With unprecedented activity in the area of precision medicine, with the successful development of several targeted therapies, the FDA has been in the forefront of efforts to ensure timely access to, and the safe and effective use of, these therapies.
Personalized (or precision) medicine has been broadly described as the administration of the right therapy to the right patient at the right dose and intensity. The idea behind personalized medicine is not new and the phrase started to appear in the English literature in the late 1800s.1 Emphasis on the therapeutic patient-doctor relationship was among the earliest strategies for tailoring care to the specific needs of the patient. For example, house calls were a common method for delivering medical care until the early 20th century and allowed doctors to incorporate both quantitative (eg, discrepancies in medication regimens) and qualitative (eg, a patient’s performance status and support at home) information into an individualized care plan.2 Modern concepts in personalized medicine are defined by their focus on utilizing advances in technology for tailoring care. Blood typing to guide transfusions, monitoring the international normalized ratio for dosing warfarin, and predicting hypersensitivity reactions to the antiretroviral drug abacavir based on the presence of the HLA-B*5701 allele are well-known examples of a biomarker-driven approach to personalizing care in modern medicine.3
Recently, key stakeholders have articulated widespread support for bringing greater focus to personalized medicine. This commitment is fueled by recent advances in molecular biology, genomics, and health information technology.4 In his 2015 State of the Union address, President Obama announced the Precision Medicine Initiative. The president’s 2016 Budget includes a $215-million investment for the Initiative, the purpose of which will be to “pioneer a new model of patient-powered research that promises to accelerate biomedical discoveries and provide clinicians with new tools, knowledge, and therapies to select which treatments will work best for which patients.”5 Important components of this initiative include new funding for the National Cancer Institute to identify genomic drivers in cancer, and for the FDA to create a regulatory framework in support of innovations in precision medicine (Table 1).
The president’s Precision Medicine Initiative underscores the emphasis placed on personalizing care in the fight against the emperor of all maladies: cancer.6The field of oncology has recently seen unprecedented activity in this area with the successful development of several targeted therapies, and the FDA has been in the forefront of efforts to ensure timely access to, and the safe and effective use of, these therapies.
Targeted therapy can be defined as a treatment with a molecular target that controls biologically important processes that are central to the initiation and maintenance of cancer. Ideally, the target should be measurable in the clinic and measurement of the target should correlate with clinical benefit following administration of the targeted therapy.7 Of the 29 FDA approvals by the Office of Hematology and Oncology Products since the beginning of 2014, the majority have been of therapies with specific targets (Table 2).
The FDA’s expedited programs have provided an efficient regulatory framework for accelerating the development and review of personalized therapies.8 One of the most recent additions to the FDA’s expedited programs is breakthrough designation, outlined in Section 902 of the Food and Drug Administration Safety and Innovation Act (FDASIA), which was signed into law on July 9, 2012.9 Requests for breakthrough designation can be made when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on 1 or more clinically significant end points for the treatment of serious or life-threatening diseases such as advanced cancers. Following designation, the FDA mobilizes its resources to expedite the development and review of the designated drug. Since the program’s inception, nearly half of the requests have been for oncology drugs, most of which have been targeted therapies. The description in the following section of the approval of the targeted agent ceritinib, the first breakthrough designated drug for the treatment of advanced lung cancer, illustrates the FDA’s organizational commitment to the program.
Opportunities and Challenges in Developing Targeted Therapies
Small Molecule Kinase Inhibitors
In the late 1980s, scientists began identifying compounds with inhibitory activity against protein kinases.10 At the time, evidence emerged on the molecular genetics of chronic myeloid leukemia (CML) underpinning the cytogenetically visible shortening of chromosome 22 (ie, the Philadelphia chromosome) described in prior decades.11-13 The Philadelphia chromosome is the product of an oncogenic reciprocal translocation between chromosomes 9 and 22 [t(9;22)(q34;q11)], resulting in a fusion protein called BCR-ABL with a constitutively activated tyrosine kinase domain.14 On May 10, 2001, imatinib, a BCR-ABL tyrosine kinase inhibitor (TKI), was approved by the FDA based on demonstration of exceptional clinical activity and a favorable safety profile in patients with CML.15 The approval of the drug, heralded as a magic bullet and a new hope for cancer, created significant excitement about the promise of targeted therapies. Commenting on the contributions of his laboratory to the development of imatinib, the 2009 recipient of the Lasker-DeBakey Clinical Medical Research Award, Brian Druker, observed that maximizing the value of targeted therapies in treating cancer would require directing these agents to genetic or epigenetic changes in tumors, tumor metabolism, stem cells, and tumor-stroma interactions.16
The FDA’s accelerated approval in 2011 of the anaplastic lymphoma kinase (ALK) TKI demonstrates the value of the tailored approach articulated by Druker in delivering targeted therapies.17 While ALK gene rearrangement is present in about 5% of patients with advanced non-small cell lung cancer (NSCLC),18 ALK mutations involve oncogenic inversions within the short arm of chromosome 2 with a fusion protein product (most common being EML4-ALK) that bears a constitutively activated kinase domain.19 The accelerated approval of crizotinib was based on the demonstration of durable overall response rates (ORRs) of 51% and 60% and a favorable safety profile in patients with advanced ALK-positive NSCLC in 2 single-arm trials, a treatment effect far superior to traditional chemotherapy’s ORRs of 10% to 30% based on historical experience. A companion diagnostic assay based on an ALK break-apart fluorescence in situ hybridization kit was concurrently approved for patient selection. In 2013, crizotinib received traditional (ie, regulator) approval based on demonstration of superior progression-free survival (PFS) in a confirmatory randomized trial against second-line chemotherapy (docetaxel or pemetrexed) in patients with ALK-positive advanced NSCLC.20
Similar to the EGFR TKIs afatinib and erlotinib, which received traditional FDA approval in 2013 for use in patients with advanced EGFR mutation—positive NSCLC, patients taking crizotinib invariably have tumor progression, usually within the first year of treatment.21 Development of resistance to TKIs occurs via different mechanisms, including emergence of secondary mutations and bypass oncogenic signaling pathways. In early 2013, the FDA granted a second-generation ALK inhibitor, ceritinib, breakthrough therapy designation based on preliminary evidence of clinical activity in patients with metastatic ALK-positive NSCLC previously treated with crizotinib. Ceritinib subsequently received accelerated approval for patients with advanced ALK-positive NSCLC based on demonstration of durable ORR and favorable benefit-risk in patients whose disease had progressed on crizotinib.22 Ceritinib’s approval came only 3 years following initiation of the first-in-human trial and 4 months after submission of the new drug application, demonstrating the FDA’s commitment to expedite the development and review of promising and breakthrough-designated therapies.
Targeting oncogenic driver mutations by inhibition of constitutively activated kinase products using kinase inhibitors has also been successful in other diseases, such as BRAF-mutated melanoma. The BRAF inhibitor dabrafenib was approved in 2013 for treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation based on superior PFS improvement and a favorable safety profile in a randomized trial with dabrafenib versus a standard chemotherapeutic agent, dacarbazine.23 As with EGFR and ALK TKI in advanced NSCLC, resistance to dabrafenib usually develops within the first year of treatment.
Modern recombinant techniques that evolved in the 1990s made it possible to rapidly produce chimeric and humanized antibodies with reduced immunogenicity.24 In 1997, rituximab, a chimeric monoclonal antibody against CD20, an antigen primarily found on the surface of immune system B cells, became the first monoclonal antibody to receive FDA approval for cancer therapy.25 The initial approval of rituximab for the treatment of patients with relapsed or refractory low grade or follicular B-cell non-Hodgkin lymphoma was later expanded to include more aggressive subtypes. Evidence of the efficacy of rituximab for the initial approval was based on demonstration of durable ORR of large magnitude. Unlike most kinase inhibitors, the exact mechanism of action of rituximab and newer CD20-directed therapies is poorly understood. Likely mechanisms of action include antibody-dependent cell-mediated cytotoxicity, complement-mediated cytotoxicity, and induction of apoptosis. However, the specific role of each mechanism in vivo remains uncertain, and there is little understanding of the underlying molecular mechanisms leading to resistance.26
Greater understanding of the mechanisms of response and resistance to monoclonal antibodies can help in individualizing therapy to maximize therapeutic benefit. For example, selection of patients with breast cancer whose tumors have amplification of the human epidermal growth factor receptor 2 (HER2) gene and overexpression of HER2 is the standard and FDA approved method for treatment with the HER2-directed monoclonal antibodies trastuzumab and pertuzumab. Likewise, the discovery of KRAS mutations as a negative predictive marker for response to EGFR-directed monoclonal antibodies led to changes in the FDA approved product labels of cetuximab and panitumumab in 2009, restricting the use of these drugs to patients with KRAS wild-type tumors. Unfortunately, nearly half of patients with KRAS wild-type colorectal tumors do not derive clinical benefit from the EGFR monoclonal antibodies, which highlights the existence of additional predictive markers within a complex signal transduction milieu.27
Efforts to increase the therapeutic benefit of monoclonal antibodies have led to the strategy of combining their targeting properties with the cytotoxicity of chemotherapeutic agents through development of antibody drug conjugates. Gemtuzumab ozogamicin, a humanized IgG4 monoclonal antibody coupled with calicheamicin, in 2000 became the first antibody drug conjugate approved by the FDA under the accelerated approval program for the treatment of acute myeloid leukemia.28 The drug was, however, withdrawn a decade later due to concerns about the product’s safety and its failure to demonstrate clinical benefit to patients enrolled in clinical trials. Brentuximab vedotin (a chimeric monoclonal antibody anti CD-30 coupled with monomethyl auristatin E) and ado-trastuzumab emtansine (the HER2-targeting monoclonal antibody trastuzumab conjugated to the cytotoxic compound DM1) were approved by the FDA for the treatment of Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma in 2011 and for HER2-positive metastatic breast cancer in 2013.
Several new biopharmaceutical technologies, such as cell-penetrating peptides and non-Ig based protein scaffolds, are currently under investigation. Many of these new technologies rely on target-specific internalization of the therapeutic agent, a process that aims to either alter the intracellular environment or deliver toxic payloads to the cytoplasm and/or specific subcellular compartments, with the end result of targeted cell death.29
Despite over a century of debate on the capacity of the immune system to fight malignant tumors, it was not until the 1960s that immunologists began to recognize the fact that a major function of the immune system is to eliminate malignant cells—a phenomenon largely based on a hypothesis proposed by Frank Macfarlane Burnet.30,31 Decades later, administration of high doses of IL-2 became the first immunotherapy to show complete and durable responses, its approval by the FDA for treatment of patients with renal cancer and melanoma coming in 1992 and 1998, respectively.32 However, significant toxicities associated with the administration of high-dose IL-2 have limited its use in clinical practice.
In the early 2000s, accumulating preclinical evidence of the role of cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) showed that it acted as an immunologic checkpoint that negatively regulates T-cell responses; further, blocking CTLA-4 was discovered to inhibit interaction of the protein with its ligands, leading to antitumor activity via T-cell activation and proliferation. These findings led to the development of the anti-CTLA-4 antibody ipilimumab.33 In 2011, the FDA approved ipilimumab for the treatment of unresectable or metastatic melanoma based on demonstration of superior improvement in overall survival (OS) in previously treated patients with advanced melanoma.
Selective blockade of immune checkpoint receptor, programmed cell death 1 (PD-1) or its ligand PD-L1, has also been shown to induce antitumor responses. Unlike CTLA-4, which is expressed exclusively on T cells and normally counteracts the activity of the T-cell costimulatory receptor CD28, the main role of PD-1 is to dampen the activity of T cells in peripheral tissues at the time of an inflammatory response to infection and to limit autoimmunity.34 Inhibition of PD-1 or PD-L1 have been successful strategies to illicit clinically significant antitumor responses. Several PD-1, PD-L1, and CTLA-4 antibodies are currently in development, many of which are being investigated in diseases such as lung cancer not traditionally thought to be amenable to immunotherapies. In 2015, the anti-PD-1 antibody nivolumab received FDA approval for the treatment of advanced melanoma in patients previously treated with ipilimumab, as well as in patients with squamous non-small cell lung cancer (SQ NSCLC) with progression on or after platinum-based chemotherapy. Treatment with nivolumab in SQ NSCLC was associated with clinically significant OS prolongation compared with standard second-line chemotherapy.
Emerging data suggest that tumor positivity for PD-L1 expression is a predictor of response to anti-PD-1 and anti-PD-L1 antibodies. However, there is currently no standard definition for PD-L1 positivity. Development plans for immunohistochemical characterization of PD-L1 in tumor tissue can benefit from standardized methods for analytical and clinical validation of companion diagnostic assays for patient selection.
Recent technological advances in development of targeted therapies using kinase inhibitors and monoclonal antibodies have paved the way for personalization of therapy in a growing segment of cancer patients. In cases where validated predictive biomarkers are available, administration of targeted therapies such as ALK inhibitors in NSCLC have been associated with unprecedented tumor response and clinical benefit. However, significant challenges remain, and curative interventions for advanced malignancies are extremely rare. Efforts to design tolerable combination therapies involving immune checkpoint and kinase inhibition are rational means of maximizing clinical benefit in the targeted delivery of anticancer therapies.35,36 These efforts can greatly benefit from appropriate patient selection based on molecular or immunohistochemical characterization of tumors and application of liquid biopsy techniques to supplement traditional disease classification schemes. Given that most cancers may be caused by random mutations arising from stem cell divisions of normal self-renewing cells, application of our evolving understanding of cancer genomics to secondary prevention for detection of early oncogenic events is an important strategy for reducing the burden of cancer-related deaths that can augment personalization of care in the global fight against cancer.37
Sean Khozin, MD, MPH, is a senior medical officer at the FDA’s Office of Hematology and Oncology Products.
Gideon Blumenthal, MD, is team leader of thoracic oncology at the FDA’s Office of Hematology and Oncology Products.
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