Incremental Advance or Seismic Shift? The Need to Raise the Bar of Efficacy for Drug Approval

Abstract

Targeted agents have improved outcomes in many common solid tumors and are available for clinical practice in most countries. There are many more drugs in the developmental pipeline that have the potential to improve the treatment of some of the most deadly cancers. It is estimated that there are more than 350 antineoplastic agents in clinical development for cancer indications. This number is likely to increase in the future since the most important breakthroughs will most likely come from the development of targeted agents rather than from new cytotoxic chemotherapy. However, there is no question that both the costs of drug development and the price of approved biologics is very high. Table 1 summarizes the key efficacy results of the pivotal phase III registration trials on biologics for the treatment of solid tumors. Unlike imatinib that plays the role of a superstar in the first-line treatment of advanced gastrointestinal stromal tumors (GISTs), the data indicate that the benefit of approved biologics in the much more common solid tumors is much smaller. These agents appear more incremental than superstars. In fact, the median HR for PFS and OS in the pivotal phase III trials used for registration of new biologic agents approved for advanced colorectal, breast, pancreatic, non–small-cell lung cancer (NSCLC), renal cell carcinoma, and hepatocellular carcinoma are 0.57 and 0.73, respectively (Table 1). This translates into median PFS and OS gains of 2.7 and 2.0 months, respectively. The huge median benefit of cetuximab in head and neck cancer refers to the locally advanced setting (Table 1), not to the metastatic condition, common to the other trials in the Table. The enthusiasm for the demonstrated proof of principle in these diseases does not match the impact on patients. There are ambivalent positions on this problem. There is pressure for the rapid development and approval of drugs against diseases for which there are no or little effective therapies. In contrast, many of these new agents carry a very high price tag, especially considering the relatively modest gain in overall survival offered in the palliative setting. No matter how limited these gains are, the overall outcomes for patients have improved. One example of that improvement can be seen in colorectal cancer. Ten to 15 years ago there were only one or two active drugs, and now there are seven US Food and Drug Administration–approved drugs. Median survival has more than doubled, from 10 to 12 months in the era of fluorouracil plus leucovorin to 20 to 24 months now. This is the reason why many current studies designed to evaluate new agents in colorectal cancer (and most other solid tumors) are looking for incremental differences in efficacy, typically 0.75 to 0.80 HR for PFS. The question is whether we should continue to look for such a small, incremental , if we will not be able to afford the new, more expensive agents. This article describes the concept of the target for registration trials. That is, the difference that should be sought that will not only meet statistical measures of efficacy, but meet meaningful clinical criteria of efficacy. While there are many other equally important issues, such as the end point to be pursued, the relation between cost and pricing, the approval process, and the time from approval to market, consideration of those issues is beyond the scope of this report. In addition, we will focus on advanced stage solid tumors since the target for trials in the adjuvant setting of these diseases are based on completely different principles as a function of the treatment aims in this condition.