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Assistant Professor of Medicine
Division of Hematology/Oncology
Department of Medicine
Harvard Medical School
Massachusetts General Hospital Cancer Center
Lipika Goyal, MD, MPhil, has disclosed that she has received consulting fees from Agios, Alentis, AstraZeneca, Debiopharm, H3 Biomedicine, Incyte, QED Therapeutics, Sirtex, and Taiho.
Chief of Hepatology
Medical Director, Liver Tumor Program
Professor, Department of Internal Medicine
UT Southwestern Medical Center
Amit G. Singal, MD, MS, has disclosed that he has received consulting fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Exact Sciences, Exelixis, Genentech/Roche, Glycotest, GRAIL, Merck, and Wako.
For patients with advanced hepatocellular carcinoma (HCC), the multitargeted TKI sorafenib was established as the standard of care in 2007, with the phase III SHARP study demonstrating an OS improvement with this agent vs placebo. In the 10 years following the approval of sorafenib, despite numerous trials, no agent or regimen demonstrated improved outcomes compared with sorafenib as first-line systemic therapy for patients with advanced HCC. One agent, the multikinase inhibitor lenvatinib, showed noninferiority to sorafenib in the first-line treatment of advanced HCC and gained FDA approval for this indication. Since 2017, several agents have received FDA approval in the post-sorafenib setting, including regorafenib, cabozantinib, ramucirumab, nivolumab (with or without ipilimumab), and pembrolizumab.
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. In this study, atezolizumab plus bevacizumab was associated with improved OS, PFS, ORR, and quality of life compared with sorafenib, marking the first time an agent or regimen was associated with improved survival compared with sorafenib as first-line systemic therapy for patients with advanced HCC. For most patients, atezolizumab plus bevacizumab should now be considered the standard of care in the first-line systemic therapy setting.
This shift in first-line treatment paradigms does, however, create a new challenge for clinicians tasked with selecting treatment for patients who progress and require second-line therapy following atezolizumab plus bevacizumab: Each of the second-line options listed above was approved based on studies in patients who received first-line sorafenib, and there is little data to guide treatment following an immunotherapy-based first-line treatment regimen. In this commentary, Amit G. Singal, MD, MS, and Lipika Goyal, MD, MPhil, discuss how they approach treatment selection for patients with advanced HCC who require second-line therapy following atezolizumab plus bevacizumab.
Selecting Second-line Treatment After Atezolizumab Plus Bevacizumab
Amit G. Singal, MD, MS
As mentioned, treatment options after therapy with atezolizumab plus bevacizumab could include historical post-sorafenib second-line treatments such as the TKIs cabozantinib and regorafenib, the VEGFR2 inhibitor ramucirumab, and the immune checkpoint inhibitors nivolumab (with or without ipilimumab) and pembrolizumab; sorafenib and lenvatinib are also options. At present, there is no single correct answer for how to treat patients following atezolizumab plus bevacizumab. In my practice, I would most likely recommend a TKI as the second-line treatment for patients with HCC who progress on atezolizumab plus bevacizumab. I should note, however, that we are early in our experience with these patients.
A number of approaches can be used to select the optimal TKI in this situation. In a “T-1” type of approach, sorafenib or lenvatinib could be considered as second-line options, with previous second-line therapies reserved for third-line treatment. Another approach would be to consider all the TKIs as options for second-line therapy, which also makes sense as we don’t know how many lines of therapy a patient might eventually need. In my opinion, the optimal TKIs for a patient with HCC that has progressed on atezolizumab plus bevacizumab would include sorafenib, lenvatinib, or cabozantinib. I would be less likely to consider regorafenib prior to assessment of tolerance to sorafenib, as regorafenib was approved based on the phase III RESORCE trial, which restricted inclusion to patients who tolerated first-line sorafenib. Ramucirumab and bevacizumab are both antiangiogenic agents, so there may be limited benefit with ramucirumab following atezolizumab plus bevacizumab. Likewise, there may be limited benefit with single-agent nivolumab or pembrolizumab in a patient who progressed on atezolizumab plus bevacizumab, as nivolumab, pembrolizumab, and atezolizumab all inhibit PD-1/PD-L1 signaling. That said, the idea of adding the CTLA-4 inhibitor ipilimumab to nivolumab following atezolizumab plus bevacizumab is interesting but requires further evaluation.
My final recommendation for these patients, which would likely be one of the 3 TKIs—sorafenib, lenvatinib, or cabozantinib—or possibly nivolumab plus ipilimumab would depend on why they require second-line therapy after atezolizumab plus bevacizumab. Were they intolerant to bevacizumab or the immune checkpoint inhibitor? Or did they tolerate the therapy but simply have progression after a period of treatment?
Lipika Goyal, MD, MPhil
That’s how I approach this situation as well. In addition, I consider whether the patient might benefit from enrolling on a clinical trial. With the combination of atezolizumab plus bevacizumab having recently been approved, new clinical trials are emerging to explore second-line options following this combination. If there are opportunities for a patient to enter a trial and possibly use a TKI later, this is something I would discuss with the patient.
Selecting Second-line Immunotherapy After Sorafenib or Lenvatinib
Lipika Goyal, MD, MPhil
Briefly, let’s discuss second-line immunotherapy for patients who did not receive atezolizumab plus bevacizumab in the first-line setting. This may include patients who have baseline portal hypertension and varices or an autoimmune disorder. For these patients, sorafenib or lenvatinib may be a more appropriate recommendation in the first-line setting. When do you consider an immune checkpoint inhibitor as second-line therapy after sorafenib or lenvatinib?
Amit G. Singal, MD, MS
While there are several second-line therapies approved in this setting, there are unfortunately few data to guide the choice between these options. Personally, I look at how the patient responded to their first-line TKI—for example, a patient with many TKI-related adverse events or who has progression rapidly on this therapy might be a better candidate for immunotherapy in the second line instead of further TKI-based treatment. This decision remains challenging and somewhat reflects the current “art” of HCC therapy.
Lipika Goyal, MD, MPhil
I think about HCC treatment very similarly. Another aspect to consider is the quality of data vs potential for long-term benefit. Positive data from randomized, placebo-controlled phase III trials support the use of second-line regorafenib, cabozantinib, ramucirumab, and apatinib, but the data suggest a relatively short OS benefit (approximately 2-3 months or less with these agents). Positive data from single-arm, early phase studies of nivolumab and pembrolizumab alone show ORRs of ~15% and the possibility of durable remission and possibly even cure, but we also have phase III trials showing no OS benefit with first-line nivolumab (vs sorafenib) or second-line pembrolizumab (vs placebo). Nivolumab plus ipilimumab has shown early promise, with the regimen associated with an ORR of 31% in an early phase trial. Phase III data with this regimen are awaited, with a current trial ongoing in the first-line treatment setting.
So do we offer patients drugs based on higher quality randomized phase III data or based on lower quality early phase data with the chance of a durable long-term response? In my practice, I do think that, today, no eligible patient with HCC should go without a discussion of immunotherapy. In the phase III KEYNOTE-240 study of pembrolizumab as second-line therapy following sorafenib for patients with advanced HCC, only one half of patients went on to third-line therapy. In clinical practice, even fewer patients will be candidates for third-line therapy, so I often consider second-line immunotherapy following a first-line TKI. As always, this is a shared decision with patients after discussing the advantages and disadvantages of each potential treatment option.
How do you think about second-line systemic treatment for patients with advanced HCC following first-line atezolizumab plus bevacizumab? How do you select treatment following first-line sorafenib or lenvatinib? Please share your experience in the comment box below.
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