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Let’s return to our case to begin our discussion of second-line therapy for advanced HCC. The patient started treatment with atezolizumab plus bevacizumab. During treatment with this agent he developed grade 2 proteinuria, which was followed; he continued on therapy.
At 4 months, imaging confirmed a PR and he continued on therapy, tolerating his treatment well until, at 14 months, he developed 3 new right lung nodules. In my practice, the first time extrahepatic disease is observed, I recommend a biopsy to confirm HCC progression. With this patient, progression was confirmed; the patient now has metastatic HCC. He still has good performance status and well-preserved liver function. His AFP remains low (< 400 ng/mL). How should this patient be treated in the second line?
In thinking about contemporary second-line systemic treatment for advanced liver cancer, it is important to keep in mind keep that all the drugs that are currently approved in this setting (cabozantinib, nivolumab with or without ipilimumab, pembrolizumab, ramucirumab, and regorafenib) were evaluated in patients who had received previous sorafenib. Lenvatinib and atezolizumab plus bevacizumab were not approved as first-line therapy at the time these studies were initiated, so there are no clinical trial data to specifically guide our approach to second-line therapy for patients who received these recently-approved treatments. We can, however, incorporate the phase III data we do have into formulating individualized second-line treatment strategies for our patients. We will review those data here.
Let’s begin our discussion of second-line options by reviewing data with pembrolizumab, the last immunotherapy we will discuss today. The phase III KEYNOTE-240 randomized patients with advanced HCC and intolerance to or progressive disease on or after sorafenib (Child-Pugh A) to either pembrolizumab or placebo. This trial is arguably the last placebo-controlled second-line study we will see in patients with advanced HCC.
This trial confirmed the phase II efficacy observed with pembrolizumab, demonstrating a response rate of 18.3% with pembrolizumab. The duration of response associated with this treatment was quite long (> 13 months).
Pembrolizumab treatment was associated with a median OS of 13.9 months vs 10.6 months with placebo. This translated into a HR of 0.781 (95% CI: 0.611-0.998; P = .0238).
Now, without knowing further details of the statistical design, one might conclude that this met its primary endpoint and is a positive study. However, because of the coprimary endpoint of PFS as well as several prespecified interim analyses, the P value had to be lowered; to be considered a statistically significant, the P value needed to be .0174 or lower, and the P value in this study was .0238. Therefore, this study was negative. However, it did confirm a significantly higher response rate with pembrolizumab vs placebo, as well as an extended duration of response with pembrolizumab.
The safety profile with pembrolizumab was very similar to that seen with nivolumab, with a low incidence of liver events. Autoimmune events occurred with similar frequencies to those observed in studies of immune checkpoint inhibitors other malignancies, including hypothyroidism or hyperthyroidism. Both nivolumab and pembrolizumab currently have accelerated approval for use as monotherapies in the second-line setting following sorafenib.
The first positive phase III study after the SHARP study was the RESORCE study. RESORCE was a large, randomized phase III study comparing regorafenib (a multikinase inhibitor similar to sorafenib but with some specific differences in its kinase inhibition profile and its potency) with placebo (both plus best supportive care) in patients with HCC who had progressed on sorafenib. In addition, this study required patients to have tolerated sorafenib for a minimum period of time, defined as dosing ≥ 400 mg/day for ≥ 20 of the 28 days before discontinuation. Regorafenib was dosed at 160 mg/day, administered 3 weeks on and 1 week off.
The median OS was 10.6 months with regorafenib and 7.8 months with placebo (HR: 0.63; 95% CI: 0.50-0.79; P < .0001). Again, in this study, regorafenib improved survival without a high response rate: ORR was 11% with regorafenib and 4% with placebo. However, regorafenib did delay progression, essentially doubling median PFS by modified RECIST criteria from 1.5 months on placebo to 3.1 months with regorafenib (HR: 0.46; 95% CI: 0.37-0.56; P < .0001).
In this population of patients who had previous tolerance to sorafenib, the AEs observed were not unusual. Again, hand–foot skin reaction was one of the more frequent toxicities seen with use of regorafenib (grade 3/4, 13%). Other AEs observed with this class of drugs were observed with regorafenib, including fatigue and hypertension. Some increases in bilirubin and AST were also noted, but these were generally lower grade. GI toxicity also occurred with a higher frequency with regorafenib compared with placebo.
As mentioned, cabozantinib is a multikinase inhibitor that targets VEGFR, the tyrosine-protein kinase Met (c-MET), and AXL. c-MET is the hepatocyte growth factor receptor whose ligand, hepatocyte growth factor, has been implicated in the development of liver cancer, making it a promising target in this disease.
CELESTIAL was a randomized phase III study of cabozantinib 60 mg/day vs placebo in patients with advanced HCC who had progressed on sorafenib. Patients were permitted to have received up to 2 previous systemic regimens and were required to have Child‑Pugh A disease. So, unlike the RESORCE study, CELESTIAL included some patients receiving third‑line therapy, some 27% of the overall population. The primary endpoint was OS.
The CELESTIAL study met its endpoint of improving OS. Median OS with cabozantinib was 10.2 months vs 8.0 months with placebo (HR: 0.76; 95% CI: 0.63-0.92; P = .005). Looking at those patients who had only received previous frontline therapy (~ 75% of the study population), the HR became 0.71, so certainly on par with the RESORCE data.
As with regorafenib and other TKIs, this benefit was achieved without inducing significant responses: ORR was 4% with cabozantinib and < 1% with placebo. Median investigator-assessed PFS by RECIST criteria was also improved with cabozantinib vs placebo (5.2 vs 1.9 months, respectively; HR: 0.44; 95% CI: 0.36-0.52: P < .001).
The AE profile with cabozantinib was very consistent to that seen with other VEGF inhibitors. Key AEs include hand–foot skin reaction and hypertension, as well as diarrhea, fatigue, and increased AST, although these latter AEs are generally low grade.
Finally, ramucirumab, a monoclonal antibody to VEGFR, has also been approved by the FDA and EMA in the second-line setting for advanced HCC. This approval was on the phase III REACH‑2 study, which followed the phase III REACH study. In REACH, patients with progressive disease on sorafenib were randomly assigned to ramucirumab or placebo; although the primary endpoint of OS was not met, a prespecified population of patients with baseline AFP ≥ 400 ng/mL and Child-Pugh A liver function who were treated with ramucirumab demonstrated a significant OS advantage.
As such, in REACH-2, patients with advanced HCC (Child-Pugh A), AFP ≥ 400 ng/mL, and previous sorafenib were randomized to ramucirumab 8 mg IV every 2 weeks or placebo. This was the first biomarker‑driven study to have success in liver cancer.
This study met its endpoint of improving OS. Median OS with ramucirumab was 8.5 months vs 7.3 months with placebo (HR: 0.71; 95% CI: 0.531-0.949; P = .0199). This HR was on par with what was observed with TKIs.
In looking at the OS graph, there appears to be a tail to the curve with ramucirumab. At 18 months, 25% of the patients receiving ramucirumab were still alive, whereas only 11% were still alive with placebo.
Ramucirumab, as a monoclonal antibody, was very well tolerated as compared with the TKIs. The incidence of hand–foot skin reaction was low, as was the incidence of diarrhea. Some VEGF-related AEs, including proteinuria and hypertension, were observed more frequently with ramucirumab vs placebo. There is some fluid retention as well, with the incidence of peripheral edema and ascites higher with ramucirumab vs placebo.
Before continuing, let’s return to a question from earlier in the activity.
So how do we approach second-line or third-line therapy in patients who might have received first-line atezolizumab plus bevacizumab or lenvatinib when all current second‑line and third-line data were gathered in the setting of progression or intolerance to sorafenib therapy?
The BCLC staging and treatment guidance was recently updated and provides a potential paradigm. This is not based solely on phase III data, because no such data exist for treating patients following progression on atezolizumab plus bevacizumab or lenvatinib. In my opinion, it is unlikely we will have phase III data in this space, as it is not likely that all these studies will be repeated to optimize how we sequence the different therapies that are available for patients with advanced HCC.
Many experts feel that TKIs should now be sequenced following atezolizumab plus bevacizumab based on how they were studied, meaning that following atezolizumab plus bevacizumab, sorafenib or lenvatinib would be considered, followed subsequently by other former second-line, post-sorafenib options. We saw through phase III data that all of these drugs alter the history of advanced liver cancer, and in my opinion, our goal needs to be to try to maximize exposure to active drugs. That will involve identification of patients who can benefit from specific agents or regimens.
Let’s return to our case patient in this context. Recall that this patient was diagnosed with intermediate-stage HCC and received chemoembolization. However, he subsequently progressed from intermediate to advanced stage and received atezolizumab plus bevacizumab. He demonstrated significant benefit with this regimen but progressed with extrahepatic disease. How should he now be treated?
Some agents can be excluded based on this patient’s characteristics. His AFP is not ≥ 400 ng/mL, so ramucirumab would not be recommended. I would likely transition to sorafenib or lenvatinib. This patient does have extrahepatic spread and a portal vein thrombus, which means they would have been excluded from the REFLECT study of lenvatinib. However, I think lenvatinib is a more potent TKI than sorafenib, demonstrating a higher objective response rate. I would likely try lenvatinib in this patient, but I could not fault anyone who would consider sorafenib or cabozantinib for this patient as well.
In general, patients who have intermediate disease that has progressed on locoregional treatment should be transitioned to systemic treatment before they decompensate. For patients receiving locoregional treatment who develop new lesions in other parts of the liver, careful consideration should be given to whether those patients should get another chemoembolization or transition to systemic treatments, which have been shown to improve survival.
We have seen that appropriate sequencing of effective agents can improve outcomes. In the context of the RESORCE study, again in a clinical trial population, OS for patients who received the sequence of sorafenib followed by regorafenib was 26 months. This is truly a new era in treating patients with advanced liver cancer. I suspect this survival will be confirmed, if not improved upon, with new active regimens in our armamentarium.
After a decade with only one positive phase III study of a systemic therapy (sorafenib) for patients with advanced liver cancer, we have now had 5 recent positive phase III studies. These include studies of regorafenib, lenvatinib, cabozantinib, and ramucirumab and then, this year, practice-changing data with atezolizumab plus bevacizumab in the frontline setting.
Level 1 evidence is still lacking for single-agent immune checkpoint inhibitors, although nivolumab and pembrolizumab have accelerated approval in the second-line setting and strong signals confirming their activity were observed in the CheckMate 459 and KEYNOTE 240 studies, although neither trial met their statistical endpoints.
The future, in my opinion, will include combination therapies. High response rates have been observed with immune checkpoint inhibitors when these are combined with TKIs and PD-1 inhibitors in combination with CTLA-4 inhibitors. These data are very provocative and we eagerly await phase III data with these combinations.
It is a very exciting time for our patients with advanced HCC, and I think we will continue to see progress in the near future.