Cancer treatment in unresectable HCC and other malignant solid tumors has been rapidly changing, and the combinational therapy is increasingly favored. We performed a systematic review and meta-analysis to provide targeted therapy in combination with PD-1/PD-L1 inhibitors compared with targeted monotherapy. Our analyses explored clinically relevant efficacy outcomes, including OS, PFS, and grade 3–5 TRAEs. According to the results of the present study, targeted therapy in combination with PD-1/PD-L1 checkpoint inhibitors significantly improved the OS and PFS for unresectable HCC compared with targeted monotherapy showed that for unresectable HCC.
Three phase III RCTs comparing targeted therapy in combination with PD-1/PD-L1 inhibitors with targeted monotherapy have been published so far. Finn et al. reported the combination therapy of atezolizumab (anti-PD-L1) and bevacizumab, which is a vascular endothelial growth factor A (VEGF-A) inhibitor, as compared to sorafenib targeting anti-angiogenesis multikinase receptor, with statistically significant and clinically meaningful improvement in both OS and PFS in the treatment of unresectable HCC . Ren et al. and Kelley et al., respectively, reported that sintilimab (anti-PD-1) plus bevacizumab biosimilar and atezolizumab plus cabozantinib, which is a tyrosine kinases c-Met and VEGFR2 inhibitor, compared with sorafenib, achieved clinically meaningful improvements in OS and PFS for advanced/unresectable HCC [15, 17].
In patients with unresectable/advanced HCC, to the best of our knowledge, this is the first meta-analysis on RCTs to investigate the efficacy of targeted therapy in combination with immunotherapy versus targeted monotherapy. Although several trials are still ongoing, only three RCTs have been published. Compared with sorafenib, significantly better OS and PFS were observed with sintilimab plus bevacizumab (HR = 0.57, 95% CI: 0.43–0.75; HR = 0.56, 95% CI: 0.45–0.69), and atezolizumab plus bevacizumab (HR = 0.58, 95% CI: 0.58–0.80; HR = 0.59, 95% CI: 0.46–0.75), respectively. In terms of grade 3–5 AEs, the uses of lenvatinib (HR = 1.51; 95% CI: 1.14–2.00) and linifanib (HR = 1.94, 95% CI: 1.41–2.66) were higher than sorafenib. More data from updated clinical trials are still needed to confirm the benefit of combination therapy for HCC patients.
In the analyses of TRAEs, the results showed that compared with targeted monotherapy, the combination therapy had a significantly higher incidence of grade 3–5 TRAEs. The most common grade 3 or 4 TRAE with atezolizumab + bevacizumab and sintilimab + bevacizumab biosimilar group was hypertension (both 15%), which is consistent with the established safety profile of bevacizumab . Besides, gastrointestinal disorders were the most common reasons for treatment discontinuation (5%) in both groups, as expected in patients with liver cancer and underlying cirrhosis. The most common grade 3 or 4 TRAE was alanine aminotransferase increase (9% in the cabozantinib plus atezolizumab combination treatment group). In one of the included studies, Kelley et al. reported immune-mediated adverse events of any grade requiring immunosuppressive treatment occurred in 31 (7%) of 429 patients in the combination treatment group . The most common ones were hepatitis (4%) and pneumonitis (2%). For these 3 trials, the most common TRAEs from targeted agents were hypertension and elevated alanine aminotransferase. Grade 3 or 4 TRAEs, immune mediated or non-immune mediated, leading to study treatment discontinuation were infrequent in these 3 trials, indicating that these TRAEs were manageable with immunosuppressive drugs or other treatments. Potential candidates for the combination therapy of targeted drug and immunotherapy should be provided with this information.
Unresectable HCC management is still challenged in patients with cirrhosis and varied degree of impaired liver function. Immunotherapy, such as pembrolizumab and nivolumab, has been a viable and safe option in patients with advanced HCC . Newer systemic drugs like the combination of immune checkpoint inhibitors with biologic therapy, such as ramucirumab plus durvalumab treatment, likely to be promising as a new treatment standard for patients with unresectable HCC .
Atezolizumab is also used for other cancers like non-small cell lung cancer and advanced renal cell carcinoma. The COSMIC-021 study reported the combination therapy with atezolizumab and cabozantinib for advanced renal cell carcinoma , which regimen was similar to COSMIC-312 trial , appeared to be tolerable with a manageable toxicity profile. Grade 3 or 4 TRAE occurred in 59% of patients, slightly higher than 36% of patients of COSMIC-312 trial. Grade 3 or 4 Immune-mediated events were 30%. TRAEs leading to discontinuation of drug was 19–24% for subgroups. All AEs were managed with dose modifications and supportive care.
As for the second-line treatment, regorafenib showed promising results after sorafenib failure in HCC patients . One meta-analysis evaluating the efficacy and safety of regorafenib in unresectable HCC showed that pooled objective response rate was as high as 10.1% and pooled median OS of 11.1 months, as well as TRAE greater than Grade 3 was 50-58.3%. Regorafenib represents a valuable and comparatively safe therapeutic option in patients who progress on sorafenib . HCC scenario is continuously and rapidly changing for decades due to different etiology and treatment advance, including the progressions of patients age, increased non-viral cases and an earlier stage migration . This molecular information should also be integrated in the future to guide us to deal with the cancer more precisely .
The present study included several limitations. First, this meta-analysis mainly compared combination therapy with targeted monotherapy. These included RCTs, however, used various targeted agents and immunotherapy drugs, which may have biased the data analysis from the dissimilar therapeutic effects and AEs between drugs. The efficacy and TRAEs of individual drug in the combination can be further investigated using indirect comparison in the future. Second, the comparison of combination therapy with targeted monotherapy in patients with advanced/unrespectable HCC included only three RCTs with the limited information. Some other ongoing studies, such as LEAP-002 (lenvatinib plus pembrolizumab versus lenvatinib)  may be included in the near future. Third, the cost-effective analysis was insufficient in these trials. Cost-effective issue for HCC might be important because of the higher cost for the combination therapy than targeted monotherapy. More studies, especially those with the cost-effective analysis, are warranted in the future.