A new phase III randomized clinical trial has found that adding doxorubicin to sorafenib did not improve overall survival in patients with advanced hepatocellular carcinoma (HCC). The study, known as CALGB 80802 (Alliance), also examined the impact of treatment on hepatitis C virus (HCV) titers in HCV-positive patients. Interestingly, patients with undetectable HCV at baseline had worse progression-free survival compared to those with detectable HCV, though this did not translate to differences in overall survival.
The study was conducted by the Alliance for Clinical Trials in Oncology in collaboration with several other cooperative oncology groups. It was funded in part by Bayer, Bristol Myers Squibb, and Sanofi. The results were published in March 2024 in the journal Cancer Research Communications.
HCC is a complex and heterogeneous disease, with viral hepatitis being a major risk factor in many parts of the world. Previous preclinical studies had suggested that sorafenib, a multikinase inhibitor approved for HCC treatment, could potentially inhibit HCV replication by blocking the interaction between the HCV nonstructural protein 5A (NS5A) and c-Raf. There was also a rationale that adding doxorubicin to sorafenib could enhance efficacy by overcoming resistance mechanisms. A prior phase II study had shown promising results with the combination.
The CALGB 80802 trial aimed to definitively test whether adding doxorubicin to sorafenib could improve outcomes in advanced HCC. The study enrolled 356 patients between 2010 and 2015. Eligible patients had histologically proven advanced HCC with no prior systemic therapy, Child-Pugh A liver function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Patients were randomized 1:1 to receive either sorafenib alone or sorafenib plus doxorubicin.
The primary endpoint was overall survival. Secondary endpoints included progression-free survival and objective response rate. A pre-planned correlative study examined HCV viral loads in HCV-positive patients to assess any potential antiviral effects of the treatments.
The study population was predominantly male (92.5%) with a median age of 61 years. Most patients had an ECOG performance status of 0-1. About half had metastatic disease. In terms of etiology, 83 patients (23.3%) were HCV-positive at baseline. Interestingly, HCV infection rates were significantly higher in Black/African American patients (50%) compared to White patients (23%) or other racial groups (6%).
The primary analysis found no significant difference in overall survival between the treatment arms. Median overall survival was 9.3 months (95% CI: 7.3-10.8) in the doxorubicin plus sorafenib arm versus 9.4 months (95% CI: 7.3-12.9) in the sorafenib alone arm (HR 1.05, 95% CI: 0.83-1.31). Progression-free survival was also similar between arms at 4.0 months versus 3.7 months, respectively (HR 0.93, 95% CI: 0.75-1.16).
For the HCV substudy, serum samples were available from 53 of the 83 HCV-positive patients. HCV viral loads were measured at baseline and at multiple timepoints during treatment. The key findings from this analysis were:
1. HCV viral loads remained largely stable during treatment in both arms, with no significant differences between sorafenib alone and sorafenib plus doxorubicin.
2. Only 2 patients (one in each arm) had a significant decline in HCV viral load during treatment, converting from detectable to undetectable.
3. Patients with undetectable HCV at baseline had significantly worse progression-free survival compared to those with detectable HCV (HR 3.51, 95% CI: 1.58-7.78, p=0.002). Median PFS was 2.8 months for HCV-undetectable versus 5.5 months for HCV-detectable.
4. This difference in PFS did not translate to a significant difference in overall survival (HR 1.14, 95% CI: 0.58-2.23, p=0.70).
5. The prognostic impact of HCV status was consistent across both treatment arms.
6. There were no significant differences in outcomes based on HCV genotype, though patients with undetectable genotype had worse prognosis.
The study had several limitations. First, biospecimen collection was optional, resulting in HCV data being available for only a subset of HCV-positive patients. This limits the generalizability of the HCV findings. Second, the study was conducted before the widespread availability of direct-acting antiviral therapies for HCV, so the results may not reflect current treatment paradigms. Third, the reasons for the association between undetectable HCV and worse PFS are unclear and require further investigation.
The authors concluded that adding doxorubicin to sorafenib does not improve outcomes in advanced HCC, contrary to the preclinical rationale and phase II results. They also noted that sorafenib treatment did not appear to have a significant impact on HCV viral loads, despite preclinical data suggesting it could inhibit viral replication.
The finding that patients with undetectable HCV had worse progression-free survival was unexpected and intriguing. The authors speculated that this could potentially reflect differences in tumor biology or immune responses between patients who spontaneously clear HCV versus those with chronic infection. However, they emphasized that this finding requires validation in larger cohorts and exploration of potential biological mechanisms.
This study has several potential clinical implications:
1. It definitively shows that adding doxorubicin to sorafenib should not be pursued as a treatment strategy for advanced HCC. This spares patients from additional toxicity without benefit.
2. The lack of impact on HCV viral loads suggests that any benefit of sorafenib in HCV-associated HCC is likely due to its direct anti-tumor effects rather than antiviral activity.
3. The association between undetectable HCV and worse PFS, if validated, could potentially inform prognostic assessments. However, the authors caution against using this clinically without further study.
4. The racial disparities in HCV prevalence among HCC patients highlight the need for targeted screening and prevention efforts in high-risk populations.
5. The overall negative results of this large phase III trial underscore the challenges in developing new therapies for HCC and the importance of robust preclinical and early-phase clinical data before proceeding to phase III.
This study also raises several questions for future research. Why did the promising phase II results with doxorubicin plus sorafenib not translate to phase III? Are there subgroups of patients who might benefit from the combination? What are the biological mechanisms underlying the association between undetectable HCV and worse outcomes? How might modern HCV therapies impact the prognosis of HCV-associated HCC?
It's important to note that the treatment landscape for HCC has evolved significantly since this trial was conducted. Several immunotherapy-based regimens have shown efficacy in recent years, including the combination of atezolizumab plus bevacizumab, which has become a new standard of care in many regions. Future studies will need to examine how HCV status and viral loads impact outcomes with these newer regimens.
The negative results of the CALGB 80802 trial highlight the complexities of HCC biology and the challenges in drug development for this disease. While the addition of doxorubicin to sorafenib did not improve outcomes, the correlative HCV analyses provide intriguing insights into the interplay between viral hepatitis and HCC prognosis. As our understanding of HCC biology continues to evolve and new therapeutic approaches emerge, studies like this one provide valuable lessons and generate hypotheses for future investigation.
In conclusion, this large phase III trial has definitively shown that adding doxorubicin to sorafenib does not improve outcomes in advanced HCC. The correlative studies on HCV viral loads provide new insights into the complex relationships between viral hepatitis, HCC biology, and treatment outcomes. While these findings close the door on one potential treatment strategy, they open new avenues for research into the biological underpinnings of HCC and potential biomarkers of prognosis and treatment response. As the field continues to advance, integrating clinical, virological, and molecular data will be crucial in developing more effective, personalized treatment approaches for patients with this challenging disease.
References
Abou-Alfa GK, Geyer SM, Nixon AB, et al. CALGB 80802 (Alliance): Impact of Sorafenib with and without Doxorubicin on Hepatitis C Infection in Patients with Advanced Hepatocellular Carcinoma. Cancer Res Commun. 2024;4(3):682-690. doi:10.1158/2767-9764.CRC-22-0516
