Lung Cancer Setback Aids Trials of New Drug Class

BY SUSAN LONDON
Elsevier Global Medical News

CORONADO, CALIF. — Growing interest in the relationship between insulin signaling and cancer has not been dimmed by the recent failure of a phase III trial testing an insulin-like growth factor I receptor inhibitor in lung cancer.

Along with disappointment, the trial has generated information that researchers hope will improve the safety and efficacy of this class of agents, according to Dr. Michael Pollak of McGill University in Montreal.

Two dozen drugs, mainly tyrosine kinase inhibitors and antireceptor antibodies, have been developed to target the IGF-IR, Dr. Pollak told attendees at a joint conference of the American Association for Cancer Research and the International Association for the Study of Lung Cancer. About a third of them are in clinical trials.

Many human cancers, including lung cancer, express insulin receptors, IGF-IR, and hybrid receptors. “These receptors are highly homologous to the oncogenes of the tyrosine kinase class,” Dr. Pollak said. Despite some toxicity, the safety data thus far have been encouraging, he said. Anti–IGF-IR antibodies have been associated with modest hyperglycemia. Unexpectedly, the tyrosine kinase inhibitors do not cause severe metabolic toxicity, even though they target insulin receptors in addition to IGF receptors. This may be because they do not accumulate in muscle, which has a high level of insulin-dependent glucose uptake.

The drug advancing furthest clinically— Pfizer Inc.’s figitumumab (CP-751,871)— is an anti–IGF-IR antibody. It showed promising activity when it was combined with chemotherapy to treat advanced squamous cell lung cancer in a phase II trial (ASCO 2009, abstract 8072). This led to the disappointing phase III trial (NCT00596830) of figitumumab with carboplatin and paclitaxel in non–small cell lung cancer that was closed early because of lack of efficacy.

One of the most plausible explanations is acquired resistance, according to Dr. Pollak. He noted that blockade of IGF-IR in normal tissues in the body induces a compensatory response leading to increased levels of growth hormone, with a resultant rise in levels of IGF-I, glucose, and insulin. “Now we have higher insulin levels, but we have not blocked the insulin receptor,” he said. “So this is an obvious candidate resistance mechanism.”

In the diabetes field, trials of inhaled insulin were stopped, in part, because it was linked to a higher incidence of lung cancer, Dr. Pollak further noted. “It gives us some reason to think that... insulin is relevant to lung cancer.”

Tolerability was also problematic in the phase III trial, with some patients unable to withstand the hyperglycemia associated with the therapy.

Several next steps have been proposed to improve the efficacy and tolerability of IGF-IR–targeted therapy for lung cancer, said Dr. Pollak. One is to coadminister the antidiabetic agent metformin (Glucophage) or the growth hormone antagonist pegvisomant (Somavert). With one of these added drugs, “we might be able to interfere with some of these potentially undesired metabolic compensations.”

Studies from the diabetes field have also found that the cancer risk in diabetics is lower among those taking metformin, “so there are many reasons these combinations deserve our attention.”

To further address tolerability, trial enrollment could be restricted to metabolically robust patients, especially when the anti-IGF-IR therapy will be combined with chemotherapy and steroids, he said. Alternatively, the therapy could be combined with treatments other than chemotherapy, which would avoid the need for high-dose steroids; for example, figitumumab has been found to radiosensitize non–small cell lung cancer in preclinical testing.

Finally, IGF-IR–targeted therapy might be improved by identifying predictors of response. To that end, preliminary data suggest that patients having a high fraction of free IGF-I in blood have the greatest improvement in outcome when they’re treated with figitumumab (ASCO 2009, abstract 3539). “This is a paradigm shift in a sense, or a new kind of paradigm applicable to this target, where the predictive biomarker may not be on the tumor; it may be in the blood,” Dr. Pollak observed.

Dr. Pollak reported that he had no direct conflicts of interest related to his presentation.

Dr. W. Michael Alberts, FCCP, comments: Although targeted therapies have proven beneficial in some circumstances, not all such therapy or strategies are successful. While the results of trials with figitumumab are disappointing, at times, more may be learned from failed studies than from successes.