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The Sidney Kimmel Comprehensive Cancer Center
Mark Yarchoan, MD, has disclosed that he has received consulting fees from AstraZeneca, Eisai, Exelixis, and Genentech.
Several studies presented at the 2021 ASCO Gastrointestinal Cancers Symposium highlighted ongoing research into use of approved regimens and notable emerging therapeutic strategies for patients with advanced hepatocellular carcinoma (HCC). In this commentary, I briefly review the new data and share my thoughts on select studies of interest.
IMbrave150: Updated Results With First-line Atezolizumab Plus Bevacizumab
In May 2020, the FDA approved the PD-L1 inhibitor/VEGF inhibitor combination of atezolizumab plus bevacizumab as first-line systemic treatment for patients with unresectable or metastatic HCC. This approval was based on findings from the phase III IMbrave150 trial, in which patients with advanced HCC and no previous systemic therapy were randomized to either atezolizumab plus bevacizumab or sorafenib. Atezolizumab plus bevacizumab was associated with improved OS, PFS, ORR, and quality of life compared with sorafenib.
When the original IMbrave150 results were presented, the median OS had not yet fully matured in the atezolizumab plus bevacizumab arm; at ASCO GI 2021, an updated survival analysis was presented. In this update, the median OS with atezolizumab plus bevacizumab was 19.2 months, which compared favorably to the 13.4 months observed with sorafenib. The median OS observed with atezolizumab plus bevacizumab in this trial is the longest median OS demonstrated in any previous phase III trial in advanced HCC. For reference, the median OS of patients receiving sorafenib in the pivotal phase III SHARP study was just more than 10 months. Although the survival of patients with advanced HCC lags behind that seen with other tumor types, patients are clearly living longer with advanced HCC with modern combination regimens.
Several other phase III trials of immune checkpoint inhibitor combination therapy are likely to report results soon; these include the combinations of durvalumab plus tremelimumab, nivolumab plus ipilimumab, pembrolizumab plus lenvatinib, and atezolizumab plus cabozantinib. Although cross‑trial comparisons are always problematic, it will be interesting to see whether other combinations achieve similar OS results as those observed in IMbrave150, which are the new benchmark for advanced HCC. Of note, a median OS of 22 months was observed with lenvatinib plus pembrolizumab in a phase Ib study. Although OS sometimes drops from phase I to phase III, this was a large phase I trial enrolling 104 patients, suggesting that we may have more than one therapy emerging with similar OS results.
CheckMate 040: Updated Results With Nivolumab Plus Ipilimumab
The CheckMate 040 study examined different dosing schedules of the PD-1 inhibitor nivolumab plus the CTLA-4 inhibitor ipilimumab for patients who had received prior sorafenib. Findings from this study led to the accelerated approval of nivolumab plus ipilimumab and in the second-line, post-sorafenib setting. At ASCO GI 2021, an updated analysis of data from CheckMate 040 were presented. For the cohort receiving the FDA approved dose of ipilimumab at 3 mg/kg and nivolumab 1 mg/kg every 3 weeks (followed by nivolumab maintenance), the updated survival rate at 36 months was 42%. Some responses were ongoing even at 4 years from study enrollment, highlighting the durability of some responses to this combination in HCC. The combination of nivolumab plus ipilimumab is currently being evaluated in a confirmatory phase III study in the frontline setting.
KEYNOTE-224: First-line Pembrolizumab Monotherapy
Data were also presented from the single-arm phase II KEYNOTE-224 study, in which a cohort of patients with advanced HCC was treated with first-line pembrolizumab monotherapy (N = 51). This treatment was associated with a response rate of 16%, which is similar to what has been observed in other trials of PD-1 inhibitor monotherapy, including trials in the second‑line setting, where pembrolizumab was associated with a response rate of approximately 17%.
The data from this cohort of KEYNOTE‑224 are encouraging, but I think it is important to keep this in the context of other studies. Nivolumab, which is another PD-1 inhibitor, previously failed to demonstrate superiority over sorafenib in a phase III trial in the frontline setting, so I do not think the data from KEYNOTE‑224 are likely to be practice changing for most patients. For now, I think frontline PD-1 inhibitor monotherapy will continue to be considered for patients who are ineligible for VEGF‑targeted therapies.
REFLECT Post Hoc Analysis: Lenvatinib for Patients With Child-Pugh B Liver Function
REFLECT was a randomized phase III study that demonstrated OS noninferiority between first-line lenvatinib and sorafenib for patients with advanced HCC, resulting in the approval of lenvatinib in this setting. Of note, the REFLECT study specifically enrolled patients with Child‑Pugh A liver function, and the safety of lenvatinib for patients with Child‑Pugh B cirrhosis was not known. A post hoc analysis of the REFLECT study presented at ASCO GI 2021 looked specifically at a group of patients who started out with Child‑Pugh A liver function but deteriorated to Child‑Pugh B status within 8 weeks of starting therapy. In this group of patients (n = 60), lenvatinib continued to show reasonable safety and efficacy, with an ORR of 28% and a median OS of 6.8 months observed. These were numerically lower than the ORR and OS observed in patients with Child‑Pugh A liver function (43% and 13.3 months, respectively). However, these data were reassuring and the authors suggested that further study of lenvatinib for patients with Child‑Pugh B cirrhosis is warranted.
A similar analysis of the CELESTIAL study was conducted recently. CELESTIAL was a randomized phase III study of cabozantinib vs placebo in patients with advanced HCC who had progressed on sorafenib. This study suggested that cabozantinib may also have benefit for patients with Child‑Pugh B liver function. Together, these analyses provide some reassurance that VEGF-targeted TKIs can be continued in patients who have a deterioration in their liver function, although at this point, only sorafenib and nivolumab have been studied prospectively in a Child‑Pugh B population.
Use of Systemic Therapy to Downstage Patients
My group also presented data from a phase I study of neoadjuvant cabozantinib plus nivolumab for patients with borderline resectable or locally advanced HCC (N = 15). Numerous patients who initially had unresectable disease were downstaged with aggressive combination neoadjuvant systemic therapy and underwent surgical resection. Although this was a small study, I think these data highlight the potential to downstage select patients with HCC for potentially curative resections. A similar study from MD Anderson Cancer Center recently highlighted the safety and efficacy of neoadjuvant nivolumab with or without ipilimumab. Together, these studies support the feasibility of contemporary systemic therapy combinations in the perioperative setting.
Although neoadjuvant therapy for HCC remains experimental, the outstanding disease-free survival of patients in our study who were downstaged and subsequently resected suggests that patients who are started on systemic therapy for unresectable disease and attain secondary resectability should be considered for resection.Your Thoughts
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