Making Cancer Drugs Worth the Cost

As nations around the globe struggle to afford the growing cost of care for their citizens, more people are asking ‘how much is too much?’ when it comes to cancer. Although the John G. Kuhn Keynote Lecture delivered at the annual meeting of the Hematology/ Oncology Pharmacy Association was titled “The Cost of Cancer Therapy,” speaker Tito Fojo, MD, PhD, with the medical oncology branch of the National Cancer Institute (NCI), says cost is not the real issue. “If you frame the argument in terms of cost, you’re going to lose it,” he told the audience of pharmacists. Fojo said the real issues are “how effective drugs are and how toxic drugs are.”

Fojo offered examples of drugs used in clinical practice that he believes not only fail to improve survival but actually harm patients, including cetuximab (Erbitux) in metastatic colorectal cancer (mCRC) and bevacizumab (Avastin) in breast cancer. He noted that controversy surrounds these examples and not everyone shares his views—including Giuseppe Giaccone, his supervisor at the NCI and a member of the American Society of Clinical Oncology (ASCO) panel responsible for adding the combination of cetuximab and paclitaxel to the ASCO guidelines for first-line therapy of mCRC. The examples Fojo cites are also found in the National Comprehensive Cancer Network (NCCN) treatment guidelines.

Even if one disagrees with Fojo’s conclusions, his review of the pivotal trials used to support approval of cetuximab in mCRC and bevacizumab in breast cancer underscores important considerations for stakeholders when deciding how anticancer drugs should be developed, evaluated, and used. “Our drug development, drug approval, and drug consumption strategies need better focus,” said Fojo, who lamented that despite the decade that has elapsed since imatinib (Gleevec) ushered in the “targeted therapy revolution,” too many treatments are still used indiscriminately in broad patient populations.

Fojo sees room for improvement at all levels: academia, the pharmaceutical industry, government agencies like the US Food and Drug Administration (FDA), and clinicians caring for patients with cancer. All are responsible for “our failure to deliver on the promise of personalized medicine.”

The experience with cetuximab in mCRC supports Fojo’s contention that researchers need to analyze drugs prospectively, identifying predictive markers before initiating trials. Four years after cetuximab’s 2004 approval, investigators reported in the New England Journal of Medicine that it was ineffective in patients with mutated KRAS. In 2009 ASCO issued its Provisional Clinical Opinion recommending KRAS testing before prescribing cetuximab but called compliance with the opinion voluntary.

Fojo said a prospective investigation might have uncovered the KRAS issue before trials were initiated. Cetuximab inhibits epidermal growth factor receptor (EGFR), and Fojo said, “As early as 1990, Bert Vogelstein at Hopkins had reported that as many as 50% of colorectal patients harbored KRAS.” In 1998, KRAS was reported to be in the EGFR signaling pathway. “Despite this, we went ahead and conducted studies without looking at this prospectively.”

Continued investigation into the causes of poor response to cetuximab among some patients with wild-type KRAS will likely whittle the viable patient population down even further. “Eventually, we’ll be able to identify the 80% of patients that do not benefit and give it only to the 20% who benefit substantially, and a drug that was marginal to begin with will become highly effective,” explained Fojo.

Fojo said he is concerned that “increasingly, therapies that demonstrate at best marginal improvement are being used in the treatment of cancer.” With breast cancer, we might even be going backwards he said, pointing to the controversy over bevacizumab. He emphasized that his views did not represent those of the NCI or anyone else.

Fojo faulted the decision to approve bevacizumab based on data from the Eastern Cooperative Oncology Group (ECOG) 2100 study, which suggested adding it to paclitaxel significantly prolonged progression-free survival (PFS) but not overall survival (OS). Although the study showed nonsignificant improvement in OS favoring bevacizumab, Fojo said, “Nonsignificant improvement is no improvement.” He added that it was unusual for a study to reflect major discordance between PFS and OS.

Fojo and other researchers published a report in Lancet Oncology last year that reviewed major studies published since 1996 with a statistically significant PFS or OS and found “tight correlation between the two.” He therefore believes ECOG 2100 is an outlier.

Even if bevacizumab does improve PFS, in Fojo’s opinion, PFS on its own is not an important end point. “Delaying symptoms is a worthwhile goal, but delaying PFS does not equal delaying symptoms,” he said.

Studies need to focus more on whether the regimens used are harming patients. Fojo noted that in ECOG 2100, patients treated with bevacizumab experienced more than twice as many adverse events as the control group. Given its failure to improve OS and its cost, Fojo said the toxicity is unacceptable, but he acknowledged that many breast cancer specialists disagree. The FLEX trial, investigating cetuximab in mCRC, also found high rates of serious grade 3 and 4 toxicities related to cetuximab, particularly skin reactions that are sometimes disfiguring.

With the growing use of oral treatments, Fojo said it is important that studies not overlook the grade 1 and 2 toxicities. “The scale was developed for chemotherapy, but when you are taking a drug every day for months on end, a grade 1 or 2 event can be very difficult.”

While cost is relevant for drugs that cause serious adverse effects but demonstrate minimal efficacy, Fojo said it comes down to the notion that you do not harm patients for little improvement in survival. Various attempts to combine therapies have hurt patients without helping them, and Fojo called for an end to this “incremental approach” to treatment.

Finding better treatments requires determining the settings in which the drugs work best but also the ones in which they do not work. Fojo said this would require major journals to give greater weight to negative studies, which are often relegated to second- and thirdtier journals. It also requires expanding incentives for pharmaceutical companies to take a more personalized approach to drug development, where rewards are likely to be less lucrative