Dual VEGF- and Erb-receptor inhibition as an improved strategy for treating cancer

The overlapping fields of angiogenesis and growth factor biology represent two extensively investigated areas of modern day oncology (see Innovative Cancer Therapies: Targeted therapy, a clinical and commercial revolution) and the recent success of Avastin, a monoclonal antibody that binds to and neutralizes one such growth factor, VEGF has not only resulted in the introduction of an effective clinical tool for the treatment of cancer but it also helped spark a wave of optimism in the angiogenesis inhibitor arena.

Avastin (bevacizumab), developed by Genentech/Roche's, gained US approval in 2004 as a first-line treatment for metastatic colorectal cancer in combination with intravenous 5-FU-based chemotherapy. This was followed closely by European approval. Fourth-quarter financial results reported sales of Avastin to be approximately $200 million, a figure expected to swell to peak sales of between $845.3 million and $1.7 billion following its recent European approval. Within the past few months Genentech and Roche also announced that a Phase III study of Avastin plus paclitaxel chemotherapy in first-line metastatic breast cancer met its primary efficacy endpoint of improving progression-free survival, compared to chemotherapy alone. Results from an interim analysis of this study showed that patients receiving Avastin plus paclitaxel doubled the duration of surviving without cancer progression to 11 months compared to 6 months in women receiving paclitaxel alone. This was the first successful study to show that angiogenesis inhibitors can result in improved outcomes for women with first-line metastatic breast cancer and therefore broadens the potential indications for Avastin and possibly angiogenesis inhibitors in general.

Following on from the success of Avastin, researchers have attempted to target VEGF regulation of angiogenesis through a number of other approaches. The intentions of the scientific community have been to develop more specific ways of targeting VEGF as well as small molecule therapeutics rather than relying on antibody approaches.

Avastin acts systemically to neutralize VEGF both in the vicinity of the tumor and away from the tumor mileau. This relative non-selectivity could impact on side effect profiles. VEGF is known to play a role in wound healing and also has a number of effects on cardiovascular homeostasis and of note the Avastin box label warns of possible gastrointestinal perforation and wound dehiscence (wound rupture), in some instances resulting in fatality. Likewise serious, and in some cases fatal, hemoptysis (blood in the sputum) is noted in patients with non-small cell lung cancer treated with chemotherapy and Avastin.

VEGF binds to at least three receptors including VEGFR-1 (Flt-1), VEGFR-2 (KDR/flk-1) and VEGFR-3 (Flt-4). VEGFR-3 is mainly expressed on lymphatic endothelium and now though to be involved in metastasis. VEGFR-2 is exclusively expressed in endothelial cells and appears to play a pivotal role in endothelial cell differentiation and vasculogenesis. VEGF, which is up-regulated under the hypoxic conditions found within tumors, bind to and causes the dimerization of receptors on endothelial cells thereby activating receptor tyrosine kinase and consequently intracellular signaling pathways. The inhibition of VEGF receptor kinase activity has been advanced as an approach to the treatment of cancer. This has resulted in the development by Novartis and Schering of PTK 787/ZK 222584 (PTK/ZK) an inhibitor of VEGFR tyrosine kinase activity. This compound was seen, at least until recently, as providing the major competition for Avastin (see Colorectal Cancer - Avastin and Erbitux Pave The Way For Pipeline Targeted Therapies).

PTK/ZK not only inhibits VEGFR1 and VEGGFR2, receptors, it also inhibits the lymphangiogenic VEGFR3 and data from phase I/II clinical trials of PTK/ZK as a monotherapy suggested a positive safety and tolerability profile. Preliminary response, time to progression, and overall survival data were also promising.

Following demonstrations of safety in phase I/II trials the CONFIRM 1 and CONFIRM 2 phase III trials were initiated. Data from CONFIRM 1, a study investigating the effect of adding PTK/ZK to the chemotherapy regimen oxaliplatin/5FU/LV (FOLFOX-4), was reported in March 2005. These data demonstrated that although the progression free survival of previously untreated patients as assessed by central radiology review (the primary end-point) did not achieve statistical significance, progression-free survival as assessed by investigators did.

Data from CONFIRM 2 announced in July 2005 demonstrated that the primary endpoint of overall survival is unlikely to achieve statistical significance (for the press release and our editorial click here). Progression free survival of patients who progressed after irinotecan-based chemotherapy was, however, improved in patients with high lactate dehydrogenase (LDH) levels, a cohort that is considered to have a poor prognosis.  This improved efficacy was also observed in patients with high LDH levels in the CONFIRM 1 trial.

The CONFIRM 2 study is continuing with further results expected in mid-2006 however Schering and Novartis will review the regulatory filing strategy and timeline in view of data from the CONFIRM studies. Schering was forecasting combined sales of 2 billion Euros a year for PTK/ZK before CONFIRM 1 data were announced in March. However analysts had been more wary and after this announcement warier still slashing forecasts to 160 million Euros. The most recent data from CONFIRM 2 have prompted one analyst at Landesbank Rheinland-Pfalz to go as far as to claim that development of PTK/ZK will be terminated.

The modest activity of PTK/ZK in the CONFIRM studies may point to VEGF receptor kinase inhibition, on its own, being insufficient as a therapeutic approach. In the Clin Cancer Res study highlighted here Novartis researchers investigate the concept of simultaneously reducing VEGF release and receptor activity. An interesting observation reported by Sini and colleagues in this paper is that PTK/ZK causes a transient increase in serum VEGF levels in mice with human prostate cancer xenografts. This phenomenon has also been reported in phase I trials of patients with colorectal cancer and moreover this increase has been suggested as a biomarker of drug activity since the compensatory overexpression of VEGF was found to correlate with non-progressive disease over 2 months (Drevs et al, 2005). Although overexpression appears to be an indicator of PTK/ZK hitting its target, the possibility that increased levels of serum VEGF may blunt its survival advantage should be considered; this will depend on whether the ability of PTK/ZK to prevent the bioactivity of VEGF negates the potential increase in activity resulting from overexpression.

The Novartis group go on to report that blocking the EGF receptor (EGFR; ErbB1) prevents the release of VEGF by tumors and blunts elevation of serum VEGF induced by PTK/ZK and also that ErbB1 inhibition increased the efficacy of PTK/ZK.

Inhibiting the ErbB family of receptor tyrosine kinases already been demonstrated as a possible approach to cancer. This family has at least four members: ErbB1, ErbB2 (HER-2/neu), ErbB3 (HER3), and ErbB4 (HER4). ErbB1 and ErbB2 have been implicated in multiple types of human cancer, where they control proliferation, survival, and spread of metastatic cancer cells. Antagonistic monoclonal antibodies and small-molecule tyrosine kinase inhibitors of ErbB1 have shown clinical efficacy. Among these, AstraZeneca's ZD1839 (Iressa) and Novartis' PKI166 are orally active ErbB1 and ErbB1/ErbB2 TK inhibitors, respectively. ZD1839 induced durable responses in patients with various tumor types and its sale was approved in the United States and Japan. Disappointingly however a survival advantage was not demonstrated in further studies and AstraZeneca withdrew its European application for Iressa.

In addition to playing a role in tumor cell proliferation, a link has been demonstrated between angiogenesis and ErbB receptor signaling. ErbB1 impacts on the survival of endothelial cells and its blockade prevents their release of VEGF. In their study the Novartis group report that in addition to blunting the effect of PTK/ZK on VEGF levels and reducing the proliferation of prostate cancer cells, ZD1839 has direct anti-angiogenic activity. In particular, ZD1839 was found to reduce the proliferation and survival of endothelial cells.

This important study demonstrates the ability of ErbB1 inhibition to inhibit the proliferation of endothelial cells thereby having a direct effect on angiogenesis. The therapeutic use of drugs from this class may therefore directly reduce tumor growth while simultaneously inhibiting angiogensis. On the basis of the present study this class would also be expected to cooperate with VEGF receptor inhibitors, reversing compensatory VEGF overexpression and enhancing their anticancer activity. Given the promising initial studies of ZD1839 and PTK/ZK but then their subsequent failure in pivotal survival trials clinical studies evaluating the two compounds in a combinatorial setting may be of interest. Perhaps even more exciting would be the development of a dual VEGFR/ErbB1 inhibitor. Of particular note in this respect, Novartis Oncology is developing a kinase inhibitor known as AEE788 which inhibits ErbB1, HER2, and VEGFR. This molecule is currently in phase I clinical development and further development may improve on both Avastin and PTK/ZK.

Source: LeadDiscovery's TherapeuticAdvances - original article Clin Cancer Res. 2005 Jun 15;11(12):4521-32 featured in DailyUpdates-Oncology