The Reality of Targeted Therapies

Image: Courtesy of Mignon Fogarty LEARNING ABOUT RESISTANCE: Most cancers engage multiple growth factor, angiogenic, cell cycle, and apoptosis pathways. Frequently, redundant pathways exist, so that as drugs shut one pathway down another pathway takes over. This is one way that cancers become resistant to targeted agents. Early stage tumors tend to secrete a small number of pro-angiogenic factors, whereas late stage tumors secrete a larger number of pro-angiogenic factors. Targeted anticancer agents have had their ups and downs lately. While Gleevec, Herceptin, and Rituxan are proving useful in a broader array of patients with cancer than initially expected, other targeted agents have disappointed in pivotal clinical trials. In August, AstraZeneca's epidermal growth factor receptor (EGFR) inhibitor, Iressa, failed a Phase III trial in patients with non-small-cell lung cancer (NSCLC). Preclinical studies indicated that Iressa would act synergistically with chemotherapy, but the combination treatment showed no effect on survival benefit. Then, less than a month later, Avastin, Genentech's much-touted vascular endothelial growth factor (VEGF) inhibitor, joined the long list of failed angiogenesis inhibitors1 when it belly-flopped in its first Phase III trial, where it was combined with chemotherapy to treat metastatic breast cancer. And in mid-September, Theratope from Biomira failed to meet interim endpoints in a Phase III trial in patients with breast cancer. Theratope is intended to stimulate the immune system to attack a specific molecule on breast cancer cells. Despite the enthusiasm and hype surrounding these drugs, many experts did not seem surprised by the failures. Take the EGFR for example. At one level, it makes sense as an anticancer target. "Ninety percent of all human tumors come from epithelial cells, and this is one of the major regulators of epithelial regulation. [In tumors] it can function as an activated receptor in the absence of any ligand binding," says biochemistry professor Graham Carpenter, Vanderbilt University, and a longtime EGFR investigator. Moreover, many researchers acknowledge that EGFR overexpression does not mean that inhibitors will stop tumor growth. "There may be different things--for example, whether these receptors are activated," says Janet Dancey, a senior investigator, Investigational Drug Branch, National Cancer Institute (NCI). Image: Courtesy of Oregon Health & Science University Brian Druker The bottom line: companies cannot know which patients are good candidates for EGFR inhibitors. Suddenly, this "targeted therapy" does not sound so targeted. "I'm very careful with the use of the term 'molecularly targeted,'" says Brian Druker, a lead investigator in the development of Gleevec. "Every single chemotherapy agent we have is molecularly targeted. Just because you know the target, doesn't make something a good drug." But make no mistake; drug companies want targeted therapies. At least three other EGFR inhibitors are jockeying with Iressa for approval: ImClone's Erbitux, Abgenix's ABX-EGF, and Tarceva from OSI Pharmaceuticals and Genentech. And, Biomira intends to complete the full Phase III trial with Theratope, despite the negative interim results. Genentech and AstraZeneca have other trials underway for different uses, for different cancers.(Iressa is used in Japan as a single-use agent for NSCLC.) The competition is intense. "Astra-Zeneca has taken a lot of short cuts with Iressa [to be first to market]. Companies balance a lot of factors," explains Ben Weintraub, a senior analyst at BiotechTracker.com. AstraZeneca's spokeswoman, Mary Lynn Carver, counters: "Getting a drug to market as quickly as possible is both a business concern and an ethical concern. We feel a strong responsibility to patients to move as quickly as possible when you are dealing with a drug like Iressa that can make such a significant contribution to a terminal disease like lung cancer." Financial and regulatory issues often play big roles because getting to the Food and Drug Administration (FDA) first for approval can make the difference between profit and loss. Zevalin, from IDEC Pharmaceuticals, and Bexxar, from Corixa, are non-Hodgkin-lymphoma drugs that target the B-cell antigen CD20. Zevalin was approved first. A few months later, the FDA dashed Corixa's hopes for Bexxar by ruling that the drug did not meet an unmet need--in other words, with Zevalin on the market, Bexxar became superfluous. SPECIFIC MOLECULES Gleevec, which inhibits the BCR/ABL kinase that causes chronic myelogenous leukemia (CML), is the darling among developers of targeted agents. Gleevec caused quite the stir when approved by the FDA in 2001, less than three months after Novartis submitted the new drug application. Phrases like "wave of the future" and "new era" were rolling off tongues of reporters and oncologists alike. But most cancers are not like CML; the exact molecular cause is usually unknown and not likely to be reliant on one specific molecule. "We need to go back to basic biology of cancer cells and find the specific targets for specific cancers," says oncologist Herman Kattlove of the American Cancer Society. Just as EGFR overexpression probably is not critical for the growth or survival of most lung cancers, VEGF may not be that one key target that will stop blood vessels from feeding tumors. "There are many molecules that stimulate angiogenesis. Just getting at one of them may not be the answer," says Kattlove. Sugen's VEGF inhibitor, SU5416, recently failed a Phase III trial partly because other angiogenic factors compensated for the loss of VEGF.1 "What you want to do is turn off molecular pathways with drugs exactly like switches," says Weintraub. "In the perfect world, we'd know what all the biological effects of all those switches and dials are," he says. SPECIFIC PATIENTS Researchers say it is possible that Iressa will work smashingly well in some patients who have not been identified yet. "Perhaps only a small number of patients in the trial responded, and they were diluted out by the lack of response from the [other] patients," says Dancey. Oncologist James Posey, an assistant professor at the University of Alabama in Birmingham, has treated patients in EGFR inhibitor trials and agrees: "It seems to have a profound impact in a small population of patients." Companies acknowledge this issue. "It's clear that 10% to 20% of patients do respond," says Brent Vose, AstraZeneca's vice president of oncology therapy. "They are probably the ones [who] have tumors that are most driven by EGF [epidermal growth factor]." John Slack, OSI's vice president of development, says research is underway to identify better molecular predictors of Tarceva response. Effective clinical use of targeted agents will involve identifying the right dosage, the treatment combinations, or sequence of treatments. Although preclinical results say Iressa should work with chemotherapy, it is still possible that they should not be used together. "Iressa and similar agents that target EGFR have been reported to induce an arrest in G1, which might not be optimal when you're giving chemotherapy that is most effective in the S phase or M phase of the cell cycle," hypothesizes NCI's Dancey. Druker, director of the Leukemia Center at Oregon Health & Science University, concurs and points to tamoxifen, an agent that targets the estrogen receptor. "If you look at 20 years of research on tamoxifen in breast cancer, you can't find many Phase III trials where adding tamoxifen to chemotherapy does any good. But if you use it sequentially, you get good results. So maybe you have to give Iressa followed by chemotherapy or vice versa." Image: Courtesy of Vanderbilt-Ingram Cancer Center Graham Carpenter Vanderbilt's Carpenter speculates that even if EGFR is the right target, the current cadre of inhibitors does not turn down its activity enough. For example, animal experiments show that only 10% of receptor activity can promote the biological effects of EGF. "If it's like that in the tumor, then you would have to get over 90% inhibition," he says. Slack, who has reason to worry about the Iressa results since OSI's trial is also in non-small-cell lung cancer, says that in vitro Tarceva is a much stronger EGFR inhibitor than Iressa. "Tarceva has an IC50 of 2 nanomolar, and I believe the number with Iressa is 20 nanomolar," he says. [IC50 is the concentration of compound that inhibits the growth of uninfected cells by 50%.] But Carpenter notes that small-molecule drugs such as Iressa and Tarceva work by competing with ATP for the receptor's kinase domain. "The cell is just full of ATP, so trying to overcome [that] with one inhibitor always seemed to me to be a tough road to hoe," he says. Also, Carpenter notes that Iressa works on EGFR's intracellular portion, whereas Erbitux works on the extracellular portion. "It might be that by combining those ... you might get a lot more inhibition," he says. Some companies are thinking about doing combination trials with their own drugs. "We have a study at UCLA [University of California-Los Angeles] starting shortly looking at Avastin in combination with Herceptin," says Genentech spokeswoman Colleen Sweeney. Herceptin is a monoclonal antibody that targets the HER2/neu growth factor receptor. Even in targeted agents that are considered successful, issues with adverse side effects and resistance remain. In patients taking Gleevec, for example, edema or resistance to the drug has developed. "People jump on the issue that there is a case of Gleevec resistance because they expect it to be some sort of miracle drug," says Weintraub. "I'd still say that it is a miracle drug, but it also exists in the real world." Weintraub points out that expecting a home run with the first Phase III clinical trial might be too much to ask. "The average cancer drug gets approved with statistically significant, but not huge results, and then over time, people learn how to use them most effectively." Companies say they're working on it. "We did a very, very strong trial looking at whether Iressa works with cytotoxics in non-small-cell lung cancer," says Vose. "The data say that isn't how you use Iressa, but it doesn't say that if you use it in [other ways] it won't work. We just have to find out how you use these targeted therapies." Mignon Fogarty (mignon@welltopia.com) is a freelance writer in Santa Cruz, Calif. 1. M. Fogarty, "Learning from angiogenesis trial failures," The Scientist, 16[6]:33-4, March 18, 2002.

The Reality of Targeted Therapies

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