Nivolumab Plus Cabozantinib With or Without Ipilimumab for Advanced Hepatocellular Carcinoma: Results From Cohort 6 of the CheckMate 040 Trial

PURPOSE

To investigate the safety and efficacy of nivolumab plus cabozantinib with or without ipilimumab in patients with advanced hepatocellular carcinoma.

METHODS

In cohort 6 of the multicohort, open-label, phase I/II CheckMate 040 study, patients who were treatment-naive, sorafenib-intolerant, or had progressed on sorafenib were randomly assigned 1:1 to nivolumab 240 mg once every 2 weeks plus cabozantinib 40 mg once daily (doublet arm); or nivolumab 3 mg/kg every 2 weeks plus cabozantinib 40 mg once daily with ipilimumab 1 mg/kg once every 6 weeks (triplet arm). Primary objectives were safety and tolerability, objective response rate, and duration of response by investigator assessment per RECIST v1.1. Secondary objectives included progression-free survival (by blinded independent central review) and overall survival.

RESULTS

Seventy-one patients were randomly assigned: 36 to the doublet arm and 35 to the triplet arm. After 32.0-month median follow-up, objective response rate (95% CI) was 17% (6 to 33) and 29% (15 to 46) in the doublet and triplet arms, respectively. Median (95% CI) duration of response was 8.3 (6.9 to not estimable) months in the doublet arm and not reached (0.0 to not estimable) in the triplet arm. Median progression-free survival was 5.1 and 4.3 months, and median overall survival was 20.2 and 22.1 months for the doublet and triplet arms, respectively. Grade 3-4 treatment-related adverse events occurred in 50% and 74% of patients and treatment-related adverse events leading to discontinuation were reported for 11% and 23% in the doublet and triplet arms, respectively. There were no treatment-related deaths in either arm.

CONCLUSION

Nivolumab plus cabozantinib with or without ipilimumab showed encouraging preliminary antitumor activity and had consistent safety profiles with those established for the individual drugs in patients with advanced hepatocellular carcinoma.

INTRODUCTION

Liver cancer is the third leading cause of cancer-related deaths worldwide; up to 85% of cases are hepatocellular carcinoma (HCC).¹ Most patients are diagnosed with advanced disease unsuitable for potentially curative treatments such as surgery or ablation.²

CONTEXT

• Key Objective

• We hypothesized that triplet therapy with nivolumab (programmed death‐1 inhibitor), cabozantinib (multikinase inhibitor), and ipilimumab (cytotoxic T-cell lymphocyte-4 inhibitor) would have an acceptable safety profile and improve clinical outcomes compared with nivolumab plus cabozantinib doublet therapy in patients with advanced hepatocellular carcinoma who were treatment-naive, sorafenib-intolerant, or had progressed on sorafenib. To our knowledge, this is the first report of dual immune checkpoint inhibitor and tyrosine kinase inhibitor therapy in this patient population.

• Knowledge Generated

• Both the doublet (nivolumab and cabozantinib) and triplet (nivolumab, ipilimumab, and cabozantinib) combinations demonstrated durable responses, with more frequent, deeper, and longer-lasting responses observed for the triplet therapy. Both doublet and triplet therapies had manageable safety profiles.

• Relevance (A.H. Ko)

• Although not necessarily ready for prime-time use, the combination of dual immune checkpoint inhibition plus a multikinase inhibitor warrants further clinical investigation in advanced hepatocellular carcinoma, particularly in identifying the subset of individuals who may benefit from this more aggressive therapeutic strategy.*

  *Relevance section written by JCO Associate Editor Andrew H. Ko, MD.

Until recently, first-line treatment options for advanced HCC included sorafenib and lenvatinib, which inhibit cellular kinases, including vascular endothelial growth factor (VEGF) receptors (VEGFRs) and other kinases such as RET and KIT, and provide median overall survival (OS) of 12.3 and 13.6 months, respectively.^3-6 Both treatments are associated with a relatively high incidence of treatment-related adverse events (TRAEs), particularly those of grade ≥ 3 (49%-57%).⁶ Recently, atezolizumab (programmed death ligand 1 [PD-L1] inhibitor) plus bevacizumab (VEGF inhibitor) demonstrated significant improvements versus sorafenib in median OS, median progression-free survival (PFS), and objective response rate (ORR) after 15.6-month median follow-up,⁷ and is now the standard first-line treatment for advanced HCC globally. Treatment options after sorafenib in the United States, Europe, and Asia include multikinase inhibitors (eg, regorafenib and cabozantinib) and the VEGFR2 inhibitor ramucirumab,^8-10 which provide a median OS of < 1 year.^11-13 In the United States, additional options include the immune checkpoint inhibitors (ICIs) pembrolizumab (programmed death-1 inhibitor) and nivolumab (programmed death-1 inhibitor) plus ipilimumab (cytotoxic T-cell lymphocyte-4 inhibitor), which provide ORRs between 18% and 32%.^3,14,15

Nivolumab plus ipilimumab is an approved second-line treatment option for advanced HCC in the United States under the accelerated approval pathway.^16,17 This was based on the results from cohort 4 of the CheckMate 040 trial, where nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks provided a median OS of 22.8 months and an ORR of 32%, with no new safety signals identified from the combination in this indication.¹⁴ Nivolumab and ipilimumab are known to promote antitumor immune response by complementary mechanisms,¹⁸ and further combining these agents with a multikinase inhibitor could increase antitumor activity and extend survival.¹⁹ Cabozantinib (VEGFR and TAM kinase inhibitor) is approved in the United States, European Union, and other regions as a treatment option after sorafenib for advanced HCC, on the basis of the results from the CELESTIAL trial.^12,20,21 Cabozantinib also has immunomodulatory properties and can decrease tumor-induced immunosuppression and enhance tumor cell sensitivity to T-cell–mediated cell death.^22,23 Nivolumab plus cabozantinib has also shown benefit in other tumor types. The combination led to improved OS, PFS, and ORR versus sunitinib in previously untreated patients with advanced renal cell carcinoma.^21,24 Both doublet therapy (cabozantinib plus nivolumab) and triplet therapy (cabozantinib plus nivolumab plus ipilimumab) have shown clinical activity with manageable safety profiles in a phase I dose escalation trial in patients with advanced urothelial carcinoma and other genitourinary cancers; cabozantinib 40 mg/day was the recommended phase II dose for this combination.²⁵ Together, these findings provide a rationale for combining cabozantinib with nivolumab and/or ipilimumab.

We report the results from cohort 6 of CheckMate 040, which investigated nivolumab plus cabozantinib with or without ipilimumab as first- or second-line treatment for patients with advanced HCC.

METHODS

Study Design

CheckMate 040 is a multicohort, open-label, phase I/II study of nivolumab alone and in combination with other agents in patients with advanced HCC. In cohort 6, patients were recruited from 16 centers across five countries in Asia, Europe, and the United States. This study was conducted in accordance with Good Clinical Practice as defined by the International Council for Harmonisation. The institutional review board or independent ethics committee approved the study protocol at each site. All patients provided written informed consent to participate on the basis of the Declaration of Helsinki.

Patients

Eligibility criteria included age ≥ 18 years, histologically confirmed advanced HCC unsuitable for surgery or locoregional therapy, and Child-Pugh score of A5 or A6. Patients were either treatment-naive or had experienced progression following, or were intolerant to, sorafenib treatment. An Eastern Cooperative Oncology Group performance status score of 0 or 1, with at least one untreated tumor lesion measurable by RECIST v1.1, was required. Additional eligibility criteria are provided in the Data Supplement (online only).

Random Assignment and Blinding

Patients were enrolled via interactive voice response system (block size 4) and randomly assigned 1:1 to the doublet or triplet therapy arm. This was an open-label study.

Procedures

In the doublet arm, patients received nivolumab 240 mg once every 2 weeks plus cabozantinib 40 mg once daily; in the triplet arm, patients received intravenous infusions of nivolumab 3 mg/kg once every 2 weeks and ipilimumab 1 mg/kg once every 6 weeks plus oral cabozantinib 40 mg once daily. Treatment continued until RECIST v1.1 radiographic progression, clinical deterioration (further treatment benefit unlikely), unacceptable toxicity, or other protocol-defined criteria for discontinuation. Dose delay and reduction criteria and criteria for treatment beyond progression are provided in the Data Supplement.

Outcomes

The primary objectives were safety and tolerability, investigator-assessed ORR (RECIST v1.1),²⁶ and duration of response (DOR). Secondary objectives included time to response, time to progression and PFS (per blinded independent central review [BICR] and/or investigator assessment), and OS. Exploratory objectives included ORR by BICR and disease control rate (DCR). See the Data Supplement for definitions of objectives.

Tumor imaging was conducted 6 weeks after random assignment and every 6 weeks until week 48, then every 12 weeks until radiographic progression or treatment discontinuation, whichever occurred later. Adverse events (AEs) and TRAEs were reported by worst grade according to National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. See the Data Supplement for additional assessments.

Statistical Analyses

ORR, DCR, and corresponding 95% CIs were determined using the Clopper-Pearson method. Median (95% CI) DOR and OS were determined using the Kaplan-Meier method. Safety was analyzed by descriptive statistics, including TRAEs, discontinuation because of TRAEs, and TRAEs of potential immunologic etiology. See the Data Supplement for definitions of TRAEs and additional methods.

RESULTS

Patient Baseline Characteristics

Between July 13, 2017 and January 30, 2018, 98 patients with advanced HCC were enrolled and 71 patients were randomly assigned 1:1 to the doublet (n = 36) or triplet (n = 35) arm (Fig 1). At database lock on September 30, 2020, the median (range) follow-up (from random assignment to clinical data cutoff) was 32.0 (28.5-36.2) months. Overall, 62 patients (87%) were male, and the median (range) age was 65.0 (23-87) years. Barcelona Clinic Liver Cancer (BCLC) stage C, vascular invasion, extrahepatic spread, alpha-fetoprotein ≥ 400 μg/L, and prior sorafenib treatment were less frequent in the doublet arm than in the triplet arm. Furthermore, the proportion of patients who had previously received systemic therapy was lower in the doublet arm than in the triplet arm (Table 1).

FIG 1.

CONSORT diagram. AE, adverse event; TRAE, treatment-related adverse event.

TABLE 1.

Patient Demographics and Baseline Disease Characteristics

Patient Disposition and Study Drug Exposure

At the time of analysis, 19% of patients in the doublet arm and 20% in the triplet arm were still receiving study treatment. Disease progression was the reason for discontinuation in 64% and 51% of patients in the doublet and triplet arms, respectively.

Overall, 75% of patients in the doublet arm and 57% in the triplet arm received ≥ 90% of the intended nivolumab dose, while 42% and 46% received ≥ 90% of the intended cabozantinib dose, respectively; 71% of patients in the triplet arm received ≥ 90% of the intended ipilimumab dose. In the doublet arm, 69% of patients experienced at least one nivolumab dose delay, and 67% experienced at least one cabozantinib dose delay. In the triplet arm, 66%, 69%, and 57% of patients experienced at least one nivolumab, cabozantinib, or ipilimumab dose delay, respectively. Median (95% CI) duration of treatment overall was 7.1 months (3.9 to 13.6) in the doublet arm and 7.8 months (3.3 to 11.5) in the triplet arm. Median (range) number of doses received in the doublet arm was 13.5 (1-77) nivolumab doses and 118.0 (10-1,094) cabozantinib doses, corresponding to approximately 16 weeks of cabozantinib treatment, regardless of dose delays. Median (range) number of doses received during the treatment period in the triplet arm was 15.0 (1-79) nivolumab doses, 5.0 (1-26) ipilimumab doses, and 73.0 (14-964) cabozantinib doses, corresponding to approximately 10 weeks of cabozantinib treatment, regardless of dose delays. Median average daily cabozantinib dose received during the treatment period was 34.1 mg once daily and 30.0 mg once daily in the doublet and triplet arms, respectively. Median (range) cumulative cabozantinib dose was 4,570 mg (400-43,760) and 2,600 mg (540-38,560) in the doublet and triplet arms, respectively. Nineteen (53%) and 15 (43%) patients had cabozantinib dose reductions in the doublet and triplet arms, respectively (Data Supplement).

Thirteen patients in each arm received subsequent anticancer therapy, including radiotherapy (one patient in each arm) and systemic therapy (doublet arm: 12 patients; triplet arm: 13 patients). Some patients received more than one subsequent therapy (Data Supplement).

Response

In the doublet and triplet arms, investigator-assessed ORR (95% CI) was 17% (6 to 33) and 29% (15 to 46; Table 2), respectively. ORR (95% CI) by BICR was 14% (5 to 30) in the doublet arm and 29% (15 to 46) in the triplet arm. Responses per BICR were observed in both arms regardless of baseline alpha-fetoprotein status, tumor cell PD-L1 expression, or HCC etiology (Data Supplement). Investigator-assessed median (95% CI) DOR was 8.3 months (6.9 to not estimable [NE]) in the doublet arm and not reached in the triplet arm; median DOR by BICR was 21.6 months (10.8 to NE) and not reached, respectively. Of the 10 responders in the triplet arm, 90% maintained response for ≥ 6 months, 80% for ≥ 12 months, and 70% for ≥ 18 months. One patient in the doublet arm and three in the triplet arm had complete response (CR) by BICR. DCR, progressive disease (PD) rate, and median time to response were generally similar across treatment arms and assessment methods (Table 2).

TABLE 2.

Response, Disease Control, and Durability

Nineteen patients in the doublet arm and 23 in the triplet arm had received prior sorafenib. In the doublet arm, ORR (95% CI) by BICR was 6% (< 1 to 29) for sorafenib-naive patients and 21% (6 to 46) for sorafenib-pretreated patients; corresponding rates in the triplet arm were 25% (6 to 57) and 30% (13 to 53), respectively.

Of 31 evaluable patients in each of the doublet and triplet arms, 17 (55%) and 27 (87%), respectively, had decreases in the sum of diameters of target lesions from baseline by BICR (Fig 2). Tumor burden was reduced regardless of baseline viral etiology or prior sorafenib treatment. Among responders, target lesion reductions were deep and durable in both arms (Fig 3).

FIG 2.

Best change in target lesions (per BICR) by HCC etiology in the (A) NIVO 240 + CABO 40 treatment group and the (B) NIVO3 + IPI1 + CABO 40 treatment group, and by prior sorafenib in the (C) NIVO 240 + CABO 40 treatment group and the (D) NIVO3 + IPI1 + CABO 40 treatment group. Horizontal reference line indicates the 30% reduction consistent with a response per RECIST v1.1; ^aResponders. BICR, blinded independent central review; CABO 40, cabozantinib 40 mg once daily; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IPI1, ipilimumab 1 mg/kg once every 6 weeks; NIVO3, nivolumab 3 mg/kg once every 2 weeks; NIVO 240, nivolumab 240 mg once every 2 weeks.

FIG 3.

Change in target lesions over time by investigator assessment in the (A) NIVO 240 + CABO 40 treatment group and the (B) NIVO3 + IPI1 + CABO 40 treatment group, and by BICR assessment in the (C) NIVO 240 + CABO 40 treatment group and the (D) NIVO3 + IPI1 + CABO 40 treatment group. Response-evaluable patients with BOR of CR, PR, SD, or PD; target lesions assessed at baseline; and at least one on-study time point with all baseline target lesions assessed. Horizontal reference line indicates the 30% reduction consistent with a response per RECIST v1.1. BICR, blinded independent central review; BOR, best overall response; CABO 40, cabozantinib 40 mg once daily; CR, complete response; IPI1, ipilimumab 1 mg/kg once every 6 weeks; NIVO3, nivolumab 3 mg/kg once every 2 weeks; NIVO 240, nivolumab 240 mg once every 2 weeks; PD, progressive disease; PR, partial response; SD, stable disease.

PFS and OS

Median PFS (95% CI) by BICR was 5.1 (2.8 to 10.9) months in the doublet arm and 4.3 (3.6 to 11.9) months in the triplet arm (Fig 4A). Twelve-month PFS rates (95% CI) were 29% (15 to 44) in the doublet arm and 32% (17 to 49) in the triplet arm. Twenty-four-month PFS rates were 11% (3 to 25) and 29% (14 to 45), respectively.

FIG 4.

(A) PFS by BICR assessment and (B) OS on the basis of Kaplan-Meier estimates. BICR, blinded independent central review; CABO 40, cabozantinib 40 mg once daily; IPI1, ipilimumab 1 mg/kg once every 6 weeks; NE, not estimable; NIVO3, nivolumab 3 mg/kg once every 2 weeks; NIVO 240, nivolumab 240 mg once every 2 weeks; OS, overall survival; PFS, progression-free survival. Symbols represent censored observations.

Median OS (95% CI) was 20.2 (13.1 to 32.2) months in the doublet arm and 22.1 (15.2 to NE) months in the triplet arm (Fig 4B). Twelve-month OS rate (95% CI) was 70% for both arms (doublet arm: 52 to 83 months; triplet arm: 51 to 83 months). Corresponding 24-month rates were 39% (23 to 55) and 45% (27 to 61), respectively. Among patients with a CR or partial response, median OS was not reached for 6- or 9-month landmark analysis in either arm (Data Supplement). Among nonresponders (stable disease [SD]/PD/non-CR/non-PD), median OS (95% CI) from 6 months was 20.9 months (14.8 to 32.2) and 23.2 months (15.2 to NE) in the doublet and triplet arms, respectively; from 9 months, median OS (95% CI) was 21.5 months (15.3 to NE) and 22.1 months (15.2 to 26.7), respectively.

Safety

Any-grade TRAEs were reported for 32 patients (89%) in the doublet arm and 33 (94%) in the triplet arm (Table 3). The most frequently reported grade 3-4 TRAEs were diarrhea, hypertension, and AST increase in the doublet arm, and AST increase, hypertension, and lipase increase in the triplet arm. Treatment-related serious adverse events (SAEs) of any grade were reported for 11% of patients in the doublet arm and 34% in the triplet arm; grade 3-4 SAEs were reported for 8% and 34% of patients, respectively. Hyponatremia, diarrhea, immune-mediated hepatitis, ALT increase, and AST increase were each reported for 3% of patients (all grade 3-4); all other SAEs were reported in 1% of patients. Any-grade TRAEs leading to discontinuation were reported in 11% of patients in the doublet arm and 23% in the triplet arm; one (3%) and seven (20%) patients, respectively, reported grade 3-4 TRAEs leading to discontinuation. Among patients who discontinued because of TRAEs, none in the doublet arm and three (9%) in the triplet arm had CR/partial response, and three (8%) and five (14%) patients, respectively, had SD.

TABLE 3.

Treatment-Related Adverse Events

Select TRAEs of potential immunologic etiology (sTRAEs) were mostly grade 1-2 in each treatment arm (Data Supplement). The most frequent grade 3-4 sTRAEs were hepatic events (doublet arm: 11%; triplet arm: 26%), which led to one discontinuation in the doublet arm (grade 3) and four discontinuations in the triplet arm (two grade 3 and two grade 4). Most sTRAEs were treated with corticosteroids for a median of 4-6 weeks, except endocrine events, for which four patients received corticosteroids for a median of 50 weeks. Overall, five patients (20%) in the doublet arm and 10 (36%) in the triplet arm received systemic corticosteroids for sTRAEs. Corticosteroids (≥ 40 mg prednisone or equivalent) were required by two patients (8%) in the doublet arm for a median of 4.6 weeks and eight (29%) in the triplet arm for a median of 1.7 weeks.

No deaths related to study treatment occurred. The most frequently reported cause of death was disease progression (doublet arm: 53%; triplet arm: 46%). In four patients, cancer-related death was reported without radiographic (BICR or investigator assessment) or clinical progression but with liver function deterioration, indicated by worsening albumin/bilirubin grade and/or Child-Pugh score shortly before death (two patients in each arm). Another patient in the triplet arm, who died from an AE unrelated to study drug, also had liver function deterioration shortly before death. Other causes of death unrelated to study treatment included intracranial hemorrhage, stroke, lower GI bleeding, and unspecified.

DISCUSSION

ICIs and VEGF inhibitors have independently demonstrated clinical benefits in patients with advanced HCC.^{6,12,14,27-29} To our knowledge, this is the first report of dual ICI plus tyrosine kinase inhibitor (triplet therapy) in patients with advanced HCC. In cohort 6 of CheckMate 040, both doublet (nivolumab and cabozantinib) and triplet (nivolumab, ipilimumab, and cabozantinib) combinations demonstrated durable responses in sorafenib-naive or sorafenib-pretreated patients with advanced HCC, with more frequent, deeper, and longer-lasting responses observed for triplet therapy.

The observed ORRs for doublet and triplet arms were comparable with those of previous studies of ICI combinations in first-line (ORR, 30% by RECIST v1.1)²⁹ and second-line settings (ORR, 15%-32%)^14,15 and ICI monotherapy (ORR, 15%).²⁷ Notably, we observed numerically longer median DOR by BICR in the triplet arm (not reached) than in the doublet arm (21.6 months) after 32-month median follow-up. With other ICIs, DOR between 13.8 and 21.7 months has been reported in first- and second-line settings.^14,15,27,29 Median OS in our study (20.2-22.1 months) was consistent with that reported for first-line atezolizumab plus bevacizumab (19.2 months)²⁹ and second-line nivolumab plus ipilimumab (22.8 months).¹⁴

Although the triplet arm had numerically higher rates of TRAEs than the doublet arm, including those leading to discontinuation, the overall safety profiles were consistent with those reported previously, with no new safety signals identified.^14,30 In contrast to atezolizumab plus bevacizumab,²⁸ no treatment-related bleeding events were reported during our study. Grade 3-4 AEs were more frequent in the triplet arm than the doublet arm, but were mainly laboratory abnormalities not expected to have major clinical impact. In both arms, TRAEs were effectively managed by nivolumab and/or ipilimumab dose delay and cabozantinib dose reduction or interruption. Similarly, most sTRAEs were effectively managed using standard treatment algorithms; 8% of patients in the doublet arm and 29% in the triplet arm required corticosteroids (≥ 40 mg prednisone or equivalent) for a median of 4.6 and 1.7 weeks, respectively. In both arms, some patients who discontinued because of TRAEs had ongoing response or SD. No treatment-related deaths occurred in either arm.

It is of interest to determine the contributions of ICIs and VEGF inhibitors when used in combination to treat advanced HCC, as immune evasion and angiogenesis are interdependent and can facilitate tumor development,^31,32 and VEGF inhibition has been shown to enhance PD-L1 immunotherapy by targeting angiogenesis and regulatory T-cell proliferation.³³ Triplet therapy including cabozantinib in the current CheckMate 040 cohort produced an ORR similar to that of second-line nivolumab plus ipilimumab therapy (cohort 4), a higher DCR (80% v 50%, respectively), and a lower proportion of patients with PD (11% v > 40%, respectively).¹⁴ These findings suggest that cabozantinib might work synergistically with dual ICIs in this setting. Conversely, triplet therapy in the current study increased the frequency of treatment discontinuation compared with the nivolumab plus ipilimumab arm of cohort 4.¹⁴ However, comparisons across cohorts and with other trials are not ideal because of differences in study designs and patient populations.

The IMbrave150 trial demonstrated the potential synergy between first-line atezolizumab plus bevacizumab versus sorafenib in patients with advanced HCC.²⁸ Further molecular analyses of this combination versus atezolizumab alone have shown that bevacizumab might synergize with atezolizumab by targeting angiogenesis, the proliferation of regulatory T cells, and myeloid cell inflammation.³³ However, recently reported results from several phase III trials of ICI plus tyrosine kinase inhibitor (TKI) combinations in the first-line setting in patients with advanced HCC are conflicting. In the COSMIC-312 trial (cabozantinib plus atezolizumab v sorafenib), PFS was significantly improved with the combination, but not interim OS.³⁴ In the LEAP-002 trial (lenvatinib plus pembrolizumab v lenvatinib), neither PFS nor OS was significantly improved with the combination, although median OS with combination therapy was approximately 21 months.³⁵ By contrast, in the camrelizumab plus rivoceranib trial, both PFS and OS were significantly improved with this combination (median OS approximately 22 months³⁶). These mixed results might be partly attributed to differences between the efficacy and safety profiles of each TKI, differences in patient populations, and variations in trial design. The optimal TKI to use with ICIs in treating advanced HCC has yet to be determined.

Ideally, to determine the contribution of each component of this type of combination therapy to efficacy and safety, a multiarm trial would have to be designed in which patients are randomly assigned to receive monotherapy with an ICI, TKI, or angiogenesis inhibitor or combination therapy with one or two ICIs with different mechanisms of action, one or two ICIs plus a TKI, or one or two ICIs plus an angiogenesis inhibitor. Given the complexity of conducting such of trial, the possibility of exposing some patients to ineffective or toxic combinations, and the fact that some multiple drug combinations could not be used in patients with HCC and comorbidities, such a multiarm trial is unlikely ever to be conducted. Finally, the question of whether an antiangiogenic agent should be used in combination with ICIs as concurrent or sequential therapy can also only be addressed by future clinical trials.

Our study had some limitations. The phase II design and safety-based sample-size determination meant that patient numbers were relatively low for efficacy analyses. It was not possible to evaluate the impact of tumor burden and declining liver function on OS because few patients had high tumor burden and rapid liver function decline. Although assignment to treatment arms was randomized, no stratification was applied, and the study design did not permit formal statistical comparisons between arms, nor was an active comparator arm included. The open-label design might have influenced tumor responses by investigator assessment and assessment of AE causality. Our study population included sorafenib-naive and sorafenib-pretreated patients, limiting interpretation of the results in context with other studies.

In conclusion, nivolumab plus cabozantinib with or without ipilimumab showed clinical activity and a manageable safety profile in sorafenib-naive or sorafenib-pretreated patients with advanced HCC. Larger studies may be warranted to further characterize benefit/risk profiles of these combinations, especially triplet therapy.

DATA SHARING STATEMENT

Bristol Myers Squibb's policy on data sharing may be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html.

AUTHOR CONTRIBUTIONS

Conception and design: Thomas Yau, Fabio Piscaglia, Armando Santoro, Anthony B. El-Khoueiry, Bruno Sangro, Christian Scheffold, Jaclyn Neely

Provision of study materials or patients: Thomas Yau, Vittorina Zagonel, Mirelis Acosta-Rivera, Su Pin Choo, Aiwu Ruth He, Bruno Sangro, Jordi Bruix, Gina M. Vaccaro

Collection and assembly of data: Thomas Yau, Mirelis Acosta-Rivera, Su Pin Choo, Ana Matilla, Aiwu Ruth He, Antonio Cubillo Gracian, Tarek E. Eldawy, Giovanni Luca Frassineti, Gina M. Vaccaro, Jaclyn Neely, Fabio Piscaglia

Data analysis and interpretation: Thomas Yau, Vittorina Zagonel, Su Pin Choo, Ana Matilla, Aiwu Ruth He, Antonio Cubillo Gracian, Bruno Sangro, Jordi Bruix, Gina M. Vaccaro, Marina Tschaika, Christian Scheffold, Petra Koopmans, Jaclyn Neely, Fabio Piscaglia

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Nivolumab Plus Cabozantinib With or Without Ipilimumab for Advanced Hepatocellular Carcinoma: Results From Cohort 6 of the CheckMate 040 Trial

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