|Photo credit: Dąbrowa Górnicza
Last year, in the United States, more than 1.5 million new cancer cases were identified, with lung, prostate and breast cancer at the top of the list. Cancer was the cause of more than 500,000 deaths, 28 percent due to lung cancer. According to a report from the American Society of Clinical Oncology titled “Clinical Cancer Advances 2010: Annual Report on Progress Against Cancer,” “Death rates dropped 1.6 percent annually from 2001 to 2006, mainly due to reductions in new cases and death rates for the three most common cancers in men (lung, prostate and colorectal cancers) and for two of the three leading cancers in women (breast and colorectal cancer).”
The report is very informative for basic scientists and clinicians alike and leaves the reader with the impression that major breakthroughs are happening every day. For example, “a randomized, phase III drug trial in patients with metastatic pancreatic cancer was the first to demonstrate a significant survival improvement in individuals with stage IV adenocarcinoma of the pancreas … treatment with FOLFIRINOX – a combination of the chemotherapy drugs 5-fluorouracil, leucovorin, irinotecan and oxaliplatin – resulted in better response rates, progression-free survival and overall survival compared to standard single-drug treatment with gemcitabine (Gemzar).
“A phase III trial found that adding the anti-angiogenesis drug bevacizumab [Avastin, Genentech/Roche] – which targets tumor blood vessel growth and development – to the standard chemotherapy drug combination carboplatin and paclitaxel helped women with advanced ovarian cancers live significantly longer without their disease progressing than chemotherapy alone.”
A dramatic discovery involved a BRAF inhibitor for advanced melanoma: “Researchers showed that the majority of advanced melanoma patients with a specific BRAF gene mutation (V600E mutant BRAF) responded to a new BRAF inhibitor, PLX4032 (Roche). In the second part of a phase I trial, tumors either completely or partially regressed, including metastases in the bone and liver, in 81 percent of patients.”
However, nowhere in the report did the authors mention the fact that these targeted, molecular therapies did relatively little to prolong survival. The FOLFIRINOX study reported a 6.4 versus 3.3 month progression-free survival for metastatic pancreatic cancer; women who took Avastin during standard chemotherapy for ovarian cancer lived about four months longer. And frustratingly, many of the most dramatically responsive BRAF patients relapsed within a year.
More encouraging are the data for ipilimumab, a monoclonal anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody that Bristol Myers Squibb is testing as a treatment for metastatic melanoma and other cancers, including prostate and lung cancers. Ipilimumab blocks the inhibitory signal of CTLA-4, thereby sustaining an active immune attack on cancer cells. In a Phase III trial, about 45 percent of patients treated with ipilimumab were alive at one year compared with 25 percent of patients in the control arm. At two years, 22 to 24 percent of patients treated with ipilimumab were alive compared with 14 percent of patients in the control arm. This is the first therapy ever to show a survival benefit for metastatic melanoma in a randomized clinical trial; it currently is under priority review by the U.S. Food and Drug Administration. If ipilimumab is approved for the treatment of melanoma, physicians will be at liberty to prescribe this drug off-label for the treatment of other appropriate conditions, possibly including prostate and lung cancer.
Do these data make us feel encouraged or discouraged? To be fair, these studies targeted the most aggressive cancers possible. Clearly more work is needed; the cures are not yet in hand. An added challenge is the fact that the pharmaceutical industry estimates that it costs more than $800 million to bring a single drug to market if one includes the cost of products that fail along the way (and most do). Although some have criticized this estimate as difficult to verify, no one disputes the high costs of years of drug development and animal studies followed by the clinical trials and testing required for FDA approval. For each exciting new agent, combination trials also will be needed, and one can imagine a number of combinations and additional indications that deserve further study. If only it were easier (and cheaper).