IMbrave150: Exploratory Efficacy and Safety Results in Patients With Hepatocellular Carcinoma Without Macrovascular Invasion or Extrahepatic Spread Treated With Atezolizumab + Bevacizumab or Sorafenib
The global, open-label phase 3 IMbrave150 trial evaluated the combination of atezolizumab, a programmed death ligand-1 inhibitor, plus bevacizumab among patients with previously untreated, unresectable hepatocellular carcinoma (HCC).1 The combination of atezolizumab (1200 mg) plus bevacizumab (15 mg/kg) was administered every 3 weeks, and sorafenib (400 mg) was administered twice daily. The primary endpoints were overall survival (OS) and progression-free survival (PFS), evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.2
The intention-to-treat population consisted of 336 patients in the atezolizumab/bevacizumab arm and 165 in the sorafenib arm. The primary analysis revealed a superior survival benefit with atezolizumab plus bevacizumab vs sorafenib (hazard ratio [HR] for death, 0.58; 95% CI, 0.42-0.70; P<.001).1 The 12-month OS was 67.2% with atezolizumab plus bevacizumab vs 54.6% with sorafenib. The median PFS was 6.8 months vs 4.3 months, respectively (HR, 0.59; 95% CI, 0.47-0.76; P<.001). After an additional 12 months of follow-up, the median OS was 19.2 months with atezolizumab plus bevacizumab vs 13.4 months with sorafenib.3 The median PFS was 6.9 months vs 4.3 months, respectively.
The rates of grade 3/4 adverse events (AEs) were similar in the 2 treatment arms. Grade 3/4 hypertension was observed in 15.2% of patients in the atezolizumab/bevacizumab arm vs 12.2% of those in the sorafenib arm. The trial established the combination of atezolizumab plus bevacizumab as the standard of care for the first-line treatment of unresectable HCC.
An exploratory analysis of the updated data from the IMbrave150 study compared the safety and efficacy of atezolizumab plus bevacizumab vs sorafenib in the subgroup of patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C disease who did not have extrahepatic spread or macrovascular invasion.4 The study evaluated data for 70 patients in the atezolizumab/bevacizumab arm and 38 patients in the sorafenib arm. The efficacy analysis included 66 patients and 37 patients, respectively. The baseline characteristics were generally well-balanced across the 2 arms. Among patients treated with atezolizumab plus bevacizumab, the etiology of HCC was nonviral in 46% of patients, associated with hepatitis B virus in 29% of patients, and associated with hepatitis C virus in 26% of patients. BCLC stage B disease was reported in 70% of patients, and 30% had BCLC stage C disease. In the sorafenib arm, the etiology of HCC was nonviral in 42% of patients, linked to hepatitis B virus in 24%, and linked to hepatitis C virus in 34% of patients. Two-thirds of patients had BCLC stage B disease, and one-third had BCLC stage C disease. Previous treatment with transarterial chemoembolization (TACE) was reported in 44% of patients in the atezolizumab/bevacizumab arm vs 53% in the sorafenib arm.
Among patients with BCLC stage B disease, the exploratory analysis yielded a median OS of 25.8 months with atezolizumab plus bevacizumab vs 18.1 months with sorafenib (HR, 0.61; 95% CI, 0.29-1.27; Figure 1).4 Among patients with BCLC stage C disease, the median OS was 24.6 months vs 16.9 months, respectively (HR, 0.48; 95% CI, 0.19-1.22; Figure 2). Among patients with BCLC stage B disease, the median PFS was 12.6 months vs 8.6 months, respectively (HR, 0.63; 95% CI, 0.36-1.10). In patients with BCLC stage C disease, the median PFS was 7.0 months vs 4.8 months (HR, 0.83; 95% CI, 0.36-1.88). Based on RECIST 1.1, the confirmed objective response rate (ORR) was 43% with atezolizumab/bevacizumab vs 25% with sorafenib in patients with BCLC stage B HCC. The confirmed ORR was 15% in both cohorts of patients with BCLC stage C disease.
The safety profile of the atezolizumab/bevacizumab regimen was consistent with the known safety profiles of the individual antibodies. Grade 3/4 AEs were reported in 70% of patients treated with atezolizumab plus bevacizumab and 65% of those treated with sorafenib. AEs led to dose modification or interruption of any study treatment among 65% of patients in both treatment arms.
References
1. Finn RS, Qin S, Ikeda M, et al; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905.
2. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.
3. Finn RS, Qin SQ, Ikeda M, et al. IMbrave150: updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC) [ASCO GI abstract 267]. J Clin Oncol. 2021;3(suppl).
4. Kudo M, Finn RS, Galle PR, et al. IMbrave150: exploratory efficacy and safety results in patients with hepatocellular carcinoma without macrovascular invasion (MVI) or extrahepatic spread (EHS) treated with atezolizumab (atezo) + bevacizumab (bev) or sorafenib (sor) [ESMO abstract 932P]. Ann Oncol. 2021;32(suppl 5).
IMMUTACE: A Phase 2 Single-Arm, Open-Label Study of Transarterial Chemoembolization in Combination With Nivolumab Performed for Intermediate-Stage Hepatocellular Carcinoma
Real-world data show that 60% of patients with intermediate-stage HCC are treated with TACE.1 The treatment is not curative, and the median OS is less than 20 months.1 Local treatment increases the release of antigens, and therefore the addition of nivolumab to TACE could provide synergistic antitumor activity. The open-label, single-arm phase 2 IMMUTACE study investigated the safety and efficacy of TACE combined with nivolumab among patients with intermediate-stage HCC.2 The trial enrolled patients with histologically confirmed, intermediate-stage HCC, an Eastern Cooperative Oncology Group (ECOG) score of 0 to 2, and a Child-Pugh score of A. The patients could have limited metastatic disease. The primary objective was the ORR, with an ORR of 55% or greater considered promising enough for further investigation. The secondary objectives included PFS, time to failed strategy, OS, quality of life, and safety. Patients received an initial TACE treatment, followed by nivolumab within 2 to 3 days. Nivolumab (240 mg) was administered every 2 weeks until the patient developed progressive disease. A second TACE procedure was permitted, based on the investigator’s decision. PFS was evaluated after the first indication of disease progression.
The patients were a median age of 66 years (range, 42-83 years), and 81.6% were male.2 The ECOG performance status was 0 in 85.7% of patients and 1 in 14.3%. Nonviral etiology was reported in 69.4% of patients. HCC was associated with hepatitis B virus in 8.2% of patients and hepatitis C virus in 14.3% of patients. Previous therapies included resection (22%) and radiotherapy (2%). The patients had a median of 3 tumors (range, 1-12), and the median tumor size was 3 cm (range, 0.6-14.7). The BCLC stage was A in 18.4%, B in 59.2%, and C in 2.0%.
The ORR was 71.4% (95% CI, 56.8%-83.4%), which consisted of complete responses (CRs) in 16.3% and partial responses (PRs) in 55.1% (Figure 3). A subgroup analysis did not identify any differences in treatment response, although the number of patients in each group was small.
Treatment was generally well tolerated.2 The most common AEs of any grade were fatigue (30.6%), increase in aspartate aminotransferase (24.5%), and increase in alanine aminotransferase (22.4%). The most common AEs of grade 3 or higher were increases in aspartate aminotransferase (14.3%), gamma-glutamyl transferase (10.2%), and alanine aminotransferase (8.2%). An ongoing correlative analysis is evaluating whether treatment efficacy corresponds with genetic alterations, gene expression patterns, and/or changes in immune cell populations.
References
1. Prince D, Liu K, Xu W, et al. Management of patients with intermediate stage hepatocellular carcinoma. Ther Adv Med Oncol. 2020;12:1758835920970840.
2. Vogel A, Saborowski A, Hinrichs J, et al. IMMUTACE: a phase II single-arm, open-label study of transarterial chemoembolization in combination with nivolumab performed for intermediate stage hepatocellular carcinoma [ESMO abstract LBA37]. Ann Oncol. 2021;32(suppl 5).
Prognostic Factor Analysis of Atezolizumab-Bevacizumab in Unresectable Hepatocellular Carcinoma: Korean Cancer Study Group Study
In the phase 3 IMbrave150 trial, atezolizumab plus bevacizumab improved PFS and OS in patients with previously untreated, unresectable HCC.1 A retrospective, multicenter analysis by the Korean Cancer Study Group evaluated real-world data to identify prognostic factors among patients with advanced HCC treated with first-line atezolizumab plus bevacizumab.2
The trial enrolled 121 patients with a Child-Pugh score of A5 (74.4%) or A6 (25.6%) and BCLC stage B (20.7%) or C (79.3%) disease.2 Their median age was 61 years, and most patients (84%) were male. Macrovascular invasion was reported in 37.2% of patients, and 70.2% of patients had extrahepatic spread. The cause of HCC was hepatitis B in 76.9% and hepatitis C in 5%. Prior treatment included TACE in 57.9% of patients, radiotherapy in 37.2%, surgery in 31.4%, and radiofrequency ablation in 14.9%.
The ORR was 24.0%, with a CR rate of 1.7%.2 The median OS was not reached (95% CI, not evaluable; Figure 4), and the median PFS was 6.5 months (95% CI, 4.1-9.0). Based on multivariate analysis, the PFS and OS were significantly better in patients with a neutrophil-to-lymphocyte ratio of less than 5 (Figure 5). The hazard ratio for the neutrophil-to-lymphocyte ratio (≥5 vs <5) was 2.23 (95% CI, 1.12-4.45; P=.023) for PFS and 4.68 (95% CI, 1.87-11.73; P<.001) for OS. The median PFS was superior in patients who achieved a CR or PR vs those with stable or progressive disease (P<.001), as well as in those with an increase in alpha-fetoprotein vs those with a decrease (P=.002).
A grade 3/4 AE was reported in 28.9%. The most common grade 3/4 AEs were elevated aspartate aminotransferase in 10.7%, hypertension in 6.6%, and thrombocytopenia in 4.9%.
The study investigators concluded that the results of their real-world analysis were similar to those reported in the IMbrave150 trial.1,2 They noted that careful assessment of treatment response is needed in patients with an elevated neutrophil-to-lymphocyte ratio, who had lower survival outcomes in this analysis.
References
1. Finn RS, Qin S, Ikeda M, et al; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905.
2. Cheon J, Yoo C, Hong JY, et al. Prognostic factor analysis of atezolizumab-bevacizumab in unresectable hepatocellular carcinoma: Korean Cancer Study Group (KCSG) study [ESMO abstract 955P]. Ann Oncol. 2021;32(suppl 5).
Updated Survival and Secondary Safety and Efficacy Analyses From CA 209-678: A Phase 2, Open-Label, Single-Center Study of Y90-Radioembolization in Combination With Nivolumab in Asian Patients With Advanced Hepatocellular Carcinoma
As separate therapies, nivolumab and Yttrium-90 (Y90) are effective in patients with advanced HCC.1,2 Previous data have suggested that there may be synergy between these 2 treatments.3 The open-label, single-center phase 2 CA 209-678 trial investigated Y90 embolization combined with nivolumab in patients with advanced HCC.4
The trial enrolled 40 patients, of whom 36 were evaluable.4 All patients had a Child-Pugh score of A and were not candidates for curative surgery. The patients’ median age was 64 years (range, 23-79 years), 78% were male, and 69% were of Chinese ethnicity.
The patients received a median of 7 cycles (range, 1-66+) of nivolumab. After a median follow-up of 24.8 months, the ORR according to RECIST 1.1 was 30.6% and the disease control rate was 61.1%. The median time to response was 3.8 months. The median PFS was 3.6 months (95% CI, 2.1-8.8 months), and the median OS was 16.9 months (95% CI, 8.1-27.6 months). Outcomes differed according to the patient’s baseline hepatitis B status and level of alpha-fetoprotein (Table).
Treatment-related AEs occurred in 81% of patients. These events were grade 3/4 in 14% of patients. There were no grade 5 treatment-related AEs. The most common treatment-related AEs were pruritus, which occurred in 50% of patients, and rash, which occurred in 39%.
References
1. Zhu AX, Finn RS, Edeline J, et al; KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19(7):940-952.
2. Salem R, Mazzaferro V, Sangro B. Yttrium 90 radioembolization for the treatment of hepatocellular carcinoma: biological lessons, current challenges, and clinical perspectives. Hepatology. 2013;58(6):2188-2197.
3. Zhan C, Ruohoniemi D, Shanbhogue KP, et al. Safety of combined Yttrium-90 radioembolization and immune checkpoint inhibitor immunotherapy for hepatocellular carcinoma. J Vasc Interv Radiol. 2020;31(1):25-34.
4. Lee J, Tan SH, Hennedige T, et al. Updated survival and secondary safety and efficacy analyses from CA 209–678: a phase II open-label single-centre study of Y90-radioembolisation (Y90) in combination with nivolumab in Asian patients with advanced hepatocellular carcinoma [ESMO abstract 947P]. Ann Oncol. 2021;32(suppl 5).
A Phase 2 Clinical Trial of the Phosphatidylserine-Targeting Antibody Bavituximab in Combination With Pembrolizumab in Patients With Advanced Hepatocellular Carcinoma
Phosphatidylserine is expressed on the inner leaflet of the plasma membrane of normal cells.1 However, phosphatidylserine becomes externalized on the outer leaflet of the plasma membrane of tumor cells and other cells in the tumor microenvironment, making it a potential target for therapy. Bavituximab is a chimeric antibody that binds to phosphatidylserine, thus increasing the antitumor immune response.2 A single-arm, open-label phase 2 study evaluated the combination of bavituximab plus pembrolizumab among patients with advanced HCC.3
The trial enrolled patients with locally advanced or metastatic HCC that could not be treated with locoregional therapy. Patients received pembrolizumab (200 mg every 3 weeks) plus bavituximab (3 mg/kg weekly). The primary endpoint was the ORR according to RECIST 1.1, with secondary endpoints of OS, 6-month PFS, duration of response, and safety.4
The 25 study participants had a median age of 63.5 years, and 88% were male.3 Among 16 evaluable patients, the ORR was 31%, with no CRs. PRs were confirmed by radiographic assessment performed at least 4 weeks after the initial assessment.
Pembrolizumab plus bavituximab was generally well tolerated. Most AEs were grade 1 or 2. Grade 1 increased alanine transaminase and grade 2 acute renal insufficiency each occurred in 1 patient. Grade 3/4 AEs included diarrhea and shortness of breath, observed in 1 patient each. The study has a planned enrollment of 28 patients.
References
1. Belzile O, Huang X, Gong J, et al. Antibody targeting of phosphatidylserine for the detection and immunotherapy of cancer. ImmunoTargets Ther. 2018;7:1-14.
2. Gerber DE, Stopeck AT, Wong L, et al. Phase I safety and pharmacokinetic study of bavituximab, a chimeric phosphatidylserine-targeting monoclonal antibody, in patients with advanced solid tumors. Clin Cancer Res. 2011;17(21):6888-6896.
3. Hsieh D, Kainthla R, Zhu H, et al. A phase 2 clinical trial of the phosphatidylserine-targeting antibody, bavituximab, in combination with pembrolizumab in patients with advanced hepatocellular carcinoma [ESMO abstract 939P]. Ann Oncol. 2021;32(suppl 5).
4. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.
Highlights in Hepatocellular Carcinoma From the 2021 European Society for Medical Oncology Congress: Commentary
Catherine T. Frenette, MD
Director, Liver and Hepatocellular Cancer Program
Scripps MD Anderson Cancer Center
La Jolla, California
Several abstracts presented at the 2021 European Society for Medical Oncology (ESMO) congress provided important insights into the management of patients with hepatocellular carcinoma (HCC). Studies provided new data for treatments such as atezolizumab plus bevacizumab, systemic treatment plus locoregional therapy or resection, and novel regimens.
Atezolizumab Plus Bevacizumab
The combination of atezolizumab plus bevacizumab is at the forefront of recommendations for systemic first-line treatment of patients with HCC. At the 2021 ESMO congress, there were several abstracts that focused on the use of atezolizumab plus bevacizumab, including how this regimen works among various patient populations. Dr Masatoshi Kudo presented an analysis of the phase 3 IMbrave150 study, which compared atezolizumab plus bevacizumab vs sorafenib in patients with advanced HCC.1,2 Updated results, which were presented at the 2021 American Society of Clinical Oncology Gastrointestinal Cancers symposium, showed that the median overall survival was 19.2 months with atezolizumab plus bevacizumab vs 13.4 months with sorafenib.3 The median progression-free survival was 6.9 months vs 4.3 months, respectively. The analysis by Dr Kudo and colleagues focused on patients who had Barcelona Clinic Liver Cancer (BCLC) stage B or C disease without macrovascular invasion or extrahepatic spread, who are likely to be early in their disease course.2 More than half of these patients had undergone locoregional therapy. The analysis showed that atezolizumab plus bevacizumab was still superior to sorafenib in this patient population for both overall survival and progression-free survival. The safety analysis was consistent with the previous data for atezolizumab plus bevacizumab,1 which was reassuring.
The study separately analyzed outcome for patients with BCLC stage B vs stage C disease, which led to an interesting finding.2 The benefit of atezolizumab/bevacizumab was greater in patients with BCLC stage C disease. The median overall survival was 24.6 months with atezolizumab/bevacizumab vs 16.9 months with sorafenib, for a hazard ratio of 0.48. It would be expected that patients with BCLC stage B disease are earlier in their disease course and therefore would have a better response to the investigative treatment. For these patients, however, the median overall survival was 25.8 months with atezolizumab/bevacizumab vs 18.1 months with sorafenib, for a hazard ratio of 0.61. The Kaplan-Meier curves crossed each other in this patient population. It should be noted that the population with BCLC stage B disease was small (n=74). For patients with BCLC stage B HCC, treatment often consists of locoregional therapy, which is recommended over systemic therapy in guidelines.4 There is the possibility that patient characteristics may have impacted response to treatment in the IMbrave150 study. This subgroup analysis of the IMbrave150 trial supports the overall data previously reported for the combination of atezolizumab plus bevacizumab.
Dr Jaekyung Cheon presented results from a real-world study of atezolizumab plus bevacizumab in patients with unresectable HCC from the Korean Cancer Study Group.5 This study aimed to identify prognostic factors for atezolizumab/bevacizumab. Currently, there are no specific prognostic factors that predict whether a patient will respond to systemic treatment. This multicenter, retrospective analysis included 138 patients. The median overall survival was not reached, and the median progression-free survival was 6.5 months. Many of these patients had viral hepatitis; 77% had hepatitis B and 5% had hepatitis C. There have been some data suggesting that immunotherapies are more effective in patients with viral hepatitis.6 It was reassuring to see that atezolizumab/bevacizumab was beneficial in these patients. These data support the use of immunotherapy in patients with HCC and viral hepatitis.
This multivariate analysis identified several predictors of survival outcomes. Previous studies have evaluated the potential of the neutrophil-to-lymphocyte ratio (NLR) as a disease biomarker.7,8 Currently, the application of the NLR is unclear. Patients with a high NLR generally have disease that is more aggressive and that progresses earlier. Studies have used different cutoff values for the NLR. The study by Dr Cheon and colleagues compared outcomes among patients with an NLR of less than 5 vs 5 or higher.5 Patients with an NLR below 5 had much better overall survival and progression-free survival. For overall survival, the hazard ratio for the NLR (≥5 vs <5) was 4.68 (95% CI, 1.87-11.73; P<.001). For progression-free survival, the hazard ratio was 2.23 (95% CI, 1.12-4.45; P=.023). Physicians might consider this finding when deciding whether to proceed with systemic therapy.
This analysis evaluated whether an increase or decrease of alpha-fetoprotein at the first evaluation after treatment could predict prognosis.5 As expected, patients with a decrease in alpha-fetoprotein had better overall survival and progression-free survival. It might be possible to use this value as a marker early in the course of therapy. The investigators also evaluated prognosis according to best response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.9 Patients who had a complete response or partial response after treatment with atezolizumab plus bevacizumab had much better overall survival and progression-free survival compared with those who had stable disease or progressive disease. Again, this marker cannot be used until after treatment is initiated.
Systemic Treatment Plus Locoregional Therapy or Resection
Many studies of systemic therapy in HCC are evaluating the use of this treatment earlier in the course of the disease, before patients progress to BCLC stage C and are no longer candidates for more invasive treatments, such as resection or locoregional therapy with transarterial chemoembolization (TACE) or Yttrium-90 (Y90). Presentations at the 2021 ESMO congress included multiple studies that evaluated the combination of systemic treatments with locoregional therapy or resection. In a late-breaking oral abstract, Dr Arndt Vogel presented results from IMMUTACE, a single-arm, phase 2 study of TACE in combination with nivolumab for intermediate-stage HCC.10 Immunotherapy is very helpful for advanced HCC.11 The immune system is active earlier in the course of the disease, particularly after locoregional therapies, such as TACE. After local treatments, tumors release more neoantigens. The impact of immunotherapy might be increased if administered when these neoantigens are circulating. The premise behind this study was that a synergistic benefit might be seen if systemic therapies, such as immunotherapy, are combined with a locoregional therapy, such as TACE.
The trial enrolled 49 patients with intermediate-stage HCC. Patients were permitted to have limited metastatic disease. In the United States, locoregional therapy is generally not considered for patients with metastatic disease, except in rare instances. The study’s primary objective was to assess the overall response rate. Progression-free survival was a secondary objective.
The patients underwent an initial course of TACE. After they recovered—which took anywhere from a few days to a few weeks—they began treatment with nivolumab. They were able to receive a second course of TACE if needed. Patients with a response to nivolumab continued treatment. Among patients with progressive disease, those who were candidates for further locoregional therapy were permitted to undergo a third course of TACE, ablation, or resection. The treatment strategy was deemed unsuccessful in patients who were not candidates for further locoregional therapy and those who did not respond to the third course of TACE.
The enrolled patients reflected the standard HCC population. Most patients were men, and the median age was 66 years. In general, the patients had a good performance status. Most patients had nonviral hepatitis. Given the concerns regarding the use of immunotherapy in patients with nonviral-related HCC, it was good to see data showing some benefit. The patients had relatively advanced disease. The median number of tumors was 3, with a range of 1 to 12. The median tumor size was 3 cm, and the range was 0.6 cm to almost 15 cm. Most patients had BCLC stage B disease. All patients had Child-Pugh class A disease. The albumin-bilirubin score was 1 in 61.2% of patients and 2 in 34.7% of patients.
The study investigators reported a promising overall response rate of 71.4%, which is better than that expected with either of these treatments alone.10-12 A complete response was seen in 16.3% of patients, and a partial response occurred in 55.1%. Stable disease was reported in 4.1% of patients, and progressive disease was reported in 14.3%. Safety was a secondary objective. The combination of TACE plus nivolumab was safe, with no unexpected adverse events based on the use of either treatment alone. A subgroup analysis did not identify any groups with particularly better or worse outcomes. However, the low number of enrolled patients may have limited the subgroup analysis. Overall, this study suggests that there may be some benefit to combining immunotherapy with TACE. The data will need to be confirmed in larger prospective, randomized controlled trials, but they are promising.
An open-label, single-center phase 2 trial evaluated the combination of Y90 plus nivolumab.13 This small study enrolled 40 patients, and 36 were evaluable. Approximately 60% of patients had hepatitis B, so there was a large amount of viral hepatitis in this population. The time to response was 3.8 months. The median progression-free survival was 3.6 months, with a median overall survival of 16.9 months. The overall response rate was approximately 30.6%, and the in-field overall response rate according to RECIST 1.1 was 36.1%.9 There were no new or unexpected treatment-related adverse events. This combination of locoregional and systemic therapy therefore appears to be safe and has the potential to improve responses in patients with HCC.
An interesting phase 2 study presented by Dr Xin-Rong Yang from Fudan University in Shanghai, China evaluated combination systemic therapy after resection in earlier-stage disease.14 This study combined camrelizumab, a programmed cell death protein 1 (PD-1) immune checkpoint inhibitor, with apatinib, a tyrosine kinase inhibitor that is more selective to vascular endothelial growth factor receptor 2. These 2 drugs are not routinely used to treat HCC in the United States, although other agents from these classes are used frequently in this setting.
The study enrolled patients who were undergoing resection of HCC.14 Resection is associated with recurrence rates as high as 70% at 5 years after the procedure. To make resection successful, and even curative, it would be helpful to have adjuvant therapy or neoadjuvant therapy that improves overall survival and recurrence rates. The enrolled patients had pathologically confirmed HCC, with no evidence of extrahepatic metastases. According to protocol, the trial excluded patients with peri-resection mortality, although the number of these patients was not reported. The investigators assessed 76 patients for eligibility and excluded 31 patients for a variety of reasons, including history of other tumor types and issues with baseline laboratory parameters, anticoagulation, and informed consent. A total of 45 patients were allocated to receive a combination of camrelizumab and apatinib after resection of their HCC.
The patients were a median age of 54 years, and most were men. This study also had a very strong viral hepatitis population; 40 out of 45 patients had hepatitis B. The patients had good laboratory parameters and good liver function, as would be expected given that they were undergoing resection. However, the patients had very aggressive disease, as reflected in their characteristics. Among countries in Asia, HCC resection is used much more liberally than in the United States. This is partly because the availability of transplant is more limited in Asia. In addition, many of these patients have hepatitis B and do not have cirrhosis. Their liver function is excellent, so resection can be considered more readily. Among the 45 patients in this study, 19 had portal vein invasion. In the United States, resection would not have been offered to many of these patients.
The median number of tumors was 2, and the mean tumor size was 6.7 cm. Only 13 patients had tumor encapsulation, which is a good prognostic indicator. Many of the patients had more advanced tumor differentiation and a more advanced stage of liver cancer. These patients had advanced HCC for a resection procedure, which provided a good opportunity for the use of a potentially curative therapy.
The median follow-up was 21.5 months.14 The median recurrence-free survival was 11.7 months, with a recurrence-free survival rate of 48.9% at 1 year and a 1-year overall survival rate of 97.8%. These results are very promising in patients with such advanced tumors.
There were adverse events related to camrelizumab and apatinib, but they did not cause any patient to stop treatment. Adverse events were treated and controlled. This tolerability is also promising.
The study results suggested that the combination of a PD-1 inhibitor and a tyrosine kinase inhibitor could prolong overall survival and potentially improve recurrence-free survival in patients with HCC who are undergoing resection.14 The data will need to be confirmed in a larger, prospective, randomized clinical trial. However, the promising results raise the possibility that the use of a systemic therapy earlier in the disease may improve outcomes.
Novel Treatments
Several abstracts evaluated new treatments for HCC. Dr David Hsieh presented results of a phase 2 clinical trial of the phosphatidylserine-targeting antibody bavituximab combined with pembrolizumab among patients with HCC.15 Phosphatidylserine is an immunosuppressive molecule that becomes externalized in cells that line tumor blood vessels and in tumor cells. Phosphatidylserine is active in the tumor microenvironment. Currently, bavituximab is used to modulate the tumor microenvironment by driving innate and adaptive immunity. The addition of bavituximab to pembrolizumab could potentially increase the clinical activity of the latter agent.
The trial enrolled only 25 patients, and was a pilot study.15 Bavituximab combined with pembrolizumab did not lead to any complete responses. Partial responses were reported in 31% of patients, and 25% of patients had stable disease. These efficacy results are better than would be expected with pembrolizumab alone in this patient population.11 Treatment was well tolerated and had a good safety profile. The results of this study hint that by combining this phosphatidylserine-targeting antibody with pembrolizumab, it may be possible to improve the efficacy of PD-1/programmed death ligand 1 therapies.
The phase 2 LEOPARD study, presented by Dr Masafumi Ikeda from Japan, evaluated lenvatinib plus hepatic arterial infusional chemotherapy (HAIC) with cisplatin.16 In the United States, lenvatinib is used in advanced HCC, but HAIC is not a standard treatment. In Japan and some other countries, HAIC is a frequent treatment for HCC. Physicians strongly recommend this treatment to many patients.
This pilot study enrolled 36 patients. The patients’ median age was 68 years. Most patients were male, and they had a good performance status. Approximately one-quarter of patients had hepatitis B, and one-quarter of patients had hepatitis C. Nearly half of patients had portal vein invasion, and approximately a quarter of patients had extrahepatic metastases.
The combination of lenvatinib plus HAIC with cisplatin led to an overall response rate of nearly 65% by modified RECIST assessment and of 45% by RECIST 1.1.9,16,17 The disease control rate was approximately 75%. The median progression-free survival was 6.3 months, and the median overall survival was 17.2 months. These outcomes are better than those reported in the REFLECT study of lenvatinib monotherapy.18 Larger, multiphase, randomized, prospective clinical trials are needed to further evaluate the combination of lenvatinib plus HAIC with cisplatin.
Disclosures
Dr Frenette is a member of the advisory boards of Eisai, Exelixis, Genentech, and AstraZeneca. She is a consultant for Bayer, Eisai, Merck, and Genentech. She has received research support from Bayer, Merck, and Exelixis. She was a member of the speakers bureaus (all discontinued June 1, 2021) of Bristol Myers Squibb, Gilead, AbbVie, Eisai, Salix, Exelixis, Genentech, and Intercept. She does not own any stocks or have any other financial interests to report.
References
1. Finn RS, Qin S, Ikeda M, et al; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905.
2. Kudo M, Finn RS, Galle PR, et al. IMbrave150: exploratory efficacy and safety results in patients with hepatocellular carcinoma without macrovascular invasion (MVI) or extrahepatic spread (EHS) treated with atezolizumab (atezo) + bevacizumab (bev) or sorafenib (sor) [ESMO abstract 932P]. Ann Oncol. 2021;32(suppl 5).
3. Finn RS, Qin SQ, Ikeda M, et al. IMbrave150: updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC) [ASCO GI abstract 267]. J Clin Oncol. 2021;3(suppl).
4. Vogel A, Martinelli E; ESMO Guidelines Committee. Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO Clinical Practice Guidelines. Ann Oncol. 2021;32(6):801-805.
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