Platelet-derived growth factor receptor inhibitors for non-small cell lung cancer: is the odyssey over?

KEYWORDS:

• Non-small cell lung cancer
• angiogenesis
• platelet-derived growth factor receptor
• tyrosine kinase inhibitors

1. Targeting PDGF pathway in non-small cell lung cancer

Angiogenesis is a complex and dynamic process involving a continuous cross talk of several pathways beyond the universally known vascular endothelial growth factor (VEGF) signaling. Among these, the platelet-derived growth factor (PDGF) signaling pathway, including four polypeptide chains (PDGF-A to PDGF-D) functioning as ligands for two PDGF receptors (PDGFR-α and PDGFR-β), has been demonstrated to play a crucial role in non-small cell lung cancer (NSCLC) aberrant vascularization.[1]

The activation of pathways alternative to the VEGF signaling, such as the fibroblast growth factor (FGF), the hepatocyte growth factor (HGF), and the PDGF pathways, represents a potential mechanism of resistance to anti-VEGF or anti-VEGF receptor (VEGFR) agents, which emerges as a compensatory signaling to overcome the VEGF inhibition.[2] Given the crucial role of angiogenesis in lung cancer development and proliferation, a series of agents targeting simultaneously multiple mediators of this process has been extensively evaluated both in clinical and in preclinical settings. The strategy to concurrently targeting multiple molecules in NSCLC has been developed in order to improve the results obtained with the single inhibition of the VEGF pathway, which resulted to be sometimes statistically significant but often clinically questionable, and to overcome the resistance to anti-VEGF/VEGFR agents.[3] Notwithstanding these premises, controversial and disappointing results have been obtained from clinical trials conducted with tyrosine kinase inhibitors (TKIs) targeting PDGF and other signaling pathways as single agents or in combination with chemotherapy or other TKIs, reflecting the complex biology behind the angiogenesis and the non-oncogene-addicted lung cancer disease.

In this regard, to date, only nintedanib, a potent TKI targeting the PDGFR, VEGFR, and FGF receptor, has been approved on November 2014 by the European Medicines Agency. The approval of nintedanib in combination with docetaxel for second-line treatment of patients affected by locally advanced, locally recurrent, or metastatic NSCLC with adenocarcinoma histology was granted on the basis of the LUME-Lung 1 and 2 phase III trials’ results. Indeed, according to the subgroups analysis of the LUME-Lung 1 study, patients with adenocarcinoma histology experienced a significant median overall survival (OS) improvement of 2.3 months by the combination of nintedanib with docetaxel compared with docetaxel alone (HR: 0.83; 95% confidence interval [CI]: 0.70–0.99; p = 0.04). In the overall study population, only a modest median progression-free survival (PFS, primary end point) benefit (3 weeks) of adding nintedanib to docetaxel was demonstrated (HR: 0.79; 95% CI: 0.68–0.92; p = 0.0019).[4]

In the LUME-Lung 2 trial (early stopped at the preplanned interim analysis for futility), the association of nintedanib with pemetrexed in patients affected by non-squamous NSCLC resulted in a statistically significant improvement of less than a month in PFS (HR: 0.83; 95% CI: 0.70-0.99; p = 0.04).[5] As for the LUME-Lung 1 trial, no difference in OS was detected between arms. To draw definitive conclusions about the impact of nintedanib in association with docetaxel for the second-line treatment of NSCLC patients with adenocarcinoma histology, results from an ongoing phase III trial (LUME-Columbus) should be awaited.

However, even if the LUME-Columbus trial will demonstrate a benefit from the addition of nintedanib to docetaxel, it is necessary to consider that the comparator arm (docetaxel plus placebo) today is no longer the best therapeutic option available for the second-line treatment of advanced NSCLC. Indeed, recent results of clinical trials exploring immunotherapy in pretreated NSCLC patients have demonstrated the superiority of immune checkpoint inhibitors in comparison to docetaxel monotherapy, revolutionizing the standard strategy for this disease setting.

As for nintedanib, based on the encouraging results coming from phase II trials, many other TKIs targeting PDGF and other angiogenetic pathways have been evaluated in phase III trials conducted in advanced NSCLC, both in first-line setting and after disease progression (Table 1). However, all these agents failed to demonstrate a sufficient outcome benefit to be included in the therapeutic strategy for NSCLC. For example, the ESCAPE and the NEXUS trials, investigating sorafenib in combination with cytotoxic agents in first-line setting, did not meet the primary end point of prolonging OS in comparison to chemotherapy alone.[6,7] Similarly, cediranib and motesanib failed to show a survival benefit when added to carboplatin and paclitaxel as first-line therapy.[8,9]

Table 1. Completed phase III trials with anti-platelet-derived growth factor receptor (PDGFR) agents for NSCLC.

Agent	Trial	Histology	Setting	Arms	N pts	Primary end point	Primary end point (medians in months)	HR (p-value)
Nintedanib	LUME-Lung 1	NSCLC	2nd line	Docetaxel + nintedanib	655	PFS	3.4	0.79 (p = 0.002)
				Docetaxel + placebo	659		2.7
	LUME-Lung 2	Non-squamous	2nd line	Pemetrexed + nintedanib	353	PFS	4.4	0.83 (p = 0.043)
				Pemetrexed + placebo	360		3.6
Sorafenib	ESCAPE	NSCLC	1st line	Carboplatin/paclitaxel + sorafenib	464	OS	10.7	1.15 (p = 0.915)
				Carboplatin/paclitaxel + placebo	462		10.6
	NEXUS	Non-squamous	1st line	Cisplatin/Gemcitabine + Sorafenib	385	OS	12.4	0.98 (p = 0.401)
				Cisplatin/Gemcitabine	387		12.5
	MISSION	Non-squamous*	3rd–4th line	Sorafenib	350	OS	8.2	0.99 (p = 0.47)
				Placebo	353		8.3
Cediranib	BR29	NSCLC	1st line	Carboplatin/paclitaxel + cediranib	153	OS	12.2	0.94 (p = 0.72)
				Carboplatin/paclitaxel + placebo	153		12.1
Sunitinib	SUN1087	NSCLC	2nd–3rd line	Erlotinib + Sunitinib	480	OS	9.0	0.92 (p = 0.139)
				Erlotinib	480		8.5
Pazopanib	EORTC 08092	NSCLC	Switch	Pazopanib	50	OS	17.4	0.72 (p = 0.257)
			Maintenance	Placebo	52		12.3
Motesanib	MONET1	Non-Squamous	1st line	Carboplatin/paclitaxel + motesanib	541	OS	13.0	0.90 (p = 0.14)
				Carboplatin/paclitaxel + placebo	549		11.0
		Squamous	1st line	Carboplatin/paclitaxel + motesanib	182	OS	11.1	0.89 (p = 0.031)
				Carboplatin/paclitaxel + placebo	178		10.7

N pts: number of patients; HR: hazard ratio; NSCLC: non-small cell lung cancer; PFS: progression-free survival; OS: overall survival.

*Predominantly.

Recently, a further failure of motesanib was beforehand announced by its pharmaceutical company since that the phase III MONET-A study, including Asian patients with advanced non-squamous NSCLC randomized to motesanib in combination with carboplatin and paclitaxel or chemotherapy alone, did not meet the primary end point of improving PFS. The MONET-A trial started among Asian patients, following the completion of a previous phase III trial (MONET1) which compared motesanib in combination with carboplatin and paclitaxel versus placebo in patients with non-squamous NSCLC. Although the MONET1 trial failed to demonstrate a statistically significant improvement in OS, a subgroup preplanned analysis revealed a significant benefit in term of response rate, PFS, and OS in the Asian population, providing the rationale for further investigation in the MONET-A trial.[9] In the context of pretreated patients with NSCLC, sorafenib and sunitinib employing as single agent did not improve OS compared with placebo or erlotinib, respectively.[10,11]

Moreover, the employment of anti-PDGFR agents has been also adopted in the context of the switch maintenance strategy. In this regard, a phase III trial evaluating pazopanib following a platinum-based chemotherapy has been early stopped for futility due to the lack of PFS improvement at an interim analysis.[12]

Besides these anti-PDGFR drugs investigated in phase III trials, new agents are currently under investigation in phase I and II studies both as single agents and in combination with chemotherapy or other target agents in NSCLC, including dovitinib, imatinib, lenvatinib, linifanib, lucitanib, and vatalanib.[13] More recently, given the promising results obtained with immunotherapy in both hematological and solid tumors, a phase Ib/II trial of lenvatinib plus an anti-programmed death receptor-1 agent (pembrolizumab) in patients with solid tumor, including NSCLC, is currently ongoing. With regard to the preclinical setting, the anticancer activity of specific inhibitors of PDGFR, such as tyrphostin AG1296, is currently under evaluation in different tumor type cells.

As previously mentioned, although the whole mechanism of bevacizumab resistance remains unclear, presumable factors include increased expression of VEGF/VEGFR and the development of non-VEGF-dependent mechanisms of stimulating tumor vascular growth. In this regard, a trial with anti-PDGRF agent (pazopanib), conducted in the context of patients with metastatic non-squamous NSCLC who progressed during a bevacizumab-containing therapy, showed a limited activity, emphasizing once again the need of additional efforts to clarify the underlying mechanisms of tumor angiogenesis.

In order to increase the narrowed therapeutic window obtained with the anti-PDGFR agents in the context of an unselected NSCLC population, many investments have been spearheaded to identify reliable predictive factors for these agents. Unfortunately, to date, no validated specific biomarkers are able to identify those patients most likely to benefit from these antiangiogenic-targeted therapies for clinical practice. Among putative biomarkers, baseline serum angiotensin-converting enzyme and VEGFR levels may be predictive of benefit from the addition of cediranib to chemotherapy. Indeed, according to an exploratory analysis of the BR24 trial, NSCLC patients with low-angiotensin-converting enzyme and soluble VEGFR-2 and VEGFR-3 levels showed a survival benefit when receiving cediranib, underlying a potential role of the renin–angiotensin–aldosterone system in the angiogenesis regulation.[14]

A similar predictive value of baseline serum-soluble VEGFR-2 and VEGFR-3 levels has been identified in an exploratory analysis of patient samples from randomized studies of chemotherapy with and without cediranib in colorectal cancer and sunitinib treatment in renal cell carcinoma, respectively. With regard to the predictive value of the fluctuation in the biomarker levels during anti-PDGFR treatments, in the retrospective analysis of the BR24 trial an increase in VEGF-A and a decrease in serum VEGFR-2 or VEGFR-3 levels from baseline to on-treatment may be predictive of better outcome from cediranib plus chemotherapy compared with chemotherapy alone.[14]

2. Conclusion

The strategy to targeting the PDGF pathway, by anti-PDGFR agents adopted as single agents or in combination with chemotherapy or other target agents, has not changed the natural history of NSCLC. The absence of predictive specific biomarkers calls for additional efforts to better understand the underlying mechanisms of tumor angiogenesis and to select patients more benefit from a specific PDGF inhibitor, based on reliable biomarkers.

3. Expert opinion

Although promising evidences of activity emerged in preclinical setting and early phase trials, to date, the anti-PDGFR agents did not significantly affect the survival of NSCLC patients. In addition, the modestly positive results of nintedanib in terms of OS in the LUME-Lung 1 trial should be anyway considered in the context of an exploratory analysis. Indeed, given the exiguity of the benefit and the cost of the combination of nintedanib with docetaxel, the National Institute for Health and Care Excellence (NICE) agency turned down the approval.

Moreover, it should be emphasized that the addition of these TKIs to chemotherapy usually increases the adverse event rate, a matter not certainly negligible in the context of patients affected by NSCLC. In this regard, the addition of nintedanib in both LUME-Lung trials caused a higher rate of gastrointestinal toxicities (e.g. in LUME-Lung 1, diarrhea in the experimental arm was 42.3% versus 21.8% for single-agent docetaxel), elevation of liver enzymes and hematological side effects, whereas the incidence of side effects usually related to antiangiogenic agents (such as hypertension, bleeding, and thrombosis) did not differ between the two arms. Moreover, in a meta-analysis of randomized clinical trials including patients with any primary tumor type, the use of antiangiogenic TKIs was associated with an increased risk of fatal adverse events (1.5%) compared with control arm (0.7%, relative risk of 2.23 [95% CI: 1.12–4.44; p = 0.023]).[15]

Nowadays, the identification and validation of predictive biomarkers of benefit (or resistance) for angiogenesis inhibition represent the main challenges of current translational research.

Only a careful selection of patients based on reliable biomarkers could finally stop the odyssey of poor results obtained with anti-PDGFR agents, sparing cost and class toxicities for patients that will not benefit from antiangiogenic agents. In this regard, the preclinical evidences that potent and selective PDGFR inhibitors, such as crenolanib, are able to inhibit the growth of NSCLC cells, suggest the hypothesis to investigate these agents in the specific context of NSCLC patients with deregulated PDGF signaling.[16]

The difficulty in identifying a biomarker for antiangiogenic agents might be linked to the dynamism of the angiogenesis process where multiple signaling pathways cooperate with each other, resulting in continuous escape mechanisms. A future prospective includes also the combination of antiangiogenic treatment with the immunotherapy, the targeted inhibition of epidermal growth factor receptor and other molecular alterations already included in NSCLC therapeutic strategy.

Declaration of interest

The authors are supported by a grant of the Italian Association for Cancer Research (AIRC-MFAG 14282) and a Fellowship Award of the International Association for the Study of Lung Cancer (IASLC). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.