was defined as the duration from first physician-documented response until the date of physician-documented disease progression. Patients who did not respond at the last visit date were censored. The response reflects the physician-assessed impression of tumor reduction of unspecified degree on the scans. Using RECIST criteria to assess tumor response is usually not considered part of the routine in real-world clinical practice. PFS was defined as the duration from the initiation of index treatment until the date of physician-documented disease progression or death. Patients who were still alive at the end of the study observation period and did not progress at the last visit date were censored. TTD was defined as the duration between index treatment initiation and treatment discontinuation, including any treatment interruptions or other breaks of no more than 90 consecutive days in length. Patients with ongoing treatment were censored on the study end date or the last visit date available in the data set, whichever occurred first. OS was defined as the duration (in months) from the initiation of index treatment until the date of death from any cause. Patients who did not die within the study observation period were censored on the study end date or the last visit date available in the data set, whichever occurred first.
      Each patient was assigned 1 BOR based on all physician-reported response assessments captured during chart review, during the index treatment, and up to 30 days beyond treatment discontinuation as long as a next treatment was not initiated. Among all patients with a response assessment, ORR was defined as the proportion of patients who had evidence of response, including with complete response.
      DOR was defined as the time between the first physician-reported response and the date of provider-documented physician-reported progression, censoring patients without evidence of physician-reported progression at the last visit date. PFS was defined as the time between initiation of index treatment and the earliest date of progression or date of death attributable to any cause, censoring patients who did not die and did not progress by the end of the study observation period at the last visit date. TTD was defined as the interval between index treatment initiation and treatment discontinuation. OS was defined as the interval between the initiation of the index treatment and the date of death. Patients alive at the end of the study observation period were censored on the study end date or the last visit date available in the data set, whichever occurred first.

       Statistical Analysis

      Patients’ characteristics, treatment patterns and outcomes were assessed for all patients as well as for the subgroups of patients receiving Len/Eve post-IO or post-TKI. Classification of patients into the post-IO and post-TKI subgroups was based on the treatment regimen(s) they received immediately before Len/Eve. For example, if a patient began nivolumab monotherapy and advanced to a new LOT with a combination of Len/Eve, that patient was a post-IO subgroup member.
      Demographic and clinical characteristics at baseline and treatment patterns were assessed descriptively for the overall population and were obtained from structured data. Categorical variables (e.g., Eastern Cooperative Oncology Group performance status [ECOG PS]) were reported as frequency and percentage. Continuous variables such as age were reported as mean, SD, median, and range (minimum to maximum). In the case of missing observations, the number and percentage of missing values were reported. Time-to-event outcomes, including TTD, OS, DOR, and PFS, were assessed for the overall study population and for the Len-Eve post-IO and post-TKI groups using the Kaplan-Meier method with 95% CIs, and were all available from both structured and unstructured data. Tumor response data were obtained from unstructured data. Landmark probabilities of PFS and OS were reported at 6, 12, 18, and 24 months. Results were reported in aggregate using SAS 9.4 (SAS Institute Inc, Cary, NC).

      Results

       Baseline Demographic and Clinical Characteristics for Patients With a/mRCC Treated With ≥ 2L Len/Eve

      A total of 79 patients were included in the study population. The median age was 64.8 years, 73.4% were male, 78.5% were Caucasian, 70.9% were in the western US region, and 50.6% had never smoked (Table 1). At initial diagnosis, 55.7% of patients had stage IV disease, and clear cell carcinoma accounted for 86.1% of the population, followed by papillary histology (7.6%), and 1 (1.3%) patient each had chromophobe, microphthalmia transcription factor family translocation, and unclassified histology. A majority (68.4%) of patients had a history of nephrectomy. The lung was the most common site for distant metastases, in 53.2% of patients, followed by the bones and distant lymph nodes, each with 25.3%. An ECOG PS score of 0 or 1 was found in 78.5% of the study population. Twenty-three patients (29.1%) received Len/Eve as 2L or 3L, and 70.9% received Len/Eve as ≥ 4L. The median number of prior lines of therapy was 3 (range, 1-8), and the median overall follow-up time from the index date was 8.8 months (range, 0.5-34.6) (Table 2).
      Table 1Baseline Demographic and Clinical Characteristics for Patients With a/mRCC Treated With ≥ 2L Len/Eve
      Baseline Characteristicsn = 79
      Age at index (years)
       Mean (SD)63.2 (11.3)
       Median (min, max)64.8 (33.5, 85.3)
      Sex, n (%)
       Female21 (26.6)
       Male58 (73.4)
      Race, n (%)
       Caucasian62 (78.5)
       African American1 (1.3)
       Asian3 (3.8)
       Other9 (11.4)
       Not documented4 (5.1)
      Ethnicity, n (%)
       Hispanic or Latino9 (11.4)
       Not Hispanic or Latino62 (78.5)
       Not documented8 (10.1)
      Geographic region, n (%)
       Midwest9 (11.4)
       Northeast1 (1.3)
       South13 (16.5)
       West56 (70.9)
      Smoking status, n (%)
       Current8 (10.1)
       Former29 (36.7)
       Never40 (50.6)
       Not documented2 (2.5)
      Time since a/mRCC diagnosis to initiation of Len/Eve (months)
       Patients with available data79
       Mean (SD)34.3 (22.4)
       Median (min, max)26.9 (5.4, 106.6)
      Stage of initial RCC diagnosis, n (%)
       I8 (10.1)
       II9 (11.4)
       III12 (15.2)
       IV44 (55.7)
       Not documented6 (7.6)
      Histology at initial RCC diagnosis, n (%)
       Clear cell68 (86.1)
       Papillary6 (7.6)
       Chromophobe1 (1.3)
       Translocation1 (1.3)
       Unclassified1 (1.3)
       Not documented2 (2.5)
      Sarcomatoid features, n (%)
       No61 (77.2)
       Yes5 (6.3)
       Not documented13 (16.5)
      Previous history of nephrectomy before index date
       Yes54 (68.4)
       No/not documented25 (31.6)
      Time since nephrectomy to index date (months)
       Patients with available data54
       Mean (SD)66.4 (54.6)
       Median (min, max)50.0 (10.4, 305.0)
      Distant metastatic site(s), n (%)
      The distant metastatic sites were measured at diagnosis of a/mRCC.
      Patients with available data79
      Lung42 (53.2)
      Distant lymph nodes
       Patients with available data79
       Mean (SD)1.6 (0.8)
       Median (min, max)1.0 (1.0, 5.0)
      ECOG PS, n (%)
      The ECOG PS status and IMDC classification were measured at the time of Len/Eve treatment initiation (ie, index date).
       09 (11.4)
       153 (67.1)
       212 (15.2)
       31 (1.3)
       Not documented4 (5.1)
      IMDC score, n (%)
      The ECOG PS status and IMDC classification were measured at the time of Len/Eve treatment initiation (ie, index date).
       Favorable15 (19.0)
       Intermediate42 (53.2)
       Poor10 (12.7)
       Not documented12 (15.1)
      Abbreviations: a/m RCC = advanced/metastatic renal cell carcinoma; ECOG PS = Eastern Cooperative Oncology Group performance status; IMDC = International Metastatic RCC Database Consortium.
      a The distant metastatic sites were measured at diagnosis of a/mRCC.
      b The ECOG PS status and IMDC classification were measured at the time of Len/Eve treatment initiation (ie, index date).
      Table 2Baseline Treatment Characteristics for Patients With a/mRCC Treated With ≥ 2L Len/Eve
      Baseline Characteristicsn = 79
      Follow-up duration from initiation of index treatment (months)
       Patients with available data79
       Mean (SD)11.2 (8.8)
       Median (min, max)8.8 (0.5, 34.6)
      Time since initial RCC diagnosis to metastatic disease (months)
        Patients with available data79
       Mean (SD)30.7 (62.3)
       Median (min, max)4.9 (0.0, 379.7)
      Time since a/mRCC diagnosis to index date (months)
       Patients with available data79
       Mean (SD)34.3 (22.4)
       Median (min, max)26.9 (5.4, 106.6)
      Number of prior lines of treatments
        Mean (SD)3.4 (1.6)
        Median (min, max)3 (1-8)
      Line of therapy for index treatment (ie, Len/Eve), n (%)
        2L5 (6.3)
        3L18 (22.8)
        4L25 (31.6)
        5L16 (20.3)
        ≥ 6L15 (19.0)
      Starting dose of index treatment (mg/day), lenvatinib, n (%)
       < 1816 (20.3)
        1863 (79.7)
      Starting dose of index treatment (mg/day), everolimus, n (%)
       2.51 (1.3)
       5.074 (93.7)
       7.51 (1.3)
       103 (3.8)
      Dose reduction of index treatment, lenvatinib, n (%)
       No50 (63.3)
       Yes29 (36.7)
      Dose reduction of index treatment, everolimus, n (%)
       No70 (88.6)
       Yes9 (11.4)
      Treatment discontinuation rate, Len/Eve, n (%)a64 (81.0)
      Reason for treatment discontinuation, n (%)
       Progression36 (56.2)
       Toxicity21 (32.8)
       Death6 (9.4)
       Physician Preference1 (1.6)
      Treatment regimen immediately prior to index, n (%)
       IO-TKI10 (12.7)
       TKI only40 (50.6)
       IO monotherapy or IO-IO combo21 (26.5)
       mTOR inhibitor3 (3.9)
       Chemotherapy5 (6.3)
      Abbreviations: a/mRCC = advanced/metastatic renal cell carcinoma; IO = immuno-oncology; TKI = tyrosine kinase inhibitor.
      At the time of starting Len/Eve, patients were predominately intermediate risk, with 42 (53.2%) having an IMDC intermediate risk score, 15 (19.0%) favorable risk, 10 (12.7%) poor risk, and 12 (15.1%) with a missing score. Patients had received their diagnosis of a/mRCC at a median of 26.9 months (range, 5.4-106.6) before the index date.

       Treatment Patterns for Patients With a/mRCC Treated With ≥ 2L Len/Eve

      Approximately 39.2% of patients received an IO-based regimen, of which 12.7% were IO/TKI combination therapy, and 50.6% received TKI treatments only as the most recent treatment prior to starting Len/Eve (Table 2). More specifically, cabozantinib monotherapy was the most frequent treatment given immediately prior to the index at 40.5%, followed by nivolumab monotherapy and combination therapy of ipilimumab/nivolumab, at 24.1% and 5.1%, respectively. Progression (56.2%) was the most common reason for treatment discontinuation for Len/Eve, followed by toxicity and death at 32.8% and 9.4%, respectively. Lastly, 37% of the patients had dose reduction in Len, and 11% of the patients had dose reduction in Eve during the course of treatment.

       Clinical Outcomes for Patients With a/mRCC Treated With ≥ 2L Len/Eve

      For the study population assessed for tumor responses (n = 61; Len/Eve post-IO, n = 25; Len/Eve post-TKI, n = 31; response data obtained from unstructured data), ORR was 55.7% (1.6% complete response; 54.1% partial response) (Table 3), and median DOR was 9.7 months (95% CI, 5.8-17.1). The post-IO group ORR was 52.0% (4.0% complete response; 48.0% partial response), and the post-TKI group ORR was 58.1% (0.0% complete response; 58.1% partial response). Post-IO and post-TKI groups reported median DOR of 8.8 months (95% CI, 2.8-17.1) and 17.1 months (95% CI, 3.1-22.1), respectively.
      Table 3Tumor Response: Based on Physician-Assessed Responses Associated With Len/Eve in Overall Study Population and Stratified by Post-IO and Post-TKI Subgroups
      VariableOverallPost-IO
      Post-IO and Post-TKI refer to the treatment immediately prior to Len/Eve.
      Post-TKI
      Post-IO and Post-TKI refer to the treatment immediately prior to Len/Eve.
      Total patient count612531
      Best overall response, n (%)
      Best overall response was defined as, among all patients’ physician-assessed responses, the superior response from those ranked in order from best to worst: complete response, partial response, stable disease, mixed response, progressive disease, or not evaluated.
      Complete response
      Complete response: when in the charts it is documented as “a complete response” to therapy, there is indication that he patient is in “remission” or “all lesions” have disappeared, or there is NED (no evidence of disease).
      1 (1.6)1 (4.0)0
      Partial response
      Partial response: This is based on any physician (medical oncologist) documentation in the patients’ medical charts of either partial response or response not otherwise specified (evidence of response) and not including complete response. This also does not imply that RECIST was used in these assessments.
      33 (54.1)12 (48.0)18 (58.1)
      Stable disease
      Stable disease: when in the charts it is documented that the disease is stable (not progressed or not improved)—eg, stable appearance of lobe nodules.
      9 (14.8)4 (16.0)5 (16.1)
      Mixed response
      Mixed response: when in the charts there is indication of a combination of improved and worsened disease (different results in different lesions).
      4 (6.6)1 (4.0)3 (9.7)
      Progressive disease
      Progressive disease: when in the charts it is documented that the disease has “progressed” or worsened of disease or when there is disease relapse or recurrence.
      14 (23.0)7 (28.0)5 (16.1)
      Real-world objective response rate, n (%)
      Real-world objective response rate: among all patients with a response assessment, the proportion of patients with complete response or partial response as defined above.
      34 (55.7)13 (52.0)18 (58.1)
      Abbreviations: IO = immuno-oncology; TKI = tyrosine kinase inhibitor.
      a Post-IO and Post-TKI refer to the treatment immediately prior to Len/Eve.
      b Best overall response was defined as, among all patients’ physician-assessed responses, the superior response from those ranked in order from best to worst: complete response, partial response, stable disease, mixed response, progressive disease, or not evaluated.
      c Complete response: when in the charts it is documented as “a complete response” to therapy, there is indication that he patient is in “remission” or “all lesions” have disappeared, or there is NED (no evidence of disease).
      d Partial response: This is based on any physician (medical oncologist) documentation in the patients’ medical charts of either partial response or response not otherwise specified (evidence of response) and not including complete response. This also does not imply that RECIST was used in these assessments.
      e Stable disease: when in the charts it is documented that the disease is stable (not progressed or not improved)—eg, stable appearance of lobe nodules.
      f Mixed response: when in the charts there is indication of a combination of improved and worsened disease (different results in different lesions).
      g Progressive disease: when in the charts it is documented that the disease has “progressed” or worsened of disease or when there is disease relapse or recurrence.
      h Real-world objective response rate: among all patients with a response assessment, the proportion of patients with complete response or partial response as defined above.
      The median PFS for the overall study population was 6.1 months (95% CI, 4.4-9.0) (Figure 1; available online). The median PFS for the post-IO subgroup was 6.4 months (95% CI, 4.1-10.8), and the post-TKI subgroup was 5.7 months (95% CI, 4.1-10.5). The median OS for the overall study population was 14.8 months (95% CI, 10.2-23.9), and the 6- and 12-month landmark survival probabilities were 71.0% (95% CI, 59.3-79.8) and 57.7% (95% CI, 45.0-68.5), respectively (Figure 1; available online). The median OS for the post-IO and post-TKI subgroups was 15.9 months (95% CI, 6.1 to not applicable) and 14.8 months (95% CI, 6.3-NA), respectively.
      Figure 1
      Figure 1Kaplan-Meier Curves for OS and PFS—Online Only
      Abbreviations: OS= overall survival; PFS progression-free survival.
      The median TTD was 5.7 months (95% CI, 3.3-6.9) for the overall study population and 5.8 months (95% CI: 3.2-9.0) and 5.6 months (95% CI, 3.3-8.4) for the post-IO and post-TKI groups, respectively.

      Discussion

      There is increasing interest among providers, patients, industry, the FDA, and other stakeholders in leveraging real-world data outside of the traditional controlled clinical trial setting to assist in the development of new drugs or expand labeled indications. This has become particularly relevant for oncology treatments such as Len/Eve in a variety of tumor types, including renal cell cancers. RCC accounts for 4.1% of all adult malignancies, representing the eighth most common cancer in the United States.
      • Siegel RL
      • Miller KD
      • Jemal A
      Cancer statistics, 2020.
      As such, since FDA approval of ≥ 2L Len/Eve settings for a/mRCC, little evidence has been available that shows the effectiveness of this combination therapy in real-world settings.
      To the best of our knowledge, this is the first and largest study of its kind to examine patient characteristics, treatment patterns, and clinical outcomes of Len/Eve for a/mRCC in a community oncology setting. This information provides critical insight into providers’ decision-making processes and, consequently, how Len/Eve is being used in real-world clinical practice. Moreover, this is the first study to show that clinical outcomes of patients receiving Len/Eve in the community oncology setting are comparable to those of patients in clinical trials.
      A total of 79 patients with a/mRCC treated with ≥ 2L Len/Eve were included in this study. Their demographic and clinical characteristics were similar to results reported in previous clinical trials and retrospective studies
      • Motzer RJ
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      • et al.
      Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: A randomised, phase 2, open-label, multicentre trial.
      ,
      • Matsubara N
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      • et al.
      Lenvatinib in combination with everolimus in patients with advanced or metastatic renal cell carcinoma: A phase 1 study.
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      A phase 1b clinical trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC).
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      • et al.
      Lenvatinib with or without everolimus in patients with metastatic renal cell carcinoma after immune checkpoint inhibitors and VEGFR-TKI therapies.
      because our study patients were predominantly male (73.4%), had a median age of 64.8 years, and were Caucasian (78.5%), and the majority had a distant metastatic site at the lung (53.2%). More than one-third (39.2%) of our study population received IO-based treatments that were not available at the time of the clinical trials of Len/Eve.
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      • Glen H
      • et al.
      Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: A randomised, phase 2, open-label, multicentre trial.
      ,
      • Matsubara N
      • Naito Y
      • Nakano K
      • et al.
      Lenvatinib in combination with everolimus in patients with advanced or metastatic renal cell carcinoma: A phase 1 study.
      ,
      • Molina AM
      • Hutson TE
      • Larkin J
      • et al.
      A phase 1b clinical trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC).
      Further, this was a heavily pretreated population, and therefore these patients had a shorter median follow-up period postindex date (8.8 months; range, 0.5-34.6) than what has been previously reported in clinical trials. Our results were similar to a recent retrospective study, where Wiele et al (2021) identified a heavily pretreated population of patients with a/mRCC treated with Len (n = 13) or Len/Eve (n = 42).
      • Wiele AJ
      • Bathala TK
      • Hahn AW
      • et al.
      Lenvatinib with or without everolimus in patients with metastatic renal cell carcinoma after immune checkpoint inhibitors and VEGFR-TKI therapies.
      The same study reported an ORR of 21.8%.
      • Wiele AJ
      • Bathala TK
      • Hahn AW
      • et al.
      Lenvatinib with or without everolimus in patients with metastatic renal cell carcinoma after immune checkpoint inhibitors and VEGFR-TKI therapies.
      The phase 2 clinical trial reported an ORR of 43.0% (n = 51).
      • Motzer RJ
      • Hutson TE
      • Glen H
      • et al.
      Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: A randomised, phase 2, open-label, multicentre trial.
      This study found an ORR of 55.7% in a real-world setting (albeit not based on RECIST) and supported its clinical benefit and the use of Len/Eve for this population.
      In the Wiele et al study, 47.2% of patients had grade 3 adverse events, 50.9% of patients had dose reduction. and 7.3% of patients discontinued the treatment of Len or Len/Eve because of toxicity.
      • Wiele AJ
      • Bathala TK
      • Hahn AW
      • et al.
      Lenvatinib with or without everolimus in patients with metastatic renal cell carcinoma after immune checkpoint inhibitors and VEGFR-TKI therapies.
      Our study found that 37% of patients had a dose reduction in Len and 11% of patients had a dose reduction in Eve. Twenty-one (27%) out of the 79 patients discontinued the treatment of Len/Eve because of toxicity. Our data on the dose reduction and treatment discontinuation are consistent with prior research, but further research is warranted to assess the reasons for dose reduction. Findings from previous clinical trials have shown that Len/Eve is well tolerated, which may speak to the efficacy seen in our results via OS and PFS. Relative to the previously published phase 2 clinical trial,
      • Motzer RJ
      • Hutson TE
      • Glen H
      • et al.
      Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: A randomised, phase 2, open-label, multicentre trial.
      we found an overall median PFS of 6.1 months (95% CI, 4.4-9.0), and 6.4 months and 5.7 months for the post-IO and post-TKI groups, respectively. In the phase 2 clinical trial, a sample of 51 patients had a median PFS of 14.6 months (95% CI, 5.9-20.1).
      • Motzer RJ
      • Hutson TE
      • Glen H
      • et al.
      Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: A randomised, phase 2, open-label, multicentre trial.
      Wiele et al found a median PFS of 6.2 months (95% CI, 4.8-9.4) versus 6.1 months (95% CI, 4.4-9.0) in our study.
      • Wiele AJ
      • Bathala TK
      • Hahn AW
      • et al.
      Lenvatinib with or without everolimus in patients with metastatic renal cell carcinoma after immune checkpoint inhibitors and VEGFR-TKI therapies.
      The median OS estimates in our study were 14.8 months (95% CI, 10.2-23.9), and 15.9 months and 14.8 months for the post-IO and post-TKI subgroups, respectively. In comparison, Wiele et al reported a median OS of 12.1 months (95% CI, 8.8-16.0).
      • Wiele AJ
      • Bathala TK
      • Hahn AW
      • et al.
      Lenvatinib with or without everolimus in patients with metastatic renal cell carcinoma after immune checkpoint inhibitors and VEGFR-TKI therapies.
      Motzer et al (2015) identified estimates for OS as 25.5 months (95% CI, 16.4-NA), with a minimum of 18 months of follow-up in 2L treatment in the phase 2 clinical trial.
      • Motzer RJ
      • Hutson TE
      • Glen H
      • et al.
      Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: A randomised, phase 2, open-label, multicentre trial.
      The population in our real-world data study was heavily pretreated and received different prior treatments than what has been reported by other clinical trial studies,
      • Motzer RJ
      • Hutson TE
      • Glen H
      • et al.
      Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: A randomised, phase 2, open-label, multicentre trial.
      ,
      • Matsubara N
      • Naito Y
      • Nakano K
      • et al.
      Lenvatinib in combination with everolimus in patients with advanced or metastatic renal cell carcinoma: A phase 1 study.
      ,
      • Molina AM
      • Hutson TE
      • Larkin J
      • et al.
      A phase 1b clinical trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC).
      which may speak to differences seen in outcomes. However, results still provide further evidence of ≥ 2L Len/Eve treatment real-world effectiveness for a/mRCC.
      In a recent network meta-analysis, researchers found that through an indirect treatment comparison, efficacy estimates for Len/Eve showed superior PFS to nivolumab, axitinib, and everolimus monotherapies.
      • Tremblay G
      • McElroy HJ
      • Westley T
      • Meier G
      • Misurski D
      • Guo M
      Indirect treatment comparisons including network meta-analysis: Lenvatinib plus everolimus for the second-line treatment of advanced/metastatic renal cell carcinoma.
      Furthermore, a network meta-analysis found that Len/Eve had the highest probability (61%) of being the most effective treatment compared with cabozantinib, nivolumab, and everolimus monotherapies.
      • Karner C
      • Kew K
      • Wakefield V
      • Masento N
      • Edwards SJ
      Targeted therapies for previously treated advanced or metastatic renal cell carcinoma: Systematic review and network meta-analysis.
      Future research should include a comparative subgroup analysis to assess differences in outcomes for those who received prior TKI-based therapies versus prior IO-based therapies. In addition, further research is warranted for patients diagnosed with clear cell and non–clear cell advanced RCC, respectively.
      Because the introduction of Len/Eve for patients diagnosed with a/mRCC in 2016, there have been few studies on the clinical outcomes associated with Len/Eve in the real-world setting. To our knowledge, this is the largest study to generate real-world data on the clinical effectiveness outcomes of ≥ 2L Len/Eve post-TKI and post-IO treatments that have been recently approved.

       Limitations

      The data from this study were collected within USON; thus, results in this study may be limited in generalizability to all Len/Eve-treated patients with advanced RCC in the United States. There was the potential for documentation bias if there were omissions or errors, given the inherent limitations of retrospective observational studies. In addition, the sample size was small, and a few key variables (ie, IMDC score and lab values such as PD-1, PD-L1, and FGFR) had a high proportion of missing structured data. It is important to note that the definition of tumor response was not based on RECIST criteria (eg, at least 30% tumor regression for PR) but based on physician assessment from medical charts, meaning any statement in the patients’ records that mentioned that the patient responded (without that statement being verified as meaning > 30% tumor regression). Therefore, the high ORR may be inflated. Lastly, this study did not capture safety data to report on adverse events. Nonetheless, despite these limitations, our study represents one of the largest reports in this setting, providing further evidence on systemic therapy outcomes using Len/Eve. Table 4
      Table 4OS and PFS in Overall Study Population and Stratified by Post-IO and Post-TKI Subgroups
      VariablesOS OverallOSPFS OverallPFS
      Post-IO
      Post-IO and Post-TKI refer to the treatment immediately prior to Len/Eve.
      Post-TKI
      Post-IO and Post-TKI refer to the treatment immediately prior to Len/Eve.
      Post-IO
      Post-IO and Post-TKI refer to the treatment immediately prior to Len/Eve.
      Post-TKI
      Post-IO and Post-TKI refer to the treatment immediately prior to Len/Eve.
      n793140793140
      Censored, n (%)
      OS censorship criteria: patients who did not die within the study observation period will be censored on the study end date or the last visit date available in the data set, whichever occurred first.
      ,
      PFS censorship criteria: patients who did not die and did not progress at the end of the study observation period or at the last visit date or initiated a new treatment will be censored.
      40 (50.6)15 (48.4)20 (50.0)18 (22.8)6 (19.4)11 (27.5)
      Events, n (%)39 (49.4)16 (51.6)20 (50.0)61 (77.2)25 (80.6)29 (72.5)
      Median (95% CI) in months14.8 (10.2, 23.9)15.9 (6.1, NE)14.8 (6.3, NE)6.1 (4.4, 9.0)6.4 (4.1, 10.8)5.7 (4.1, 10.5)
      Min, max0.5, 34.60.8, 34.60.5, 34.50.5, 32.00.8, 24.80.5, 32.0
      Landmark survival, % (95% CI)
      6 months71.0 (59.3, 79.8)72.8 (52.9, 85.4)68.9 (51.8, 81.0)51.5 (39.7, 62.0)59.5 (39.8, 74.6)48.0 (31.5, 62.6)
      12 months57.7 (45.0, 68.5)60.2 (39.3, 75.9)53.2 (35.5, 68.0)26.6 (16.5, 37.8)26.6 (11.4, 44.6)28.1 (14.2, 43.9)
      18 months39.4 (26.2, 52.3)39.5 (19.6, 58.9)39.9 (22.3, 57.0)13.4 (5.7, 24.4)13.3 (3.4, 29.9)15.6 (3.9, 34.5)
      24 months35.0 (21.2, 49.2)31.6 (12.5, 52.8)39.9 (22.3, 57.0)5.3 (1.1, 15.2)4.4 (0.3, 18.4)7.8 (0.7, 27.4)
      Abbreviations: CI = confidence interval; IO = immuno-oncology; NE = not estimable; OS = overall survival; PFS = progression-free survival; TKI = tyrosine kinase inhibitor.
      a Post-IO and Post-TKI refer to the treatment immediately prior to Len/Eve.
      b OS censorship criteria: patients who did not die within the study observation period will be censored on the study end date or the last visit date available in the data set, whichever occurred first.
      c PFS censorship criteria: patients who did not die and did not progress at the end of the study observation period or at the last visit date or initiated a new treatment will be censored.

      Conclusion

      The results of this retrospective, real-world data study suggest a favorable clinical profile for Len/Eve, demonstrating real-world clinical benefits in tumor response and survival for patients with a/mRCC. Future research can expand on these findings to explore patient characteristics related to Len/Eve outcomes in clinical practice.

       Clinical Practice Points

      RCC accounts for 4.1% of all adult malignancies, representing the eighth most common cancer in the United States. As such, since FDA approval of ≥ 2L Len/Eve for patients diagnosed with a/mRCC, there have been few studies on the clinical outcomes associated with Len/Eve in the real-world setting. To our knowledge, this is the largest study to generate real-world data on the clinical effectiveness outcomes of ≥2 L Len/Eve post-TKI and post-IO treatments that have been recently approved.
      Seventy-nine patients were assessed. At initial diagnosis, 78.5% had an ECOG PS score of 0/1, and 65.8% had IMDC risk scores of intermediate/poor. Thirty-one (39.2%) patients received IO-based regimens, and 50.6% received TKIs directly before Len/Eve initiation. ORR was 55.7% (1.6% complete response; 54.1% partial response). The median PFS was 6.1 months (95% CI, 4.4-9.0). The median PFS for patients receiving Len/Eve post-IO was 6.4 months (95% CI, 4.1-10.8) and for post-TKI was 5.7 months (95% CI, 4.1-10.5). The median OS was 14.8 months (95% CI, 10.2-23.9).
      The results of this retrospective, real-world study suggest a favorable clinical profile for Len/Eve, demonstrating real-world clinical benefits in tumor response and survival for patients with a/mRCC. This information provides critical insight into providers’ decision-making processes and, consequently, how Len/Eve is being used in real-world clinical practice. Moreover, this is the first study to show that clinical outcomes of patients receiving Len/Eve in the community oncology setting are comparable to those of patients in clinical trials. Future research can expand on these findings to explore patient characteristics related to Len/Eve outcomes in clinical practice.

      Declarations of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgments

      The authors would like to thank the patients and all investigational site members involved in this study, specifically Janet Espirito, PharmD, of Ontada, and Shrividya Iyer, PhD, of Eisai Inc, for their help guiding the study design, as well as Lisa Kaspin-Powell, PhD, of Ontada, for modifying the manuscript.

      Funding

      This study was funded by Eisai Inc., Woodcliff Lake, NJ, and Merck Sharp & Dohme Corp, a subsidiary of Merck & Co Inc, Kenilworth, NJ. The sponsors of this study were involved in the study design, interpretation of data, the writing of the report, and the decision to submit the article for publication. Medical writing support for the manuscript was provided by Ontada, Woodlands, TX.

      Ethics Approval

      Institutional review board and compliance/privacy approval was gained prior to initiation of the retrospective research. Because this project involved the analysis of existing data and records, study information was analyzed in such a manner that research participants could not be directly identified. Patient-informed consent was not required because of the nature of the study design. Thus, exemption status and a waiver of informed consent were approved by the US Oncology Inc institutional review board. Data were handled in compliance with HIPAA and the Health Information Technology for Economic and Clinical Health Act.

      Author Contributions

      Concept and design: N.J.V., Y. Wang, Y.W., Y.X., N.J.R., and N.M.T. Collection and assembly of data: A.M.M., Y.W., and Y.X.. Data analysis and interpretation: All authors. Manuscript writing: All authors. Final approval of manuscript: All authors.

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