Treatment Paradigm of Advanced HCC Displays Exciting Growth in the First and Later Lines

Amit Singal, MD

Patients with hepatocellular carcinoma (HCC), especially those with advanced disease, have historically had a poor prognosis with few effective treatment options. However, recent progress in the systemic treatment landscape has dramatically expanded treatment options for these patients in the frontline setting and beyond.

During a recent OncLive Peer Exchange^®, leading experts in the field of liver cancer contextualized how recent data are influencing the treatment paradigm in HCC. The group discussed the efficacy of the current frontline standard of care for patients with advanced disease, available treatment options in the second line and beyond, and ongoing trials showing promise in both settings.

“When we can do curative therapies, we should do curative therapies,” Amit Singal, MD, said. “If [a patient] is noncirrhotic, we have to think of resection first. Resection is the standard of care for most patients with HCC in the absence of cirrhosis. Now, as we know in the Western world, most patients present in the setting of cirrhosis, and you really need good liver function to consider surgical resection.”

First-Line Systemic Treatment Options in Advanced HCC

For patients who are not candidates for surgical resection, the current standard of care in the frontline treatment of advanced HCC is the humanized monoclonal antibody combination of atezolizumab (Tecentriq) and bevacizumab (Avastin). This regimen was confirmed as the standard of care based on updated findings from the phase 3 IMbrave150 trial (NCT03434379). The randomized, open-label study compared the safety and efficacy of atezolizumab plus bevacizumab with that of sorafenib (Nexavar). The primary end points were overall survival (OS) and progression-free survival (PFS) by independent assessment using RECIST 1.1 criteria.¹

At a median follow-up of 15.6 months (range, 0-28.6), patients who received the combination (n = 336) achieved a median OS of 19.2 months (95% CI, 17.0-23.7) vs 13.4 months (95% CI, 11.4-16.9) in the 165-patient sorafenib arm (HR, 0.66; 95% CI, 0.52-0.85; P < .001). Moreover, the combination regimen improved median PFS compared with sorafenib at 6.9 months (95% CI, 5.7-8.6) vs 4.3 months (95% CI 4.0-5.6) respectively (HR, 0.65; 95% CI 0.530.81; P < .001). Atezolizumab plus bevacizumab was generally well tolerated; study investigators noted that toxicities were manageable and consistent with the safety profiles of the individual agents. ^1-14

Following the positive findings, the FDA approved the combination on May 29, 2020, for the frontline treatment of patients with unresectable or metastatic HCC who have not received prior systemic therapy.²

In addition, an alternative treatment option is emerging in the first-line setting of advanced HCC: the VEGF inhibitor lenvatinib (Lenvima). Investigators compared the safety and efficacy of the agent with that of sorafenib in the phase 3 REFLECT trial (NCT01761266) in patients with unresectable HCC. The primary end point was OS.^3,4

Initial findings from the trial showed that lenvatinib was not inferior to sorafenib in terms of OS; the median OS was 13.6 months (95% CI, 12.1-14.9) vs 12.3 months (95% CI, 10.4-13.9), respectively (HR, 0.92; 95% CI, 0.79-1.06). Further data exhibited that patients who received lenvatinib (n = 478) achieved an objective response rate (ORR) of 18.8%, with a median time to response of 2.8 months (range, 1-29). Notably, among responders, the median OS was 23.4 months.^3,4

“Interestingly enough, lenvatinib worked slightly better in patients with aggressive tumors,” Josep Llovet, MD, said. “[This includes] patients with high α-fetoprotein, extrahepatic spread, or vascular invasion.”

Another regimen that has shown promise in the frontline setting is STRIDE, which is made up of a single priming dose of the antiCTLA-4 antibody tremelimumab (Imjudo) plus regular interval dosing of the anti-PD-L1 agent durvalumab (Imfinzi). In the phase 3 HIMALAYA trial (NCT03298451), investigators compared the safety and efficacy of STRIDE vs durvalumab monotherapy vs sorafenib. The primary end point was OS for STRIDE compared with sorafenib^.5

Patients who were treated with STRIDE (n = 393) experienced a significantly improved median OS: 16.4 months (95% CI, 14.2-19.6) vs the median of 13.8 months (95% CI, 12.3-16.1) in the 389 patients in the sorafenib arm (HR, 0.78; 95% CI, 0.65-0.92; P = .0035). Additionally, the 24- and 36-month PFS rates were 40.5% and 30.7%, respectively, in the STRIDE arm compared with 32.6% and 20.2% in the sorafenib arm. Study authors concluded that the STRIDE regimen displayed superior efficacy and a favorable benef it-risk profile vs sorafenib, tabbing the regimen as a potential novel frontline standard of care.⁵

On October 21, 2022, the FDA approved STRIDE for adult patients with unresectable HCC.⁶

“In brief, what we saw [in a real-world US study] was that the effectiveness of lenvatinib was similar, if not actually slightly higher, than what we saw in the REFLECT trial,” Singal said. “[This goes back to] the point of feeling more and more comfortable using lenvatinib in clinical practice. And we saw continued effectiveness across different subgroups.”

Multiple other immunotherapy-based combinations as well as monotherapy approaches are being evaluated in the frontline setting of HCC. In a phase 3 trial (NCT03764293), investigators examined the anti-PD-1 IgG4 monoclonal antibody camrelizumab plus the VEGFR2-targeted tyrosine kinase inhibitor (TKI) rivoceranib (Apatinib) vs sorafenib in treatment-naïve patients with unresectable HCC. The primary end points were PFS per RECIST v1.1 and OS.⁷

Patients in the combination arm (n = 272) achieved a median OS of 22.1 months (95% CI, 19.1-27.2) compared with 15.2 months (95% CI, 13.0-18.5) in the sorafenib arm (n = 271; HR, 0.62; 95% CI, 0.49-0.80; P < .0001). The median PFS was 5.6 months (95% CI, 5.5-6.3) compared with 3.7 months (95% CI, 2.8-3.7), respectively (HR, 0.52; 95% CI, 0.41-0.65; P < .0001).

Additional findings showed that the PFS and OS HRs favored the combination in most subgroups. Grade 3 or greater treatment-emergent adverse effects occurred in 80.9% of patients in the combination arm compared with 52.4% of patients in the monotherapy arm. Study authors noted that this was the first positive pivotal trial that displayed a survival benefit in this disease setting with a PD-1/PD-L1 inhibitor combined with an antiangiogenic TKI for unresectable HCC.

“We should not only talk about the OS,” Arndt Vogel, MD, said. “The survival is great, but we have hypertoxicity in 30% of cases. We have a different [safety] profile for the TKI. We have [to] restart learning with [how] to work with this drug. Nevertheless, [OS is] 22 months; it’s a new bar, [and] it’s a positive study. We have to wait and see with the regulatory agencies, but I also think we need to see more data at this point. It’s really too early, and we have to see whether it’s really strong enough to replace atezolizumab/bevacizumab, which I think will not be the case.”

Another combination approach is being evaluated for treatment-naïve patients with advanced HCC in the phase 3 LEAP-002 trial (NCT03713593). In this study, investigators compared lenvatinib plus pembrolizumab (Keytruda) vs lenvatinib alone. The trial had dual primary end points of OS and PFS per RECIST 1.1.⁸

Patients in the lenvatinib-plus-pembrolizumab arm (n = 395) experienced a median OS at final analysis of 21.2 months (95% CI, 19.023.6) compared with 19.0 months (95% CI, 17.2-21.7) in the 399-patient monotherapy arm (HR, 0.84; 95% CI, 0.708-0.997; P = .0227). Additionally, the median PFS at final analysis was 8.2 months (95% CI, 6.3-8.3) vs 8.1 months (95% CI, 6.3-8.3), respectively (HR, 0.834; 95% CI, 0.712-0.978).⁸

Study authors concluded that although the primary end points did not meet the prespecified threshold for statistical significance, lenvatinib plus pembrolizumab displayed the longest median OS ever reported in phase 3, first-line trials in patients with HCC. No new safety signals were reported with the combination regimen.

Finally, in the phase 3 RATIONALE-301 trial (NCT03412773), monotherapy with the anti-PD-1 monoclonal antibody tislelizumab was compared with sorafenib as a first-line treatment for patients with unresectable HCC. The primary end point of the trial was OS.⁹

Findings from the study showed that patients who received tislelizumab (n = 342) achieved a median OS of 15.9 months vs 14.1 months in the sorafenib arm (n = 332; HR, 0.85; 95% CI, 0.712-1.019). Tislelizumab was associated with an improvement in terms of ORR—14.3% vs 5.4%, respectively.⁹

Responses with tislelizumab were also more durable than those observed with sorafenib, with a median DOR of 36.1 months vs 11.0 months, respectively.9 Tislelizumab demonstrated a clinically meaningful benefit in terms of OS with a favorable safety profile, meeting the primary end point of the trial.

“We now have these multiple choices in the first line [for which] we need to continue gathering data, both in registries as well as prospectively on how to use [and] how to find the best clinical biomarkers, as well as [the] ongoing collection of actual blood and tumor specimens to really stratify which patients are more likely to respond or benefit,” R. Katie Kelley, MD, said.

Treatment Approaches Continue to Evolve in the Second Line and Beyond

Beyond the front line, multiple treatment options are currently available for patients with advanced HCC. Antiangiogenic systemic therapies have been examined in several clinical trials.

In the phase 3 CELESTIAL trial (NCT01908426), patients were randomly assigned 2:1 to receive either the TKI cabozantinib (Cabometyx; n = 470) or matching placebo (n = 237). The primary end point was OS. Results from the trial showed that patients treated with cabozantinib achieved a median OS of 10.2 months (95% CI, 9.1-12.0) vs 8.0 months (95% CI, 6.8-9.4) among patients who received placebo (HR, 0.76; 95% CI, 0.63-0.92;P = .005). Additionally, the median PFS was 5.2 months (95% CI, 4.0-5.5) vs 1.9 months (95% CI, 1.9-1.9), respectively (HR, 0.44; 95% CI, 0.360.52; P < .001).10 R. Katie Kelley, MD TREATMENT APPROACHES CONTINUE TO EVOLVE IN THE SECOND LINE AND BEYOND Beyond the front line, multiple treatment options are currently available for patients with advanced HCC. Antiangiogenic systemic therapies have been examined in several clinical trials. In the phase 3 CELESTIAL trial (NCT01908426), patients were randomly assigned 2:1 to receive either the TKI cabozantinib (Cabometyx; n = 470) or matching placebo (n = 237). The primary end point was OS. Results from the trial showed that patients treated with cabozantinib achieved a median OS of 10.2 months (95% CI, 9.1-12.0) vs 8.0 months (95% CI, 6.8-9.4) among patients who received placebo (HR, 0.76; 95% CI, 0.63-0.92; P = .005). Additionally, the median PFS was 5.2 months (95% CI, 4.0-5.5) vs 1.9 months (95% CI, 1.9-1.9), respectively (HR, 0.44; 95% CI, 0.360.52; P < .001).¹⁰

The FDA approved cabozantinib on January 14, 2019, for patients with HCC who had previously undergone treatment with sorafenib.¹¹

Another kinase inhibitor, regorafenib (Stivarga), was evaluated in previously treated patients with HCC in the phase 3 RESORCE trial (NCT01774344). The agent was compared with placebo in patients with HCC who had progressed following treatment with sorafenib. The primary end point was OS.¹²

Patients in the investigational arm (n = 379) achieved a median OS of 10.6 months (95% CI, 9.1-12.1) compared with 7.8 months (95% CI, 6.3-8.8) in the 194-patient placebo arm (HR, 0.63; 95% CI, 0.500.79; P < .0001).¹² The positive findings from the trial supported the April 27, 2017, FDA approval of regorafenib for patients with HCC who previously received sorafenib.¹³

The phase 3 REACH trial (NCT01140347) compared the IgG1 monoclonal antibody ramucirumab (Cyramza), a VEGF-2 antagonist, with placebo in patients with advanced HCC following treatment with sorafenib. The primary end point was OS.¹⁴

Findings from the study showed that patients in the investigational arm (n = 283) achieved a median OS of 9.2 months (95% CI, 8.0-10.6) compared with 7.6 months (95% CI, 6.0-9.3) in the placebo arm (n = 282; HR, 0.87; 95% CI, 0.72-1.05; P = .14). Investigators concluded that ramucirumab did not significantly improve survival compared with placebo.¹⁴

Immunotherapy approaches have also been evaluated in the second line for patients with HCC in the phase 3 KEYNOTE-240 trial (NCT02702401) and the phase 1/2 CheckMate040 trial (NCT01658878).¹⁵

In KEYNOTE-240, investigators compared the safety and efficacy of pembrolizumab with that of placebo in patients with advanced HCC who previously received sorafenib. The trial had dual primary end points of OS and PFS per RECIST 1.1.

Findings from the trial showed that patients in the pembrolizumab arm (n = 278) achieved a median OS of 13.9 months (95% CI, 11.6-16.0) vs 10.6 months (95% CI, 8.3-13.5) in the placebo arm (n = 135; HR, 0.771; 95% CI, 0.617-0.964). Pembrolizumab was also found to slightly improve median PFS compared with placebo, at 3.3 months (95% CI, 2.8-4.1) vs 2.8 months (95% CI, 1.6-3.0), respectively (HR, 0.703; 95% CI, 0.559-0.885).¹⁵ Pembrolizumab monotherapy was subsequently granted accelerated approval on November 9, 2018, by the FDA for patients with HCC following treatment with sorafenib.¹⁶

Similarly, in CheckMate040, the PD-1–directed immune checkpoint inhibitor nivolumab (Opdivo) was evaluated in patients with advanced HCC. Previous treatment with sorafenib was permitted. The primary end point was safety and ORR.¹⁷

In the dose-escalation phase of the trial, the ORR was 15% (95% CI, 6%-28%) among 214 patients, including 3 patients who achieved a complete response. Additionally, the disease control rate was 58% (95% CI, 43%-72%) and the median DOR was 17 months (95% CI, 6-24).

In another cohort of CheckMate040, nivolumab was combined with CTLA-4-directed agent ipilimumab (Yervoy). Results from this cohort showed an ORR of 32% (95% CI, 20%-47%), 13% (95% CI, 15%-41%), and 14% (95% CI, 17%-43%) across 3 different dosing schedules that enrolled 50, 49, and 49 patients, respectively.¹⁸

Following the success of tislelizumab monotherapy in the first-line treatment of patients with HCC, investigators initiated the phase 2 RATIONALE-208 study (NCT03419897) to evaluate the agent in patients who had already been treated with either sorafenib or lenvatinib. The primary end point was ORR.¹⁹

Findings from the trial showed an ORR of 13.6% (95% CI, 9.5%-18.7%), including 2 complete responses, among 249 patients. Notably, the median DOR was not reached. Investigators concluded that the agent was clinically active and well tolerated beyond the first-line setting.¹⁹

In an effort to further expand the treatment options for previously treated patients with HCC, investigators are currently recruiting patients to the phase 3 IMbrave251 trial (NCT04770896). The trial will compare the safety and efficacy of atezolizumab with lenvatinib or sorafenib with that of lenvatinib or sorafenib monotherapy in patients with HCC who previously received atezolizumab and bevacizumab. The trial is aiming to enroll approximately 554 patients. The primary end point is OS.²⁰

“My take-home message is that we’re very lucky and now we have all these options [in HCC],” Llovet said. “Twenty years ago, [it] was best supportive care for patients with advanced stage HCC. I envision another revolution in the next 2, 3, or 4 years that will be systemic therapies evaluated in combination or evaluated in head-to-head trials.”

References

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19. Edeline J, Merle P, Fang W, et al. Clinical outcomes associated with tislelizumab in patients (pts) with advanced hepatocellular carcinoma (HCC) who have been previously treated with sorafenib (SOR) or lenvatinib (LEN) in RATIONALE-208. J Clin Oncol. 2022;40(suppl 16):4072. doi:10.1200/JCO.2022.40.16_suppl.4072
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