For May 29, 2002
Report from ASCO: Trials and Tribulations of a New Cancer DrugEverything about the 38th Annual Meeting of the American Society of Clinical Oncology (ASCO) was huge. There were 26,000 attendees, including 19,000 oncologists, many of whom came from Europe, Latin America and Asia. For nearly a week in mid-May they converged on the Orange County Convention Center in Orlando, Florida, rushing to hear thousands of lectures, seminars and presentations. The Exhibition Hall was a multistoried bazaar of new therapies, each vying for the attention of those who prescribe drugs to cancer patients. Even the press room was gargantuan, with row after row of telephones and computers, and reporters busily filing stories for their newspapers, TV and radio stations, and websites. Yet, after four days, I came away with a hollow feeling. There were incremental advances, to be sure. But overall, I was disappointed by the lack of breakthroughs in the treatment of cancer. Other observers expressed a similar disappointment. One veteran science writer told me this was the most unsatisfactory cancer meeting he had ever attended, with an almost total lack of exciting results. One of the highlights of the ASCO meeting was the 2002 Karnofsky Lecture, "Targeting the EGF Receptor for Cancer Therapy," by John Mendelsohn, MD. Dr. Mendelsohn is the president of the M.D. Anderson Cancer Center in Houston and has had a distinguished medical career. Listening to him speak, I caught some of his excitement and could see why he was chosen to receive this high honor from his peers. Dr. Mendelsohn's speech, concerning the science behind a new drug called Erbitux (formerly known as IMC-C225), was enthusiastically received by an overflowing crowd. Carefully targeted drugs like Erbitux are central to the oncology profession's latest strategy for conquering cancer. As the director of the National Cancer Institute, Andrew von Eschenbach, MD, said in another lecture, these newer drugs mark a transition from the "seek and destroy" strategy of 20th century chemotherapy to the "target and control" strategy of the 21st, from "weapons of destruction" to "interventions for control and prevention." In principle, advocates of complementary and alternative medicine (CAM) support such a development, since it represents a departure from the slash-burn-and-poison school of conventional cancer treatment. There are side effects of Erbitux, but they are relatively mild, and consist mainly of an acne-like rash. Who in their right mind wouldn't want these new drugs to succeed? Dr. Mendelsohn was a pioneer in using monoclonal antibodies, or "guided missiles," to block the growth of cancer cells. As early as 1983, he and a colleague suggested that tumors could be prevented from growing by blocking the receptors for growth factors that lie on the surface of cancer cells. It was an elegant concept. The primary outcome of their work was the development of Erbitux, which targets epidermal growth factor (EGF) receptors. EGF is present in all cells that line our organs and skin, and high levels of EGF have been found to correlate with a poorer prognosis for cancer patients. Preliminary research looked highly promising, and the alleged "proof of principle" came with the clinical trial of Herceptin, a drug that targets a molecule very similar to the EGF receptor identified by Dr. Mendelsohn. In 1995, Dr. Mendelsohn and his colleagues claimed that 10 percent of patients with advanced cancer who were treated with Herceptin had a clinical response. Seemingly, a new era in cancer treatment was born. At the 2001 ASCO annual meeting, the manufacturer of Erbitux, ImClone Systems, claimed a 22.5 percent response rate in patients with advanced cancer treated with a combination of Erbitux and chemotherapy. The jubilation at ASCO culminated in a Doobie Brothers concert that ImClone sponsored for the doctors attending the conference. In his lecture this year, Dr. Mendelsohn, who serves on the board of directors of ImClone, naturally emphasized the positive aspects of Erbitux. He mentioned a clinical trial involving six patients who had previously been failed by conventional treatment: when these patients were treated with a combination of Erbitux and cisplatin, three had complete responses and three had partial responses. This 100 percent response rate may sound fantastic. However, a "response" does not imply a cure or even a prolongation of life. "Responses" are simply tumor shrinkages, which can last as little as one month. Ultimately, the most meaningful measurement of a therapy's effectiveness is its impact on quality of life and overall survival. But meaningful data about survival can only be derived from phase III randomized controlled trials (RCTs). The world's first phase III clinical trial of Erbitux was reported at ASCO 2002 a few days after Dr. Mendelsohn's inspiring speech. In it, the standard drug cisplatin was compared to combination therapy using cisplatin and Erbitux in the treatment of head and neck cancer. The results were less than stellar. Just one patient out of 44 (2.3 percent) achieved a complete response and five (11.4 percent) had a partial response. The median disease-free survival for the group as a whole was 6.7 months and the median overall survival was just 7.2 months. More details were given in a company press release. It turned out that the response rate, poor as it was, enclosed an even more sobering reality: the response rate among so-called "real world" patients (patients who received their treatment outside the rarefied atmosphere of clinical trials) was just 5.7 percent. And that was a measurement of tumor shrinkages, not survival. The trial's investigators had hoped to show that patients in the Erbitux-added group would experience a doubling of their progression-free survival compared to the cisplatin-alone group. That didn't happen. For the Erbitux-added patients, the median time until the tumors worsened was just 4.10 months, compared to 3.37 months for the control patients. This difference of three weeks was not statistically significant. Scientists reluctantly concluded that there were "no meaningful differences between the two groups in terms of progression-free survival or overall survival," according to an ImClone press release. So, while on Saturday oncologists were applauding Dr. Mendelsohn for his brilliant insights, on Monday they were hearing that a treatment based on these insights simply did not work. If it were true that EGF "plays a critical role in the process that regulates tumor cell growth and survival," as ImClone still claims on its website, then one would expect a treatment that targets EGF to yield significant clinical results. It doesn't. All this shows the danger of judging new cancer treatments by the elegance of the theory behind them. I am reminded of the 1959 statement of Dr. David Karnofsky (after whom the Karnofsky Lecture is named): "The relevant matter in examining any form of treatment is not the reputation of its proponent, the persuasiveness of his theory, the eminence of its lay supporters, the testimony of patients, or the existence of public controversy, but simply...does the treatment work?" Karnofsky was criticizing what he characterized as "cancer quackery," but his words apply equally well to conventional treatments, especially those that are over-hyped by Wall Street. Because of the weak performance of Erbitux, the FDA (much to the credit of its evaluation committees) has refused to approve it. This has led to a crisis for its manufacturer, ImClone Systems. The company's stock, which traded at $75 per share at the end of last year, now hovers around $10. In the wake of the ASCO meeting, the president and CEO, Samuel Waksal, resigned all his posts. (His brother, Harlan Waksal, took over as CEO.) According to CBS Market Watch, "The most significant challenge for ImClone will be finding a way to revive its troubled application to market the anti-cancer drug Erbitux." ImClone may have other troubles, as a congressional panel is investigating trading in ImClone stock by Waksal family members. The problems besetting this biotech firm have even dragged down the stock of the giant Bristol-Myers Squibb, which last year paid $2 billion for the right to co-market Erbitux. Bristol-Myers is said to blame Samuel Waksal's aggressive personality for Erbitux's troubles. However, a more serious problem facing ImClone and other biotech firms involved in high-stakes cancer research is the lack of effectiveness of their innovative therapies, especially in extending life. Wall Street's biotech bubble is bursting. What are the lessons for patients and their advocates? First, we should not get caught up in the hysteria surrounding new cancer treatments. A great theory, an impressive board of directors, and a well-oiled publicity machine are no substitute for randomized controlled trials that demonstrate convincingly a cancer therapy's effectiveness. We should be especially wary of drugs that are heavily touted by Wall Street. The memory of the Enron debacle is still fresh. (Coincidentally, Dr. Mendelsohn, who is on the board of directors of ImClone, is also a member of the executive committee of Enron's board of directors.) According to ASCO's disclosure statement, some of those involved in the current clinical trial of Erbitux received honoraria and funding from Bristol Myers-Squibb and own stock or serve on the board of ImClone. The search for a magic bullet for cancer is understandable, but it detracts attention from the study of approaches that actually extend the lives of cancer patients while maintaining or improving their quality of life. It also detracts attention from cancer prevention strategies using natural and nutritional substances. These less toxic (and less expensive) approaches represent for me the real promise of cancer research. Next Week: The CAM Symposium
at ASCO Here at the Moss Reports
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