Abstract
This analysis was conducted to inform dose selection of a combination of nivolumab plus ipilimumab for the treatment of sorafenib‐experienced patients with hepatocellular carcinoma (HCC). CheckMate 040 is an open‐label, multicohort, phase I/II trial in adults with advanced HCC that evaluated nivolumab monotherapy (0.1–10 mg/kg once every 2 weeks [q2w]) and the following three combinations of nivolumab plus ipilimumab: (1) nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks (q3w) for four doses, followed by nivolumab monotherapy 240 mg q2w (arm A); (2) nivolumab 3 mg/kg plus ipilimumab 1 mg/kg q3w for four doses, followed by nivolumab monotherapy 240 mg q2w (arm B); and (3) nivolumab 3 mg/kg q2w plus ipilimumab 1 mg/kg every 6 weeks continuously (arm C). Exposure‐response relationships (efficacy and safety) were characterized using nivolumab and ipilimumab concentrations after the first dose (Cavg1) as the exposure measure. Objective tumor response (OTR) and overall survival (OS) improvements were associated with increased ipilimumab exposure (OTR: odds ratio 1.45, 95% confidence interval [CI], 1.13–1.86; OS: hazard ratio 0.86, 95% CI 0.75–0.98), but not nivolumab exposure (OTR: odds ratio 0.99, 95% CI 0.97–1.02; OS: hazard ratio 1.08, 95% CI 0.89–1.32). Hepatic treatment‐related and immune‐mediated adverse events were more common in arm A than in arms B or C. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg q3w for four doses, followed by nivolumab monotherapy 240 mg q2w had the most favorable benefit:risk profile in patients with advanced HCC.
Study Highlights.
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Exposure‐response analyses of nivolumab and ipilimumab efficacy and safety have been used to optimize dosage regimens in tumor types, such as advanced non‐small cell lung cancer and advanced melanoma.
WHAT QUESTION DID THIS STUDY ADDRESS?
The exploratory exposure‐response analyses conducted here evaluated the relationship between nivolumab and ipilimumab exposures and clinical outcomes in CheckMate 040 and further evaluated the benefit:risk profile to confirm the optimal dosage regimen for nivolumab plus ipilimumab combination therapy.
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
Objective tumor response and overall survival benefits were observed regardless of nivolumab exposure across doses of 1 mg/kg every 3 weeks to 3 mg/kg every 2 weeks, demonstrating its wide therapeutic range. Clinical benefit was positively associated with increased ipilimumab exposure but with a greater incidence of hepatic treatment‐related and immune‐mediated adverse events across doses of 1 mg/kg every 6 weeks to 3 mg/kg every 3 weeks.
HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
The approved regimen of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab monotherapy 240 mg every 2 weeks, had the most favorable benefit:risk profile in the second‐line setting, supporting its consideration as second‐line therapy for advanced hepatocellular carcinoma.
INTRODUCTION
Nivolumab is a monoclonal antibody that prevents the programmed death‐1 (PD‐1) receptor from binding to its ligands, programmed death ligand 1 and programmed death ligand 2, thereby releasing PD‐1 pathway–mediated immune responses against tumor cells. 1 Ipilimumab is a monoclonal antibody that binds to cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) and blocks the interaction with its ligands, CD80 and CD86, thereby augmenting the activation and proliferation of T cells, including tumor‐infiltrating T‐effector cells. 2 , 3 This inhibition of CTLA‐4 signaling has been shown to reduce T‐regulatory cell function and contribute to a general increase in T‐cell responsiveness, including the antitumor immune response. 4 Thus, nivolumab and ipilimumab promote antitumor immune responses by distinct and complementary mechanisms mediated by different signaling pathways.
Nivolumab in combination with ipilimumab is indicated for the treatment of several tumor types, including metastatic non‐small cell lung cancer, unresectable or metastatic melanoma, advanced renal cell carcinoma, advanced or metastatic urothelial carcinoma, metastatic microsatellite instability‐high colorectal cancer, and advanced hepatocellular carcinoma (HCC). 5 The recommended dosage regimen of nivolumab in combination with ipilimumab differs for some indications. Nivolumab in combination with ipilimumab received accelerated approval for the treatment of patients with advanced HCC previously treated with sorafenib based on findings from the multicenter, open label, multicohort phase I/II CheckMate 040 trial (NCT01658878). In cohort 4 of this trial, patients with advanced HCC were randomized to receive combination therapy with one of three nivolumab plus ipilimumab treatment regimens. Of these, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks (q3w) for four doses, followed by nivolumab monotherapy 240 mg every 2 weeks (q2w), provided the most favorable efficacy outcomes, with an objective response rate (ORR; investigator assessed) of 32% and a median overall survival (OS) of 22.8 months. 6 The other two regimens, nivolumab 3 mg/kg plus ipilimumab 1 mg/kg q3w for four doses followed by nivolumab monotherapy 240 mg q2w and nivolumab 3 mg/kg q2w plus ipilimumab 1 mg/kg every 6 weeks (q6w) continuously, each had an ORR of 31%, and the median OS was 12.5 and 12.7 months, respectively. 6
Exposure‐response analyses of efficacy and safety have been used to optimize dosage regimens and determine the contribution of components in combination therapy, thereby informing the benefit:risk assessment of a treatment. 7 In patients with advanced non‐small cell lung cancer or advanced melanoma, exposure‐response analyses of nivolumab 1–10 mg/kg q2w showed that nivolumab exposure was not associated with OS, the risk of adverse events (AEs) leading to discontinuation or death, or the risk of AEs greater than or equal to grade 3, but the relatively flat exposure‐response relationships over the range of exposures demonstrated the wide therapeutic margin of nivolumab in these patients. 8 , 9
In patients with advanced melanoma, an exposure‐response analysis showed that ipilimumab 10 mg/kg q3w significantly prolonged OS but had a higher incidence of treatment‐related AEs compared with ipilimumab 3 mg/kg q3w. 10 A separate analysis was conducted on pooled data from 498 patients with advanced melanoma who received ipilimumab monotherapy at 0.3, 3, or 10 mg/kg in multiple phase II clinical trials. This analysis also showed that higher doses of ipilimumab were associated with higher steady‐state ipilimumab trough concentration, which, in turn, was a significant predictor of improved response (p < 0.001). 11 Lower trough concentrations were associated with a lower median OS in the 0.3 mg/kg group than in the 3 mg/kg group (0.85‐fold lower) and the 10 mg/kg group (0.58‐fold lower). However, increasing ipilimumab exposure was associated with an increased probability of an immune‐related AE greater than or equal to grade 2 or greater than or equal to grade 3. 11
Given the relatively flat exposure‐response relationship observed with nivolumab, the range of ipilimumab dosage regimens in cohort 4 of CheckMate 040 provided the opportunity to characterize the ipilimumab contribution to efficacy and safety outcomes for this combination therapy. Here, we report the results of exploratory exposure‐response analyses that investigated the relationship between nivolumab and ipilimumab exposures and clinical outcomes from this trial and further evaluated the benefit:risk profile to confirm the optimal dosage regimen for the nivolumab plus ipilimumab combination. 12
METHODS
Study design
The analysis included data from sorafenib‐experienced patients enrolled in cohort 1 (nivolumab monotherapy dose escalation), cohort 2 (nivolumab monotherapy dose expansion), and cohort 4 (nivolumab in combination with ipilimumab at different dose levels) of CheckMate 040, a multicenter, open‐label, multicohort, phase I/II randomized clinical trial assessing the efficacy and safety of nivolumab plus ipilimumab in adult patients with advanced HCC who were previously treated with or intolerant to sorafenib. Study design details for cohort 4 and for cohorts 1 and 2 of nivolumab monotherapy have been published previously. 6 , 13 Briefly, key inclusion criteria for these cohorts were similar: patients had histologically confirmed advanced HCC and were either not eligible for surgical or locoregional therapy or had documented radiographic progression on or after sorafenib, or patients were sorafenib intolerant; Child‐Pugh class A liver function (A or B7 for cohort 1); Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; and at least one untreated measurable target lesion using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (cohort 4). 14 Patients with non‐viral advanced HCC or hepatitis B virus (HBV) infection (as evidenced by detectable HBV surface antigen or HBV DNA; patients had to be on antiviral therapy and have HBV DNA <100 IU/mL) or hepatitis C virus (HCV) infection (active or resolved as evidenced by detectable HCV RNA or antibody) were eligible, whereas patients with active coinfection with HBV and HCV or HBV and hepatitis D virus were excluded.
Patients in cohort 4 were randomized between January 4, 2016, and September 26, 2016, to receive (1) nivolumab 1 mg/kg plus ipilimumab 3 mg/kg q3w for four doses, followed by nivolumab monotherapy 240 mg q2w (arm A); (2) nivolumab 3 mg/kg plus ipilimumab 1 mg/kg q3w for four doses, followed by nivolumab monotherapy 240 mg q2w (arm B); or (3) nivolumab 3 mg/kg q2w plus ipilimumab 1 mg/kg q6w continuously (arm C). All treatments were administered until unacceptable toxicity or disease progression. The primary end points of the trial were safety and tolerability (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0) and ORR (investigator assessed using RECIST version 1.1). A secondary end point was ORR by blinded independent central review (BICR). Tumors were assessed at baseline and every 6 weeks until week 48, then every 12 weeks until disease progression.
The CheckMate 040 trial was approved by the institutional review board or independent ethics committee at each site and was conducted in accordance with Good Clinical Practice guidelines defined by the International Council for Harmonisation. All patients provided written informed consent to participate in the study based on the principles of the Declaration of Helsinki.
The main objective of the current exposure‐response analysis was to characterize the relationship between the level of nivolumab and ipilimumab exposure and clinical outcomes, and thereby assess the contribution of ipilimumab to the efficacy and safety of the combination with nivolumab in patients with advanced HCC, and to identify the dosing regimen that provides the most favorable benefit:risk profile.
Pharmacokinetic assessments
A series of blood samples were collected for the measurement of nivolumab and ipilimumab exposure in serum. These pharmacokinetic data were pooled with similar data from other studies and used to update previously developed population pharmacokinetic models for nivolumab and ipilimumab. 15 , 16
The updated population pharmacokinetic models were applied to derive nivolumab and ipilimumab time‐averaged concentrations following the first dose (Cavg1) for sorafenib‐experienced patients in cohorts 1, 2, and 4, based upon the assigned treatment regimen. These models were used to predict nivolumab and ipilimumab Cavg1 for all patients, utilizing the empirical Bayesian estimates of pharmacokinetic parameters determined by covariate data and available concentration values (including for patients with missing concentration values). These Cavg1 exposure measures were then utilized in the exposure‐response analyses.
A total 328 sorafenib‐experienced patients were included in the exposure‐response analyses; 182 received nivolumab monotherapy (0.1–10 mg/kg q2w) and 146 received nivolumab in combination with ipilimumab (data cutoff March 2019). The 146 patients treated with nivolumab plus ipilimumab in arms A, B, and C of cohort 4 were included in the exposure‐safety analysis of ipilimumab and data from patients in cohort 2 (n = 145) are reported for comparisons of safety measures (data cutoff March 2018).
Exposure‐response analysis of efficacy
Cavg1 values of nivolumab and ipilimumab were treated as a continuous variable to assess nivolumab and ipilimumab exposure‐efficacy relationships for two efficacy end points: objective tumor response (OTR) by BICR and OS. The OTR was defined as a best OTR of complete response or partial response (per RECIST version 1.1). 14
Odds ratios for associations between the probability of an OTR (Pr[OTR]) and nivolumab and ipilimumab exposures were derived using multivariable logistic regression analyses. Odds ratios for an OTR were calculated per log‐transformed unit increase in nivolumab or ipilimumab Cavg1 (μg/mL). The relationship between exposure and Pr[OTR] was assessed after accounting for the effects of all other covariates on the OTR logit model, including etiology, baseline tumor cell programmed death ligand 1 status (<1% vs. ≥ 1%), baseline ECOG performance status (0 vs. 1), baseline tumor size, presence of extrahepatic spread/vascular invasion (yes vs. no), and baseline nivolumab clearance. It was important to include nivolumab clearance in the analysis as it has been shown to be associated with efficacy, 8 , 9 and it was possible to account for the effect of clearance independent of exposure, as data from several dose levels were available for this analysis.
Hazard ratios (HRs) for associations between OS and nivolumab and ipilimumab exposures were derived from a multivariable Cox proportional hazards (CPH) model. HRs were calculated per log‐transformed unit increase in nivolumab or ipilimumab Cavg1 (μg/mL). Exposure effects on OS were assessed after accounting for the effects of all other covariates on the CPH model, including etiology, baseline alpha‐fetoprotein level, baseline ECOG performance status (0 vs. 1), baseline tumor size, baseline albumin level, log ratio of baseline lactate dehydrogenase upper limit of normal, and baseline nivolumab clearance.
Exposure‐response analysis of safety
The focus of the exposure‐response analysis of safety was on the relationship between safety and ipilimumab exposure, as nivolumab has been shown to be well‐tolerated over a range of doses (up to 10 mg/kg q2w, 17 which produces exposure over three‐fold higher than that observed in patients in cohort 4). The exposure‐safety relationship was evaluated descriptively for selected safety end points by treatment (combination arm in cohort 4 and nivolumab monotherapy in cohort 2), which differed according to initial ipilimumab exposure. Safety end points evaluated in relation to ipilimumab exposure included any‐grade and grade 3–4 hepatic treatment‐related AEs (TRAEs) and any‐grade and grade 3–4 immune‐mediated AEs (IMAEs). TRAEs were determined according to the Medical Dictionary for Regulatory Activities version 21.1 and included events reported between the first dose and up to 30 days after the last dose of study therapy. IMAEs, defined as specific events with an autoimmune etiology, included diarrhea and colitis, hepatitis, nephritis and renal dysfunction, pneumonitis, rash, and endocrine events (adrenal insufficiency, diabetes mellitus, hyperthyroidism, hypophysitis, and hypothyroidism/thyroiditis). IMAE analyses were conducted regardless of causality within 100 days of the last dose and limited to patients who received immune‐modulating medication, with the exception of endocrine events, which were included in the analysis regardless of treatment. All safety assessments were based on the clinical assessment of the investigator.
RESULTS
Patients
At the clinical data cutoffs, the minimum follow‐up was 28 months for cohort 4 and 31 and 27 months for cohorts 1 and 2, respectively. The baseline characteristics of patients included in the exposure‐response analysis are shown in Table 1. A high proportion of patients in cohort 4 had extrahepatic spread or vascular invasion, and the most commonly reported HCC etiology in each arm was HBV infection. A summary of the treatments received by each cohort is provided in Table S1.
TABLE 1.
Baseline patient demographics and disease characteristics of exposure‐response analysis population.
| Parameter | Nivolumab + ipilimumab a | Nivolumab monotherapy b | Total (N = 328) | |
|---|---|---|---|---|
| Cohort 4 (N = 146) | Cohort 1 (N = 37) | Cohort 2 (N = 145) | ||
| Age, years, median (range) | 60 (18–83) | 58 (22–79) | 63 (19–81) | 62 (18–83) |
| Sex, n (%) | ||||
| Female | 27 (18) | 10 (27) | 33 (23) | 70 (21) |
| Male | 119 (82) | 27 (73) | 112 (77) | 258 (79) |
| Race, n (%) | ||||
| White | 46 (32) | 20 (54) | 67 (46) | 133 (41) |
| Asian | 84 (58) | 16 (43) | 50 (34) | 150 (46) |
| Black | 5 (3) | 1 (3) | 3 (2) | 9 (3) |
| Other | 11 (8) | 0 (0) | 25 (17) | 36 (11) |
| Body weight, kg, median (range) | 66 (38–130) | 72 (47–106) | 69 (42–126) | 67 (38–130) |
| ECOG performance status, n (%) | ||||
| 0 | 79 (54) | 26 (70) | 93 (64) | 198 (60) |
| 1 | 67 (46) | 11 (30) | 52 (36) | 130 (40) |
| Baseline serum albumin, g/dL, median (range) | 3.9 (2.6–4.9) | 3.8 (3.1–4.9) | 3.9 (2.8–4.8) | 3.9 (2.6–4.9) |
| Etiology, n (%) | ||||
| HBV infected | 75 (51) | 15 (41) | 43 (30) | 133 (41) |
| HCV infected | 32 (22) | 5 (14) | 30 (21) | 67 (20) |
| HCV and HBV coinfected | 7 (5) | 0 (0) | 0 (0) | 7 (2) |
| Uninfected | 32 (22) | 17 (46) | 72 (50) | 121 (37) |
| Child‐Pugh category, n (%) | ||||
| A | 142 (97) | 37 (100) | 143 (99) | 322 (98) |
| B | 4 (3) | 0 (0) | 2 (1) | 6 (2) |
| Extrahepatic spread or vascular invasion, n (%) | ||||
| No | 15 (10) | 6 (16) | 26 (18) | 47 (14) |
| Yes | 131 (90) | 31 (84) | 119 (82) | 281 (86) |
| AFP category, μg/mL, n (%) | ||||
| AFP <400 | 82 (56) | 25 (68) | 85 (59) | 192 (59) |
| AFP ≥400 | 64 (44) | 12 (32) | 55 (38) | 131 (40) |
| Missing | 0 (0) | 0 (0) | 5 (3) | 5 (2) |
Abbreviations: AFP, alpha‐fetoprotein; ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; HCV, hepatitis C virus.
Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg q3w × 4 then nivolumab 240 mg q2w (n = 49); Nivolumab 3 mg/kg + ipilimumab 1 mg/kg q3w × 4 then nivolumab 240 mg q2w (n = 49); Nivolumab 3 mg/kg q2w + ipilimumab 1 mg/kg q6w (n = 48).
Nivolumab 0.1–10 mg/kg q2w in the second‐line setting after sorafenib treatment (n = 182).
Nivolumab and ipilimumab exposures
The nivolumab exposures in arms B and C of cohort 4 were similar to that of nivolumab 3 mg/kg q2w monotherapy, whereas the nivolumab exposure in arm A was lower, reflecting the administered dose level (Figure 1). In contrast, the ipilimumab exposure in arm A was higher than those in arms B and C. The ipilimumab geometric mean Cavg1 was 16.7 μg/mL in arm A, 5.1 μg/mL in arm B, and 1.7 μg/mL in arm C. There was essentially no overlap in ipilimumab exposure between arm A and arms B and C.
FIGURE 1.
Nivolumab and ipilimumab exposures. (a) Distribution of nivolumab exposures by treatment. Nivolumab exposures in arms B and C of cohort 4 were similar to that of nivolumab 3 mg/kg q2w monotherapy, whereas nivolumab exposure in arm A was lower, reflecting the administered dose level. (b) Distribution of ipilimumab exposures by treatment. Ipilimumab exposure in arm A was higher than those in arms B and C. There was essentially no overlap in ipilimumab exposure between arm A and arms B and C. Population pharmacokinetic models were applied to derive nivolumab and ipilimumab time‐averaged concentrations following the first dose (Cavg1) based on assigned treatment regimens. These models were used to predict nivolumab and ipilimumab Cavg1 for all patients, utilizing empirical Bayesian estimates of pharmacokinetic parameters determined by covariate data and available concentration values (including for patients with missing concentration values). NIVO1 + IPI3 q3w, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg q3w × 4 then nivolumab 240 mg q2w (n = 49); NIVO3 + IPI1 q3w, nivolumab 3 mg/kg + ipilimumab 1 mg/kg q3w × 4 then nivolumab 240 mg q2w (n = 49); NIVO3 q2w + IPI1 q6w, nivolumab 3 mg/kg q2w + ipilimumab 1 mg/kg q6w (n = 48); NIVO3 q2w, nivolumab 3 mg/kg q2w in the second‐line setting after sorafenib treatment (n = 154); q#w, every # weeks.
Exposure‐response analysis of efficacy: Objective tumor response
The observed OTR by treatment regimen of the analyzed populations was similar in the three combination treatment arms (A, B, and C), and higher than that of the nivolumab 3 mg/kg q2w monotherapy arm (Table S2).
After evaluation of log‐transformed and linear‐scale Cavg1, linear‐scale nivolumab exposure, and log‐transformed ipilimumab exposure were included in the final logistic regression model. No other covariates were found to have a significant effect on OTR; therefore, they were not included in the final model.
Across all treatment arms, improvements in BICR‐assessed OTR were associated with increases in ipilimumab exposure (odds ratio 1.45, 95% confidence interval [CI], 1.13–1.86 per log‐transformed ipilimumab Cavg1 [μg/mL]), whereas responses were not significantly associated with nivolumab exposure (odds ratio 0.99, 95% CI, 0.97–1.02 per nivolumab Cavg1 [μg/mL]) over the range of exposures in the analysis dataset (Table 2). This analysis suggests that the tumor response benefit was highest in patients randomized to arm A, which had the highest ipilimumab exposure (Figure 2).
TABLE 2.
Parameter estimates of exposure‐response for BICR‐assessed objective tumor response (exposure‐response analysis population).
| Predictor | Estimate | SE | RSE% | Odds ratio (95% CI) |
|---|---|---|---|---|
| Intercept | –1.419 | 0.3522 | 24.82 | 0.242 (0.1214–0.4827) |
| Nivolumab Cavg1, μg/mL | –0.00841 | 0.01229 | 146.2 | 0.9916 (0.968–1.016) |
| Log‐transformed ipilimumab Cavg1, μg/mL | 0.3712 | 0.1263 | 34.04 | 1.45 (1.132–1.857) |
Note: Odds ratio for nivolumab represents the increase in the odds of an OTR per unit increase in Cavg1 (μg/mL), and the odds ratio for ipilimumab represents the increase in the odds of an OTR per unit increase in log‐transformed ipilimumab Cavg1 (μg/mL).
Abbreviations: BICR, blinded independent central review; Cavg1, time‐averaged concentration after the first dose; CI, confidence interval; OTR, objective tumor response; RSE%, relative standard error = (100 × SE/Estimate); SE, standard error.
FIGURE 2.
Exposure‐response analysis of efficacy: objective tumor response. Odds of objective tumor response in patients who received nivolumab as monotherapy or in combination with ipilimumab relative to the median time‐averaged concentrations following the first dose (Cavg1) of nivolumab 3 mg/kg q2w monotherapy. The odds ratio range for each treatment represents the net effect of the range of nivolumab and ipilimumab exposures of that treatment, relative to the reference nivolumab monotherapy exposure, defined as the median of nivolumab Cavg1 from NIVO3 q2w monotherapy (25 μg/mL). Tumor response benefit was highest in patients randomized to arm A, which had the highest ipilimumab exposure. NIVO1 + IPI3 q3w, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg q3w × 4 then nivolumab 240 mg q2w (n = 49); NIVO3 + IPI1 q3w, nivolumab 3 mg/kg + ipilimumab 1 mg/kg q3w × 4 then nivolumab 240 mg q2w (n = 49); NIVO3 q2w + IPI1 q6w, nivolumab 3 mg/kg q2w + ipilimumab 1 mg/kg q6w (n = 48); NIVO3 q2w, nivolumab 3 mg/kg q2w in the second‐line setting after sorafenib treatment (n = 145); q#w, every # weeks.
Exposure‐response analysis of efficacy: Overall survival
Log‐transformed nivolumab and ipilimumab exposures were included in the final CPH model. In addition, higher baseline nivolumab clearance, ECOG performance status of 1, and higher log ratio of the baseline lactate dehydrogenase upper limit of normal were significantly associated with lower OS and were also included in the final multivariate CPH model. An evaluation of the model showed that the predicted OS was consistent with the observed OS data (Figure S1). Across all treatment arms, improvements in OS were found to be associated with increases in ipilimumab exposure (HR 0.86, 95% CI, 0.75–0.98), whereas improvements in OS were observed regardless of nivolumab exposure (HR 1.08, 95% CI, 0.89–1.32) over the range of exposures in the analysis dataset (Figure 3, Table 3).
FIGURE 3.
Exposure‐response analysis of efficacy: overall survival (OS). Hazard ratio of survival in patients who received nivolumab as monotherapy or in combination with ipilimumab relative to the median time‐averaged concentrations following the first dose (Cavg1) of nivolumab 3 mg/kg q2w monotherapy. The hazard ratio range for each treatment represents the net effect of the range of nivolumab and ipilimumab exposures of that treatment, relative to the reference nivolumab monotherapy exposure, defined as the median of nivolumab Cavg1 from NIVO3 q2w monotherapy (25 μg/mL). Improvements in OS were associated with increases in ipilimumab exposure, whereas improvements in OS were observed regardless of nivolumab exposure over the range of exposures in the analysis dataset. NIVO1 + IPI3 q3w, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg q3w × 4 then nivolumab 240 mg q2w (n = 49); NIVO3 + IPI1 q3w, nivolumab 3 mg/kg + ipilimumab 1 mg/kg q3w × 4 then nivolumab 240 mg q2w (n = 49); NIVO3 q2w + IPI1 q6w, nivolumab 3 mg/kg q2w + ipilimumab 1 mg/kg q6w (n = 48); NIVO3 q2w, nivolumab 3 mg/kg q2w in the second‐line setting after sorafenib treatment (n = 145); q#w, every # weeks.
TABLE 3.
Parameter estimates of exposure‐response for overall survival.
| Predictor | Estimate | SE | RSE% | HR (95% CI) |
|---|---|---|---|---|
| Log‐transformed nivolumab Cavg1, μg/mL | 0.07747 | 0.1004 | 129.6 | 1.081 (0.8875–1.316) |
| Log‐transformed ipilimumab Cavg1, μg/mL | –0.1539 | 0.06909 | 44.91 | 0.8574 (0.7488–0.9817) |
| ECOG performance status (>0) | 0.4444 | 0.1400 | 31.5 | 1.56 (1.185–2.052) |
| Baseline nivolumab CL, mL/h | 0.05068 | 0.01682 | 33.2 | 1.052 (1.018–1.087) |
| Log ratio baseline LDH/ULN | 0.7962 | 0.2047 | 25.71 | 2.217 (1.484–3.312) |
Note: HR coefficients for nivolumab and ipilimumab represent the increase in the risk of death per unit increase in log‐transformed Cavg1 (μg/mL). HR of baseline nivolumab CL represents increase in the risk of death per unit increase in CL (mL/h). HR of baseline LDH represents the increase in the risk of death per unit increase in log‐transformed ratio of baseline LDH (normalized to the ULN).
Abbreviations: Cavg1, time‐averaged concentration after the first dose; CI, confidence interval; CL, clearance; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; LDH, lactate dehydrogenase; RSE%, relative standard error = (100 × SE/Estimate); SE, standard error; ULN, upper limit of normal.
Exposure‐response analysis of safety
Hepatic TRAEs occurred regardless of treatment arm (Table 4, Figure S2). Increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were the most common hepatic TRAEs of any grade and grades 3–4 in each treatment arm and were generally reported for higher proportions of patients in arm A than in arms B or C. Increased AST and ALT levels were also the most common hepatic TRAEs in the nivolumab monotherapy group, although at a numerically lower incidence than in the nivolumab plus ipilimumab arms.
TABLE 4.
Hepatic TRAEs and IMAEs in the nivolumab plus ipilimumab cohort and the nivolumab monotherapy cohort.
| Nivolumab + ipilimumab (cohort 4) a | Nivolumab monotherapy (cohort 2), n = 145 e , f | |||||||
|---|---|---|---|---|---|---|---|---|
| Arm A b (n = 49) | Arm B c (n = 49) | Arm C d (n = 48) | ||||||
| Grade | Grade | Grade | Grade | |||||
| Any | 3–4 | Any | 3–4 | Any | 3–4 | Any | 3–4 | |
| Hepatic TRAEs | ||||||||
| AST increased | 10 (20) | 8 (16) | 10 (20) | 4 (8) | 6 (13) | 2 (4) | 8 (6) | 5 (3) |
| ALT increased | 8 (16) | 4 (8) | 7 (14) | 3 (6) | 4 (8) | 0 | 10 (7) | 3 (2) |
| Hepatitis | 2 (4) | 2 (4) | 0 | 0 | 0 | 0 | 0 | 0 |
| Drug‐induced liver injury or liver disorder | 1 (2) | 1 (2) | 0 | 0 | 0 | 0 | 0 | 0 |
| IMAEs | ||||||||
| Rash | 17 (35) | 3 (6) | 14 (29) | 2 (4) | 8 (17) | 0 | 18 (12) | 1 (1) |
| Hepatitis | 10 (20) | 10 (20) | 6 (12) | 5 (10) | 3 (6) | 3 (6) | 6 (4) | 5 (3) |
| Adrenal insufficiency | 9 (18) | 2 (4) | 3 (6) | 0 | 3 (6) | 0 | 1 (1) | 0 |
| Diarrhea/colitis | 5 (10) | 3 (6) | 1 (2) | 1 (2) | 1 (2) | 1 (2) | 6 (4) | 2 (1) |
| Pneumonitis | 5 (10) | 3 (6) | 0 | 0 | 0 | 0 | 3 (2) | 2 (1) |
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; IMAE, immune‐mediated adverse event; IPI, ipilimumab; MedDRA, Medical Dictionary for Regulatory Activities; NIVO, nivolumab; Q#W, every # weeks; TRAE, treatment‐related adverse event.
MedDRA version 21.1.
Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg q3w × 4 then nivolumab 240 mg q2w (n = 49).
Nivolumab 3 mg/kg + ipilimumab 1 mg/kg q3w × 4 then nivolumab 240 mg q2w (n = 49).
Nivolumab 3 mg/kg q2w + ipilimumab 1 mg/kg q6w (n = 48).
MedDRA version 20.1.
Nivolumab 3 mg/kg q2w in the second‐line setting after sorafenib treatment (cohort 2) (n = 145). Presented for comparison.
Four patients in the nivolumab plus ipilimumab cohort (n = 146) had hepatic TRAEs that led to discontinuation: two in arm A (4%, ALT increased and drug‐induced liver injury) and two in arm B (4%, AST increased). In the monotherapy cohort (n = 145), one patient (1%) had an ALT increase leading to discontinuation (Table S3).
Higher frequencies of IMAEs were observed in arm A compared with arms B and C, and the incidence of IMAEs was generally similar in arms B and C. The five most frequently reported IMAEs of any grade were rash, hepatitis, adrenal insufficiency, diarrhea/colitis, and pneumonitis (Table 4; Figure S3). Of these, the incidence of any‐grade and grades 3–4 IMAEs was higher in arm A than in arms B or C. The types of IMAE reported were similar in the nivolumab monotherapy group, although the incidence of these events was numerically higher in the nivolumab plus ipilimumab arms.
DISCUSSION
This was an exploratory exposure‐response analysis of patients with advanced HCC who received one of three combination regimens of nivolumab plus ipilimumab in the CheckMate 040 trial. Cavg1 was selected as the exposure measure for patients who received nivolumab plus ipilimumab or nivolumab monotherapy to avoid confounding the analysis by the time‐varying clearance of nivolumab. 18 The change in clearance was found to be associated with OTR, so it was important to use an early exposure metric that was not influenced by the response variable. Although the nivolumab dosing regimen switched from a weight‐based dose to a flat 240 mg q2w dose after the first 12 weeks, previous analyses of nivolumab pharmacokinetics have shown that major differences in exposure are not expected from a switch in dosing regimen. 19 Furthermore, incorporation of data from a wide range of nivolumab doses (0.1–10 mg/kg) in this exposure‐response analysis likely mitigated the potential bias in the more modest changes in exposure resulting from a switch from weight‐based dosing to a flat dose. In addition, nivolumab Cavg1 was available for all patients included in the dataset who received nivolumab q2w. Overall, the analysis showed OS and OTR benefits regardless of nivolumab exposure, suggesting that nivolumab at the range of exposure levels in this analysis dataset had reached the plateau of the exposure‐response relationship.
A potential limitation of utilizing Cavg1 as the measure of exposure in the exposure‐response analysis of efficacy is that the nivolumab Cavg1 in arm A is not representative of nivolumab exposure in the monotherapy maintenance period of the study (in which nivolumab 240 mg q2w was given as monotherapy subsequent to the 12‐week induction period of four doses of nivolumab 1 mg/kg q3w in combination with ipilimumab 3 mg/kg q3w). This limitation should not have affected the exposure‐response relationship with OTR, as tumor response is an early measure of efficacy and the best OTR occurs within 12 weeks of treatment in the majority of patients. However, the relatively flat nivolumab exposure‐response relationship with OS across treatments may be due to the similar nivolumab exposures during the maintenance period in the combination treatment arms.
Notably, improvements in OTR and OS were associated with increases in ipilimumab exposure. The greatest OS benefit was seen in the high‐ipilimumab exposure group of patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg q3w for four doses, followed by nivolumab monotherapy 240 mg q2w (arm A). OTR was associated with ipilimumab exposure in arms B and C, but an OTR benefit was observed regardless of ipilimumab exposure level in arm A, presumably because ipilimumab exposure in both the high‐ and low‐ipilimumab groups of arm A was greater than ipilimumab exposure in the other two arms.
Overall, AEs appeared to be more frequent with higher ipilimumab exposure. The incidence of all hepatic TRAEs was higher in arm A than in arms B or C, as was the incidence of grades 3 or 4 increases in AST and ALT.
The IMAEs of adrenal insufficiency, diarrhea/colitis, hepatitis, and pneumonitis occurred in a higher proportion of patients in arm A compared with the other two treatment arms. These findings suggest that a higher ipilimumab dose (>3 mg/kg q3w) might further increase the risk of these AEs. The types of TRAEs and IMAEs were similar in the nivolumab monotherapy group, but at a lower incidence than those reported for the nivolumab plus ipilimumab arms.
Exposure‐response analyses of nivolumab or ipilimumab monotherapy have been conducted in other tumor types. For nivolumab monotherapy, a flat dose–response relationship within a dose range of 1–10 mg/kg has been observed in patients with non‐small cell lung cancer and melanoma. 8 , 9 For ipilimumab monotherapy, a positive dose–response relationship within a dose range of 0.3–10 mg/kg was observed in patients with melanoma. 11 These findings reflect the different optimal dosage regimens for nivolumab plus ipilimumab combination therapy that are approved for each tumor type, for example, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg q3w followed by nivolumab 240 mg for metastatic melanoma, 20 nivolumab 3 mg/kg q2w plus ipilimumab 1 mg/kg q6w for non‐small cell lung cancer, 21 and nivolumab 3 mg/kg plus ipilimumab 1 mg/kg q3w followed by nivolumab 240 mg q2w for both advanced renal cell carcinoma and metastatic microsatellite instability‐high colorectal cancer. 22 , 23 The optimal dosing regimens for different tumor types are unlikely to be related to the pharmacokinetics of nivolumab, which is similar across tumor types, but rather reflect differences in the optimal benefit:risk profile of treatment for each tumor type. 24 Across tumor types, higher ipilimumab doses have generally been associated with clinical benefit but also have a higher incidence of AEs. 10 Thus, the ipilimumab dose has been limited by patient tolerability, which might vary across different patient populations. The reasons for tumor‐specific variations in clinical activity and safety are not well understood. It should be noted that no decision about treatment discontinuation can be derived from the current benefit:risk findings.
The use of ipilimumab Cavg1 overcomes the confounding effects of time‐varying clearance and is an appropriate measure of exposure for the initial 4‐month treatment period, which is critical to the induction of the response. However, the use of ipilimumab Cavg1 may under‐represent the effect of ipilimumab administered continuously relative to the induction‐only doses of ipilimumab, as suggested by the deviation of the model‐predicted OS from the observed OS after 12 weeks of treatment. Another limitation of this analysis is its post hoc exploratory nature, analyzing the relationships between nivolumab and ipilimumab exposures and clinical outcomes in three arms of the combination therapy cohort of the CheckMate 040 trial.
Although the patient numbers are small in each arm, the findings of this analysis are consistent with exposure‐response analyses of nivolumab and ipilimumab therapy in other tumor types. Comparisons of the nivolumab plus ipilimumab cohort data with the nivolumab monotherapy cohort data were exploratory in nature, as the combination therapy and monotherapy cohorts were not randomized or designed for a formal comparison.
Our exposure‐response analysis of nivolumab plus ipilimumab combinations in patients with advanced HCC support the combination of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg q3w for four doses, followed by nivolumab monotherapy 240 mg q2w as the optimal dosage regimen in this patient population compared with the other two regimens investigated, as it elicited an improved efficacy outcome while maintaining an acceptable safety profile. In this setting, efficacy was observed regardless of nivolumab exposure, whereas the ipilimumab dose showed a positive correlation with treatment response and survival in the exposure ranges elicited by nivolumab 1 or 3 mg/kg q3w plus either ipilimumab 1 or 3 mg/kg q3w or ipilimumab 3 mg/kg q6w. The approved combination regimen, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg q3w for four doses, followed by nivolumab monotherapy 240 mg q2w, offers the most favorable benefit:risk profile for the second‐line treatment of patients with advanced HCC and is now under investigation as first‐line therapy in the ongoing phase III CheckMate 9DW trial in patients with advanced HCC (NCT04039607).
AUTHOR CONTRIBUTIONS
B.S., T.Y., A.B.E.‐K., M.K., Y.S., M.T., A.R., Y.F., L.G., and U.A. wrote the manuscript, designed the research, and performed the research. Y.S., M.T., A.R., Y.F., L.G., and U.A. analyzed the data.
FUNDING INFORMATION
This study was supported by Bristol Myers Squibb (Princeton, NJ) and Ono Pharmaceutical Co., Ltd. (Osaka, Japan).
CONFLICT OF INTEREST STATEMENT
B.S. reports grants or contracts (to institution) from Bristol Myers Squibb and Sirtex Medical; consulting fees from Adaptimmune, AstraZeneca, Bayer, Bristol Myers Squibb, BTG, Eli Lilly, H3 Biomedicine, Incyte, Ipsen, Roche, Sirtex Medical, and Terumo; honoraria from Bayer, Bristol Myers Squibb, Incyte, Ipsen, Sirtex Medical, and Terumo; meeting attendance for Bayer, Bristol Myers Squibb, Incyte, Ipsen, Sirtex Medical, and Terumo; and participation on a data safety monitoring board or advisory board for Adaptimmune, AstraZeneca, Bayer, Bristol Myers Squibb, BTG, H3 Biomedicine, Incyte, Ipsen, Lilly, Roche, Sirtex Medical, and Terumo. T.Y. reports consulting fees from AbbVie, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, EMD Serono, Exelixis, H3 Biomedicine, Ipsen, Merck Sharp & Dohme, New B Innovation, Novartis, OrigiMed, Pfizer, Sillajen, Sirtex Medical, and Taiho Pharmaceutical; honoraria from AbbVie, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, EMD Serono, Exelixis, H3 Biomedicine, Ipsen, Merck Sharp & Dohme Oncology, New B Innovation, Novartis, OrigiMed, Pfizer, Sirtex Medical, Sillajen, and Taiho Pharmaceutical; and participation on a data safety monitoring board or advisory board for AbbVie, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, EMD Serono, Exelixis, H3 Biomedicine, Ipsen, Merck Sharp & Dohme, New B Innovation, Novartis, OrigiMed, Pfizer, Sirtex Medical, Sillajen, and Taiho Pharmaceutical. A.B.E.‐K. reports grants or contracts from AstraZeneca, Astex Pharmaceuticals, and Fulgent Genetics; consulting fees from ABL Bio, Agenus, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, CytomX Therapeutics, Eisai, EMD Serono, Exelixis, Gilead Sciences, Merck Sharp & Dohme, Pieris Pharmaceuticals, and Roche/Genentech; participation on a data safety monitoring board or advisory board for Agenus, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, CytomX Therapeutics, Eisai, EMD Serono, Exelixis, Gilead Sciences, Merck Sharp & Dohme, Pieris Pharmaceuticals, QED Therapeutics, and Roche/Genentech; research funding from Astex Pharmaceuticals, AstraZeneca, and Merck Sharp & Dohme. M.K. reports consulting fees from Bristol Myers Squibb, Eisai, Merck Sharp & Dohme, Ono Pharmaceutical, and Roche; honoraria from Bayer, Bristol Myers Squibb, Chugai, EA Pharma, Eisai, Eli Lilly, and Merck Sharp & Dohme; and research funding (to institution) from AbbVie, Chugai, EA Pharma, Eisai, Gilead Sciences, Ono Pharmaceutical, Otsuka, Sumitomo Dainippon Pharma, Taiho Pharmaceutical, and Takeda. Y.S. reports employment with Bristol Myers Squibb and ownership of stock in Bristol Myers Squibb. M.T. reports employment with Bristol Myers Squibb and ownership of stock in Bristol Myers Squibb. A.R. reports employment with Bristol Myers Squibb and ownership of stock in Bristol Myers Squibb. Y.F. reports employment with Bristol Myers Squibb and ownership of stock in Bristol Myers Squibb at the time the study was conducted. L.G. reports employment with Bristol Myers Squibb and ownership of stock in Bristol Myers Squibb at the time the study was conducted. U.A. reports employment with Bristol Myers Squibb and ownership of stock in Bristol Myers Squibb.
Supporting information
Data S1
ACKNOWLEDGMENTS
The authors thank the patients and their families, as well as the investigators and participating study teams, who made this study possible. The authors also thank Bristol Myers Squibb (Princeton, NJ, USA), who supported this study, and Ono Pharmaceutical Company Ltd. (Osaka, Japan). The authors thank Cognigen Corp for analysis support for the pharmacokinetic and exposure‐response analyses. Writing and editorial assistance was provided by Yvonne E. Yarker, PhD, ISMPP CMPP, of Parexel, funded by Bristol Myers Squibb.
Sangro B, Yau T, El‐Khoueiry AB, et al. Exposure‐response analysis for nivolumab plus ipilimumab combination therapy in patients with advanced hepatocellular carcinoma (CheckMate 040). Clin Transl Sci. 2023;16:1445‐1457. doi: 10.1111/cts.13544
Clinical Trial Number: NCT01658878.
DATA AVAILABILITY STATEMENT
The Bristol Myers Squibb data sharing policy can be found online at https://www.bms.com/researchers‐and‐partners/independent‐research/data‐sharing‐request‐process.html. Bristol Myers Squibb will honor legitimate requests for our clinical trial data from qualified researchers. Data will be shared with external researchers whose proposed use of the data has been approved. Complete de‐identified patient data sets will be eligible for sharing 2 years after completion of the CheckMate 040 trial. Before data are released, the researcher(s) must sign a Data Sharing Agreement, after which the de‐identified and anonymized datasets can be accessed within a secured portal.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1
Data Availability Statement
The Bristol Myers Squibb data sharing policy can be found online at https://www.bms.com/researchers‐and‐partners/independent‐research/data‐sharing‐request‐process.html. Bristol Myers Squibb will honor legitimate requests for our clinical trial data from qualified researchers. Data will be shared with external researchers whose proposed use of the data has been approved. Complete de‐identified patient data sets will be eligible for sharing 2 years after completion of the CheckMate 040 trial. Before data are released, the researcher(s) must sign a Data Sharing Agreement, after which the de‐identified and anonymized datasets can be accessed within a secured portal.