Background Systemic therapy for hepatocellular carcinoma (HCC) consisting of the tyrosine kinase inhibitor sorafenib has remained unchanged for over a decade, although results from phase III targeted therapy trials have recently emerged. This review considers available phase III evidence on the use and sequencing of targeted therapy for intermediate and advanced non-locoregional therapy (LRT) eligible HCC and discusses implications for clinical practice. Methods Published and presented literature on phase III data reporting on targeted therapy for advanced HCC that was not eligible for loco-regional therapies was identified using the key search terms “hepatocellular cancer” AND “advanced” AND “targeted therapy” AND “phase III” OR respective aliases (PRISMA). Results Ten phase III trials assessed targeted therapy first-line and eight following sorafenib. In the first-line, atezolizumab plus bevacizumab statistically significantly improved overall survival (OS) and patient-reported outcomes (PROs) compared with sorafenib, while lenvatinib demonstrated non-inferior OS. Following progression on sorafenib, statistically significant OS improvements over placebo were seen for cabozantinib and regorafenib in unselected patients and for ramucirumab in those with baseline α-fetoprotein ≥400 ng/mL. Based on improved OS and PROs, atezolizumab plus bevacizumab appears to be a preferred first-line treatment option for intermediate or advanced non-LRT eligible HCC. Phase III data informing sequencing of later lines of treatment is lacking. Therefore, sequencing principles are proposed that can be used to guide treatment selection. Ongoing trials will continue to inform optimal therapy. Conclusions Multiple targeted therapies have improved OS in intermediate or advanced non-LRT eligible HCC, although optimal sequencing is an area of ongoing investigation.

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Purpose Lung cancer is one of the most common types of cancer, resulting in approximately 1.8 million deaths worldwide. Immunotherapy using checkpoint inhibitors has become standard of care in advanced non‐small cell lung cancer (NSCLC), and there is increasing interest in further improving outcomes through combination with other therapeutics. This systematic review evaluates emerging phase III data on the efficacy and safety of checkpoint inhibitor combinations as first‐line treatment for advanced NSCLC. Materials and Methods Published and presented literature was searched using the key search terms “non‐small cell lung cancer” AND “checkpoint‐inhibitors” (OR respective aliases) AND phase III trials. Seven randomized phase III clinical trials reporting outcomes on checkpoint inhibitor combinations in first‐line advanced NSCLC were identified. Results Four first‐line trials reported outcomes for checkpoint inhibitor combinations in nonsquamous NSCLC. Pembrolizumab‐chemotherapy, atezolizumab‐chemotherapy, and atezolizumab‐bevacizumab‐chemotherapy showed significantly improved overall survival compared with controls in patients with advanced nonsquamous epidermal growth factor receptor‐negative (EGFR−)/ anaplastic lymphoma kinase gene (ALK)− NSCLC. Two trials reported outcomes for squamous NSCLC, with pembrolizumab‐chemotherapy reporting significantly improved overall survival (OS) compared with chemotherapy. The combination of nivolumab‐ipilimumab in all‐comer histology failed to improve OS compared with histology appropriate chemotherapy in patients regardless of their tumor mutational burden status. Based on improved survival and safety, either pembrolizumab monotherapy or pembrolizumab‐chemotherapy administered based on PD‐L1 status and histology is a preferred treatment option. Outcomes for atezolizumab‐bevacizumab‐chemotherapy in EGFR+/ALK+ patients are promising and require further exploration. Conclusion First‐line checkpoint inhibitors added to standard therapies improve overall survival for nonsquamous EGFR−/ALK− and squamous advanced NSCLC. Implications for Practice Single‐agent immune checkpoint inhibitors are now standard of care for advanced non‐small cell lung cancer (NSCLC), and emerging data show that combining these agents with established chemotherapy further improves outcomes. The phase III KEYNOTE‐189 and IMPower‐130 trials showed significantly improved survival using this strategy for nonsquamous NSCLC, and the phase III KEYNOTE‐407 trial showed similar results in squamous disease. Checkpoint inhibitor combinations are therefore an important new treatment option for first‐line NSCLC. Programmed death ligand‐1 expression may inform the use of checkpoint inhibitor combination therapy, and overall tumor mutation burden is also an emerging biomarker for this new treatment strategy.

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