|Year : 2019 | Volume
| Issue : 1 | Page : 54-60
Low doses in immunotherapy: Are they effective?
Vijay M Patil, Vanita Noronha, Amit Joshi, Anuja Abhyankar, Nandini Menon, Shripad Banavali, Sudeep Gupta, Kumar Prabhash
Department of Medical Oncology, Tata Memorial Centre, HBNI, Mumbai, Maharashtra, India
|Date of Web Publication||9-Sep-2019|
Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
Checkpoint inhibitors are versatile immunomodulatory agents, and they are being approved for the treatment of an increasing number of cancers, based on the demonstration of clinical benefits. While they have changed the landscape of treatment of many cancers, they remain inaccessible to most patients, especially in low-income countries because of their prohibitive costs. Conventionally, chemotherapy drug doses are decided based on the maximum tolerable dose in phase 1 studies, but this dose-finding methodology is not applicable to targeted therapies where dose-limiting toxicity is not reached at doses much higher than sufficiently active doses. This review article focuses on how lower doses of immunotherapy drugs could be as efficacious as the currently recommended doses, thus decreasing the financial burden.
Keywords: Accessibility, biologically effective dose, checkpoint inhibitor, financial toxicity, immunotherapy, low dose
|How to cite this article:|
Patil VM, Noronha V, Joshi A, Abhyankar A, Menon N, Banavali S, Gupta S, Prabhash K. Low doses in immunotherapy: Are they effective?. Cancer Res Stat Treat 2019;2:54-60
|How to cite this URL:|
Patil VM, Noronha V, Joshi A, Abhyankar A, Menon N, Banavali S, Gupta S, Prabhash K. Low doses in immunotherapy: Are they effective?. Cancer Res Stat Treat [serial online] 2019 [cited 2019 Nov 13];2:54-60. Available from: http://www.crstonline.com/text.asp?2019/2/1/54/266451
| Chemotherapy Drug Dose|| |
Chemotherapy drug doses are selected after phase 1 studies. Conventionally, phase 1 studies use a titration principle based on the concept of maximum tolerable dose (MTD). In phase 1 studies, the investigators titrate the dose of the chemotherapy agent upward until a dose-limiting toxicity (DLT) is reached. The dose which leads to a predecided proportion of DLTs is termed as the MTD. The MTD or a dose below it (dose level below MTD) is recommended for phase 2 studies (RP2D). This concept is based on the dose–response curve with an assumption that a higher dose would provide better response and/or outcomes. This dose is subsequently used in phase 3 and phase 4 studies and in routine practice if the drug becomes the standard of care (SOC).
While MTD-based determination of the RP2D may yield appropriate dosing for some cytotoxic chemotherapy drugs, targeted therapies need alternative or complementary strategies. The use of MTD-based dose selection may not be the correct strategy, because for many targeted therapies, including monoclonal antibodies (mAb) and/or immunotherapies, DLT may not occur even at doses significantly higher than sufficiently active doses.,, In such cases, the decision criteria for stopping the dose escalation can be unclear. Hence, frequently, a higher than necessary dose is used in phase 2 studies and as a result in phase 3 and 4 studies and then subsequently in routine practice.
| Dose Revision|| |
Revision in a United States Food and Drug Administration (FDA)-approved dose may be suggested either based on postmarketing surveillance showing higher toxicity or similar efficacy at lower doses. A recent example for toxicity is cabozantinib, a multiple tyrosine kinase inhibitor, which was approved at a dose of 140 mg every day, slightly lower than the MTD (175 mg every day) identified in the phase 1 study. Although lower exposure did not reduce the progression-free survival (PFS), higher exposure was associated with earlier dose reduction; at the 140 mg dose, 65% of patients had treatment gaps and 79% required dose reduction. Currently, a trial comparing the safety and activity of cabozantinib at the approved dose to those at a lower, biologically active dose is ongoing.
Another example of such a dose change happened with decitabine, a DNA methyltransferase inhibitor used in acute myeloid leukemia (AML). The phase 1 study identified the MTD, which was determined to be 1.5–2 g/m 2/course nearly three decades ago; however, these doses led to disappointing outcomes., This drug was restudied with the dose being modulated by pharmacodynamics, rather than the MTD. Gene expression-based pharmacodynamic markers of estrogen receptor 1 and cyclin-dependent kinase inhibitor 2B were used for selecting the dose. The dose selected was 20 mg/m 2/d for 10 days. When decitabine was used in this dose and schedule, its clinical effectiveness was proven. The drug was approved by the European Medicines Agency for the treatment of AML in older adults and by the FDA for myelodysplasia at the lower dose of 20 mg/m 2/day for 5 days. Similar dose changes have occurred with abiraterone and afatinib too.,,
A recent review of FDA approval of new oncology drugs between 2010 and 2015 suggests that roughly half of the drugs have labeled doses less than the MTD. This practice is increasing as now the emphasis is shifting to approving the dose based not on the MTD, but on the biologically effective dose (BED). The concept of BED is that antibodies and targeted therapies have a dose level, above which the dose–response curve plateaus, and it is frequently below the MTD. The use of BED instead of MTD puts patients at lower risk of toxicity and is more cost-effective.
| Immunotherapy: Checkpoint Inhibitors|| |
Checkpoint inhibitors constitute a versatile class of immunomodulatory agents and have demonstrated clinical benefits in the treatment of several cancers. The recent increase in the number of approvals for these agents has accelerated the development of immuno-oncology therapy in general.
- Ipilimumab (anti-CTLA-4 inhibitor) was the first checkpoint inhibitor to be made commercially available. Ipilimumab received FDA approval for the treatment of unresectable or metastatic melanoma  and as adjuvant therapy for melanoma 
- Nivolumab (anti-programmed cell death protein [PD]-1 inhibitor) was first approved for the treatment of patients with unresectable or metastatic melanoma, initially for second-line treatment after failure of ipilimumab and after a BRAF inhibitor in patients positive for BRAF V600 mutation. Subsequently, nivolumab was approved by the FDA for first-line treatment of melanoma, regardless of the BRAF status. Nivolumab has also been approved for the treatment of advanced non-small-cell lung cancer (NSCLC), metastatic renal cell carcinoma (RCC),, head-and-neck squamous cell carcinoma (HNSCC), Hodgkin's lymphoma, and urothelial cancer  as well as in combination with ipilimumab for the treatment of advanced melanoma 
- Pembrolizumab (anti-PD-1 inhibitor) was approved by the FDA as second-line treatment for metastatic melanoma, then as first-line treatment  and subsequently as adjuvant. Pembrolizumab is also approved for use in advanced NSCLC,,, HNSCC, Hodgkin's lymphoma, urothelial cancer, and microsatellite instability-high cancer 
- Atezolizumab (anti-PD-L1 inhibitor) received accelerated approval in May 2016 for locally advanced or metastatic urothelial carcinoma after failure of platinum-based chemotherapy. It is also approved for first-line treatment of advanced NSCLC, metastatic breast cancer, and RCC 
- Avelumab (anti-PD-L1 antibody) is approved for the treatment of adults and pediatric patients aged 12 years and older with metastatic Merkel cell carcinoma and for locally advanced  or metastatic urothelial carcinoma after failure of platinum-containing chemotherapy 
- Durvalumab (anti-PD-L1 antibody) is approved for locally advanced or metastatic urothelial carcinoma after failure of platinum-containing chemotherapy  and as maintenance post chemoradiation in NSCLC.
| Dosing Characteristics of Immunotherapy|| |
Multiple factors, which include the adverse event rate, drug pharmacokinetics (PK), pharmacodynamics, immunological correlates, exposure–efficacy parameters, and exposure–safety parameters, have been used for decision-making in immunotherapy doses.
Table 1 provides the details of dosing characteristics. A variety of schedules tested in phase 1 trials shown for each agent along with the schedule approved, the mode of administration, and the time of infusion are depicted in [Table 1].
A few things are common across all checkpoint inhibitors:
- Checkpoint inhibitors are antibodies and belong to either immunoglobulin G (IgG1) or IgG4 type. Hence, these are large molecules and have characteristics similar to antibodies/immunoglobulins
- Schedules are dosed based on the body weight and not the body surface area
- Schedules from 1 mg/kg to 10–20 mg/kg were tested
- Cycle durations approved are between 2 and 3 weeks
- Both dose per weight and flat doses are approved.
| Dose Selection from Phase 1 Data: Pharmacokinetics|| |
The PK of the approved checkpoint inhibitors (monoclonal antibodies or mAbs) is similar to that of endogenous IgG. The typical volume of distribution of mAbs is comparable to plasma volume (i.e., 2–4 L); however, it has been shown that mAbs administered by all routes do reach the peripheral tissues. Drug receptor binding affinity and association–dissociation kinetics play an important role in distribution. Elimination occurs by both specific (target-mediated) and nonspecific (Fc-mediated) routes, accounting for the nonlinear and linear elimination PK, respectively. Following target saturation, the linear, nonspecific route of elimination is predominant, and accordingly, the half-life of these drugs ranges from 3 to 4 weeks.
Takeaways from [Table 2] that are important for the scheduling of immunotherapy:
|Table 2: Table depicting the pharmacokinetics of the immunotherapy agents|
Click here to view
- Scheduling of any drug is primarily dependent on its half-life. Half-life is the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%. In general, drugs are dosed at intervals equal to the half-life of the drug
- The terminal half-life of all immunotherapy drugs except avelumab is longer than 21 days. Despite this, the recommendation for dosing of nivolumab is once every 2 weeks. Pembrolizumab, a drug with a shorter half-life than nivolumab, has a recommended dosing interval of once in 3 weeks. The half-life of atezolizumab permits dosing at once-in-4-weeks intervals 
- This belief is further strengthened by the fact that a 480 mg flat dose of nivolumab has been used in certain trials at once-in-4-weeks intervals. This is based on the Checkmate 384 study, in which the dose of 480 mg once in 4 weeks was found to be noninferior to the dose of 240 mg once in 2 weeks. This led to an FDA label change in April 2018, in which both the schedules were included. Similarly, a 400 mg dosing regimen of pembrolizumab leads to exposures that are similar to the approved 200 mg once-in-3-weeks dosing regimen 
- An argument could be made that a higher dose might have a longer half-life. However, this is not true. As shown in [Table 2], these agents have a 2-compartment model with linear elimination. This means that even if a higher dose is given, the half-life would remain the same
- Thus, there is a strong case for consideration of dosing of immunotherapy drugs once every 3–4 weeks.
| Dose Selection from Phase 1 Data: Pharmacodynamics (Programmed Cell Death) – a Case for Lower Dose|| |
Target: T cell
The T-cell is the primary target of checkpoint inhibitors. In general, 20%–40% of peripheral blood T cells express PD-1 and 70%–75% of these are required to be occupied for the activation of the T cell. This target occupancy is a function of affinity of the antibody and its serum concentration, while serum concentration is a function of the dose and schedule of administration [Table 3].
| Nivolumab – low-Dose Receptor Occupancy|| |
Flow cytometry has been used to demonstrate the receptor occupancy assay in peripheral blood. This analysis demonstrated that between 70% and 90% of the PD-1 molecules expressed on peripheral blood lymphocytes are occupied by anti-PD-1., Surprisingly, plateau levels of receptor occupancy are achieved at doses as low as 0.1–0.33 mg/kg, attesting to the high affinity/avidity of the clinical antibody, thus suggesting that doses of nivolumab as low as 0.1 mg/kg can theoretically be as efficacious as higher doses because the required target occupancy is achieved at lower dose levels and persists for nearly 3 months after administration. The concentration produced at the current dose is 33.7 μg/ml, whereas the required concentration is 1.2 μg/ml., In addition, high levels of receptor occupancy are maintained for as long as 90 days after cessation of antibody administration.
| Exposure–efficacy (Clinical Studies With Lower Doses)|| |
Data from phase 1 studies which used multiple dose levels suggest that, in general, response does not decrease with a decrease in the dose.,,, The dose–response curve does not seem to be linear for immunotherapy. [Table 4] which includes data for multiple tumors with multiple dose ranges for multiple immunotherapy agents suggests similar responses to different dose levels. This again suggests that lower doses might have similar efficacy. In addition, in a retrospective analysis published by Yoo et al. from Korea, low-dose immunotherapy with nivolumab was found to be as effective as a standard dose. During 5.2 months of follow-up in this study, the objective response rate was 13.8% in the standard-dose group and 16.7% in the low-dose group (P = 0.788). The median PFS of the low-dose group was 3.0 months (95% confidence intervals, 0.8 months to not reached), which was not significantly different from that of the standard-dose group at 1 month (95% confidence intervals, 0.6–1.7; P= 0.242). The median overall survival was 12.5 months in all the patients: 8.2 months in the standard-dose group and 12.5 months in the low-dose group. These findings make a strong case for exploring low-dose nivolumab.
| Rationale for Using Low Dose|| |
Taking into account the PK, mechanism of action, receptor occupancy, phase 1 clinical trial results, and the low-dose nivolumab analysis from Seoul, it can be concluded that low-dose levels of nivolumab may be adequate. The receptor occupancy (PD-1) required for effective action is 70%–90%. This receptor occupancy is achieved at a very low dose of 0.1–0.3 mg/kg. Data from phase 1 studies with nivolumab have not shown a dose–response curve, which suggests that an increase in the dose is not associated with a higher response. The recently published Korean data further strengthen the belief that low-dose nivolumab might be as effective as the standard dose.
The cost of nivolumab at the current dosing of 3 mg/kg is approximately ₹ 188,000 per dose, which is beyond what most patients can afford. Unpublished data from Tata Memorial Center revealed that only 1.61% of patients who are advised immunotherapy for an approved indication can afford the medication.
| Conclusion|| |
There appears to be a strong scientific and social rationale for the development of low-dose immunotherapy regimens. Further studies should be encouraged to fulfill this unmet need, enabling a larger number of patients to gain access to this promising treatment without being crippled by prohibitive costs.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]