The pharmacokinetics (PK) of immune checkpoint inhibitors (ICIs) are subject to target-mediated drug position and time-varying drug clearance. Moderate to high interindividual variability in PK can currently be explained, only to some extent, by differences in patient-specific characteristics. |
Surrogate clinical endpoints for ICIs lack predictive value for overall survival. |
Novel immune activation biomarkers are of relevance to further optimize treatment and trial designs with respect to the PK and pharmacodynamics of ICIs. |
1 Introduction
2 Immune Checkpoint Inhibitors (ICIs)
2.1 Ipilimumab
Generic name (receptor target) | Marketing-authorization holder | Therapeutic indication | Date of authorization (FDA/EMA) | Recommended dose (FDA) | Recommended dose (EMA) | References |
---|---|---|---|---|---|---|
Ipilimumab (CTLA-4) | Bristol-Myers Squibb | Melanoma | March 2011/July 2011 | Metastatic: 3 mg/kg; 3-weekly (four doses) Adjuvant: 10 mg/kg; 3-weekly (four doses); followed by 12-weekly | 3 mg/kg; 3-weekly (four doses) | [48] |
Renal cell carcinoma | April 2018/November 2018 | 1 mg/kg; 3-weekly (four doses) | [48] | |||
Microsatellite instability-high or mismatch repair-deficient cancer Colorectal cancer | November 2018/– | 1 mg/kg; 3-weekly (four doses) | [48] | |||
Atezolizumab (PD-L1) | Genentech/Roche | Urothelial carcinoma | May 2016/September 2017 | 1200 mg; 3-weekly | 1200 mg; 3-weekly | [49] |
Nonsmall cell lung cancer | October 2016/September 2017 | 1200 mg; 3-weekly | 1200 mg; 3-weekly | [49] | ||
Avelumab (PD-L1) | Merck Serono | Merkel cell carcinoma | March 2017/conditional approval | 10 mg/kg; 2-weekly | 10 mg/kg; 2-weekly | [21] |
Urothelial carcinoma | May 2017/– | 10 mg/kg; 2-weekly | [21] | |||
Durvalumab (PD-L1) | AstraZeneca | Urothelial carcinoma | May 2017/– | 10 mg/kg; 2-weekly | [27] | |
Nonsmall cell lung cancer | February 2018/– | 10 mg/kg; 2-weekly | [27] | |||
Nivolumab (PD-1) | Bristol-Myers Squibb | Melanoma | December 2014/June 2015 | 240 mg; 2-weekly/480 mg; 4-weekly | 3 mg/kg; 2-weekly | [31] |
Nonsmall cell lung cancer | October 2015/October 2015 | 240 mg; 2-weekly/480 mg; 4-weekly | 3 mg/kg; 2-weekly | [31] | ||
Renal cell carcinoma | November 2015/February 2016 | 240 mg; 2-weekly/480 mg; 4-weekly | 3 mg/kg; 2-weekly | [31] | ||
Classic Hodgkin lymphoma | May 2016/October 2016 | 240 mg; 2-weekly/480 mg; 4-weekly | 3 mg/kg; 2-weekly | [31] | ||
Squamous cell cancer of the head and neck | November 2016/March 2017 | 240 mg; 2-weekly/480 mg; 4-weekly | 3 mg/kg; 2-weekly | [31] | ||
Urothelial carcinoma | February 2017/– | 240 mg; 2-weekly/480 mg; 4-weekly | [31] | |||
Microsatellite instability-high or mismatch repair-deficient cancer Colorectal Cancer | August 2017/– | 240 mg; 2-weekly | [31] | |||
Hepatocellular carcinoma | September 2017/– | 240 mg; 2-weekly/480 mg; 4-weekly | [31] | |||
Pembrolizumab (PD-1) | Merck | Melanoma | September 2014/July 2015 | 200 mg; 3-weekly | 2 mg/kg; 3-weekly | [38] |
Nonsmall cell lung cancer | October 2015/December 2016 | 200 mg; 3-weekly | 200 mg; 3-weekly/2 mg/kg; 3-weekly | [38] | ||
Squamous cell cancer of the head and neck | August 2016/– | 200 mg; 3-weekly | [38] | |||
Classical Hodgkin lymphoma | March 2017/March 2017 | 200 mg; 3-weekly | 200 mg; 3-weekly | [38] | ||
Urothelial carcinoma | May 2017/July 2017 | 200 mg; 3-weekly | 200 mg; 3-weekly | [38] | ||
Microsatellite instability-high cancer | May 2017/– | 200 mg; 3-weekly | [38] | |||
Gastric cancer | September 2017/– | 200 mg; 3-weekly | [38] |
2.1.1 Pharmacokinetics
Generic name (isotype) | No. of patients | Dose range (mg/kg ) | t½ (days) | PopPK model | CL (L/day) | Vc (L) | Vp (L) | Q (L/day) | Vmax (mg/day)/Km (mg/L) | IIV (CV%) | Covariatesb,c [% of IIV attributable to covariates conjointly] | References |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Ipilimumab (IgG1) | 499 | 0.3–10 | 15 | 2-comp, LE | 0.36 | 4.15 | 3.11 | 0.9864 | CL: 35.4% Vc: 14.9% | (BW(0.642) POWER,80KG + LDH(1.13) POWER,206IU/L) ~ CL[24%] (BW(0.708) POWER,80KG) ~ Vc [52%] | [13] | |
Atezolizumab (IgG1) | 906 | 1–20 | 27 | 2-comp, LE | 0.20 | 3.28 | 3.63 | 0.546 | CL: 29% Vc: 18% Vp: 34% | (ALBU(− 1.12)40G/L + ADA(0.159)PRESENCE + BW(0.808)77KG +TB(0.125)) 63MM ~ CL[15%] (ALBU(− 0.350)40g/L + BW(0.559) 77KG + SEX(− 0.129)) Female ~ Vc[5.6%] (SEX(− 0.272))Female ~ Vp (BW)77KG ~ AUCss | [18] | |
Avelumab (IgG1) | 1629 | 1–20 | 6.1 | 2-comp, LE | 0.59 | 2.83 | 1.17 | CL: 25.2% Vc: 18.3% Vp: 1.05% | (ALBU(− 0.5)BASELINE + BW(0.358)BASELNE + CANC(− 2.24)MCC + DOSE(0.26)3MG/L + SEX(0.199)MALE + TB(0.095))BASELINE ~ CL (ACE(− 0.56)YES + CANC(− 0.864)MCC /CANC(− 0.692)NSCLC ~ Q (BW(0.367) BASELINE + SEX(0.203))MALE ~ Vc (ACE(− 0.233)YES + CANC(0.723)HNC/CANC(8.58)MCC + eGFR(− 0.507) + ADA(− 0.667))PRESENCE ~ Vp | [22] | ||
Durvalumab (IgG1) | 1324 | 0.1–20 | 21 | 2-comp, LE + NLE | 0.232 | 3.51 | 3.45 | 0.476 | 0.824/0.344 | CL: 27.2% Vc: 22.1% | (ADA(0.234)PRESENCE + ALBU(− 0.0350)POWER,38G/L + BW(0.389)POWER,69KG + CANC(0.00178)UC + CLcr(0.00149)LINEAR,87ML/MIN + ECOG(− 0.0630)SCORE=0 + LDH(0.0915)POWER,240IU/L + SEX(− 0.143)FEMALE +SPDL1(0.0844)POWER,124PG/ML) ~ CL[15%] (BW(0.406)POWER,69KG + SEX(− 0.205)FEMALE) ~ Vc; | [29] |
Nivolumab (IgG4) | 1895 | 0.1–20 | 25 | 2-comp, LE | 0.23 | 3.63 | 2.78 | 0.770 | CL: 35% Vc: 35.1% | (BW(0.566) POWER,80KG + eGFR(0.186)POWER,90ML/MIN + PS(0.172),PS=0 + RACE(− 0.125)ASIAN + SEX(18%) MALE) ~ CL[30%] (BW(0.597) POWER,80KG + SEX(0.152) MALE) ~ Vc [21%] | [32] | |
Pembrolizumab (IgG4) | 1223 | 1–10 | 27.3 | 2-comp, LE | 0.22 | 3.48 | 4.06 | 0.795 | CL: 38% Vc: 21% | (ALBU(− 0.907)POWER,39.6G/L + ECOG-PS(− 0.0739)SCORE=1 + eGFR(0.135)POWER,88ML/MIN + IPIP(0.140)PRIORTREATMENT + SEX(− 0.152)FEMALE + TB(0.0872)NSCLC) ~ CL[32%] (ALBU(− 0.208) POWER,39.6G/L + IPIP(0.0736)YES + SEX(− 0.134) FEMALE) ~ Vc | [41] | |
Not given | 0.02–10 | 14–22 | 2-comp, LE + NLE | 0.168 | 2.88 | 2.85 | 0.384 | 0.114/0.0784 | – | [39] | ||
2841 | 1–10 | 2-comp, LE, TV | 0.249 | 3.47 | 2.96 | 0.889 | CL: 30.7% Vc: 19.6% | (ALBU(− 0.9)POWER,77KG + BR(− 0.0521)POWER,8.88μmol/L + CANC(0.0774) ADDITIVE, MELANOMA=1,NSCLC=2 + eGFR(0.122) POWER,91mL/min + ECOG(0.065)ADDITIVE,BASELINE + SEX(− 0.158) ADDITIVE,FEMALE=1,MALE=2) + TB(0.102)POWER,BASELINE) ~ CL (ALBU(− 0.219) POWER,77KG + SEX(− 0.128)ADDITIVE,FEMALE=1,MALE=2) ~ Vc | [40] |
2.1.2 Exposure–Efficacy Relationship
Generic name | Cancer | No. of patients | Exposure measure | Dose range | OS | PFS | ORR | irRC | TPR | TSR | BPCTL | References |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Ipilimumab | Melanoma | 419 | Cmin,ss | 0.3–10 mg/kg | Positive relationship | Positive relationship | Positive relationship | [15] | ||||
Dose | 0.3–10 mg/kg | Positive relationship | [15] | |||||||||
Atezolizumab | Urothelial carcinoma | 306 | AUC21, AUCss, Cmax, Cmin | 1200 mg | No relationship | [18] | ||||||
Nonsmall cell lung cancer | 653 | AUCss | 1200 mg | Positive relationship | [19] | |||||||
Avelumab | Merkel cell carcinoma | 88 | AUCss, Cave, Cobs-trough,first, Cobs-trough,ss, Ctrough,first, Ctrough,ss | 10 mg/kg | AUCss and Ctrough,ss: positive relationship | AUCss and Ctrough,ss: positive relationship | Ctrough,first, AUCss, Cave, Ctrough,ss: positive relationship | [22] | ||||
Durvalumab | Urothelial carcinoma | 91 | Cmax,1, Cmin,2, and Cmin,ss | 10 mg/kg | No relationship | No relationship | [29] | |||||
Nivolumab | Melanoma | 107 | Cmin,ss | 0.1–10.0 mg/kg | Positive relationship (max. 1 mg/kg) | Inverse relationship (max. 3 mg/kg) | No relationship | [33] | ||||
Dose | 0.1–10.0 mg/kg | Numerically higher at 3 mg | No relationship | [33] | ||||||||
221 | Cavg1 | 0.1–10.0 mg/kg | No relationship | No relationship | [34] | |||||||
Nonsmall cell lung cancer | 129 | Cmin,ss | 1–10.0 mg/kg | Positive relationship (max. 3 mg/kg) | No relationship | Positive relationship (max. 3 mg/kg) | [33] | |||||
Dose | 1–10.0 mg/kg | Numerically higher at 3 mg | Numerically higher | [33] | ||||||||
Renal cell carcinoma | 34 | Cmin,ss | 1–10.0 mg/kg | No relationship | No relationship | Positive relationship (max. 3 mg/kg) | [33] | |||||
Dose | 1–10.0 mg/kg | Numerically higher at 1 and 10 mg/kg | No relationship | [33] | ||||||||
Not given | Cavg1, Cavg,ss | 0.3–10.0 mg/kg | Cavg,ss: positive relationship | [35] | ||||||||
Pembrolizumab | Melanoma | 364/1366 | AUCss–6 weeks | 2–10.0 mg/kg | No relationship | [43] | ||||||
Nonsmall cell lung cancer | 496 | AUCss–6 weeks | 2–10.0 mg/kg | No relationship | [44] |
2.1.3 Exposure–Safety Relationship
Generic name | No. of patients | Exposure measure | Dose range | irAE | AESI | TEAE | AE (grade 3 or higher) | AE-D/DC | References |
---|---|---|---|---|---|---|---|---|---|
Ipilimumab | 498 | Cmin,ss | 0.3–10 mg/kg | Positive relationship | [15] | ||||
Atezolizumab | 513 | AUC21, AUCss, Cmax, Cmin | 1–20 mg/kg/1200 mg | No relationship | No relationship | [18] | |||
1007 | AUCss | 15 mg/kg/1200 mg | Positive relationship | Positive relationship | [19] | ||||
Avelumab | 1629 | AUCss, Ctrough,first, Ctrough,ss | 1–20 mg/kg | Ctrough,ss: positive relationship | No relationship | [22] | |||
Durvalumab | 1393 | Cmax,1, Cmin,2, Cmin,ss | 10 mg/kg | No relationship | No relationship | [29] | |||
Nivolumab | 306 | Dose | 0.1–10.0 mg/kg | No relationship | No relationship | [33] | |||
336 | Cavg1 | 0.1–10.0 mg/kg | No relationship | [34] | |||||
Pembrolizumab | 544 | AUCss–6 weeks | 2–10 mg/kg | No relationship | [44] | ||||
Dose | 2–10 mg/kg | No relationship | [44] |
2.2 Atezolizumab
2.2.1 Pharmacokinetics
2.2.2 Exposure–Efficacy Relationship
2.2.3 Exposure–Safety Relationship
2.3 Avelumab
2.3.1 Pharmacokinetics
2.3.2 Exposure–Efficacy Relationship
2.3.3 Exposure–Safety Relationship
2.4 Durvalumab
2.4.1 Pharmacokinetics
2.4.2 Exposure–Efficacy Relationship
2.4.3 Exposure–Safety Relationship
2.5 Nivolumab
2.5.1 Pharmacokinetics
2.5.2 Exposure–Efficacy Relationship
2.5.3 Exposure–Safety Relationship
2.6 Pembrolizumab
2.6.1 Pharmacokinetics
2.6.2 Exposure–Efficacy Relationship
2.6.3 Exposure–Safety Relationship
3 Discussion
3.1 Pharmacokinetics
3.1.1 Linear and Nonlinear Clearance
3.1.2 Time-Varying Clearance
3.1.3 Distribution
3.1.4 Therapeutic Drug Monitoring
3.1.5 Serum Assays for ICIs
3.2 Exposure–Efficacy Relationships
3.2.1 Target Engagement
3.2.2 Overall Survival
3.2.3 Surrogate Clinical Endpoints
Cancer type | Investigated therapies | Correlation ORR/OS | Correlation PFS/OS | References |
---|---|---|---|---|
All | Anti-PD-1/PD-L1 | R2 = 0.066 (p = 0.251) | R2 = 0.432 (p = 0.032) | [80] |
Melanoma | ICIs | R2 = 0.028 (p = 0.279) | R2 = 0.192 (p = 0.154) | [80] |
Nonsmall cell lung cancer | ICIs | R = 0.452 (p = 0.141) | R = 0.473 (p = 0.120) | [81] |
Renal cell carcinoma | ICIs and other drugs | 89–96% for RD, 81–91% for SD, and 50–70% for PD | – | [82] |
Urothelial carcinoma | ICIs and other anticancer drugs | R = 0.37 (p = 0.30) | – | [83] |