Surgical resection is the primary treatment for patients with early-stage renal cell carcinoma (RCC) and can potentially be curative in up to 70% of cases.1 In many solid tumors, patients at high risk of recurrence are often treated with adjuvant (postsurgical) systemic therapy, with the idea being to eradicate any microscopic residual disease and thus decrease the likelihood of developing a local or metastatic recurrence. While adjuvant therapy is standard of care in many solid tumors, no adjuvant therapy has proven to increase disease-free survival in RCC; furthermore, cytokine therapies that have been studied in the adjuvant setting, such as interleukin and interferon-α, carry high levels of toxicity. As such, adjuvant therapy is rarely administered (approximately 26% of Stage III patients are administered adjuvant therapy in the U.S.2).
Nexavar® (sorafenib, Onyx / Amgen) and Sutent® (sunitinib, Pfizer) changed the treatment paradigm for advanced/metastatic RCC when they were first launched nearly a decade ago. Their widespread use in advanced RCC has also prompted debate whether they would be equally active in the adjuvant setting. While use of adjuvant therapy is minimal in RCC, among those patients who do receive an adjuvant regimen, Sutent and Nexavar are used off-label in approximately 45% of patients.2 Both agents have demonstrated increased efficacy in advanced/metastatic RCC and have good safety profiles, even for extended periods of administration, making them good candidates for adjuvant therapy. ASSURE (adjuvant sorafenib or sunitinib in unfavorable renal cell carcinoma; Eastern Cooperative Oncology Group 2805) is a Phase III trial investigating the clinical benefit and tolerability of these therapies in the adjuvant setting. ASSURE is a randomized, double-blind, multicenter trial that enrolled 1,943 patients with resected, intermediate and very high risk (as scored by UISS risk criteria1), clear cell and non-clear cell RCC who had no prior systemic therapy. Patients were randomized to one year treatment with Nexavar (400 mg twice daily, administered continuously for nine cycles), Sutent (50 mg once daily, administered for four weeks of a six-week cycle for nine cycles), or placebo. Notably, drug dosage was reduced to 400 mg Nexavar and 35 mg Sutent both given once daily as a result of adverse events and patient intolerance (see further detail below). Moreover, the sample size was increased from 1,332 patients to 1,943 patients to compensate for the dosage revision. Disease-free survival (DFS) was used as the primary endpoint, and secondary endpoints were overall survival (OS) and tolerability. Additionally, examination of angiogenic markers in tissue, blood, and urine was performed to determine their significance in predicting therapeutic benefit.
Initial results of ASSURE, reported at the 2015 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, demonstrated that Nexavar and Sutent do not improve clinical efficacy in the adjuvant setting.3 Median DFS was 5.8 years in the Nexavar and Sutent treatment arms and 6.0 years in the placebo arm (Nexavar vs. placebo HR = 0.97, p = 0.74; Sutent vs. placebo HR = 1.00, p = 0.96). Moreover, five-year DFS rates were 52.8% in the Nexavar arm (HR = 0.98), 53.8% in the Sutent arm (HR = 1.01), and 55.8% in the placebo arm. Five-year OS rates were 80.7% in the Nexavar arm (HR = 0.93), 76.9% in the Sutent arm (HR = 1.10), and 78.7% in the placebo arm.
Not only was efficacy not improved with the use of Sutent or Nexavar in the adjuvant setting, these regimens added significant toxicity. Both agents were associated with an increased incidence of hypertension, a class effect for VEGF pathway inhibitors (16% Nexavar, 16% Sutent, 4% placebo). Nexavar was also associated with increased incidence of hand-foot syndrome (15% vs. <1% placebo), rash (15% vs. <1% placebo), and diarrhea (9% vs. none placebo); Sutent was associated with increased incidence of fatigue (18% vs. 3% placebo), hand-foot syndrome (33% vs. 1% placebo), and diarrhea (10% vs. none placebo). The majority of worst degree of all event types was considered to be Grade 3 adverse events (67% Nexavar, 57% Sutent, 20% placebo), which were non-life-threatening but required medical intervention.
With the lack of even a trend to efficacy benefit and significant high-grade toxicity for both Nexavar and Sutent, the initial results of ASSURE do not support any use of these two drugs in the adjuvant setting for RCC. In light of the lack of effective adjuvant therapies for RCC, the outcomes of ASSURE will be further assessed to determine whether VEGF TKI therapy may be effective in a subset of intermediate- and very high-risk RCC patients. One point of interest that wasn’t reported in the ASCO GU presentation was the effect of dose, dose-reduction and drop-out rate on clinical efficacy. These analyses are being conducted now and hope to be reported at a future conference.
The ASSURE trial adds to the growing body of evidence that targeted therapeutics approved in the metastatic setting may not provide clinical benefit in the adjuvant setting. Other notable failures include Avastin® (bevacizumab, Genentech/Roche/Chugai) in adjuvant colon cancer4 and Erbitux® (cetuximab, Lilly/BMS/Merck KGaA) in adjuvant colon cancer.5 Not all targeted therapeutics have failed to improve efficacy in the adjuvant setting – Yervoy® (ipilimumab, BMS) improved DFS in melanoma, and Gleevec® (imatinib, Novartis) improved DFS in gastrointestinal stromal tumor – so it raises the question of whether the observed failures are due to ineffective agents or ineffective mechanisms of action. Nexavar and Sutent, while multitargeted, are considered anti-angiogenic in nature, as is Avastin; the failure of all three agents to improve DFS in the adjuvant setting suggests that anti-angiogenesis is not an effective approach to treatment and prevention of recurrence in the non-metastatic setting. In the example of Avastin in colon cancer, landmark analysis showed a clinical benefit for the period of time during which Avastin was being administered, but the benefit eroded after Avastin treatment was ceased. A similar effect appears to have occurred in the ASSURE trial; in the Kaplan Meyer curve for DFS, the Sutent and Nexavar arms were both overlapping and clearly separated from the placebo arm from approximately six months until approximately 20 months.
These trials raise the question of what the appropriate duration of therapy for an anti-angiogenic therapy in the adjuvant setting is. This issue is being explored in the ongoing SORCE study (NCT00492258), which is comparing placebo vs. Nexavar for one year or three years in resected clear cell and non-clear cell RCC patients. The ATLAS study (NCT01599754) is also exploring prolonged adjuvant therapy for another anti-angiogenic agent, Inlyta® (axitinib, Pfizer) by comparing placebo vs. Inlyta for three years in very high-risk (as scored by UISS criteria), clear cell RCC patients. These studies may provide answers to whether prolonged duration of treatment is necessary to observe a clinical benefit in these patients. However, even if these trials show a benefit with prolonged administration, the tolerability of these agents is still in question. In the meantime, the results of ASSURE support a change of treatment practice – the significant off-label use of Nexavar and Sutent (and by extension other VEGFR TKIs) in Stage I-III RCC should be ceased. With this, the level of unmet need for high-risk, early-stage RCC remains high, and determining the best treatment approach for this disease is anxiously awaited.
1. Lam JS, Shvarts O, Leppert JT, et al. “Renal cell carcinoma 2005: new frontiers in staging, prognostication and targeted molecular therapy.” J Urol. 2005;173:1853-62.
2. Kantar Health, CancerMPact® Treatment Architecture U.S., accessed February 27, 2015.
3. Haas NB, Manola J, Uzzo RG, et al. “Initial results from ASSURE (E2805): Adjuvant sorafenib or sunitinib for unfavorable renal carcinoma, an ECOG-ACRIN-led, NCTN phase III trial.” In American Society of Clinical Oncology Genitourinary Cancers Symposium; February 28, 2015; Orlando, Florida. Abstract 403.
4. Allegra CJ, Yothers G, O’Connell MJ, et al. “Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08.” J Clin Oncol. 2011;29(1): 11-16.
5. Huang J, Nair SG, Mahoney MR, et al. “Comparison of FOLFIRI with or without cetuximab in patients with resected stage III colon cancer; NCCTG (Alliance) intergroup trial N0147.” Clin Colorect Canc. 2014;13(2): 100-109.
By: Stephanie Hawthorne, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health and Stephanie Ritz, Analyst, Clinical & Scientific Assessment, Kantar Health