Sorafenib for lung cancer: is the “Battle” still open?

Abstract

In the recent years, the improved understanding of the biological relevance of angiogenesis as a major cancer hallmark led to the development of a heterogeneous group of agents targeting this key process. Among the anti-angiogenic drugs (including monoclonal antibodies such as Bevacizumab, and other molecules with different mechanism of action, such as the vascular disrupting agents Vadimezan), the tyrosine kinase inhibitors (TKIs, Sorafenib, Sunitinib, Pazopanib, and Axitinib), are commonly thought to inhibit angiogenesis through a most rational and promising approach. In this regard, many tyrosine kinase inibitors, such as Sorafenib, are multi-targeted, which allows for the inhibition of those multiple functional pathways which are considered to be critical for both tumor development and progression. Besides, this multi-targeted activity may theoretically increase efficacy but also toxicity. As a member of this group, Sorafenib has already been approved for the treatment of advanced renal cell carcinoma (RCC) and hepatocellular carcinoma not suitable for locoregional treatment, and it is currently under investigation for advanced non small cell lung cancer (NSCLC), either alone or in combination with other biological/cytotoxic agents.

Keywords::

• advanced renal cell carcinoma
• angiogenesis
• lung cancer
• Sorafenib
• tyrosine kinase inhibitors

Although is clearly established that angiogenesis plays a leading role in the progression of non small cell lung cancer (NSCLC), how each factor is involved in the overall process and which is its relative weight, is far to be completely understood. The role of angiogenic factors as prognosis predictors has been evaluated only in few studies, often limited by a small sample size and a retrospective nature. Vascular endothelial growth factor (VEGF) represents the main physiological and pathological inducer of the angiogenic process. Although with conflicting results, VEGF overexpression resulted to be a negative prognostic indicator in NSCLC patients for overall survival (OS), progression free survival (PFS), and lymph node metastasis as survival surrogates. More recently, single-nucleotide polymorphisms (SNPs), derived from an alternative splicing process of the VEGF gene were investigated as prognostic predictors; in particular, the high expression of VEGF189 (VEGF 189 mRNA isoform) has been significantly correlated with early disease recurrence and poor survival in surgically treated NSCLC patients. Even if convincing evidences are not available to date, with regard to VEGF receptors (VEGFR), the concurrent overexpression of 3 soluble proteins (VEGF, VEGFR-1 and -2) represents an independent predictive pattern for disease progression.

Other pro-angiogenic molecules, members of fibroblastic growth factor (FGF, especially bFGF) and platelet-derived growth factor (PDGF) families have been demonstrated to be negatively correlated with survival in NSCLC patients. Microvessel density (MVD), an immunohistochemistry (IHC) marker, represents a morphologic alternative to circulating biomarkers for the detection and quantification of angiogenic activity, even if limited by its intrinsic “invasive” nature and by the lack of standardized methods of evaluation. Other molecules, belonging to tumor-inflammatory microenvironment (interleukins), to epithelial mesenchymal transition process (epithelial- and neural-cadherin), microRNAs and some angiogenesis inhibitors (angiostatin and endostatin), are still under investigation as survival predictors in NSCLC.

The efficacy of anti-angiogenic agents in NSCLC patients has been investigated in Phase-III trials (Table 1).

Table 1. Completed Phase-III trials with anti-angiogenic agents for NSCLC.

Trial	Setting	N pts	Arms	Primary Endpoint		HR (p-value)
Escape	1st line	464	Carboplatin/Paclitaxel + Sorafenib	OS	10.7 mo	1.15 (0.915)
		462	Carboplatin/Paclitaxel		10.6 mo
Nexus	1st line non-squamous	385	Gemcitabine/Cisplatin + Sorafenib	OS	12.4 mo	0.98 (0.401)
		387	Gemcitabine/Cisplatin		12.5 mo
E4599	1st line	434	Carboplatin/Paclitaxel + Bevacizumab	OS	12.3 mo	0.79 (0.003)
		444	Carboplatin/Paclitaxel		10.3 mo
Avail	1st line	345	Cisplatin/Gemcitabine + Bevacizumab7.5	PFS	6.7 mo	0.75 (0.003)
		351	Cisplatin/Gemcitabine + Bevacizumab15		6.5 mo	0.82 (0.03)
		347	Cisplatin/Gemcitabine		6.1 mo
Beta	2nd line	319	Erlotinib + Bevacizumab	OS	9.3 mo	0.97 (0.7583)
		317	Erlotinib		9.2 mo
Atlas	Maintenance	370	Erlotinib + Bevacizumab	PFS	4.8 mo	0.722 (0.0012)
		373	Bevacizumab		3.7 mo
Avaperl-1	Maintenance	128	Pemetrexed + Bevacizumab	PFS	10.2 mo	0.50 (< 0.001)
		125	Bevacizumab		6.6 mo
Sun1087	Refractory	480	Erlotinib + Sunitinib	OS	9.0 mo	0.922 (0.1388)
		480	Erlotinib		8.5 mo
Zodiac	2nd line	694	Docetaxel + Vandetanib	PFS	4.0 mo	0.79 (< 0.0001)
		697	Docetaxel		3.2 mo
Zeal	2nd line	256	Pemetrexed + Vandetanib	PFS	17.6 mo	0.86 (0.108)
		278	Pemetrexed		11.9 mo
Zest	Refractory	623	Vandetanib	PFS	2.6 mo	0.98 (0.721)
		617	Erlotinib		2.0 mo
Zephyr	Refractory, prior EGFR TKI	617	Vandetanib	OS	8.5 mo	0.95 (0.527)
		307	Placebo		7.8 mo
Vital	2nd line	456	Docetaxel + Aflibercept	OS	10.05 mo	1.01 (0.8985)
		457	Docetaxel		10.41 mo
Attract-1	1st line	649	Carboplatin/Paclitaxel + Vadimezan	OS	13.4 mo	1.01 (0.535)
		650	Carboplatin/Paclitaxel		12.7 mo
Monet-1	1st line non-squamous	541	Carboplatin/Paclitaxel + Motesanib	OS	13.0 mo	0.90 (0.14)
		549	Carboplatin/Paclitaxel		11.0 mo

HR: Hazard ratio; mo: Months; N: Number; OS: Overall survival; PFS: Progression free survival; pts: Patients.

Sorafenib in combination with cytotoxic agents for the treatment of NSCLC patients failed to demonstrate a significant survival benefit in two Phase-III studies, as reported in the review herein published [1]. The ESCAPE trial randomized 926 patients with advanced NSCLC to receive Carboplatin and Paclitaxel with or without Sorafenib in first-line therapy. A planned interim analysis showed no significant differences between the treatment arms in OS, the primary endpoint (10.7 vs. 10.6 months; HR 1.15; 95% CI, 0.94 – 1.41; p = 0.915), nor in PFS (4.6 vs. 5.4 months) and response rate (RR) (24 vs. 27%), leading to the premature stopping of the trial. Furthermore, the study revealed that squamous cell histology treated with Sorafenib and chemotherapy had an increased risk of death, with a greater incidence of fatal bleeding compared with chemotherapy alone [2]. The Phase-III NEXUS trial evaluated Sorafenib in combination with Gemcitabine and Cisplatin in non-squamous NSCLC patients. Although demonstrating a significant benefit in PFS (HR 0.83; 95% CI, 0.71 – 0.97) and time to progression (TTP; HR 0.73; 95% CI, 0.60 – 0.88), the study did not meet the primary endpoint of prolonging OS compared with chemotherapy alone (HR 0.98; 95% CI, 0.83 – 1.16) [3].

Conflicting results derive from the combination of Sorafenib with other target agents, in particular epithelial growth factor receptors (EGFR) inhibitors such as Gefitinib and Erlotinib [4,5]. In this context, only a weak evidence of activity was demonstrated, even if the combining target therapy with Sorafenib and Erlotinib may represent an alternative therapeutic strategy for those patients harboring wild-type EGFR [6]. At the end, the most promising approach seems to be the use of Sorafenib as single agent, particularly in previously treated NSCLC patients. Based on the encouraging results of some Phase-II trials [7,8], a randomized, placebo-controlled, Phase-III study (NCT00863746 MISSION trial) was designed to compare single agent Sorafenib with placebo in heavily pretreated patients with predominantly non-squamous histology (http://clinicaltrials.gov/). An update recently released by the manufacturer announced the data to be negative.

Results obtained with other anti-angiogenic agents are not more cheering. Bevacizumab represents the only anti-angiogenic agent approved by the Food and Drug Administration (FDA), in combination with Carboplatin and Paclitaxel, for the first-line therapy in patients with non-squamous NSCLC. Further studies extensively evaluated the efficacy of Bevacizumab with other cytotoxic agents or TKIs in different treatment settings (subsequent lines or maintenance): the amount of the clinical benefit achieved with the addition of Bevacizumab to the standard treatment of an unselected NSCLC population, when present, is modest and frequently limited in time for the onset of resistance mechanism. Similar weak evidences derive from the Phase-III investigation of other anti-angiogenic agents, Sunitinib, Vandetanib, Aflibercept, Vadimezan, and Motesanib, as shown in Table 1. In addition, promising data are provided in the early phases by nintedanib (BIBF 1120) [9], which targets VEGFR, PDGFR, and FGFR as well; two Phase-III trials are ongoing to determine its efficacy for second-line treatment (LUME-Lung 1 and 2).

The paucity of relevant efficacy results could be explained considering that although angiogenesis plays a major role in the progression of NSCLC, the narrowed risk/benefit ratio of anti-angiogenic agents leads to a minimal, although sometimes significant, clinical benefit in unselected populations, burdened by a relevant toxicity. In this context, the identification and validation of biomarkers able to predict clinical outcome, sensitivity, early response or resistance to anti-angiogenic agents, are strongly required. The biomarker validation process, which should always guarantee basic biomarkers features (high sensitivity, specificity, reproducibility, applicability, and clinical relevance) is often limited by the retrospective nature of small size studies, allowed to identify few potential reliable biomarkers, starting from a large amount of putative candidates.

Considering the intrinsic “angiogenic character” of RCC, it represents an ideal model to evaluate the possible role of specific molecules as predictors of efficacy for anti-angiogenic drugs. In this regard, IL-8 overexpression has been associated with resistance to Sunitinib [10], whereas high levels of some angiogenic SNPs (VEGFA, VEGFR3) were associated with a reduced clinical benefit deriving from Pazopanib therapy [11]. In advanced RCC patients treated with Sorafenib, the analysis of cytokines and angiogenic factors (CAFs) expression identified molecules (osteopontin, VEGF, VEGFR2, carbonic anhydrase 9, collagen IV, and tumor necrosis factor-related apoptosis-inducing ligand), whose expression levels correlated with the magnitude of PFS benefit achieved with Sorafenib [12].

In NSCLC setting, few evidences regarding the potential role of biological predictors of outcome are available. An exploratory analysis evaluated the possible prognostic and predictive role of angiogenic factors in the E4599 trial (VEGF, bFGF, E-selectin, intercellular adhesion molecular-1, ICAM-1) [13]: low ICAM-1 levels were significantly correlated with response rate (Low 32 vs. High 14%, p = 0.02, regardless of treatment), and survival(p = 0.00005); high VEGF was significantly associated with an higher chance of response to Bevacizumab (33 vs. 7.7%, p = 0.01).

The impact of baseline level of VEGF was retrospectively investigated in patients enrolled in three Phase-II studies involving Vandetanib in combination with other cytotoxic/biological agents [14]. Although interesting from a notional point of view, these results were derived from an exploratory analysis and, thereby, they are statistically unpowered and require prospective validation. As clearly reported in the review by [1], those clinical studies employing Sorafenib for advanced NSCLC demonstrated a significant activity, particularly as single agent; this benefit might be potentially enhanced by identifying the subgroup of patients more likely to benefit from this TKI. With such intent, the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) study remarks that the mutational status of KRAS and EGFR may represent a potential biomarker for anti-angiogenic agents. Interestingly, Sorafenib demonstrated a surprising disease control rate (DCR) of 79% compared with 14% with Erlotinib, in those patients harboring KRAS mutation (p = 0.016) [15]. In relation to the EGFR mutational status, Sorafenib had a worse DCR in EGFR mutated patients, compared with other TKIs (p = 0.01), but in EGFR wild-type patients it contributes to a more relevant clinical benefit [6]. Those few evidences regarding the predictive power of bFGF and VEGF SNPs need to be further investigated.

The nature of the angiogenic stimulus, based on a complex interaction among multiple signaling and cross-talking pathways makes difficult the identification of those driving mutation yielding an oncogene-addiction to the neoplastic process, and, on the other hand, it facilitates the onset of resistance mechanisms. The multi-target strategy (with a single TKI or a combination of them) might partially overcome these hurdles, by blocking different functional pathways or the same pathway at different levels. However, taking into account the narrowed “therapeutic window” of these agents, the identification of subsets of patients with biological/molecular features favoring the activity of a particular agents, is dramatically necessary, taking into account the peculiar safety profile of such drugs (i.e., hypertension, cardiovascular side effects), which further limit their administration in lung cancer patients, whereas significant comorbidities are common and significantly prognostic. The BATTLE trial may be clearly labeled as a proof of principle that the early molecular selection of patients on the basis of validated predictive biomarkers could also “rehabilitate” drugs, such as Sorafenib, lacking relevant efficacy results in unselected population.

Declaration of interest

The authors are supported by grants from AIRC (IG 11930) and from MIUR-PRIN (2009X23L78_005).