Prognostic factors in patients with advanced renal cell ...

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Prognostic factors in patients with advanced renal cell carcinoma treated with VEGF-targeted agents Expert Rev. Anticancer Ther. Early online, 1–20 (2014)

Yann-Alexandre Vano*1, Eric Tartour2, Laure S Fournier3, Benoit Beuselinck4, Arnaud Mejean5 and Stephane Oudard1,2 1 Department of Medical Oncology, Georges Pompidou European Hospital, Assistance Publique – Hoˆpitaux de Paris (AP-HP), Descartes University, Paris, France 2 INSERM U970 PARCC, Descartes University, Paris, France 3 Department of Radiology, Georges Pompidou European Hospital, Assistance Publique – Hoˆpitaux de Paris (AP-HP), Descartes University, Paris, France 4 Department of General Medical Oncology and Laboratory for Experimental Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium 5 Department of Urology, Georges Pompidou European Hospital, Assistance Publique – Hoˆpitaux de Paris (AP-HP), Descartes University, Paris, France *Author for correspondence: Tel.: +33 156 093 471 Fax: +33 156 092 573 [email protected]

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The medical treatment of metastatic renal cell carcinoma (mRCC) has undergone a paradigm shift during the last decade with the approval of five drugs targeting vascular endothelial growth factor (VEGF) or its receptors (bevacizumab, sunitinib, sorafenib, pazopanib and axitinib) and of two drugs inhibiting the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway (temsirolimus and everolimus). Median survival has now reached 2 years in mRCC patients receiving first-line targeted treatment. A considerable body of work was conducted on the identification of prognostic factors of survival in the earlier era of immunotherapy of mRCC. The current challenge is to pursue this work on biomarkers of prognosis for targeted therapy and, even more importantly, to identify predictive factors of response to such therapy. This review provides an overview of recent key work on prognostic and predictive factors in patients with advanced clear cell RCC treated with VEGF-targeted agents. KEYWORDS: mTOR • predictive factor • prognostic factor • renal cell carcinoma • TKI • VEGF-targeted therapy

Renal cell carcinoma (RCC) is the 10th most common malignancy in Europe and the 3rd most common malignancy of the urinary tract [1]. In the USA, about 38,000 new cases of kidney cancer are diagnosed each year, which corresponds to 5% of cancers [2]. RCC is a highly heterogeneous group of malignancies, both histologically and molecularly [3,4]. The clear cell subtype (ccRCC) accounts for 75% of all RCCs; the papillary, chromophobe and oncocytoma subtypes account for most of the remaining 25%. Most ccRCCs are diagnosed when still organ confined and can be cured by surgery although 30% will recur at some time, mostly at distant sites; 20% of RCCs are diagnosed with synchronous metastases [5]. Over the last decade, a better understanding of RCC biology has led to the development and subsequent marketing authorization of seven new targeted agents for the treatment of metastatic RCC (mRCC). At their origin was the discovery of two driving pathways in the pathogenesis of RCC – the hypoxiainducible factor (HIF)/VEGF pathway and the PI3K/AKT/mTOR (mammalian target of 10.1586/14737140.2014.882773

rapamycin) pathway. Five effective agents targeting VEGF or its receptors have been developed (bevacizumab, sunitinib, sorafenib, axitinib and pazopanib) and two effective mTOR inhibitors (temsirolimus and everolimus). Bevacizumab is an antibody to the VEGF-A ligand, whereas sunitinib, sorafenib, axitinib and pazopanib are multityrosine kinase receptor inhibitors (TKIs), that is, they inhibit the TK domain of several receptors including VEGF receptor (VEGFR) and are inhibitors of angiogenesis. Sunitinib, the first TKI to be developed, has become the standard first-line treatment for advanced RCC ever since a randomized Phase III trial established its superiority over IFN-a in terms of progressionfree survival (PFS) [6,7]. Survival data from pivotal Phase III trials for all these agents are summarized in TABLE 1. The latest European Society of Medical Oncology guidelines for the first- and second-line treatment of advanced RCC are given in TABLE 2 [8]. Over the last 10 years, median survival has increased from less than 1 year with the earlier standard immune therapy (the cytokine IFN-a) to nearly 2 years with targeted therapy [9,10]. The

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ISSN 1473-7140

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Vano, Tartour, Fournier, Beuselinck, Mejean & Oudard


Table 1. Final survival data from pivotal Phase III trials of targeted agents in patients with advanced renal cell carcinoma. Therapy

Population

Comparator

PFS (months)

HR (p-value)

OS (months)

HR (p-value)

Ref.

Sunitinib

First line

IFN-a

11 vs 5

0.53 (1 t diagn – tt 1 t diagn – tt 1.5 ULN Bone metastases

Ref.

† VEGF(R)-targeted agents included: sunitinib, sorafenib, axitinib, pazopanib, bevacizumab. Hb: Hemoglobin; HECOG: Hellenic Co-operative Oncology Group; IMDC: International Metastatic Database Consortium; LDH: Lactate dehydrogenase; LLN: Lower limit of normal; na: Not applicable; nr: Not reported; MSKCC: Memorial Sloan Kettering Cancer Center; OS: Overall survival; PS: Performance status; t diagn – tt: Time from diagnosis to treatment; ULN: Upper limit of normal; VEGF(R): VEGF or its receptor.

(1–2 risk factors), or a poor (3 or more risk factors) prognosis, with a median overall survival (OS) of 20, 10 and 4 months, respectively. The MSKCC score was updated in 2002 to include only patients treated with IFN-a (n = 463) [13]. Four of the five factors were validated. The fifth – nephrectomy status – was replaced by time from diagnosis to start of IFN-a therapy. In 2004, Motzer et al. further adapted their score to IFN-a-treated patients (n = 251) about to receive second-line treatment within clinical trials. The MSKCC score was whittled down to just three factors: Karnofsky performance status, hemoglobin and corrected calcium [14]. Although the MSKCC models were developed in patients undergoing cytokine therapy, they have been used to stratify patients in Phase III trials of targeted therapies. The 1999 MSKCC model was an independent prognostic factor (HRintermediate_vs_low = 2.39; p < 0.001), together with Fuhrman grade (HR3–4_vs_1–2 = 1.59; p = 0.002) and previous cytokine therapy (HRyes_vs_no = 1.50; p = 0.005), in a www.expert-reviews.com

multivariate analysis of data on 336 mRCC patients of whom 295 (87.8%) had received either first-line sorafenib or sunitinib [15]. Median follow-up was 43 months, and median OS was 24 months. The 2002 MSKCC criteria have, however, recently been updated for use in patients undergoing targeted therapy by analyzing the pooled data for 1059 mRCC patients treated with sunitinib in six clinical trials (TABLE 3) [16]. Sunitinib was administered as first-line treatment to 783 patients (76%) and as second-line treatment to 276 patients (24%) refractory to cytokines. Median PFS was 9.7 months, and median OS was 23.4 months. Nine independent predictors were identified for PFS and 10 for OS. These included the MSKCC criteria, prior cytokine use, neutrophils, platelets, as well as bone metastases and ethnicity. White patients had a better PFS and OS than nonwhite, non-Asian patients (10.5 vs 5.7 months [p < 0.001] and 23.8 vs 17.4 months [p = 0.03], respectively). The better outcome was not doi: 10.1586/14737140.2014.882773

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Table 4. Overall survival according to risk group as given by the International database consortium model for patients with advanced renal cell carcinoma receiving VEGF or its receptor targeted agents†.

The Hellenic Co-operative Oncology Group identified three independent preInitial cohort Overall 645 22 [18] dictors of survival in a series of (Heng et al. [2009]) 109 mRCC patients treated with sunitinib, namely, Eastern Cooperative OncolFavorable 133 (23) NR ogy Group PS, time from diagnosis to Intermediate 301 (51) 27 treatment and number of metastatic sites Poor 152 (26) 8.8 (TABLE 3) [23]. The relevance of these three factors was confirmed in an expanded [19] External validation Overall 672 18.8 development cohort of 170 patients and cohort (Heng et al. [2013]) in an external validation cohort of Favorable 117 (17) 43.2 266 patients [24]. The Hellenic CoIntermediate 347 (52) 22.5 operative Oncology Group model comprises four risk groups (0, 1, 2 or 3 risk Poor 208 (31) 7.8 factors). The group with the poorest † VEGF(R)-targeted agents: sunitinib, sorafenib, axitinib, pazopanib, bevacizumab. ‡ Favorable: 0 factors; intermediate: 1–2 factors; poor: 3–6 factors. prognosis (three risk factors) had a NR: not reached; OS: Overall survival; VEGF(R): VEGF or its receptor. median OS of 5.9 months and showed explained by lesser toxicity in white patients as they in fact no apparent benefit from sunitinib treatment. The c-index was experienced more adverse events (AEs) (mainly dyspepsia 0.712 and 0.634 for the development and external validation and stomatitis) than nonwhites. BM proved to be a strong cohorts, respectively, and compared favorably with the IMDC independent predictor of poor OS (median OS: 16.1 [with c-index of 0.71 [19]. BM] vs 27.8 months [without BM], p < 0.0001). BM was In 2011, Patil et al. identified prognostic factors for PFS and also an independent prognostic factor in patients with OS from a randomized Phase III trial of first-line sunitinib verlong-term OS (‡30 months). On analysis of a subset of sus IFN-a in 375 mRCC patients (TABLE 3) [25]. Independent patients with over 1-year follow-up, belonging to the good predictors of OS were the five 2002 MSKCC criteria and BM. MSKCC risk group and lack of BM or lung metastases pre- The relevance of BM as an independent predictor of OS was dicted long-term response to sunitinib (>18 months) [17]. also observed by Beuselinck et al. [26]. and confirmed by Motzer et al. in their 2013 update [16]. In Beuselinck et al.’s International metastatic database consortium prognostic analysis of 200 cc-mRCC patients treated with sunitinib, which model took account of PS, corrected serum calcium, neutrophils, plaThe International Database Consortium (IMDC) developed telets, time from diagnosis to systemic treatment, number of a prognostic scoring system on the basis of a series of metastatic sites and presence of BM, median PFS and OS were 645 mRCC patients receiving first-line treatment with tar- significantly shorter in patients with than without BM (8.2 vs geted drugs that included sunitinib, sorafenib and bevacizu- 19.1 months for PFS, p < 0.0001; 19.5 vs 38.5 months, mab [18]. Four of the five 2002 MSKCC criteria for OS p < 0.0001 for OS). On multivariate analysis, BM was the were independent predictors of short survival (PS, baseline independent variable most significantly associated with poor hemoglobin, baseline corrected calcium and time from diag- PFS (p < 0.0001) and OS (p = 0.001), after adjusting for the nosis to treatment) as well as elevated baseline neutrophil factors of the IMDC model. and platelet counts (TABLE 3). This model was externally validated in 1028 mRCC patients receiving first-line VEGF(R)- Biological prognostic factors related to inflammation or targeted treatment and has been compared with four prog- hypoxia nostic models developed in the cytokine era [19]. The prede- Potential biological prognostic factors (markers of inflammation fined IMDC risk factors were all independent predictors of and hypoxia-related proteins) in mRCC patients receiving poor OS. OS values obtained in the initial IMDC study VEGF(R)-targeted therapy are listed in TABLE 5 together with and in the external validation study are given in TABLE 4 for survival data. each risk category. The concordance index (c-index) of 0.71 obtained for the IMDC model compared favorably Markers of inflammation with the c-index obtained for the four other tested models: C-reactive protein Cleveland Clinic Foundation model (0.662) [20], French C-reactive protein (CRP) is an early, sensitive and specific marker model (0.640) [21], International Kidney Cancer Working of the inflammatory response produced by the liver. In early group model (0.668) [22] and the 2002 MSKCC model studies in patients with localized RCC, an elevated postnephrec(0.657). tomy CRP level predicted metastatic relapse and poor OS [27–30]. Risk group‡


Other prognostic models: the Hellenic Cooperative Oncology Group model & Patil et al. model

doi: 10.1586/14737140.2014.882773

Patients, n (%)

OS (months)

Ref.

Expert Rev. Anticancer Ther.

Prognostic factors in patients with advanced RCC treated with VEGF-targeted agents

Review

Table 5. Biological prognostic factors of survival for metastatic renal cell carcinoma patients treated by VEGF or its receptor targeted agents. Biological factor

Treatment

p-value of impact of treatment on PFS

OS

Ref.

41

Sunitinib

0.036

nr

[31]

45

Sorafenib

0.046

nr

[32]

52

Sunitinib/sorafenib

nr

0.003

[33]

200

Sunitinib

T

rs2276707

PFS: 10.8 (CC and CT) vs 6.7 (TT)

0.025

[65]

NR1/3

7837 T > G

rs4073054

PFS: 21 (TG and GG) vs 12 (TT) OS: 35 vs 22

0.04 0.03

[66]

NR1/3

CAT copy in the haplotype of the 3 SNP ID from next column

rs2307424 rs2307418 rs4073054

PFS: 13.3 vs 8 if a CAT copy absent in the NR1/3 haplotype

0.017

[65]

FGFR2

906 C > T

rs2981582

PFS: 7.5 (TT) vs 14 (CC)

0.012

[66]

FGFR2

906 C > T

rs2981582

OS: 28 (CC) vs 21.4 (TT)

0.009

[69]

VEGFR3

1480 A > G

rs307826

PFS: 19 (AA) vs 10 (AG and GG) OS: 31 vs 22 resp.

0.002 0.0058

[66]

VEGFR3

1480 A > G

rs307826

PFS: 13.7 (AA) vs 3.6 (AG)

0.0079

[64]

VEGFR3

1480 A > G

rs307826

OS: 26 (AA), 23 (AG), 3.2 (GG)

0.04

[69]

An SNP was selected if at least two studies reported its influence on the outcome of sunitinib therapy in RCC patients. OS: Overall survival; PFS: Progression-free survival; SNP: Single nucleotide polymorphism.

would-be role as predictor of response to sorafenib could be hypothesized as tumors with high CAIX expression were observed to shrink more than those with low CAIX expression (-13 vs +9%, p = 0.005) [60]. However, in a retrospective analysis of data from the TARGET trial, CAIX expression, as measured by immunohistochemistry, had no prognostic value following cytokine therapy nor was it predictive of clinical benefit for treatment with sorafenib [61]. On using an ELISA measurement method, CAIX expression was prognostic of survival in the placebo arm only (p = 0.034), but the relationship was not significant in a multivariate analysis that included MSKCC score and several other biomarkers [55]. Finally, a recent retrospective analysis looking at several cytokine and angiogenic factors including CAIX plasma levels in mRCC patients treated by pazopanib in Phases II and III trials detected no association between CAIX levels and TS or PFS during initial screening of the candidate biomarkers [41]. Molecular & cellular prognostic factors Single nucleotide polymorphisms

The study of inherited genetic variability, especially in genes involved in renal carcinogenesis and in the pharmacokinetics or molecular targets of antiangiogenic therapy, may lead to the development of biomarkers associated with the natural history of RCC or that are predictive of response to targeted therapy. In a recent study, 70 genes involved in the pathogenesis of RCC (including the VHL/HIF/VEGF and PI3K/AKT/mTOR pathways, and genes involved in immune regulation and www.expert-reviews.com

metabolism) were genotyped for single nucleotide polymorphisms (SNPs) in 554 patients with localized RCC who had undergone nephrectomy [62]. The polymorphism rs11762213, which causes a synonymous amino acid change in MET (144G!A, located in exon 2), was associated with recurrencefree survival. Patients with one or two copies of the minor (risk) allele had an increased risk of recurrence or death. MET is the transmembrane TK receptor for hepatocyte growth factor. Activating MET mutations in the TK domain have been identified in patients with type 1 hereditary papillary RCC. MET may also cooperate with VEGFR in promoting tumor growth [63]. Several studies have attempted to link SNPs with response to TKIs (sunitinib or pazopanib) in patients with mRCC (TABLE 6). SNPs in genes involved in sunitinib pharmacokinetics (ABCB1, NR1/2 and NR1/3), sunitinib pharmacodynamics (VEGFR1 and VEGFR3) and VEGF-independent proangiogenic pathways (FGFR2) have been correlated with sunitinib therapeutic outcomes in mRCC patients [64,65]. These SNPs have now been validated as predictors of response to sunitinib [66,67]. In addition, the change in plasma-soluble VEGFR3 concentration on sunitinib administration to mRCC patients has been associated with sunitinib efficacy [52,68]. In patients with advanced RCC receiving pazopanib, SNPs in the ABCB1 and FGFR2 genes have been linked to clinical response [69] and three polymorphisms in IL8 and HIF1A and five polymorphisms in HIF1A, NR1I2 (a regulator of CYP3A4 expression) and VEGFA showed a nominally significant association (p = 0.05) with PFS and clinical response rate, respectively [70]. doi: 10.1586/14737140.2014.882773

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Biomarkers linked to immunosuppression

During cancer development, tumor cells can evade from the antitumor immune response by recruiting immunosuppressive cells (M2 macrophages, regulatory T cells and myeloid-derived suppressive cells). The tumor and its microenvironment can also favor T-cell anergy by inducing the expression of costimulatory molecules (e.g., programmed cell death 1 [PD-1], CTLA) on these cells [71]. Antiangiogenic molecules might reverse some of these immunosuppressive loops [72]. Preliminary studies have indicated that these immune cells might be potential prognostic factors or predictive factors of response to antiangiogenic therapy in RCC. For instance, an increase in blood or tumor Foxp3+ regulatory T cells has been associated with reduced survival in patients with ccRCC [73–75]. Our group has shown that OS is longer in patients with than without a fall in regulatory T cell number during sunitinib therapy [76]. Experimental work has established that the presence of myeloid-derived suppressive cells is associated with resistance to antiangiogenic drugs [77,78]. PD-1 is a costimulatory molecule that is expressed on exhausted or anergic T cells. By binding to its ligand PDL-1, which is overexpressed in RCC, PD-1 delivers a negative signal to T cells [79]. In a series of 268 patients with localized RCC, tumor PDL-1 was significantly associated with metastatic cancer progression, even after adjusting for stage, grade and PS [80]. In line with these results, RCC patients at diagnosis with PD-1+ immune cells were at significantly higher risk of cancer-specific death than PD-1-negative patients [81]. Tumor tissue PDL-1 expression was a positive predictive factor of response to anti-PD-1 monoclonal antibody [82]. Infiltration of T cells in the tumor microenvironment

Infiltration of T cells is related to a poor prognosis in RCC patients [83]. This is in contrast to findings for other solid tumors where intratumoral CD8+ T cells have shown positive prognostic value. In RCC, intratumoral CD8+ T cells, CD4+ T cells and CD45R0 memory T cells were associated with an increased risk of tumor recurrence and with poor OS [84–87]. High intratumoral CD8+ T cell density was associated with short OS in both primary and mRCC, whereas high natural killer (NK) cell infiltration was associated with longer OS [88]. These paradoxical findings would be due to a defect in signaling and cytotoxic molecules in T cells from RCC patients [89,90]. In addition, high VEGF levels in RCC patients directly suppress T cell activation [91]. Sarcomatoid component

Two studies with sizeable patient numbers have revealed that TKIs can show benefit in the treatment of sarcomatoid mRCC but that the benefit might be less than in patients presenting tumors without sarcomatoid dedifferentiation [92,93]: in a study of 43 patients with sarcomatoid mRCC (detected on the primary tumor) receiving VEGF(R)-targeted therapy (sunitinib [n = 21], sorafenib [n = 12], bevacizumab [n = 8] or bevacizumab + sunitinib [n = 2]), PR was observed in 19% of doi: 10.1586/14737140.2014.882773

patients, SD in 49% and early PD in 33% [92]. Median PFS and OS were 5.3 and 11.8 months, respectively. PRs were confined to patients with tumors with 20% of sarcomatoid elements. The trend toward a longer PFS (6.8 vs 4.3 months) and OS (14.9 vs 8.6 months) in the group of patients with