Top stories of 2009: Great progress in targeted therapies

This year, Harry Jacob, MD, and I, with the assistance of our other Editorial Board members, again chose to emphasize some of HemOnc Today’s recently published articles. This column presents some comments about several oncology contributions to the top stories of 2009.

The top story of 2009 was the revision of the prescribing information for cetuximab concerning patients with KRAS mutations.

Research presented earlier this year indicated that cetuximab (Erbitux, ImClone), an antibody that targets the epidermal growth factor receptor, had no treatment benefit for patients with tumors that had a KRAS mutation. Guidelines from the ASCO and National Comprehensive Cancer Network subsequently recommended that tumors from patients with metastatic colorectal cancer be tested for KRAS mutations.

Due to this research, the FDA revised the prescribing information for the drug. Cetuximab is now indicated for metastatic colorectal cancer alone or in combination with irinotecan after failure with oxaliplatin or irinotecan regimens in patients without KRAS mutations. Although only 20% of patients benefited from cetuximab plus irinotecan, this percentage should increase as only patients lacking KRAS mutations are treated.

Joseph R. Bertino

Unfortunately, at this time, no useful therapy for patients failing first-line treatments has emerged for patients with KRAS mutations, and finding new therapies for these patients is an urgent endeavor.

Another marker study toward the goal of personalized medicine also made the top 10 stories of 2009. In previous smaller studies, patients with adenocarcinoma of the lung with EGFR mutations were more likely to benefit from the EGFR inhibitors gefitinib (Iressa, AstraZeneca) or erlotinib (Tarceva, OSI). The study, reported by Masahiro Fukuoka, MD, PhD, compared 261 Japanese patients with the mutation — more common in Asians and never smokers — with 176 patients without the mutation. Patients that were positive for an EGFR mutation had a median PFS of 9.5 months with gefitinib vs. 6.3 months with carboplatin/paclitaxel. As expected, patients negative for the EGFR mutation treated with gefitinib only had a PFS of 1.5 months

New indications for approved drugs

Kidney cancer, after years of negative trials with new drugs, now has six approved drugs for treatment of patients with recurrent or metastatic disease. One of the drugs approved in 2009 was everolimus (Afinitor, Novartis), for treatment of patients failing other therapies.

Everolimus is one of the kinase inhibitors currently in the clinic that blocks mTOR, an important link in the survival pathway for tumors. In the RECORD-1 trial, everolimus doubled the time without tumor growth compared with placebo (4.9 months vs. 1.9 months) and reduced the risk for disease progression or death by 67%. The drug is orally administered and is not without toxicities: 20% of patients had mucositis, weakness, poor appetite, rash and fever.

Given that six drugs are now approved for metastatic kidney cancer, efforts to combine drugs rationally should have the highest priority for future studies of untreated patients. mTOR inhibitors, in particular, may enhance effects of other approved agents.

Bevacizumab (Avastin, Genentech) has been around for several years and was already approved for use in colorectal, breast and non–small cell lung tumors. However, this year, based on two phase-2 studies that showed significant responses in patients with glioblastoma, the drug was given accelerated approval by the FDA.

In one study, patients previously treated with temozolomide (Temodar, Schering) were randomly assigned to receive either bevacizumab alone (n=85) or in combination with irinotecan (n=82). The objective response rate to bevacizumab alone was 26% and the median PFS was 4.2 months. A second phase-2 study of 56 patients treated with bevacizumab alone showed a response of 20% and a 3.9 month median duration of response.

Although, clearly, additional effective treatments are needed for patients with this disease, the stage is set for combination use of bevacizumab with temozolomide for treatment of recurrent disease and as adjuvant treatment.

Prostate cancer prevention: winner and losers

Although small studies suggested that the antioxidants vitamin E and selenium may prevent prostate cancer, data from the SELECT study, a randomized, placebo-controlled trial, did not show any benefit for men receiving selenium, vitamin E or the combination of selenium plus vitamin E. In this study, 35,533 men older than 50 years were randomly assigned to receive one of these three treatment arms or placebo. After a median follow-up of 5.6 years, the monitoring committee recommended the study to be stopped because of the lack of efficacy to prevent prostate cancer.

In a second study that enrolled physicians, the efficacy of vitamins E and C in reducing the risk of prostate cancer was examined. The 14,641 male physicians older than the age of 50 were randomly assigned to 400 IU of vitamin E every other day or 500 mg of vitamin C daily or placebo. Neither vitamin E or C prevented prostate cancer.

Previous research published in The New England Journal of Medicine had reported the value of finasteride, a 5-alpha-reductase inhibitor; however, in the study, there was an increased risk for more aggressive prostate tumors among men treated with the drug. This result had decreased physicians’ enthusiasm for using finasteride for cancer prevention. However, a new clinical practice guideline issued jointly by ASCO and the American Urologic Association suggested that the use of 5-alpha–reductase inhibitors may reduce the risk of prostate cancer by 25%.

Committee members from these two organizations reviewed records from nine randomized trials that reported on the risk for prostate cancer period prevalence.

The panel found that men with PSAs less than 3 ng/mL had a rate of prostate cancer over seven years of 3.5% if treated with finasteride, while men on placebo had a rate of 4.9%, a relative decrease of 25%.

Importantly, there was not an increase in aggressive tumors in men who received finasteride.

There were no serious adverse events in men taken finasteride. It will be of interest to see if physicians will now accept these guidelines soon to be published in the Journal of Clinical Oncology and the Journal of Urology.

Racial disparities?

Rounding out our top stories of the year, Albain et al reviewed data from 25 years of phase-3 trials and suggested that disparity remains even when black patients with breast cancer received the same treatment as white women.

The same investigators also evaluated outcomes of women receiving adjuvant treatment for breast cancer. There was a strong association between race and mortality between black and white premenopausal women (HR=1.41) and postmenopausal women (HR=1.49).

Data collected from the SEER database on 244,786 women from 1973 to 2004 also showed that mortality was higher in black women. Otis W. Brawley, MD, chief medical officer for the ACS, said in an editorial that black women have less ER-positive tumors than white woman, which may contribute to the results.

Although Kathy S. Albain, MD, concluded that the disparity could not be ascribed to lack of quality care, Brawley disagreed and stated, “It’s OK to talk about biologic differences, but let’s not downplay access to quality care.” Thus, biologic differences and quality of care appear to be important factors in the poorer outcome of black women with breast cancer compared with white women.