Bevacizumab in combination with IFN-α in metastatic renal cell carcinoma: the AVOREN trial

Metastatic renal cell carcinoma (mRCC) is tumor resistant to all cytotoxic agents. During the last decade, effective targeted therapies emerged including sunitinib, pazopanib and the combination of bevacizumab with IFN-α. The use of bevacizumab plus IFN-α combination in mRCC is supported by the AVOREN trial. Although the primary end point of the AVOREN trial was overall survival, progression-free survival was used to evaluate efficacy and served as the basis of regulatory submission owing to the advent of targeted agents that probably resulted in the prolongation of overall survival in both experimental and control arms. The doubling of median progression-free survival in the AVOREN trials (from 5.4 to 10.2 months) is remarkably similar compared with the results of Phase III trials with sunitinib and pazopanib. Bevacizumab plus IFN-α is the only combined regimen currently used in mRCC and serves as a comparator in the trials combining bevacizumab with other agents.     

Health-related quality of life in patients with metastatic renal cell carcinoma treated with sunitinib vs interferon-�� in a phase III trial: final results and geographical analysis

Background:

In a randomised phase III trial, sunitinib significantly improved efficacy over interferon-α (IFN-α) as first-line therapy for metastatic renal cell carcinoma (mRCC). We report the final health-related quality of life (HRQoL) results.

Methods:

Patients (n=750) received oral sunitinib 50 mg per day in 6-week cycles (4 weeks on, 2 weeks off treatment) or subcutaneous IFN-α 9 million units three times weekly. Health-related quality of life was assessed with nine end points: the Functional Assessment of Cancer Therapy–General and its four subscales, FACT–Kidney Symptom Index (FKSI-15) and its Disease-Related Symptoms subscale (FKSI-DRS), and EQ-5D questionnaire''s EQ-5D Index and visual analogue scale. Data were analysed using mixed-effects model (MM), supplemented with pattern-mixture models (PMM), for the total sample and the US and European Union (EU) subgroups.

Results:

Patients receiving sunitinib reported better scores in the primary end point, FKSI-DRS, across all patient populations (P<0.05), and in nine, five, and six end points in the total sample, in the US and EU groups respectively (P<0.05). There were no significant differences between the US and EU groups for all end points with the exception of the FKSI item ‘I am bothered by side effects of treatment'' (P=0.02). In general, MM and PMM results were similar.

Conclusion:

Patients treated with sunitinib in this study had improved HRQoL, compared with patients treated with IFN-α. Treatment differences within the US cohort did not differ from those within the EU cohort.     

RECORD-2: phase II randomized study of everolimus and bevacizumab versus interferon α-2a and bevacizumab as first-line therapy in patients with metastatic renal cell carcinoma

BackgroundThe open-label, phase II RECORD-2 trial compared efficacy and safety of first-line everolimus plus bevacizumab (EVE/BEV) with interferon plus bevacizumab (IFN/BEV) in patients with metastatic renal cell carcinoma.Patients and methodsPreviously untreated patients were randomized 1:1 to bevacizumab 10 mg/kg every 2 weeks with either everolimus 10 mg/day (EVE/BEV) or interferon (9 MIU 3 times/week, if tolerated) (IFN/BEV). Tumor assessments occurred every 12 weeks. The primary objective was the assessment of treatment effect on progression-free survival (PFS), based on an estimate of the chance of a subsequent phase III trial success (50% threshold for phase II success).ResultsBaseline characteristics were balanced between the EVE/BEV (n = 182) and IFN/BEV (n = 183) arms. The median PFS was 9.3 and 10.0 months in the EVE/BEV and IFN/BEV arms, respectively (P = 0.485). The predicted probability of phase III success was 5.05% (hazard ratio = 0.91; 95% confidence interval 0.69–1.19). The median duration of exposure was 8.5 and 8.3 months for EVE/BEV and IFN/BEV, respectively. The percentage of patients discontinuing because of adverse events (AEs) was 23.4% for EVE/BEV and 26.9% for IFN/BEV. Common grade 3/4 AEs included proteinuria (24.4%), stomatitis (10.6%), and anemia (10.6%) for EVE/BEV and fatigue (17.1%), asthenia (14.4%), and proteinuria (10.5%) for IFN/BEV. The median overall survival was 27.1 months in both arms.ConclusionsThe efficacy of EVE/BEV and IFN/BEV appears similar. No new or unexpected safety findings were identified and, with the exception of proteinuria in about one-fourth of the population, EVE/BEV was generally well tolerated.Clinical trial registry and trial registration numberClinicalTrials.gov: NCT00719264.     

Circulating proteins as potential biomarkers of sunitinib and interferon-α efficacy in treatment-naïve patients with metastatic renal cell carcinoma

Purpose

We investigated potential biomarkers of efficacy in a phase III trial of sunitinib versus interferon-alpha (IFN-α), first-line in metastatic renal cell carcinoma (mRCC), by analyzing plasma levels of vascular endothelial growth factor (VEGF)-A, VEGF-C, soluble VEGF receptor-3 (sVEGFR-3) and interleukin (IL)-8.

Methods

Seven hundred and fifty mRCC patients were randomized to oral sunitinib 50 mg/day in repeated cycles of a 4-week on/2-week off schedule or IFN-α 9 million units subcutaneously thrice weekly. Plasma samples collected from a subset of 63 patients on days 1 and 28 of cycles 1–4 and at end of treatment were analyzed by ELISA.

Results

Baseline characteristics of biomarker-evaluated patients in sunitinib (N = 33) and IFN-α (N = 30) arms were comparable to their respective intent-to-treat populations. By univariate Cox regression analysis, low baseline soluble protein levels were associated with lower risk of progression/death (all P < 0.05): in both treatment arms, baseline VEGF-A and IL-8 were associated with overall survival (OS) and baseline VEGF-C with progression-free survival (PFS); in the sunitinib arm, baseline VEGF-A was associated with PFS and baseline sVEGFR-3 with PFS and OS; in the IFN-α arm, baseline IL-8 was associated with PFS. In multivariate analysis, baseline sVEGFR-3 and IL-8 remained independent predictors of OS in the sunitinib arm, while no independent predictors of outcome remained in the IFN-α arm. Pharmacodynamic changes were not associated with PFS or OS for any plasma protein investigated.

Conclusions

Our findings suggest that, in mRCC, baseline VEGF-A and IL-8 may have prognostic value, while baseline sVEGFR-3 may predict sunitinib efficacy.     

Q-TWiST analysis to estimate overall benefit for patients with metastatic renal cell carcinoma treated in a phase III trial of sunitinib vs interferon-α

Background:

In a randomised phase III trial of treatment-naive patients with metastatic renal cell carcinoma, sunitinib showed significant improvement in progression-free survival (PFS) compared with interferon (IFN)-α. We assessed between-treatment differences in overall benefit using a quality-adjusted Time Without Symptoms of disease progression or Toxicity of treatment (TWiST; Gelber and Goldhirsch) analysis.

Methods:

In this analysis, in which only grade 3/4 treatment-related toxicities were included, overall survival was partitioned into three health states: toxicity (time with toxicity after randomisation and before progression), time without symptoms of disease progression or toxicity, and time from progression until death. Between-treatment differences in the mean duration of each state were calculated. A threshold utility analysis was used to assess quality-adjusted TWiST (Q-TWiST) outcomes.

Results:

Q-TWiST scores showed that quality-adjusted survival time was greater with sunitinib than with IFN-α, even though certain grade 3/4 toxicities occurred more frequently with sunitinib. For both treatments, the mean number of days with toxicity was small compared with PFS. This effect was more pronounced with sunitinib in which time spent without progression or toxicity was 151 days greater than with IFN-α.

Conclusion:

Patients randomised to sunitinib had longer clinical benefit, defined as Q-TWiST scores, than patients randomised to IFN-α.     

Sunitinib (SUTENT®) for the treatment of metastatic renal cell carcinoma

Kidney cancer accounts for approximately 2% of new cancers and conventional treatment with nephrectomy followed by IL-2 or IFN-α treatment does not provide long-term survival benefit in many patients. Increased understanding of the pathophysiology of renal cell carcinoma has prompted the development of targeted therapies for patients with this disease, including sunitinib. This paper reviews the most recent efficacy and safety data for sunitinib, as well as currently ongoing and planned studies for this receptor tyrosine kinase inhibitor. Results from a large-scale, long-term, Phase III trial have established sunitinib as the standard of care for first-line treatment of patients with advanced renal cell carcinoma, and it is now the reference standard against which other therapies for this cancer should be evaluated.     

Efficacy of the nanoparticle–drug conjugate CRLX101 in combination with bevacizumab in metastatic renal cell carcinoma: results of an investigator-initiated phase I–IIa clinical trial

BackgroundAnti-angiogenic therapies are effective in metastatic renal cell carcinoma (mRCC), but resistance is inevitable. A dual-inhibition strategy focused on hypoxia-inducible factor (HIF) is hypothesized to be active in this refractory setting. CRLX101 is an investigational camptothecin-containing nanoparticle–drug conjugate (NDC), which durably inhibits HIF1α and HIF2α in preclinical models and in gastric cancer patients. Synergy was observed in the preclinical setting when combining this NDC and anti-angiogenic agents, including bevacizumab.Patients and methodsPatients with refractory mRCC were treated every 2 weeks with bevacizumab (10 mg/kg) and escalating doses of CRLX101 (12, 15 mg/m²) in a 3 + 3 phase I design. An expansion cohort of 10 patients was treated at the recommended phase II dose (RP2D). Patients were treated until progressive disease or prohibitive toxicity. Adverse events (AEs) were assessed using CTCAE v4.0 and clinical outcome using RECIST v1.1.ResultsTwenty-two patients were response-evaluable in an investigator-initiated trial at two academic medical centers. RCC histologies included clear cell (n = 12), papillary (n = 5), chromophobe (n = 2), and unclassified (n = 3). Patients received a median of two prior therapies, with at least one prior vascular endothelial tyrosine kinase inhibitor therapy (VEGF-TKI). No dose-limiting toxicities were observed. Grade ≥3 AEs related to CRLX101 included non-infectious cystitis (5 events), fatigue (3 events), anemia (2 events), diarrhea (2 events), dizziness (2 events), and 7 other individual events. Five of 22 patients (23%) achieved partial responses, including 3 of 12 patients with clear cell histology and 2 of 10 patients (20%) with non-clear cell histology. Twelve of 22 patients (55%) achieved progression-free survival (PFS) of >4 months.ConclusionsCRLX101 combined with bevacizumab is safe in mRCC. This combination fulfilled the protocol's predefined threshold for further examination with responses and prolonged PFS in a heavily pretreated population. A randomized phase II clinical trial in mRCC of this combination is ongoing.     

Is change in blood pressure a biomarker of pazopanib and sunitinib efficacy in advanced/metastatic renal cell carcinoma?

AimPazopanib, an oral antiangiogenic agent, is associated with improved outcomes in patients with metastatic renal cell carcinoma. In this retrospective analysis, we explore hypertension, an on-target adverse event, as a predictive marker.MethodsData from the pazopanib arm of the phase III COMPARZ trial (NCT00720941) comprised the test set. Pooled data from phase II (NCT00244764) and III (NCT00334282) pazopanib trials comprised the validation set. Data from the sunitinib arm of COMPARZ were analysed separately. Measures of efficacy were response rate, progression-free survival (PFS), and overall survival (OS). Mean arterial blood pressure (MAP) was the primary metric, and systolic hypertension (S-HTN) and diastolic hypertension (D-HTN) were secondary metrics; 4- and 12-week landmark analyses were performed.ResultsAnalyses revealed no significant associations at the landmarks between response and MAP. We observed a trend towards improved PFS with S-HTN at week 4 (hazard ratio [HR] = 0.79, P = 0.060) and week 12 (HR = 0.75, P = 0.073) among pazopanib-treated patients in COMPARZ. This trend was not confirmed at week 12 in the validation set or in sunitinib-treated patients. In the test set, there was a trend towards increased OS in patients with S-HTN by week 4 (HR = 0.76, P = 0.062) and with D-HTN by week 4 (HR = 0.71, P = 0.016) but not by week 12. No significant differences in OS were observed in sunitinib-treated patients for S-HTN or D-HTN.ConclusionNeither hypertension nor any blood pressure elevation above baseline was associated with efficacy outcomes of pazopanib or sunitinib. Accordingly, management of tyrosine kinase inhibitor-induced hypertension is unlikely to compromise outcome.     

Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma—Results of the REchallenge with SUnitinib in MEtastatic RCC (RESUME) Study

AimTo assess the efficacy and tolerability of sunitinib rechallenge in the third-line or later setting in patients with metastatic renal cell carcinoma (mRCC).Patients and methodsThis observational study comprised 61 mRCC patients at 19 centres in France who received sunitinib rechallenge between January 2006 and May 2013. Patients received first-line sunitinib, ≥1 different targeted therapies, and then sunitinib rechallenge. Patient/disease characteristics, tolerability, treatment modalities, and outcomes of therapeutic lines were recorded. The primary end-point was progression-free survival (PFS) in sunitinib rechallenge.ResultsAnalyses included 52 patients; median age was 59 years, 75% were male, and 98% had clear-cell mRCC and prior nephrectomy. At sunitinib rechallenge versus first-line, patients had poorer performance (Karnofsky performance status 90–100: 30% versus 81%) and Memorial Sloan Kettering Cancer Centre prognostic risk (poor risk: 18% versus 3%). Overall, 20%, 65%, 12%, and 4% received sunitinib rechallenge as third-, fourth-, fifth-, and sixth-line therapy, respectively, at 14.6 months (median) after stopping initial treatment. With first-line sunitinib and rechallenge, median PFS was 18.4 and 7.9 months, respectively; objective response rate was 54% and 15%. Two of eight rechallenge responders had not achieved first-line response. Median overall survival was 55.9 months. The sunitinib rechallenge safety profile was as expected, with no new adverse events reported.ConclusionsSunitinib rechallenge is a feasible treatment option with potential clinical benefit for mRCC patients. Disease progression with first-line sunitinib may not be associated with complete or irreversible resistance to therapy.     

What is the impact of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma?

The impact of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma (RCC) is discussed herein with consideration of prolonged survival and quality of life. A nephrectomy can be indicated in a patient with good performance status and pulmonary metastases when adjuvant immunotherapy is an option. In contrast, in a patient with poor performance status and/or metastases including multiple organs, a nephrectomy is not indicated. To relieve symptoms, options other than nephrectomy should be considered.     

Is treatment with interferon-α effective in all patients with metastatic renal carcinoma? A new approach to the investigation of interactions

The first analysis of the MRC RE01 trial in metastatic renal carcinoma identified a 28% reduction in the hazard of death for patients treated with interferon-alpha compared with medroxyprogesterone acetate (MPA). No subgroup was identified in which treatment with interferon-alpha was more or less effective than MPA. We used a new approach based on fractional polynomials to investigate the updated data from this trial for the possible interaction of treatment with prognostic factors. In the spirit of hypothesis generation, we considered 10 possible prognostic variables, of which white cell count (WCC) was found to influence the effectiveness of interferon treatment. In patients treated with MPA, there was no prognostic effect of WCC, whereas, in patients treated with interferon, the risk of dying increased significantly with WCC level. We defined subgroups of patients based on WCC levels and estimated a hazard ratio of 0.53 in favour of interferon in patients with WCC <6.5 x 10(9), whereas for patients with WCC >10 x 10(9) the risk appears to be similar between the treatment groups, or even slightly raised in the interferon group. Since our results are derived from flexible statistical models, they may be interpreted as a new hypothesis and require validation in independent data.     

Cytokine therapy: a standard of care for metastatic renal cell carcinoma?

Metastatic renal cell carcinoma (RCC) is refractory to standard cytotoxic chemotherapy regimens. The rationale for the use of cytokines in RCC is based on compelling evidence that RCC is sensitive to immunologic manipulation. Cytokine-based therapy with interleukin-2 (IL-2) or interferon (IFN)-α can result in objective tumor responses in as many as 15% of patients, and in selected patients, these responses can be durable. The development of targeted therapies for clear-cell RCC with the potential for greater antitumor activity and less toxicity has brought into question the role of cytokines in this patient population. However, no noncytokine therapy to date has proven curative in patients with metastatic RCC. Until results from ongoing trials clearly demonstrate superiority of newer agents over IFN-α or IL-2, these agents should remain a standard of care for the treatment of RCC.     

Combination therapy in metastatic renal cell carcinoma: Back to the future?

The treatment landscape of metastatic renal cell carcinoma (mRCC), a chemotherapy-resistant disease, has dramatically changed in the last decade after the introduction of small molecule inhibitors targeting the vascular endothelial growth factor receptor and mammalian target of rapamycin kinases. The CheckMate 025 phase III trial in second line mRCC also introduced immunotherapy with immune-checkpoint inhibitors as an option in the management of mRCC. Both small molecules and immunotherapy are used as single agents and they are associated with different toxicities. Recent data demonstrated that the combination of 2 immunotherapies, nivolumab and ipilimumab, is more effective than tyrosine kinase inhibitors (TKI) monotherapy as first line treatment in intermediate and poor risk mRCC. Furthermore, combination of immunotherapies and TKI has been tested in several trials to evaluate if the combo with agents presenting a different mechanism of action is more effective than monotherapy with TKI. During the past several years, combined therapy of cytokines doublets or cytokines and bevacizumab doublets demonstrated little improvement in clinical outcomes and a relevant toxicity profile. Conversely, the combination of new agents has been recently shown to improve survival in patients with metastatic disease, thus changing the treatment landscape of mRCC. This comprehensive review aims at summarizing the recent advances in the treatment of mRCC.