New Challenges Facing Systemic Therapies of Advanced HCC in the Era of Different First-Line Immunotherapy-Based Combinations
Abstract
:Simple Summary
Abstract
1. Introduction
2. New Standard of Care and Possible Challengers
2.1. Results of the Atezolizumab-Bevacizumab Combination Have Been Disruptive
2.2. Two Different Types of Combination Are Currently Tested in First-Line Versus Sorafenib or Lenvatinib
2.2.1. Immunotherapy Combined with an Anti-Angiogenic Tyrosine-Kinase Inhibitor (TKI)
2.2.2. Immunotherapy Combinations with an Anti-CTLA-4 Antibody
2.3. Potential Criteria of Choice between the Validated Combinations
2.4. Is There Still a Role for Monotherapy in the First-Line Setting?
3. Current and Future Second-Line Options in the Area of First-Line Immunotherapy-Based Combination
3.1. Available Guidelines for Treatment after Progression on Atezolizumab-Bevacizumab
3.2. What Will Be the Optimal Sequence of Treatment?
3.3. New Treatment Strategies for Advanced Disease
3.4. Development of Immunotherapy-Combination in Earlier Stages, and Potential Difficulties
4. Challenges for Future Development
4.1. Building Evidence on Sequencial Treatment
4.2. Backbone for New Combinations
4.3. Predictive Biomarkers of Response for Personalized Therapy
4.4. Financial Burden
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Combination | Control Arm | Trial Name and Reference | Selected Characteristics Population Included | n Main Comparison | OS Experimental vs. Control | PFS Experimental vs. Control | RECIST 1.1 ORR Experimental vs. Control | Treatment-Emergent Grade 3/4 Toxicities Experimental vs. Control |
---|---|---|---|---|---|---|---|---|
Atezolizumab-bevacizumab | sorafenib | IMbrave150 [17,18] | MVI: 40% (14% Vp4) Non-viral: 30.5% | 501 | Median 19.2 vs. 13.4 months, HR = 0.66, p < 0.001 | Median 6.8 vs. 4.3 months, HR = 0.29, p < 0.001 | 30% vs. 11%, p < 0.001 | 63% vs. 57% |
Lenvatinib-pembrolizumab | lenvatinib | LEAP-002 [24] | MVI: 17% (0% Vp4) Non-viral: 39% | 794 | Median 21.2 vs. 19.0, HR = 0.840, p = 0.0227 * | Median 8.2 vs. 8.0 months, HR = 0.87, p = 0.0466 * | 26% vs. 18% | 62% vs. 57% |
Camrelizumab-rivoceranib | sorafenib | Qin et al. [26] | MVI: 17% (0% Vp4) Non-viral: 19.2% | 543 | Median 22.1 vs. 15.2 months, HR = 0.62, p < 0.001 | Median 5.6 vs. 3.7 months, HR = 0.52 p < 0.001 | 35.2% vs. 8.9% | 81% vs. 52% |
Cabozantinib-atezolizumab | sorafenib | COSMIC-312 [22] | MVI: 30% (18% Vp4) Non-viral: 39% | 649 | Median 15.4 vs. 15.5 months, HR = 0.90, p = 0.44 | Median 6.8 vs. 4.2 months, HR = 0.63, p = 0.0012 | 11% vs. 4% | 64% vs. 46% |
Durvalumab-tremelimumab | sorafenib | HIMALAYA [30] | MVI: 26% (0%Vp4) Non-viral: 42% | 782 | Median 16.4 vs. 13.8 months, HR = 0.78, p = 0.0035 | Median 3.8 vs. 4.1 months, HR = 0.90 | 20% vs. 5% | 51% vs. 52% |
Anti-Angiogenics-Based | Anti-CTLA-4-Based | ||
---|---|---|---|
Bevacizumab-Based | TKIs-Based | ||
Strong criteria of choice | Pre-existing untreated auto-immune disorder (psoriasis…) | Severe vascular comorbidities Significant Portal Hypertension | |
Criteria of choice subject to interpretation | Better toxicity profile | Non-severe vascular comorbidities Equilibrated arterial hypertension | |
Low-risk auto-immune disorder (diabetes, thyroid disorder…) |
Second-Line Options | Further-Line Options | |
---|---|---|
BCLC [3] | Clinical trials | |
EASL [44] | Multi-TKI and VEGFR2 inhibitor as per off-label availability | |
ILCA, https://ilca-online.org/education/ilca-guidances/ (accessed on 24 November 2022) | sorafenib, lenvatinib, cabozantinib | regorafenib |
NCCN preferred treatments | sorafenib, lenvatinib, regorafenib, cabozantinib, ramucirumab | |
ESMO https://www.esmo.org/guidelines/gastrointestinal-cancers/hepatocellular-carcinoma (accessed on 24 November 2022) | sorafenib, lenvatinib, cabozantinib, ramucirumab | regorafenib (for TKI-experienced patients) |
French recommendation (TNCD) | sorafenib, lenvatinib | regorafenib, cabozantinib, ramucirumab |
Trial Name | Context | Treatment | Planned Number of Patients | Clinicaltrials.gov Identifier |
---|---|---|---|---|
IMbrave 050 | After curative-intent resection or ablation | Atezolizumab-bevacizumab vs. surveillance | 668 | NCT04102098 |
EMERALD-2 | After curative-intent resection or ablation | Durvalumab +/− bevacizumab vs. placebo | 908 | NCT03847428 |
Checkmate-9DX | After curative-intent resection or ablation | Nivolumab vs. placebo | 545 | NCT03383458 |
Keynote-937 | After curative-intent resection or ablation | Pembrolizumab vs. placebo | 950 | NCT03867084 |
ABLATE-2 | Before and after ablation | Atezolizumab-bevacizumab + ablation vs. ablation alone | 202 | NCT04727307 |
ML42612 | With TACE | Atezolizumab-bevacizumab + TACE vs. TACE alone | 342 | NCT04712643 |
EMERALD-1 | With TACE | Durvalumab +/− bevacizumab + TACE vs. placebo + TACE | 724 | NCT03778957 |
EMERALD-3 | With TACE | Durvalumab-tremelimumab +/− lenvatinib + TACE vs. TACE alone | 525 | NCT05301842 |
TACE-3 | Before and after TACE | nivolumab + TACE vs. TACE alone | 522 | NCT04268888 |
LEAP-012 | With TACE | pembrolizumab-lenvatinib + TACE vs. placebo + TACE | 950 | NCT04246177 |
ROWAN | With SIRT | durvalumab-tremelimumab vs. SIRT alone | 150 | NCT05063565 |
ABC-HCC | In lieu of TACE | atezolizumab-bevacizumab vs. TACE | 434 | NCT04803994 |
INTRATACE | In lieu of TACE | regorafenib-tislelizumab vs. TACE | 496 | NCT04777851 |
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Edeline, J.; Meyer, T.; Blanc, J.-F.; Raoul, J.-L. New Challenges Facing Systemic Therapies of Advanced HCC in the Era of Different First-Line Immunotherapy-Based Combinations. Cancers 2022, 14, 5868. https://doi.org/10.3390/cancers14235868
Edeline J, Meyer T, Blanc J-F, Raoul J-L. New Challenges Facing Systemic Therapies of Advanced HCC in the Era of Different First-Line Immunotherapy-Based Combinations. Cancers. 2022; 14(23):5868. https://doi.org/10.3390/cancers14235868
Chicago/Turabian StyleEdeline, Julien, Tim Meyer, Jean-Frédéric Blanc, and Jean-Luc Raoul. 2022. "New Challenges Facing Systemic Therapies of Advanced HCC in the Era of Different First-Line Immunotherapy-Based Combinations" Cancers 14, no. 23: 5868. https://doi.org/10.3390/cancers14235868
APA StyleEdeline, J., Meyer, T., Blanc, J. -F., & Raoul, J. -L. (2022). New Challenges Facing Systemic Therapies of Advanced HCC in the Era of Different First-Line Immunotherapy-Based Combinations. Cancers, 14(23), 5868. https://doi.org/10.3390/cancers14235868