Abstract
Background
We characterized clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib who were long-term responders (LTRs), defined as patients having progression-free survival (PFS) >18 months.
Patients and Methods
A retrospective analysis of data from 5714 patients with mRCC treated with sunitinib in eight phase II/III clinical trials and the expanded access program. Duration on-study and objective response rate (ORR) were compared between LTRs and patients with PFS ≤18 months (“others”). PFS and overall survival (OS) were summarized using Kaplan–Meier methodology.
Results
Overall, 898 (15.7%) patients achieved a long-term response and 4816 (84.3%) patients didn’t achieve long-term response. The median (range) duration on-study was 28.6 (16.8–70.7) months in LTRs and 5.5 (0–68.8) months in others. ORR was 51% in LTRs versus 14% in others (P < .0001). Median PFS in LTRs was 32.11 months and median OS was not reached. LTRs had higher percentage of early tumor shrinkage ≥10% at the first scan (67.1% vs. 51.2%; P=.0018) and greater median maximum on-study tumor shrinkage from baseline (−56.9 vs.−27.1; P<.0001) versus others. White race, Eastern Cooperative Oncology Group performance status 0, time from diagnosis to treatment ≥1 year, clear-cell histology, no liver metastasis, lactate dehydrogenase ≤1.5 upper limit of normal (ULN), corrected calcium ≤10 mg/dL, hemoglobin >lower limit of normal, platelets ≤ULN, BMI ≥25 kg/m2, and low neutrophil-to-lymphocyte ratio were associated with LTR.
Conclusion
A subset of patients with mRCC treated with sunitinib achieved long-term response. LTRs had improved ORR, PFS, and OS.
Trials registration numbers
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Keywords: Renal cell carcinoma, Sunitinib, Progression-free survival, Long-term response
MicroAbstract
A subset of patients with metastatic renal cell carcinoma treated with sunitinib achieved longterm response (ie, progression-free survival [PFS] > 18 months). Long-term responders had improved objective response rate, PFS, and overall survival versus others. Patient baseline characteristics predictive of long-term response to sunitinib were identified.
INTRODUCTION
Sunitinib malate (Sutent®), a multitargeted tyrosine kinase inhibitor, is approved globally for the treatment of metastatic renal cell carcinoma (mRCC).1 Sunitinib has demonstrated efficacy in many clinical trials,2–6 and is a standard-of-care first-line treatment for patients with mRCC.7 In the pivotal trial, the median progression-free survival (PFS) was significantly longer in patients with mRCC treated with sunitinib versus interferon-alfa (11 vs. 5 months, respectively).3 Efficacy of sunitinib was confirmed by almost all subsequent trials performed in the first-line setting.2,8–12 Median PFS with sunitinib in the first-line setting ranged between 9 and 11 months.2,8,10–12 Median PFS with other targeted therapies in the first-line ranged between 8 and 11 months,4,13,14 and in the second-line setting ranged between 4 and 8 months.15–18
Molina et al reported a subset of patients (n = 34) with mRCC treated in clinical trials at Memorial Sloan Kettering Cancer Center (MSKCC) who achieved a long-term response with sunitinib, defined as patients achieving durable complete response or remaining progressionfree for > 18 months.19 Of this group, three patients achieved complete response and 24 achieved partial response at 18 months after treatment start; the median PFS at a landmark time point of 18 months post treatment initiation was 17.4 months (95% confidence interval [CI], 7.0–29.9 months).19 Lack of bone or lung metastases and favorable MSKCC risk status were found to be associated with long-term response.19
The goal of this retrospective study was to identify and characterize sunitinib long-term responders (LTRs), defined as patients with mRCC having PFS > 18 months while on sunitinib therapy. We used a large, contemporary clinical trial database of patients with mRCC who were treated with sunitinib to describe the clinical characteristics, duration of treatment, and clinical outcome of patients identified as LTRs, and to identify risk factors that may predict long-term response.
METHODS
Patients and Study Design
A retrospective analysis of data in patients (N = 5714) with mRCC treated with sunitinib in eight phase II or III clinical trials (n = 1173) and patients (n = 4543) treated in the expanded access program (EAP; supplemental Table S1). In six trials (n = 5199), sunitinib was started at 50 mg daily for 4 weeks followed by a 2-week break (“4/2 schedule”) 3,5,6,10,11,20–22; in two trials (n = 226), the starting dose was 37.5 mg administered on a continuous once-daily dosing (CDD) regimen 8,23; and, in one trial (n = 289), the starting dose was 50 mg 4/2 schedule or 37.5 mg CDD.9
Phase II or III trials included patients with histologically confirmed clear-cell RCC with measurable disease, metastases (except for one study by Motzer et al,9 wherein patients could have locally recurrent or metastatic RCC), adequate organ function, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1 or Karnofsky performance score > 70.3,5,6,8,9,20,22,23 In the EAP trial, patients had histologically confirmed metastatic RCC (of all histological subtypes) with adequate organ function.10,11 In all trials, tumor response was assessed according to Response Evaluation Criteria in Solid Tumors criteria. A central independent review of response was conducted in 3 trials.3,6,22 All trials were registered on ClinicalTrials.gov and were previously reported (supplemental Table S1).
Statistical Analysis
Dose reduction/interruptions, treatment discontinuation, and treatment-related adverse events (AEs) were summarized between LTRs and patients who had PFS ≤ 18 months (“others”).
Multiple univariable logistic regression analyses were conducted to identify potential baseline characteristics associated with LTRs. Baseline characteristics assessed included: age, race, sex, ECOG PS, time from diagnosis, histology, metastasis, serum lactate dehydrogenase (LDH), corrected serum calcium, hemoglobin, platelets, prior nephrectomy, prior therapy, body mass index (BMI), and neutrophil-to-lymphocyte ratio (NLR). A multivariable logistic regression analysis was further conducted for the baseline characteristics that were statistically significant (P < .05) in the univariable analyses to identify the independent baseline factors associated with LTRs.
A Cox proportional analysis was conducted to identify baseline and post-baseline characteristics associated with overall survival (OS).
Tumor burden was determined based on the sum of the longest diameters of the target lesions by the investigators. Median tumor burden at baseline was compared between LTRs and others. Early tumor shrinkage, defined as ≥10% reduction in sum of the longest diameters of target lesions at the first scan after initiation of sunitinib treatment, was calculated and compared between LTRs and others. The 10% threshold was selected based on a study showing that early tumor shrinkage ≥10% at first post baseline assessment could serve as a putative early end point in patients with mRCC.24 Patients from the EAP were excluded from the analysis of tumor burden and tumor shrinkage because tumor response assessments were not mandated and were performed at the discretion of the investigators. Because early decline in NLR is associated with favorable outcome and early increase in NLR with worse outcome,25 these trends were compared separately.
RESULTS
Patients
A total of 898 (15.7%) patients met the definition of LTRs. The remaining 4816 (84.3%) had PFS < 18 months that included stable disease, progressive disease, or death (ie, others). Patient demographics were similar between the LTRs and others (supplemental Table S2). Patient disease characteristics were mostly similar between the two groups, except for ECOG PS 0, time from diagnosis to treatment ≥ 1 year, and low MSKCC risk group that were more common in the LTR versus others. LTRs also had favorable laboratory findings versus others (supplemental Table S2).
Sunitinib Treatment and Adverse Events
Overall, 14.9% of LTRs and 14.0% of others received sunitinib as first-line therapy, whereas 85.1% of LTRs and 86% of others received sunitinib as second-line therapy. Most patients (865 [96.3%] of LTRs and 4406 [91.5%] of others) received sunitinib on a 4/2 schedule; 33 (3.7%) of LTRs and 410 (8.5%) of others received sunitinib on CDD. The median (range) duration on study was 28.6 (16.8–70.7) months in LTRs and 5.5 (0–68.8) months in others.
A similar number of patients discontinued treatment due to insufficient clinical response in the two groups (34.9% in LTRs and 36.1% in others). Dose reduction/interruption occurred in 58.5% of LTRs and 31.5% of others and discontinuation of treatment due to AEs occurred in 11.1% of LTRs and 16.5% of others (see summary in Table 1). The most common grade ≥ 3 treatment-related AEs reported by LTRs were hypertension (12.8%), palmar-plantar erythrodysesthesia (12.5%), diarrhea and neutropenia (10.2% each), and fatigue (10.1%; Table 2).
Table 1.
Dose Reduction/Interruptions and Treatment Discontinuation Over the Entire Duration Of Therapy
| LTRs n = 898 | Others n = 4816 | All Patients N = 5714 | |
|---|---|---|---|
| Dose reductions/interruptions | |||
| Yes | 525 (58.5) | 1518 (31.5) | 2043 (35.8) |
| Reason for Discontinuation | |||
| Adverse event | 100 (11.1) | 794 (16.5) | 894 (15.6) |
| Completed | 144 (16.0) | 249 (5.2) | 393 (6.9) |
| Global deterioration of health status | 0 | 16 (0.3) | 16 (0.3) |
| Insufficient clinical response | 313 (34.9) | 1739 (36.1) | 2052 (35.9) |
| Insufficient response | 13 (1.4) | 63 (1.3) | 76 (1.3) |
| Lost to follow-up | 20 (2.2) | 118 (2.5) | 138 (2.4) |
| Objective progression or relapse | 10 (1.1) | 197 (4.1) | 207 (3.6) |
| Other | 82 (9.1) | 364 (7.6) | 446 (7.8) |
| Protocol violation | 4 (0.4) | 16 (0.3) | 20 (0.4) |
| Study terminated by sponsor | 102 (11.4) | 24 (0.5) | 126 (2.2) |
| Died | 48 (5.3) | 879 (18.3) | 927 (16.2) |
| No longer willing to participate in study | 51 (5.7) | 319 (6.6) | 370 (6.5) |
| Refused continued treatment for reason other than adverse event | 1 (0.1) | 13 (0.3) | 14 (0.2) |
| Withdrew consent | 9 (1.0) | 20 (0.4) | 29 (0.5) |
| Other | 0 | 1 (0.0) | 1 (0.0) |
| Missing | 1 (0.1) | 4 (0.1) | 5 (0.1) |
Values are n (%).
Abbreviation: LTR = long-term responder.
Table 2.
Treatment-Related Adverse Events Occurring in > 20% of Patients in Any Group
| LTRs n = 898 | Others n = 4816 | All Patients N = 5714 | ||||
|---|---|---|---|---|---|---|
| MedDRA Preferred Term | All Grade | Grade ≥ 3 | All Grade | Grade ≥ 3 | All Grade | Grade ≥ 3 |
| Diarrhea | 683 (76.1) | 92 (10.2) | 2161 (44.9) | 238 (4.9) | 2844 (49.8) | 330 (5.8) |
| Fatigue | 519 (57.8) | 91 (10.1) | 1972 (41.0) | 446 (9.3) | 2491 (43.6) | 537 (9.4) |
| Nausea | 413 (46.0) | 26 (2.9) | 1804 (37.5) | 127 (2.6) | 2217 (38.8) | 153 (2.7) |
| Decreased appetite | 344 (38.3) | 12 (1.3) | 1448 (30.1) | 113 (2.4) | 1792 (31.4) | 125 (2.2) |
| Stomatitis | 328 (36.5) | 32 (3.6) | 1320 (27.4) | 130 (2.7) | 1648 (28.8) | 162 (2.8) |
| Mucosal inflammation | 337 (37.5) | 30 (3.3) | 1296 (26.9) | 132 (2.7) | 1633 (28.6) | 162 (2.8) |
| Dysgeusia | 340 (37.9) | 3 (0.3) | 1291 (26.8) | 27 (0.6) | 1631 (28.5) | 30 (0.5) |
| PPE | 454 (50.6) | 112 (12.5) | 1163 (24.2) | 317 (6.6) | 1617 (28.3) | 429 (7.5) |
| Vomiting | 259 (28.8) | 23 (2.6) | 1354 (28.1) | 154 (3.2) | 1613 (28.2) | 177 (3.1) |
| Hypertension | 393 (43.8) | 115 (12.8) | 1072 (22.3) | 266 (5.5) | 1465 (25.6) | 381 (6.7) |
| Thrombocytopenia | 253 (28.2) | 64 (7.1) | 973 (20.2) | 395 (8.2) | 1226 (21.5) | 459 (8.0) |
| Asthenia | 222 (24.7) | 54 (6.0) | 979 (20.3) | 307 (6.4) | 1201 (21.0) | 361 (6.3) |
| Dyspepsia | 317 (35.3) | 12 (1.3) | 881 (18.3) | 18 (0.4) | 1198 (21.0) | 30 (0.5) |
| Rash | 266 (29.6) | 15 (1.7) | 801 (16.6) | 35 (0.7) | 1067 (18.7) | 50 (0.9) |
| Anemia | 197 (21.9) | 45 (5.0) | 760 (15.8) | 206 (4.3) | 957 (16.8) | 251 (4.4) |
| Neutropenia | 232 (25.8) | 92 (10.2) | 667 (13.9) | 283 (5.9) | 899 (15.7) | 375 (6.6) |
| Epistaxis | 198 (22.1) | 6 (0.7) | 634 (13.2) | 33 (0.7) | 832 (14.6) | 39 (0.7) |
| Hypothyroidism | 321 (35.8) | 17 (1.9) | 362 (7.5) | 21 (0.4) | 683 (12.0) | 38 (0.7) |
| Pain in extremity | 218 (24.3) | 16 (1.8) | 416 (8.6) | 43 (0.9) | 634 (11.1) | 59 (1.0) |
Values are n (%).
Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities coding dictionary; LTR = long-term responder; PPE = palmar-plantar erythrodysesthesia syndrome.
Efficacy
Based on univariable logistic regression analyses of baseline characteristics, white race, ECOG PS 0, or 1–2 (vs. ECOG > 2), time from diagnosis to treatment ≥ 1 year, clear cell histology, no liver or bone metastasis, serum LDH ≤ 1.5 upper limit of normal (ULN), corrected serum calcium ≤10 mg/dL, hemoglobin > lower limit of normal (LLN), platelets ≤ ULN, BMI ≥ 25 kg/m2, prior nephrectomy, and low (≤ 3) NLR were associated with longer PFS (Table 3).
Table 3.
Univariable Logistic Regression of Baseline Characteristics Predictive of LTRs vs. Others
| Parameter | Odds Ratio | 95% CI | P-value |
|---|---|---|---|
| Age, yr (< 65 vs. ≥ 65) | 1.014 | 0.871–1.180 | .8602 |
| Sex (female vs. male) | 0.895 | 0.760–1.054 | .1853 |
| Race (Asian vs. White) | 0.753 | 0.568–0.998 | .0481 |
| Race (Black vs. White) | 0.315 | 0.098–1.013 | .0526 |
| Race (not applicable vs. White) | 0.414 | 0.191–0.897 | .0255 |
| Race (other vs. White) | 0.971 | 0.751–1.253 | .8186 |
| ECOG PS (0 vs. 1–2) | 2.078 | 1.793–2.409 | < .0001 |
| ECOG PS (> 2 vs. 1–2) | 0.277 | 0.087–0.881 | .0297 |
| Time from diagnosis to treatment (≥ 1 yr vs. < 1 yr) | 1.709 | 1.458–2.003 | < .0001 |
| Histology (non-clear cell histology vs. clear cell) | 0.677 | 0.524–0.875 | .0029 |
| Histology (not reported vs. clear cell) | < 0.001 | <0.001–>999.999 | .9519 |
| Liver metastasis (no vs. yes) | 1.458 | 1.226–1.735 | < .0001 |
| Lung metastasis (no vs. yes) | 1.171 | 0.991–1.384 | .0631 |
| Bone metastasis (no vs. yes) | 1.466 | 1.248–1.722 | < .0001 |
| Other-site metastasis (no vs. yes) | 1.073 | 0.927–1.241 | .3471 |
| LDH (> 1.5 ULN vs. ≤ 1.5 ULN) | 0.401 | 0.296–0.544 | < .0001 |
| Corrected calcium (> 10 mg/dL vs. ≤ 10 mg/dL) | 0.414 | 0.330–0.520 | < .0001 |
| Hemoglobin (> LLN vs. ≤ LLN) | 2.375 | 2.050–2.753 | < .0001 |
| Platelets (≤ ULN vs. > ULN) | 2.975 | 2.329–3.802 | < .0001 |
| Prior nephrectomy (no vs. yes) | 0.567 | 0.433–0.742 | < .0001 |
| Prior therapy (no vs. yes) | 1.030 | 0.875–1.213 | .7193 |
| BMI (< 25 kg/m2 vs. ≥ 25 kg/m2) | 0.565 | 0.482–0.662 | < .0001 |
| Neutrophil-to-lymphocyte ratio (low [≤ 3] vs. high [> 3]) | 2.366 | 2.037–2.748 | < .0001 |
| Baseline tumor burden (<median vs. ≥median) | 0.990 | 0.711–1.379 | 0.9517 |
Abbreviations: BMI = body mass index; CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group performance status; LDH = lactate dehydrogenase, LLN = lower limit of normal; LTR = long-term responder; PFS = progression-free survival; ULN = upper limit of normal.
Using a multivariable logistic regression analysis, white race, ECOG PS 0, time from diagnosis to treatment ≥ 1 year, clear cell histology, no liver metastasis, serum LDH ≤ 1.5 ULN, corrected serum calcium ≤ 10 mg/dL, hemoglobin > LLN, platelets ≤ ULN, BMI ≥ 25 kg/m2, and low (≤ 3) NLR were associated with longer PFS (Table 4).
Table 4.
Multivariable Logistic Regression Comparison of Baseline Characteristics Predictive of LTRs vs. Others
| Parameter | Odds Ratio | 95% CI | P-value |
|---|---|---|---|
| Race (Asian vs. White) | 0.711 | 0.515–0.981 | .0380 |
| Race (Black vs. White) | 0.584 | 0.172–1.985 | .3891 |
| Race (not applicable vs. White) | 0.107 | 0.026–0.443 | .0020 |
| Race (other vs. White) | 0.980 | 0.716–1.341 | .8977 |
| ECOG PS (0 vs. 1–2) | 1.583 | 1.317–1.902 | < .0001 |
| ECOG PS (> 2 vs. 1–2) | 0.393 | 0.094–1.643 | .2009 |
| Time from diagnosis to treatment (≥1 yr vs. < 1 yr) | 1.337 | 1.097–1.629 | .0040 |
| Histology (non-clear cell histology vs. clear cell) | 0.666 | 0.483–0.918 | .0132 |
| Histology (not reported vs. clear cell) | < 0.001 | < 0.001–>999.999 | .9819 |
| Liver metastasis (no vs. yes) | 1.240 | 1.003–1.531 | .0463 |
| Bone metastasis (no vs. yes) | 1.132 | 0.926–1.384 | .2252 |
| LDH (> 1.5 ULN vs. ≤ 1.5 ULN) | 0.663 | 0.475–0.926 | .0158 |
| Corrected calcium (> 10 mg/dL vs. ≤ 10 mg/dL) | 0.572 | 0.438–0.748 | < .0001 |
| Hemoglobin (> LLN vs. ≤ LLN) | 1.353 | 1.121–1.633 | .0016 |
| Platelets (≤ ULN vs. > ULN) | 1.793 | 1.325–2.425 | .0002 |
| Prior nephrectomy (no vs. yes) | 0.889 | 0.631–1.253 | .5017 |
| BMI (< 25 kg/m2 vs. ≥ 25 kg/m2) | 0.801 | 0.662–0.969 | .0226 |
| Neutrophil-to-lymphocyte ratio (low [≤ 3] vs. high [> 3]) | 1.514 | 1.262–1.816 | < .0001 |
Abbreviations: BMI = body mass index; CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group performance status; LDH = lactate dehydrogenase, LLN = lower limit of normal; LTR = long-term responder; PFS = progression-free survival; ULN = upper limit of normal.
A Cox proportional analysis of OS demonstrated that age < 65 years, ECOG PS 0, time from diagnosis to treatment ≥ 1 year, lack of metastasis (lung, liver, bone, or other site), hemoglobin > LLN, platelets ≤ ULN, and NLR ≤ 3 were associated with longer OS (supplemental Table S3).
Objective response rate (ORR; complete or partial response) was 51.0% in LTRs versus 14.0% in others (P < .0001; Table 5). For LTRs, median PFS (95% CI) was 32.11 (30.30–33.76) months and median OS was not reached (Figure 1). For Others, median PFS (95% CI) was for 7.16 (6.86–7.62) months and median OS was 14.74 months.
Table 5.
Best Observed Objective Response
| LTRs n = 898 | Others n = 4816 | All Patients N = 5714 | |
|---|---|---|---|
| Complete response | 55 (6.1) | 23 (0.5) | 78 (1.4) |
| Partial response | 403 (44.9) | 652 (13.5) | 1055 (18.5) |
| Stable disease | 437 (48.7) | 2422 (50.3) | 2859 (50.0) |
| Progressive disease | 3 (0.3) | 710 (14.7) | 713 (12.5) |
| Othera | 0 | 1009 (21.0) | 1009 (17.7) |
| ORR | 458 (51.0) | 675 (14.0) | 1133 (19.8) |
Values are n (%).
Includes early death, indeterminate, no post-baseline tumor assessment, not assessed, not evaluable, symptomatic deterioration, and missing response.
Abbreviations: LTR = long-term responder; ORR = objective response rate.
Figure 1.
Kaplan–Meier Estimates of Overall Survival in LTRs
LTR = long-term responder; mo = months; mOS = median overall survival; NE = not estimable.
Of the 1171 patients included in the tumor shrinkage analysis, 167 were LTRs and 1007 were others. Median tumor burden at baseline differed significantly between LTRs and others (85.0 vs. 100.5, respectively; P = .0041). Median tumor shrinkage at the first post-baseline scan also differed significantly between LTRs and others (change from baseline,−17.1 vs. −11.5, respectively; P < .0001). More patients in the LTR group had early tumor shrinkage ≥ 10% at the first scan versus others (67.1% vs. 51.2%, respectively; P = .0018). The median maximum on- study tumor shrinkage from baseline was −56.9 for LTRs versus −27.1 for others (P < .0001).
More LTRs (63.9%) had low NLR at baseline versus others (46.7%; supplemental Table S4). In both groups, there were significant differences in OS, PFS, and ORR in patients who had low (≤ 3) NLR both at baseline and after 6 weeks versus patients with low NLR at baseline and high (> 3) NLR (supplemental Table S4). NLR change from high at baseline to low at 6 weeks was also associated with better outcome versus NLR high at baseline and high after 6 weeks, although the differences were not statistically significant (supplemental Table S4).
Long-term Responders Over Time
Among the 898 LTR patients who achieved PFS > 18 months, 532 (59.2%) achieved PFS > 2 years, 226 (25.2%) achieved PFS > 3 years, 98 (10.9%) achieved PFS > 4 years, and 35 (3.9%) achieved PFS > 5 years (supplemental Figure 2). The number of patients censored in the others group (ie, PFS < 18 months) over time (using the 2, 3, 4, and 5 year cut-offs) is also reported (supplemental Figure 2).
DISCUSSION
In this analysis, we identified a subset of patients with mRCC who were LTRs, defined as patients who had PFS > 18 months while on sunitinib therapy. Not surprisingly, LTRs had improved PFS and OS (median PFS, 32.11 months; median OS, not reached). Furthermore, objective response was achieved in 51% of LTRs compared with 19.8% in the overall population in this study and the 38% of patients reported previously for sunitinib-treated patients.26
LTRs remained on study longer than others (median duration on study, 28.6 vs. 5.5 months, respectively). As expected of patients treated for a longer duration, LTRs experienced more treatment-related AEs versus others. However, the safety profile of sunitinib in LTRs was similar to previous reports of short- and long-term safety of sunitinib treatment in patients with mRCC.2,3,10,27 Previous studies have shown that hypertension and neutropenia were associated with improved clinical outcome in patients treated with sunitinib.28,29 Indeed, hypertension and neutropenia in our analysis were found to be higher among LTRs versus others (43.8% vs. 22.3%, and 25.8% vs. 13.9%, respectively).28,29 Furthermore, LTRs had a numerically higher rate of dose reductions/interruptions and a numerically lower rate of treatment discontinuations due to AEs versus others; this higher incidence of AEs is in line with the known relation between toxicity and efficacy. The lower rate of treatment discontinuation in LTRs might be due to better AE management in patients who had better efficacy, and better baseline ECOG PS in the LTRs group.
Retrospective analyses showed early tumor shrinkage ≥ 10% at first scan post baseline may have predictive and prognostic value for PFS and OS in patients with mRCC.24,30,31 In our analysis, although early tumor shrinkage ≥ 10% was significantly more common in LTRs (67%) versus others (51%), it occurred in most patients in both groups. A study by Grünwald and colleagues showed that the magnitude of tumor shrinkage correlated with a better survival rate in mRCC patients.32 The current analysis found the median maximum on-study tumor shrinkage was significantly greater in LTRs versus others, potentially contributing to improved PFS and OS in LTRs.
An elevated baseline NLR has been shown to be associated with a poor prognosis in patients with mRCC.33,34 Our results showed that a decrease in NLR from baseline to week 6 was associated with better ORR, PFS, and OS, whereas an increase in NLR was associated with worse outcome. These findings are consistent with a previous study that showed early decline of NLR in response to targeted therapy was associated with favorable outcomes, and an increase in NLR was associated with the opposite effect.25
In the current study, risk factors associated with long-term response included white race, ECOG PS 0, time from diagnosis to treatment ≥ 1 year, clear cell histology, no liver metastasis, serum LDH ≤ 1.5 ULN, corrected serum calcium ≤ 10 mg/dL, BMI ≥ 25 kg/m2, and favorable hematology values. These baseline characteristics associated with long-term response are consistent with previously reported predictors for survival in mRCC patients treated with sunitinib2,26,35 and with other inhibitors of the vascular endothelial growth factor pathway.36 Four of the risk factors identified in this study (ie, hemoglobin < 1.5 ULN, corrected calcium, LDH > 1.5 ULN, and time from initial RCC diagnosis) constitute the 5-factor MSKCC model that is the most commonly used prognostic model.37 Because of the variations in patients characteristics, identifying early predictors of LTRs may help guide the treatment selection for particular patients with specific baseline characteristics. Tailoring treatment to the patient characteristics may improve outcome in patients with mRCC.
Although this study is based on a large, contemporary clinical trial database of patients with mRCC treated with sunitinib, it has limitations. In addition to the inherent issues associated with a retrospective analysis, the patient population was heterogeneous and included treatmentnaive patients, as well as previously treated patients who received different dosing regimens. The majority of patients were excluded from the tumor shrinkage analysis because tumor assessment was not mandated in the EAP study. Another potential limitation of this study is the selection of the 18-month cutoff to define LTRs. However, a cut point of 18 months is 64% longer than the median PFS observed in the sunitinib pivotal study, and is longer than the median PFS observed in the first-line setting with other targeted therapies (range, 64%–125%).12–14 Finally, > 85% of patients in this study received sunitinib as second-line of therapy, prior to sunitinib becoming the standard of care in many countries, so it is likely that patients with poorer prognosis at diagnosis were not able to survive long enough to receive sunitinib. Therefore, the results from this study are probably different from what might now be expected with sunitinib.
CONCLUSIONS
A subset of patients with mRCC treated with sunitinib in multiple clinical trials were LTRs; 15.7% achieved PFS > 18 months, and 3.9% achieved PFS > 5 years. Long-term treatment with sunitinib was associated with a numerically higher rate of dose reductions/interruptions but a numerically lower rate of treatment discontinuations due to AEs. LTRs had improved ORR, PFS, and OS. Moreover, LTRs had higher percentage of early tumor shrinkage ≥ 10% at the first scan and greater median maximum on-study tumor shrinkage from baseline versus others. Patient baseline characteristics predicting for LTR include white race, ECOG PS 0, time from diagnosis to treatment ≥ 1 year, clear cell histology, no liver metastasis, serum LDH ≤ 1.5 ULN, corrected serum calcium ≤ 10 mg/dL, hemoglobin > LLN, platelets ≤ ULN, BMI ≥ 25 kg/m2, and low (≤ 3) NLR.
Supplementary Material
Figure 2.
LTRs and Others Over Time
LTR = long-term responder.
Clinical Practice Points.
Sunitinib, a multitargeted tyrosine kinase inhibitor, has demonstrated efficacy in many clinical trials, and is a standard-of-care first-line treatment for patients with mRCC.
Of the 5714 patients with mRCC treated with sunitinib in eight phase II/III clinical trials and in the expanded access program, 898 (15.7%) patients achieved a long-term response, defined as patients having PFS > 18 months while on sunitinib therapy.
LTRs had improved ORR, PFS, and OS. The median maximum on-study tumor shrinkage was significantly greater in LTRs versus others, potentially contributing to improved PFS and OS in LTRs.
The safety profile of sunitinib in LTRs was similar to previous reports of short- and long-term safety of sunitinib treatment in patients with mRCC.
White race, ECOG PS 0, time from diagnosis to treatment ≥1 year, clear cell histology, no liver metastasis, serum LDH ≤ 1.5 ULN, corrected serum calcium ≤ 10 mg/dL, hemoglobin > LLN, platelets ≤ ULN, BMI ≥ 25 kg/m2, and low (≤ 3) NLR were associated with long-term response.
Acknowledgments
This study was sponsored by Pfizer. Medical writing support was provided by Vardit Dror, PhD, of Engage Scientific Solutions and was funded by Pfizer Inc.
Footnotes
Conflict of Interest
NM Tannir reports research funding and consultation fees from Pfizer, Novartis, and Exelixis and research funding from BMS. RA Figlin reports research funding from Argos, Bristol-Myers Squibb, GlaxoSmithKline, and Immatics and research funding and consultation fees from Novartis and Pfizer. MD Michaelson reports research funding and consultation fees from Pfizer, Novartis, and Eisai; consultation fees from Medivation and Astellas; and research funding from Millennium, Argos, and Tracon. RJ Motzer reports research funding and consultation fees from Pfizer, Novartis, and Eisai and research funding from BMS, Exelixis, and GlaxoSmithKline. C Porta reports research funding from Pfizer and consultation fees from Pfizer, Novartis, BMS, Roche-Genentech, Exelixis, Peloton, and EUSA Pharma. BI Rini reports research funding and consultation fees from Pfizer, GlaxoSmithKline, and Merck and research funding from BMS, Genentech, and Acceleron. B Escudier received an honorarium from Pfizer, Novartis, GlaxoSmithKline, Bayer, and Exelixis. ME Gore has declared no conflict of interest. C Hoang and X Lin are full-time employees of Pfizer.
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