Similarly, another study aimed to lower the duration of trastuzumab even more. This study was presented as an abstract at the European Society for Medical Oncology (ESMO) 2018 Congress in Munich, Germany. To further assess whether a full year of therapy could provide the same clinical outcomes with less toxicity, in the Short-HER trial, 1254 patients were randomly selected to receive either 9 weeks or 1 year of treatment with trastuzumab.4
The median study follow-up was 6 years. However, the study was underpowered, and noninferiority between the 2 regimens could not be shown. Ultimately, the 9-week arm had significantly fewer cardiac events compared with the individuals who had been receiving the standard of care for 1 year (4.5% vs 12.8%, respectively; relative risk [RR] 2.88, 95% confidence interval [CI], 1.85-4.47).4
In addition to studies evaluating lower doses and shorter-duration regimens in patients requiring biologic agents, similar studies are taking place in oral chemotherapeutic agents as well. Ibrutinib is an oral agent that irreversibly binds the Bruton’s tyrosine kinase (BTK) and is used in chronic lymphocytic leukemia (CLL).5 The current FDA-approved dose for patients with CLL is 420 mg daily. This dose was derived from the phase 1 studies that included patients with relapsed or refractory disease.
Therefore, it could be possible that “de novo” patients may not need as much drug, while at the same time, there could be an opportunity to limit some of the side effects associated with high doses of a medication (eg, atrial fibrillation, bleeding, infections). Lisa S. Chen, MD Anderson Cancer Center, Houston, Texas, and colleagues conducted a pilot study evaluating a stepwise dose reduction of ibrutinib in patients with CLL over 3 cycles: 420 mg daily for 28 days followed by 280 mg daily for 28 days and then 140 mg daily for 28 days.
Even at the 140-mg dose, greater than 95% of the BTK protein was inhibited. Additional biomarkers (CCL3 and CCL4) also had comparable reductions in the lower dose cycle. As this was a pilot study, the number of patients (11 individuals) and duration of treatment (3 cycles) was limited, therefore, future studies are required to further evaluate the long-term effects of such a dosing strategy.
If these types of studies continue to performed, there will have to be more dedicated post-FDA–approval dosing studies conducted. Performing these types of studies earlier on in the drug-development process may prolong regulatory review, however. An extended follow-up period is crucial to determine if outcomes are unchanged by using lower doses or shorter-duration regimens.
- Senkus E, Kyriakides S, Ohno S, et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(Suppl5):v8-v30.
- Earl HM, et al. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): Randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results [published online June 1, 2018]. J Clin Oncol. 2018;36(15_suppl):506-506. doi: 10.1200/JCO.2018.36.15_suppl.50
- Earl HM, Vallier AL, Dunn J, et al. Trastuzumab-associated cardiac events in the Persephone trial. Br J Cancer. 2016;115(12):1462-1470.
- Conte PF, Guarneri V, Bisagni G, et al. 9 weeks versus 1 year adjuvant trastuzumab for HER2+ early breast cancer: subgroup analysis of the ShortHER trial allows to identify patients for whom a shorter trastuzumab administration may have a favourable risk/benefit ratio [abstract 191PD_PR]. Ann Oncol. 2018;29(suppl_8): mdy424.005. doi: 10.1093/annonc/mdy424.005
- Chen LS, Bose P, Cruz ND, et al. A pilot study of lower doses of ibrutinib in patients with chronic lymphocytic leukemia. Blood. 2018;132(21):2249-2259.