Innovation in Oncology Drug Development

Abstract

Significant progress has been made in our understanding of the molecular lesions responsible for tumor cells to exhibit uncontrolled growth while circumventing normal mechanisms of apoptosis and their ability to migrate and invade normal tissues while evading recognition and destruction by the immune system. This understanding has enabled the development of therapies specifically targeted to these lesions coupled to innovative treatment regimens to most effectively use these new targeted therapies with precision in selected subpopulations of patients. Innovation at the scientific and clinical levels has been appropriately embraced and supported at the FDA, resulting in regulatory innovation to facilitate and adapt to the Precision Medicine environment.

Figure 1

Typical Clinical Development Pathway for a Cytotoxic Cancer Chemotherapy Drug. Commonly used preclinical and clinical development pathway for cytotoxic chemotherapy drugs. A typical pathway for the development of cytotoxic cancer drugs started with demonstration of differential cytotoxicity in human cancer cell lines compared to nontransformed human umbilical cord endothelial cells (HUVECs). This was routinely followed by tumor xenograft studies in nude mice with nontoxic doses of the test drug (doses that did not produce weight loss) that are growing subcutaneous or orthotopic human tumor tumors. Efficacy was based upon slowing down of human tumor growth rate or even tumor regressions. This was followed by compliance with the regulatory requirements needed for approval of an IND to be able to treat patients in phase 1. Phase 1: the purposes of phase I studies for cytotoxic drugs are to assess the initial safety/tolerability and identify the maximal tolerated dose (MTD) and the recommended dose for phase 2 studies (RDP2). Phase I studies for cytotoxic cancer drugs are typically conducted in cancer patients since the drug is predicted to have safety concerns. Phase 2: with the identification of an acceptable dose/schedule from phase 1, supported by PK and even potentially PD data, it is possible to proceed to phase II exploratory therapeutic/efficacy trials in selected patient populations to get an initial estimate on antitumor efficacy in one or more tumor types while concomitantly expanding the safety data base on the investigational oncology compound. Phase 3: typically for registration and marketing approval. Commonly compares the overall safety and efficacy of the new treatment to the standard of care in a randomized, statistically rigorous, and blinded trial. However, it must be recognized, that by definition, these trials generate data from a highly controlled setting, which may not be reflective of “real-world” settings. Phase 4: phase 4 trials are also known as postmarketing surveillance trials. Phase 4 trials involve the safety surveillance or pharmacovigilance and ongoing technical support of a drug. Phase 4 trials generate additional important data that require longer periods of time or large patient populations to emerge, such as rare side effect profiles. These postapproval safety signals may result in the drug being withdrawn from the market or the label being more restrictive. Phase 4 studies may be required by regulatory authorities or may be initiated by the sponsoring company. MTD, maximal tolerated dose; PDP2, recommended dose for phase 2; HUVEC, human umbilical cord vascular endothelial cells; SOC, standard of care; NDA, new drug application.

Figure 2

Precision Medicine verse Personalized Medicine. Personalized Medicine is defined as the creation of drugs that are unique to an individual patient and as the development of lesion-specific targeted drugs and the precise and selective use of those targeted therapies in specific subpopulations of patients whose tumors harbor those specific lesions.

Figure 3

Innovation = Precision Medicine + FDA Adaptability. Innovation in cancer drug development has resulted from both the maturation of Precision Medicine and the forward thinking and flexibility of the FDA to recognize that targeted therapies require innovative targeted trials.

Figure 4

FIH Protocol (PN001) for pembrolizumab—Multiple Expansion Cohorts. Illustration Merck FIH pembrolizumab clinical development program. The initial IND submitted in 2010 was to enroll 18 patients with melanoma plus 14 additional patients in an EC with melanoma and renal cell cancer. Over the next 2.5 years, 8 protocol amendments were filed, enabling the FIH study to be expanded to 9 distinct ECs enrolling a planned 1,100 patients [–23]. Successful implementation of this strategy resulted in accelerated approval for refractory, unresectable or metastatic melanoma and was supportive for approval in NSCLC.

Figure 5

Basket and umbrella trials. Basket trial: single targeted therapy evaluated in patients with multiple different tumor types but only including patients having the target lesion. Umbrella trial: single tumor histology with different genetic lesions treated with different lesion-specific drugs.