BRUSSELS—Striking responses to a new drug targeting insulin-like growth factor (IGF) have been achieved in patients with locally advanced bulky squamous non-small-cell lung cancer (NSCLC) in a Phase II study reported here at the European Congress on Lung Cancer.
There was also a marked improvement of overall response rates in the study of patients with locally advanced or metastatic NSCLC of any histology randomized to receive standard carboplatin/paclitaxel chemotherapy with or without the addition of IGF type 1 receptor (IGF-1R) inhibitor figitumomab, also known as CP-751,871.
Silvia Novello, MD, PhD, from the Thoracic Oncology Unit at the University of Turin and the Department of Clinical and Biological Sciences in San Luigi Hospital in Orbassano, Italy, gave an early report of the study's findings to a satellite symposium of the Brussels congress ahead of publication in the Journal of Clinical Oncology.
She said that 13 out of 18 patients with squamous cell carcinoma (78%) responded to treatment in the arm that included figitumomab—a fully human IgG2 monoclonal antibody that her group is investigating jointly with teams from the University of Texas M. D. Anderson Cancer Center, Virgen del Rocio University in Seville, Turin University, Mayo Clinic, Arizona Cancer Center, Catalan Institute of Oncology in Barcelona, West Clinic in Memphis, and Fox Chase Cancer Center in Philadelphia.
Dr. Novello said the agent represents a new class of targeted therapy that appears to be at least as powerful as the molecular agents already validated for treating cancer such as those targeting the epidermal growth factor receptor (EGF-R) and vascular endothelial growth factor receptor (VEGF-F) pathways, and that its benefit appears to be additive—or even synergistic—to the other molecular drugs—opening up the possibility of combining it with them or using it as an alternative therapy to overcome resistance.
In an interview during the Brussels meeting she called IGF one of the most critical molecules for tumor growth, and explained why it was considered important in non-small-cell lung cancer and other malignancies: “Our interest is due to the fact that there is overexpression of IGF-1 receptor in lung cancer. So our first approach was to find a monoclonal antibody directed to the ligand to block this kind of signal. Another possibility was to use a small molecule to block—downregulate—this kind of receptor.”
There was evidence from other studies, she continued, that monoclonal antibodies were more effective in this role than small molecule inhibitors are because monoclonal antibodies are more specific for the IGF-1 receptor.
In the study, 150 patients were randomized to receive standard paclitaxel (T) at a dose of 200mg/m2 plus carboplatin (C) with an area under the curve (AUC) of 6 as a two-drug comparator regimen or the same combination with either of two doses of figitumomab (I): 10 or 20 mg/Kg every three weeks for up to six cycles.
After this, patients who had a response or stable disease were eligible to continue with figitumomab monotherapy until disease progression. Patients whose disease progressed after having TC alone were also eligible to receive figitumomab as a single agent or in combination with TC at the judgment of the investigator.
The median number of treatment cycles was four, and the TCI regimen was well tolerated with acceptable Grade 3/4 toxicities: hyperglycemia increased form 4% (TC) to 11% (TCI); fatigue was little changed at 9% (TC) compared with 7% (TCI); and there was no difference in neutropenia with an incidence of 14% (for both TC and TCI).
The objective response rate went up with the inclusion of figitumomab: from 41% (21 of 58 patients) on TC alone to 54% with TCI (52 of 97 patients). All but five out of the 18 patients receiving TCI who had squamous cell carcinoma responded to treatment; and there were six “striking responses” in patients with bulky disease, she said.
One patient with squamous cell disease had a rapid resolution of a superior vena cava obstruction after a single dose of TCI. The objective response rate was 78% in patients with squamous histology receiving the higher dose (20 mg/Kg) of figitumomab.
“Because at one point of the study there were good results on squamous carcinoma, there was an amendment: We decided to design a ‘step three’ only for patients with squamous carcinoma. All of them were treated with carboplatin/paclitaxel plus figitumomab.”
It was clear that the responses to the IGF-1R inhibitor were better among patients whose tumors had higher expression of the IGF tumor marker. Response was higher in squamous NSCLC than in adenocarcinoma, and was low in tumors with very low expression of the IGF-1R (in “not otherwise specified” [NOS] tumors).
Dr. Novello said that this knowledge has guided the design of the ongoing randomized Phase III ADVIGO 1016 study in which patients with non-adenocarcinoma NSCLC receive carboplatin/paclitaxel therapy first-line with or without figitumomab. The study is designed to discover whether the promise of figitumomab revealed from the Phase II study will be fulfilled.
Dr. Novello said she believes that the good responses seen in squamous cell carcinoma bode well for the ADVIGO study: “The interesting point is that the response rate was higher. And the quality of response was different from what we normally see in our clinical practices—nine out of 14 patients with squamous carcinoma got an improvement of more than 30 percent in the primary tumor. This is uncommon for lung cancer, and uncommon for squamous carcinoma.”
Relevance of ‘Cross Talk’
Dr. Novello also drew attention to the relevance of “cross talk” between the different molecular pathways available to manipulate cancer cell growth, any of which could be used to complement each other in therapy: “We have to remember that all pathways could have cross talk between them—for instance, with the IGF-1 receptor there is cross talk with EGFR pathways. This is why there is an ongoing trial in second-line, using the IGF monoclonal antibody and an EGFR inhibitor together.”
Biological Mechanisms of IGF Signaling
Also at the Brussels symposium Adrian V. Lee, PhD, Associate Professor in the Department of Molecular and Cellular Biology at Baylor College of Medicine, discussed the known facts about the biological mechanisms of IGF signaling in cancer, showing that:
* IGFs are potent mitogens and thus are survival factors for cancer cells.
* Circulating levels of IGF-1R predict the risk of lung, breast, prostate, and colon cancers.
* IGF-1R is overexpressed and hyperactive in many tumors.
* IGF-1R can cause resistance to anti-cancer therapies—so blocking it can be a help.
* IGF molecular “signature” is associated with poor prognosis (JCO 2008;26:4078–4085).
IGF-1 Receptor Emerging as Important Target in Several Cancers
In another interview during the Brussels Congress, the chair of the symposium on insulin-like growth factor and co-chair of the meeting overall, Giorgio V. Scagliotti, MD, PhD, Professor of Respiratory Medicine at the University of Torino, acknowledged the IGF-1 receptor as one of the emerging targets in NSCLC—“But not only in non-small-cell lung cancer, but also in other types of cancer. Although there are preclinical data showing that the expression of the receptor is mainly in squamous cell carcinoma, it's not only in squamous cell carcinoma.”
He said that he thought that the relevance of the IGF pathway was even clearer in light of the Phase II clinical data reported by Dr. Novello: “Even with all the limitations of data coming from a Phase II study there is higher activity with the combination of carboplatin/paclitaxel plus the monoclonal antibody against the insulin growth factor receptor 1.”
Although the new drug's activity in squamous cell carcinoma was higher than in non-squamous, he pointed out that the activity in adenocarcinoma was still higher than in the control arm of patients receiving just the carboplatin/paclitaxel combination alone, reinforcing the observation that adenocarcinoma lung cancer is still influenced to some extent by the IGF axis.
Dr. Scagliotti was enthusiastic about the prospect of cross talk between the different growth factor receptors: “It's quite likely that this new pathway will be found to be important when there is resistance to the other pathways, or when there is cross talk between the pathways.”
He said that he foresaw the possibility of using inhibitors of two different growth factors together: “You could have one monoclonal antibody or one tyrosine kinase inhibitor [TKI] against one pathway, and another monoclonal antibody or TKI against the other pathway and probably end up with better results.”
Dr. Scagliotti said he thought that the real ‘molecular drivers’ of cancer cells controlling cell proliferation are now being elucidated and that the insulin-like growth factor—although a ‘new kid on the block’—could be a significant player: “It's beginning to look like this. We need to do clinical studies. But we need to avoid doing huge clinical studies without a solid basis, and this Phase II study [from Novello] gives some of the solid basis for further clinical research.”
Dr. Scagliotti said he was looking forward to hearing results from the study investigating the possibility of simultaneously blocking the epidermal growth factor pathway and the IGF pathway; and that he thought such molecular blockade could become a significant way to improve the treatment for patients with advanced NSCLC.
“The rationale is there. Obviously we need to take into account the fact that although potentially we are increasing activity, we are also potentially increasing side effects. What is clear progressively over time is that targeted therapies don't come for free. They bring toxicities. And we need to learn about these toxicities and how to manage them.”
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