|LETTER TO EDITOR
|Year : 2019 | Volume
| Issue : 2 | Page : 265
Reducing the dose: Balancing act between just right and too little?
Bharath Rangarajan, Ram Abhinav Kannan, Vignesh Kandakumar
Kovai Medical Center and Hospital, Coimbatore, Tamil Nadu, India
|Date of Web Publication||20-Dec-2019|
Kovai Medical Center and Hospital, Coimbatore, Tamil Nadu
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Rangarajan B, Kannan RA, Kandakumar V. Reducing the dose: Balancing act between just right and too little?. Cancer Res Stat Treat 2019;2:265
The review article on checkpoint inhibitor (CPI) dosing published in the last issue of the journal was both thought-provoking and relevant to clinical practice. The story of multiple dosing schedules with a lack of definite clarity on maximal tolerated dose in Phase I/II and an almost arbitrary dose selection in Phase III studies have been the norm for many if not all the checkpoint inhibitor agents. Dose escalation trial with 0.3, 3, and 10 mg/kg of ipilimumab confirmed the superior efficacy achieved with 10 mg/kg (response rates of 0%, 4.2%, and 11.1% at 0.3, 3, and 10 mg/kg, respectively). However, the doses chosen for the Phase III trials have ranged from 3 mg/kg to as low as 1 mg/kg when combined with a second CPI., Similar dosing schedule inconsistencies are also seen with other agents such as ipilimumab, tremelimumab, nivolumab, and pembrolizumab. However, this is not the first class of drugs that has faced this dosing conundrum. The dosage of rituximab and monoclonal antibodies such as bevacizumab remain at best an educated guess even today after nearly a decade. The differences of the dose and scheduling of CPI, i.e., 2-weekly vis-à-vis 3- or 4-weekly, have also been discussed by Renner et al.
The authors have highlighted the flow cytometry-assessed occupancy of programmed cell death (PD)-L1 sites in peripheral blood at low concentrations of nivolumab. This hypothesis has been clinically evaluated with low doses of nivolumab (20 mg or 100 mg) in a very small set of Korean patients where dose de-escalation did not prove to abrogate response or survival parameters. Similar research validating the preclinical/ex-vivo observations of dose reductions are especially needed as we forge ahead in cancer immunotherapy if we have to ensure that more eligible patients come under the treatment umbrella. The need of the hour is well-conducted, dose de-escalation trials to prove the noninferiority and collation of real-world data when nonapproved doses of these agents are used. While it is enticing to reduce doses and reduce costs as a direct consequence, we must not do it at the cost of reducing efficacy of the agent and risk giving too little.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Patil VM, Noronha V, Joshi A, Abhyankar A, Menon N, Banavali S, et al
. Low doses in immunotherapy: Are they effective? Cancer Res Stat Treat 2019;2:54-60. [Full text]
Hamid O, Chin K, Li J, Neyns B, Linette G Negrier S, et al
. Dose effect of ipilimumab in patients with advanced melanoma: Results from a phase II, randomized, dose-ranging study. J Clin Oncol 2008;26:489s.
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al
. Improved survival with ipilimumab in patients with metastatic melanoma. N
Engl J Med 2010;363:711-23. Erratum in: N
Engl J Med 2010;363:1290.
Renner A, Burotto M, Rojas C. Immune checkpoint inhibitor dosing: Can we go lower without compromising clinical efficacy? J Glob Oncol 2019;5:1-5.
Yoo SH, Keam B, Kim M, Kim SH, Kim YJ, Kim TM, et al
. Low-dose nivolumab can be effective in non-small cell lung cancer: alternative option for financial toxicity. ESMO Open 2018;3:e000332.
Noronha V. Making a case for cancer research in India. Cancer Res Stat Treat 2018;1:71-4. [Full text]