The drug development path for a new chemotherapeutic agent can be a challenging process. A significant amount of time and money are spent to ensure that the new agent is both safe and effective. A key clinical question to answer both in early- and late-stage studies is, “What dose provides the best clinical outcome with the fewest amount of side effects?” Preclinical and phase 1 studies will often help lay the groundwork for determining specific doses and dose schedules to pursue in subsequent studies.
As the medication continues to progress through different phases, the eventual dose and corresponding regimen, along with duration, is finalized in phase 3. Should the US Food and Drug Administration grant the investigational drug’s approval, the drug could then be required to enter into a phase 4 postmarketing surveillance period, during which time data are collected from “real-world” patients; some of these data are then made available to the public and can be evaluated further.
One potential scenario that arises during this process is determining if the chemotherapeutic agent can be used at even lower doses or shorter durations than those that were originally approved by FDA, but still provide the same clinical outcomes. This could lead to less exposure to potentially harmful chemotherapeutic agents and provide cost savings — reducing both physical and financial toxicity.
One recent example includes the evaluation of the role of trastuzumab in HER2-positive breast cancer. Patients with HER2-positive early-stage breast cancer are currently recommended to have 1 year of anti-HER2 antibody therapy in conjunction with adjuvant chemotherapy.1 The PERSIPHONE study aimed to evaluate 6 months compared with 12 months of trastuzumab in these patients and how it would affect both safety and efficacy outcomes. The preliminary efficacy data presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting.2 In this noninferiority trial, 4089 patients were randomly selected across 152 sites in the United Kingdom.
The median follow-up was 4.9 years. Both the 6-month and 12-month arms had a disease-free survival (DFS) of 89% (95% confidence interval [CI], 88%-91%) with a hazard ratio [HR] of 1.05 (95% CI 0.88-1.25), which indicated noninferiority of the 6-month regimen.
Additionally, there was less cardiotoxicity seen in the 6-month group (4% vs 8%, P < .0001). These data are also in line with the previously published safety data from the PERSEPHONE trial, which showed that the 6-month group had less of the following: delays in treatment (4% vs 6%, P = .01) and overall treatment discontinuation (4% vs 8%, P < .0001) secondary to cardiotoxicity.3 Between 7 months and 12 months of the study, the 6-month group had fewer patients with left ventricular ejection fractions of less than 50% (5% vs 8%, P = .004).