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Thema: Presse: ASCO-Meeting

Presse: ASCO-Meeting
08.07.2001 11:15:01
Researchers Optimistic About Sea Change in Cancer Treatment

Joan Stephenson, PhD

San FranciscoSuccessful trials of a drug designed to counter the deadly genetic glitches responsible for two forms of cancer portend a coming wave of novel therapies that will transform the way cancer is treated, said researchers gathered here for the annual meeting of the American Society of Clinical Oncology (ASCO).

The new therapies, the result of decades of basic research aimed at understanding the molecular biology of cancer, herald "the beginning of a sea change in how we practice cancer medicine," said ASCO President Larry Norton, MD, of Memorial Sloan-Kettering Cancer Center, New York.

Such molecularly targeted therapies are expected to be the pharmaceutical equivalent of a smart bomb, homing in on a defined target and inflicting far less of the collateral damage to noncancerous cells than results from conventional chemotherapy and radiation.

But because many malignancies may be caused by an accumulation of gene mutations, and cancer cells often develop resistance to anticancer drugs, some experts predict that few, if any, of the new drugs ultimately will be used as a single agent.

Rather, an anticancer cocktail of several drugs, each of which targets a gene involved in a patient´s cancer, may prove to be a relatively nontoxic way of keeping the disease in check, suggested John Mendelsohn, MD, president of M. D. Anderson Cancer Center, Houston.

A new oral drug, imatinib mesylate (formerly called STI-571), has proven so effective in clinical trials involving patients with chronic myelogenous leukemia (CML) that the US Food and Drug Administration approved it last month in record time. Now, in two studies presented at the ASCO meeting, American and European researchers have revealed that the drug (known by the trade names Gleevec [in the United States] and Glivec [in Europe]) also shows remarkable promise against a type of solid tumor, the gastrointestinal stromal tumor (GIST).

Experts caution, however, that despite Gleevec´s early success in these two malignancies, the drug hasn´t been used long enough to determine whether it will prolong long-term survival, whether it will be useful in combination with other agents, and whether long-term toxicity or drug resistance will emerge.

Scientists have known for some time that patients with CML have a genetic mutation in their leukemic cells that causes the activity of a specific proteinan aberrant tyrosine kinase enzyme called ABLto remain inappropriately switched on, signaling the cancerous white blood cells to keep dividing. Gleevec specifically targets ABL and blocks this protein´s ability to drive runaway cell proliferation.

Researchers had previously demonstrated that Gleevec also is able to block the enzyme action of a defective version of another tyrosine kinase, KIT, which is the product of a mutation in a gene called c-kit. Some cancers, including GISTs, have c-kit mutations causing KIT-driven uncontrolled cell growth.

GISTs arise from the connective tissue of the gut and are resistant to radiation and standard chemotherapy. Patients whose tumors cannot be completely resected through surgery typically die within a year or so.

Laboratory studies by researchers at Dana-Farber Cancer Institute in Boston showed that Gleevec could block the activity of GIST cells, causing the cells to die. Those findings, and the experimental drug´s striking success in shrinking tumors in a patient with GIST treated at Helsinki University Central Hospital in Finland, prompted the launching of clinical trials last year.

In one phase 2 study, 148 patients with GIST from four centers in the United States and Finland were randomized to receive a 400-mg/d or 600-mg/d dosage of Gleevec. Of the 86 patients who had been treated long enough for drug response to be assessed (with a median follow-up of 4.5 months), 85% had some shrinkage of their tumors and more than half (59%) had tumors shrink by at least 50%, noted Charles D. Blanke, MD, of Oregon Health Sciences University, Portland. "Many of these continue to have tumor shrinkage, including some on study for more than 10 months."

About 13% of the patients had progression of their disease. None of the patients who achieved remission and are still taking the drug has relapsed, said Blanke.


The researchers also analyzed tumor specimens from about half the patients to see how mutational status correlated with patients´ response to Gleevec. About 86% of patients had detectable mutations in c-kit, and were more likely to respond to the drug than those with no detectable c-kit mutations.

Individuals with the most common type of mutation (71% of the patients who had tumors genotyped) had a remission rate of 78%, compared with 29% for those with no detectable c-kit mutations. The response rate of people with the second most common mutation (14% of those with genotyped tumors) lay somewhere between these two extremes.

"Our trial is one of the first to inhibit the product of a mutant gene that drives tumor growth," said Blanke. The new findings are exciting not only because they provide validation for the concept of targeted therapy, but also because patients with GIST have had no other options, he explained.

In the second study, a phase 1 dose-escalation trial of 36 patients with GIST conducted by the European Organization for Research and Treatment of Cancer, researchers also saw dramatic responses. In the first 8 weeks of treatment, 25 (69%) had shrinkage of their tumors, seven (19%) had stable disease, and four (11%) had progression of their cancer, reported Allan T. van Oosterom, MD, of the UZ Gasthuisberg, Leuven, Belgium.

Adverse effects seen in clinical trials of GIST and CML generally have been mild to moderateincluding nausea, swelling of the lower limbs or around the eyes, muscle cramps, diarrhea, vomiting, skin rash, and headache. However, some individuals had to stop taking the drug because of more serious drug-related effects, including internal bleeding (believed to be related to the drug´s effect on the tumors rather than to gastrointestinal irritation), elevated liver enzyme levels, neutropenia, and severe edema.

Large-scale clinical trials of Gleevec for GIST are in progress in Europe and the United States. Studies are also under way or planned to evaluate the drug´s effectiveness in other cancers, such as small-cell lung cancer, glioblastoma, and prostate cancer. These are malignancies in which c-kit mutations or mutations in a gene that encodes yet another cell-signaling protein, the PDG-F receptor, play a role.


Researchers also described the latest findings of a clinical trial of an experimental agent that takes aim at another molecular target, epidermal growth factor receptor (EGFR). About 30% of human tumors express EGFR, and its presence correlates with poor prognosis, increased risk of metastasis, and shorter disease-free and overall survival with some tumor types.

Investigators have been developing a variety of agents that target EGFR, including tyrosine kinase inhibitors and monoclonal antibodies. One such agent, a monoclonal antibody called IMC-C225, or cetuximab, shows promise in treating people with colorectal cancer that is resistant to standard drug therapy, said Leonard Saltz, MD, of Memorial Sloan-Kettering Cancer Center. The agent appears to block signals in the cancer cell that instruct it to survive and continue to grow.

The drug´s action "can make cancer cells far more vulnerable to chemotherapy," said Saltz, who reported findings from a phase 2 trial involving 120 patients with tumors that no longer responded to two drugs that are mainstays of treatment for the disease, fluorouracil (5-FU) and CTP-11.

The patientsall of whom had tumors that expressed EGFRwere then given IMC-C225 plus the same dosage of CTP-11 that had previously been ineffective. Nearly 23% of patients had tumors shrink by at least 50%, and another 7% had stable disease. The most common drug-related adverse effect was an acnelike skin rash, and a small percentage of patients had severe allergic reactions to the drug.

Such a response rate in the most refractory patients is "quite remarkable," and these preliminary findings suggest that the drug may offer an approach to treating patients with no other therapeutic options, noted Saltz. Plans are under way to launch a clinical trial this summer, testing IMC-C225 combined with standard chemotherapy as an initial treatment, before patients´ tumors have an opportunity to develop resistance.

A number of other EGFR inhibitors are also in the drug development pipeline and are being tested for their effectiveness in lung cancer, head and neck cancer, and other malignancies.

The promise offered by molecularly targeted therapies suggests that in the future, clinical oncologists will use a dramatically different approach to diagnosing and treating malignancies, one that reflects the specific genetic flaws underlying a given tumor.

"In the next 5 to 10 years, I predict that we will classify cancers on the basis of their molecular phenotype, and organ sitewhile clearly importantmay be secondary to the molecular phenotype," said Charles Sawyer, MD, of the University of California, Los Angeles.

© 2001 American Medical Association. All rights reserved.