From: Approaches to modernize the combination drug development paradigm
Challenges | Examples | |
---|---|---|
Target validity and engagement | • Discordance between nonclinical and clinical data • Difficulty characterizing biological relevance and functionality of the target(s), target engagement and modulation by the investigational agent(s), and pathway interactions due to absent or poorly designed pharmacodynamics studies in early clinical studies | Selumetinib (MEK inhibitor) + MK-2206 (AKT inhibitor) in metastatic CRC (phase II) • Promising nonclinical data • Target inhibition not consistently reached • Other potential reasons for failure include possible activation of compensatory mechanisms and overlapping toxicities [129] |
Pharmacological effect of drug combination | • Effect of drug combinations, which may be additive, synergistic, or antagonistic, has a direct impact on antitumor activity and toxicity • Often poorly understood in both nonclinical and clinical environments | Adjuvant tamoxifen + anthracycline-based chemotherapy in breast cancer found to be inferior to sequential tamoxifen following chemotherapy (phase III) • Antagonistic effect suggested by nonclinical data [130, 131] |
Patient selection | • Being able to accurately select the subgroup of patients who would derive maximal benefit can substantially broaden the therapeutic window. However, identification, validation, and standardization of predictive biomarkers remain very difficult | IMC-A12, R1507 or CP-751,871 (IGF-1R inhibitors) + erlotinib (EGFR inhibitor) in metastatic NSCLC in three separate trials (phase I/II, phase II and phase III, respectively) • Promising nonclinical data • Three negative studies with limited activity in unselected patients • No biomarker identified from the studies |
Toxicity | • Poor drug tolerance affects the maintenance of dose intensity and duration, thereby limiting efficacy, particularly if two agents share the same target or have overlapping side effects • Small-molecule TKI combinations may be more likely than mAb combinations to cause increased off-target toxicities and pharmacokinetic interactions via the cytochrome P450 system [65] | Four phase I studies • Ipilimumab (CTLA-4 inhibitor) + vemurafenib (BRAF inhibitor) led to hepatotoxicity [135] • Tremelimumab (CTLA-4 inhibitor) + sunitinib (VEGFR inhibitor) led to renal toxity [136] • Bevacizumab (VEGF inhibitor) + sunitinib led to vascular/hematological toxicities [137] • Temsirolimus (mTOR inhibitor) + sunitinib led to skin/hematological toxicities [138] |