Michael R. Harrison, MD
Associate Professor of Medicine
Division of Medical Oncology
Duke Cancer Institute
Duke University Health System
Durham, North Carolina
Keywords:adjuvant therapy, locoregional, cytokine therapy, S-TRAC, ARISER, ASSURE, PROTECT, disease-free survival, sunitinib, pazopanib.
Corresponding Author: Michael R. Harrison, MD, Duke Cancer Center 20 Duke Medicine Circle Durham, NC 27710 Email: email@example.com
Numerous studies have taken aim at what still appears to be a moving target—optimal use of adjuvant therapy. The volume of literature on this treatment setting has grown rapidly in the past several years and ongoing studies will soon add to the wealth of information—often discordant—on the clinical dilemma in this disease space. A review of the key studies suggests overarching issues and the salient questions still to be addressed. Studies of immune checkpoint inhibitors provide a potential path forward.
Clinical decision making in the adjuvant therapy setting for renal cell carcinoma (RCC) remains challenging. Despite a dramatic evolution in therapy that has ushered in novel approaches in metastatic disease with the promise of improving outcomes in the adjuvant setting, it remains a hotbed of controversy with the results of pivotal trials decisively at odds with one another. The discrepancy in the results of these trials has not helped to resolve the unmet need for an effective strategy for high risk locoregional kidney cancer. There is still clinical equipoise as to whether targeted therapy improves outcomes significantly, highlighted by the placebo comparator (as opposed to sunitinib) in recently designed adjuvant trials. The topic of adjuvant therapy for high risk localized RCC remains a controversy in search of a consensus.
The 5-year survival rate is 53% for locoregional (stage III) disease and 8% for metastatic (stage IV) disease.1 Overall, locoregional disease is diagnosed in 16% of patients with RCC, and the unmet need is plainly evident when one considers that up to 40% of these patients have a relapse with metastasis after nephrectomy.2,3 This relapse risk has been assessed with validated models, including the University of California Los Angeles Integrated Staging System (UISS). One of the challenges in validating an effective adjuvant therapy is the relatively long duration to observe a benefit in disease-free survival: the S-TRAC Trial, for example, required a median of 5.4 years follow up before a benefit became apparent. Practically speaking, this means that patients were enrolled to the study from September 2007 to April 2011. The study was presented at a scientific congress and published simultaneously in October 2016, and sunitinib received FDA approval in November 2017.
Initial Results in Cytokine Era Disappointing
Initial efforts to improve the prognosis in the adjuvant setting began in the cytokine era. Prior to the approval of targeted agents, IFN-alpha was used as a reference standard for phase III studies in metastatic (mRCC). IL-2 was approved for mRCC in 1992, and in comparison with IFN-alpha, the agent had greater potential for inducing durable responses (occurring in roughly 5-10% of treated patients.4 However, the use of IL-2 has generally been restricted to younger patients with good performance status and more limited metastases.5
These earlier efforts in the cytokine era, however, met with a lack of success.5 A study led by the Cytokine Working Group, for example, is typical of the disappointing results: the study was prematurely closed after an interim analysis suggested futility for the primary endpoint—2-year DFS. One of the earlier trials of a targeted approach for adjuvant therapy was ARISER.6 It examined a carbonic anhydrase IX inhibitor (girentuximab), a chimeric monoclonal antibody that binds a cell surface glycoprotein ubiquitously expressed in clear cell RCC. Adjuvant girentuximab failed to improve disease-free or overall survival vs placebo in a cohort of patients with fully resected, high-risk clear cell renal cell carcinoma. Although ARISER was disappointing, it signified a transition to a new generation of studies and an evolution in the rationale for treatment as cytokine therapy, at least in the adjuvant setting, began to fade because of a lack of efficacy. As the cytokine era was brought to a close by the emergence of novel targeted therapies, signaling the beginning of the targeted therapy era in 2006, investigations turned toward the use of antiangiogenic strategies. The proven efficacy of antiangiogenic therapies, including sunitinib and pazopanib in metastatic RCC, supports the evaluation of these drugs as adjuvant therapy.
This report seeks to present a fair and balanced view of the latest findings from pivotal trials on the use of targeted therapies in the adjuvant setting. As Haas et al point out, RCC is arguably the most biologically rational setting in which to assess the adjuvant role of anti-angiogenic therapies, given their single agent activity in patients with advanced disease.7 To date, sunitinib is the only one of these agents given FDA approval as adjuvant therapy for RCC based on the positive results of the S-TRAC phase III trial. Meanwhile, three other phase III trials of adjuvant antiangiogenic strategies have been negative. Among the key questions to address is what accounts for the discrepancy in results from the major. Why, for example, do the results from S-TRAC, the second adjuvant trial reported in the targeted therapy era, suggest a benefit from the use of adjuvant sunitinib while the data from ASSURE, the first trial reported in the targeted therapy era, indicate no difference in the primary endpoint of disease free-survival?7 The discrepancies between the ASSURE trial and S-TRAC resulted in uncertainty regarding the benefit of adjuvant sunitinib, with advocates and skeptics focusing on methodological details as limitations of each study. This uncertainty only continued with the negative results of two subsequent trials, PROTECT and ATLAS.
ASSURE and S-TRAC: A Mixed Picture for Use of Antiangiogenic Therapy
In deciphering the different messages from each of these two trials, Lenis et al8 highlighted these key points:
- The first key difference is the baseline risk of the study populations: ASSURE included patients with pT1b or greater grade 3 to 4 disease, whereas S-TRAC included more advanced locoregional (pT3 or greater disease).
- In ASSURE more than a third of the patients had high grade T1 or T2 disease and would not have met the inclusion criteria of S-TRAC. This can be seen in the median DFS of the placebo groups—one year longer in ASSURE.
- Because S-TRAC had a higher risk population, Lenis et al suggest that they were more likely to have had micrometastatic disease and potentially more to gain from adjuvant therapy.
- The percentage of patients with nonclear cell histology is also a factor—20% in ASSURE. VEGF inhibitors have a poorer track record in nonclear cell histology mRCC (lower response rates and progression free survival compared with clear cell histology mRCC).
- Dosing adjustments were also identified as a potential factor. ASSURE had a decreased dose exposure to sunitinib, potentially reducing the observed efficacy of the active treatment arm to the control group.
- Lenis et al underscore the importance of optimal patient selection as the key factor in delineating whether patients are likely to benefit from adjuvant sunitinb. Thus, patients with high risk locoregional clear cell cancer may be offered the option of adjuvant sunitinib for 1 year following surgery in the context of known risk of side effects.
S-TRAC Produced Positive But Controversial Outcomes
Drawing on updated information on S-TRAC and providing further evidence for its benefits, Motzer et al9 offered additional insights on the relationship between baseline factors and DFS, pattern of recurrence, and new overall survival. In addition to the positive outcome in the overall population of the S-TRAC study, the majority of subgroups defined according to baseline characteristics experienced longer DFS on sunitinib compared to placebo, including the prespecified subgroup of patients with higher risk of recurrence (defined as T3, no or undetermined nodal involvement, Fuhrman grade≥ 2, and ECOG PS≥ 1; or T4 and/or nodal involvement) compared to the overall population, as well as the subgroup of patients with Fuhrman grade 3/4. Still unresolved, however, is the impact of adjuvant sunitinib on OS. The updated data from Motzer et al were not mature enough to derive a reliable conclusion on this issue as there were still relatively few events (i.e. deaths) Nevertheless, this study did not observe a detrimental effect on OS and it should be noted that the trial was not powered to show an OS benefit.
The controversial nature of adjuvant therapy was again reflected in an updated analysis of the ASSURE trial focusing on a high risk, clear cell histology subset similar to that in S-TRAC.7 The key question asked by these investigators was whether high-risk clear cell RCC patients (pT3 or more or node-positive) receiving sunitinib or sorafenib have improved DFS, and does the dose intensity of either drug affect outcome? This study sought to investigate whether the results from S-TRAC could be achieved in a similar subset in ASSURE. DFS and OS at 10 years postactivation were calculated for 1069 patients in US and Canadian cooperative groups with high-risk patients who had ccRCC histology and pT3, pT4, or node-positive disease accrued between 2006 and 2010. to the double-blind randomized placebo-controlled phase 3 trial. The groups included 243 [67.9%] men, 115 [32.1%] women) who received sunitinib; 248 [69.9%] men, 107 [30.1%] women) received sorafenib, and 356 received placebo as adjuvant therapy. The mean age for each group was 58.3 (10.6) years, 56.8 (10.3) years, and 57.5 (10.4) years, respectively. Five-year DFS rates were 47.7%, 49.9%, and 50.0%, respectively for sunitinib, sorafenib, and placebo (HR, 0.94 for sunitinib vs placebo; and HR, 0.90; 97.5%CI, 0.71-1.14 for sorafenib vs placebo) with 5-year OS of 75.2%, 80.2%, and 76.5 (HR, 1.06; 97.5%CI, 0.78-1.45; P = .66, sunitinib vs placebo; and HR, 0.80; 97.5%CI, 0.58-1.11; P = .12 for sorafenib vs placebo). The authors also concluded that lack of difference in DFS and OS was not altered by prognostic category or dose intensity in patients with high risk, clear cell histology RCC.
Subsequent Analyses Focused on Adverse Events
and Immune Correlates in S-TRAC
Despite the analysis by Haas et al, the debate has continued to seesaw with the publication of other findings, one current study related to the management of adverse effects of sunitinib and the other exploring whether immune biomarkers could be predictive for DFS in high-risk patients in S-TRAC. A study by Staehler et al10 found that AEs in S-TRAC were predictable, manageable, and reversible via dose interruptions, dose reductions, and/or standard supportive medical therapy. Patients on sunitinib did report increased symptoms and reduced HRQoL, but these changes were generally not clinically meaningful, apart from appetite loss and diarrhea, and were expected in the context of known sunitinib effects. Management of sunitinib AEs has been continuously evaluated in numerous studies over the past decade, but this paper, focusing primarily on the S-TRAC database, could have implications for interpreting the S-TRAC results and adopting strategies to minimize significant AEs affecting whether patients continue on the drug.
In another study conducted by George et al,11 a prospectively designed exploratory analysis of tissue samples from a subset of patients from S-TRAC, identified predictive biomarkers that could facilitate future patient selection for adjuvant sunitinib and facilitate an improved understanding of mechanisms of interaction that might explain the durable treatment effect, potentially leading to future combination approaches. Tumor tissue expression levels of CD4, CD8, CD68, and PD-L1 using IHC staining of formalin-fixed, paraf-fin-embedded tissue blocks were compared with efficacy outcomes. The observed association between higher CD8+ T-cell density in tumor tissue with longer DFS with sunitinib, but not placebo, suggested predictive potential of CD8+ T-cell density, which would warrant further independent cohort validation studies. The prognostic value of PD-L1 expression in primary tumors in this setting should also be further explored, according to another report.12
CD8+ T-cell density is interesting for two reasons. First, this is a measure of T-cell recognition and infiltration of the tumor and suggests a level of immune activation de novo. Although it is not prognostic, the predictive association with sunitinib treatment would suggest that CD8+ T cells may play a role in the treatment effect of sunitinib (Figure 1).
In the setting of VEGF/VEGFR inhibition and tumor hypoxia, CD8+ T cells might be able to better recognize tumors through the exposure of neoantigens. Still other implications from the report by George et al is that the CD8+ T-cell infiltration and subsequent activation could potentially explain the lasting treatment effect beyond 1 year associated with patients in the sunitinib treatment group (Figure 2).
The second interesting point of this predictive association between CD8+ T cells and sunitinib treatment is the link between the immune system and antiangiogenic therapy. This association would take the narrative beyond just the use of antiangiogenic therapy as adjuvant. Available evidence from randomized phase II testing of bevacizumab and atezolizumab, as well as avelumab and axitinib, suggests the combination of PD-L1 or
PD-1 inhibition with VEGF/VEGFR inhibition is additive.13,14 Thus, potentially, VEGF/VEGFR inhibition could increase PD-L1 expression in tumors or otherwise prime tumors for PD-1/PD-L1 inhibition. It is worth noting that the 16-gene signature assay of the samples from the S-TRAC trial indicated an association between lower expression of immune response and vascular normalization genes with higher risk of disease recurrence, with the strongest effects observed in the placebo arm.15
PROTECT: Evidence Suggestive of a Relationship
Between Outcomes and Dose Intensity
One of the unresolved issues from the ASSURE and S-TRAC trials remains the importance of dose intensity and whether maintaining it can result in an improvement in DFS. The PROTECT study pursued this avenue as it provided more data on the relationship between dose and benefit and whether adjustments in exposure to pazopanib could have a significant impact. The PROTECT study evaluated the efficacy of pazopanib as an adjuvant therapy for patients with locally advanced RCC at a high risk of relapse after surgery. The primary objective of the study had to be amended to examine DFS in a cohort that received a reduced dose of pazopanib (600 mg daily instead of the initial 800 mg) due to toxicity.16 In the 600 mg cohort, a DFS benefit for pazopanib over placebo was not observed. Although a DFS benefit was observed in the sustained 800 mg cohort, it was not considered tolerable. Sun et al introduce the intriguing concept of whether the potential benefit of adjuvant therapy is not completely driven by the starting dose of the drug but rather by blood concentration levels.
This was the focus of another recent report by Sternberg et al17 who evaluated the relationship between pazopanib exposure (Ctrough) and efficacy and safety. One of the issues elucidated in this report is whether higher pazopanib exposure as indicated by Ctrough values could improve DFS without increasing treatment discontinuations of grade 3 and 4 AEs. Sternberg et al found that higher pazopanib exposure was associated with an improved DFS without an increase in the AEs. The analysis also reviewed pharmacokinetic simulations showing overlapping pazopanib exposure with 600 and 800 mg doses. Therefore, some patients achieve higher pazopanib exposure—associated with improved DFS—regardless of whether the starting dose is 600 or 800 mg. Clearly, further study is needed to delineate to what extent the potential benefit of adjuvant therapy is driven by a pharmacokinetic benefit rather than by dose. An additional issue up for debate is whether the results from this study could be extrapolated to sunitinib and other VEGFR receptor TKIs. If the controversy over adjuvant therapy needed yet another focus to stimulate debate, then the challenge has been issued.
Pooled Analysis, a Fourth Trial of Targeted
Therapy and Future Directions
Skeptics of S-TRAC can also point to another report by Sun et al16 who took a different approach to examining the data with a pooled analysis from ASSURE, S-TRAC and PROTECT. This analysis, based on eight articles and five studies of the three trials, revealed:
- No statistically significant effect between adjuvant VEGFR-targeted therapy and improved DFS or OS in patients with intermediate/high risk local or regional fully resected RCC.
- No evidence that dose intensity could significantly improve DFS. Any effect on DFS, they suggest, could be too costly in terms of the toxicity experienced by a majority of patients.
In April of 2018, Pfizer announced by press release that the independent data monitoring committee for the Phase III ATLAS trial (randomized to adjuvant axitinib for up to 3 years vs placebo, NCT01599754) recommended stopping the trial at a planned interim analysis due to futility.18 This represented the fourth trial of adjuvant therapy with a targeted therapy agent and the third to suggest no benefit. However, the full results have not been presented at a scientific congress, nor have they been published; they are eagerly awaited. Three other ongoing randomized clinical trials are evaluating the clinical benefit of adjuvant targeted therapies, including SORCE (adjuvant sorafenib vs placebo, NCT00492258), EVEREST (adjuvant everolimus vs placebo, NCT01120249), and E2810 (adjuvant pazopanib vs placebo in patients with no evidence of disease following metastasectomy, NCT01575548).10
Currently, there are several trials evaluating anti-PD-1 or anti-PD-L1 antibodies in the adjuvant setting: CheckMate 914 (combination of nivolumab and ipilimumab vs placebo), PROSPER (nivolumab neoadjuvantly for 2 doses then adjuvantly vs immediate nephrectomy then observation), IMmotion 010 (atezolizumab vs placebo), and KeyNote 564 (pembrolizumab vs placebo) (ClinicalTrials.gov: NCT03138512, NCT03024996, NCT03142334, NCT03055013). However, there are no combination adjuvant studies of VEGF/VEGFR inhibition with PD-1 or PD-L1 inhibition. The available data would support such an approach in the adjuvant setting.
The landscape of adjuvant therapy remains unsettled and many issues need to be resolved before a consensus can be reached. Four pivotal trials, ASSURE, S-TRAC, PROTECT and ATLAS, have provided discordant results as to whether antiangiogenic therapy in the setting of locoregional RCC can meet the endpoint of DFS. The question of OS is also unresolved. The focus of the initial debate, in large part related to selection of the high risk cohort, dose intensity, independent radiographic review for the DFS endpoint, histology, and independent pathologic review of histology, has shifted as new reports highlight the potential importance of biomarkers and pharmacokinetic factors in determining the optimal approach. Maintaining high-dose intensity has been the tenet of the pivotal trials but it may no longer be the most important question to be addressed. Ongoing trials, including the examination of immune checkpoint inhibitor immunotherapies, will need to address many of these concerns as a consensus remains elusive.
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18.https://www.pfizer.com/news/press-release/press-release detail/pfizer_provides_update_on_phase_3_trial_of_axitinib_as_adjuvant_treatment_for_patients_at_high_risk_of_renal_cell_carcinoma_recurrence_after_surgery. KCJ