Adjuvant Systemic Therapy for High Risk Kidney Cancer

Adjuvant targeted therapy

Tyrosine kinase inhibitors (TKIs) quickly became standard of care for patients with metastatic renal cell carcinoma following their introduction in the early 2000s. They have subsequently been investigated as adjuvant therapy in 4 published randomized trials to our knowledge. In addition, the SORCE trial was presented at ESMO 2019 at the end of September 2019.

The ASSURE trial (Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma; ECOG-ACRIN E2805) randomized 1943 patients to one of three arms: sorafenib adjuvant therapy, sunitinib adjuvant therapy, or observation². Patients were eligible for inclusion if they had pT1b or higher, high-grade N0 M0 or node-positive M0 renal cell carcinoma with clear cell or non-clear cell histology. The Pazopanib As Adjuvant Therapy in Localized/Locally Advanced RCC After Nephrectomy investigators enrolled 1135 patients with pT2 high grade, pT3-4, N0, M0, or node-positive non-metastatic disease, and randomized them to receive either pazopanib for 1 year or placebo³. The S-TRAC trial, in contrast, was limited to patients with stage III-IV M0 (UISS modified criteria) clear cell renal cell carcinoma⁴. These investigators randomized a total of 615 patients to adjuvant sunitinib for 1 year or placebo. More recently, Gross-Goupil and colleagues reported the results of the randomized ATLAS trial which was a Phase III trial of axitinib versus placebo in the adjuvant treatment of patients following nephrectomy for locoregional renal cell carcinoma with >50% clear cell histology and no evidence of macroscopic residual or metastatic disease⁵. The investigators randomized 724 patients to oral, twice-daily axitinib for a minimum of 1 (baring toxicity or progression) and maximum of 3 years.

The ASSURE investigators found no benefit in disease-specific survival for either sunitinib (hazard ratio (HR) 1.02, 97.5% confidence interval (CI) 0.85 to 1.23) or sorafenib (HR 0.97, 97.5% CI 0.80 to 1.17). Updated results of the high-risk subset of the ASSURE cohort were published in 2017⁶. In this cohort of 1069 patients, the authors could demonstrate no benefit in disease-specific or overall survival with the use of adjuvant therapy.

The Pazopanib As Adjuvant Therapy in Localized/Locally Advanced RCC After Nephrectomy trial investigators demonstrated no benefit in disease-free survival for the adjuvant use of pazopanib compared to placebo (HR 0.86, 95% CI 0.70 to 1.06)³.

The S-TRAC trial is the only study in this disease space to demonstrate a benefit to the use of TKIs, demonstrating a disease-free survival benefit of 1.2 years (HR 0.76, 95% CI 0.59 to 0.98). These data led to the FDA approval of sunitinib in adjuvant therapy for patients with locoregional clear cell renal cell carcinoma at high risk for recurrence. However, data presented in the manuscript's supplement demonstrated no overall survival benefit to this approach.

Based on an independent review committee, the ATLAS trial was stopped for futility at a preplanned interim analysis demonstrated no improvement in disease-free survival (HR0.87, 95% CI 0.66 to 1.15). There was a suggestion of potential benefit in the highest risk sub-populations. Axitinib was associated with increased grade 3 and 4 adverse events but similar rates of overall and serious adverse events.

Very recently, the results of SOCRE which randomized 1711 patients to observation, sorafenib for 1 year or sorafenib for 3 years were reported at ESMO 2019 in Barcelona. Regardless of the duration of adjuvant therapy, there was no evidence of benefit in disease-free survival or overall survival.

In general, treatment was poorly tolerated and required significant dose reduction. In the ASSURE trial, 44% of patients on sunitinib and 45% of patients on sorafenib had toxicity related treatment discontinuation. This led to a protocol amendment and dose reduction. This underdosing of therapy may have contributed to the null findings of the trial. Patients receiving pazopanib in the adjuvant setting experienced increased hepatic transaminases leading to treatment discontinuation in almost 20% of patients. Interestingly, while there was significant treatment-related toxicity in the other trials, rates of serious adverse events in the S-TRAC study were relatively similar (22% in sunitinib treated patients and 17% in those receiving placebo).

Sun et al. provide a systematic review and meta-analysis of the ASSURE, S-TRAC, and Pazopanib As Adjuvant Therapy in Localized/Locally Advanced RCC After Nephrectomy trials⁷. Pooled analysis demonstrated no significant improvement in disease-free survival (HR 0.92, 95% CI 0.82 to 1.03) or overall survival (HR 0.98, 95% CI 0.84 to 1.15) with the use of adjuvant TKI compared to placebo. However, patients receiving adjuvant therapy had significantly increased rates of grade 3 or 4 adverse events (odds ratio 0.59, 95% CI 4.85 to 7.15). Interestingly, based on the hypothesis that dose reduction may compromise the efficacy of adjuvant therapy, the authors found that the subgroup of patients who started full-dose therapy had improved disease-free survival (HR 0.83, 95% CI 0.73 to 0.95).

Among a survey of urologists, Spek et al. found that most place significant weight on overall survival outcomes as well as the data from ASSURE when making decisions regarding adjuvant therapy in patients with locoregional kidney cancer⁸. As a result, the minority would recommend adjuvant therapy. This agrees with the perspective of medical oncologists who, in general, recommend against the routine use of adjuvant sunitinib due to the lack of definitive survival benefit and high incidence of adverse events^{9, 10}. Additionally, the authors highlight the lack of prognostic or predictive biomarkers to guide adjuvant therapy.

The most recent European Association of Urology guidelines highlight that three are no randomized Phase III data demonstrating a survival benefit to adjuvant therapy in resected renal cell carcinoma¹¹. As a result, they do not recommend the use of VEGFR-TKI therapy for patients at high risk of recurrence following nephrectomy.

Adjuvant immunotherapeutic approaches

There is a significant body of ongoing investigation with respect to the use of immunotherapeutic approaches, including checkpoint inhibitors in the adjuvant treatment of renal cell carcinoma. These will be discussed below in the “Ongoing investigations” section. Here, I will summarize the available published data.

In 2008, Wood et al. published the results of an open-label Phase III trial of an adjuvant autologous therapeutic vaccination (HSPPC-96; vitespen) in patients with high-risk of recurrence following resection of locally advanced renal cell carcinoma¹². A total of 818 patients were randomly assigned to HSPPC-96 or observation. Of these, 90 were ineligible on the basis of post-surgical inclusion criteria. Recurrence rates were comparable between patients receiving adjuvant therapy and those undergoing observation alone (HR 0.92, 95% CI 0.73-1.17) with overall survival immature at the time of publication. There was the suggestion of potential benefit in patients with stage I or II disease (HR 0.58, 95% CI 0.32-1.02).

In 2011, Aitchison et al. presented the results of the EORTC/NCRI trail assessing adjuvant interleukin-2, interferon alpha (IFN) , and 5-fluorouracil in patients at high risk of relapse following resection of renal cell carcinoma¹³. To date, to our knowledge, these data remain otherwise unpublished. In their abstract, they found no benefit in disease-free survival or overall survival for patients receiving adjuvant therapy, despite significant toxicity.

In a prospective non-randomized study assessing the role of low-dose granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon alpha and interleukin 2 (IL-2), Tsimafeyeu et al. found no benefit to this approach¹⁴.

More recently, the Phase III ARISER clinical trial reported the results of weekly girentuximab (up to 24 weeks of therapy) as adjuvant therapy following nephrectomy for high-risk renal cell carcinoma. Girentuximab is a chimeric monoclonal antibody that binds carbonic anhydrase IX. They found no survival benefit, either with respect to disease-free survival (HR 0.97, 95% CI 0.79 to 1.18) or overall survival (HR 0.99, 95% CI 0.74 to 1.32).

Ongoing investigations

There are many lines of ongoing investigation aimed at optimizing outcomes for patients with kidney cancer at high risk of recurrence following resection.

Utilizing the mTOR inhibitor everolimus, the EVEREST trial is a multi-center, phase III trial coordinated by SWOG which has randomized 1545 patients with intermediate-high or high-risk renal cell carcinoma (either clear cell or non-clear cell histology) who have undergone full survival resection to everolimus or observation.

Recently, three large randomized trials have demonstrated the superiority of immunotherapy (nivolumab plus ipilimumab) or immunotherapy and targeted therapy treatment (pembrolizumab plus axitinib and avelumab plus axitinib) regimes over sunitinib in patients with first-line treatment of metastatic renal cell carcinoma^15-17. This follows previous data demonstrating the role of immunotherapy in second-line treatment of metastatic RCC. It is therefore not surprising that these approaches are being explored in the adjuvant space. However, despite excitement, some caution may be warranted as in a sub-group analysis of the CheckMate214 trial, patients with low volume metastatic RCC had better survival with sunitinib than with nivolumab plus ipilimumab¹⁵. That said, there are a number of ongoing trials of immunotherapy approaches in the adjuvant setting in RCC.

The RAMPART trial is a phase III multi-arm, multi-stage randomized controlled trial in advanced kidney cancer somewhat akin to the STAMPEDE trial in prostate cancer. Patients with Liebovich scores from 3 to 11 have been randomized to one of three arms: durvalumab alone (1 year of therapy), durvalumab (1 year of therapy) plus tremelimumab (2 cycles), or observation. This trial opened July 19, 2018 and is actively recruiting with a target enrollment of 1750 patients. There are two primary outcome measures (disease free-survival and overall survival) with two planned comparisons (observation versus durvalumab alone and observation versus durvalumab plus tremelimumab).

KEYNOTE-564 is a Phase III trial of adjuvant pembrolizumab versus placebo in patients who have undergone nephrectomy for intermediate-high risk, high-risk, or completely resected M1 renal cell carcinoma. A total of 950 patients were accrued and randomized to up to 17 cycles of adjuvant therapy or placebo saline infusion. Follow-up is ongoing to assess the primary outcome of disease-free survival as well as secondary outcomes of overall survival and adverse events.

The IMmotion010 trial is a multi-center, phase III trial comparing atezolizumab to placebo in patients at high risk of recurrence following resection of renal cell carcinoma. A total of 778 patients were enrolled following radical or partial nephrectomy with lymphadenectomy. Patients in the active arm received atezolizumab every 3 weeks for 16 cycles or 1 year total, whichever occurred first. Follow-up is ongoing to assess the primary outcome of disease-specific survival, as well as numerous secondary outcomes including overall survival, disease-free survival, metastasis-free survival, and toxicity.

CheckMate 914 is an ongoing trial of nivolumab and ipilimumab among patients with resected renal cell carcinoma in any of the following elevated risk categories: pT2a, grade 3 or 4, N0, M0; pT2, any grade, N0, M0; pT3, any grade, N0, M0, pT4, any grade, N0, M0; any tumor stage, any grade, node-positive, M0 disease. The trial is currently accruing with a target of 800 patients and designed to assess the primary outcome of disease-free survival, as well as secondary outcomes of overall survival and adverse events.

Conclusions