Historically, objective response rate (ORR) has been considered a surrogate for clinical benefit, even where OS benefit is unknown. The need for rapid drug approval in this setting will have to be balanced against long-term outcomes of patients treated with novel therapeutics. As clinical trials move more to response-based end points, it is possible that we will see more drugs that demonstrate excellent initial responses but lead to rapid development of secondary resistance. If a drug is effective at decreasing or controlling disease for an extended period of time, it is generally felt to be a positive outcome, which can lead to a regulatory approval.
The established clinical trial infrastructure is designed to assess the safety and efficacy of drugs largely based on objective response, progression-free survival (PFS), and OS. We will outline a few of the reasons why this research has been difficult to conduct but also why, in the age of targeted therapeutics, it is of utmost importance. Until recently, there have been few attempts to study secondary therapeutic resistance in large-scale clinical trials. Historical Limitations in Assessing Secondary Resistance Despite these caveats, it is helpful to understand therapeutic resistance fundamentally in terms of whether a therapy is “not effective” or “no longer effective” in order to better understand and target the underlying mechanisms driving resistance. For example, biochemical or molecular assessment of response may be discordant with imaging studies, which may either be a function of disease natural history, imaging frequency, or-in the case of immunotherapy-pseudoprogression. 4 Although these terms will be used throughout this review, it is important to note that this simple division becomes less clear as the precision of surveillance imaging and/or blood-based tests improves. Secondary resistance is defined as therapeutic resistance that emerges after a period of disease stability or response. Primary resistance is defined as a lack of objective clinical or radiographic response to therapy. Resistance to cancer-directed therapy is generally divided into primary and secondary (acquired) resistance. Therapeutic resistance develops in nearly all patients with advanced cancer who are treated with palliative systemic therapy.
In this review, we will discuss some of the drivers of therapeutic resistance in patients with mCRC and present some novel strategies to overcome resistance.ĭefining Primary and Secondary Resistance Understanding the mechanisms by which malignant cells evade treatment could unlock novel therapeutic strategies that overcome resistance and improve survival. Despite these improvements, however, nearly all patients treated with palliative chemotherapy will eventually develop resistance and ultimately succumb to progression of metastatic disease. 3 These improvements are due, in large part, to the introduction of multiple novel agents during the last 3 decades. 2 In more recent studies, this median has more than doubled and is commonly reported at more than 25 to 30 months. 1 In the mid-1980s, the median overall survival (OS) for patients with mCRC ranged from 10 to 12 months from the time of initial diagnosis. Metastatic colorectal cancer (mCRC) is the second most common cause of cancer-related death worldwide.