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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 4  |  Page : 127-133

Success is not final, failure is not fatal: The changing landscape of systemic therapy for advanced hepatocellular carcinoma


Graduate Institute of Oncology, National Taiwan University College of Medicine; Department of Medical Oncology, National Taiwan University Cancer Center; Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan

Date of Submission20-Jun-2021
Date of Decision26-Jul-2021
Date of Acceptance06-Aug-2021
Date of Web Publication3-Dec-2021

Correspondence Address:
Dr. Chiun Hsu
Department of Medical Oncology, National Taiwan University Cancer Center, No. 57, Ln. 155, Sec. 3, Keelung Road, Da'an District, Taipei City 106
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCRP.JCRP_21_21

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  Abstract 


Objective: To review the history of development of systemic therapy for advanced hepatocellular carcinoma (HCC). Data Sources: Published clinical trials of single-agent targeted agents, single-agent immune checkpoint inhibitors (ICI), and ICI-based combination regimens. Results: Key lessons learned from previous positive and negative clinical trials included design of more efficient clinical trials and incorporation of trial endpoints most relevant to clinical benefit. Major challenges included prioritization of novel combination therapies for clinical trials and development of predictive biomarkers. Conclusion: The improved efficacy and safety of systemic therapy will impact on future multi-disciplinary management of HCC through more extensive integration with liver-directed therapy for different stages of HCC patients.

Keywords: Clinical trial, combination therapy, immune checkpoint inhibitor, targeted therapy


How to cite this article:
Hsu C. Success is not final, failure is not fatal: The changing landscape of systemic therapy for advanced hepatocellular carcinoma. J Cancer Res Pract 2021;8:127-33

How to cite this URL:
Hsu C. Success is not final, failure is not fatal: The changing landscape of systemic therapy for advanced hepatocellular carcinoma. J Cancer Res Pract [serial online] 2021 [cited 2022 Aug 10];8:127-33. Available from: https://www.ejcrp.org/text.asp?2021/8/4/127/331651




  Introduction: The Changing Landscape of Hepatocellular Carcinoma Management in the 21st Century Top


The clinical manifestations and treatment options of newly diagnosed hepatocellular carcinoma (HCC) patients are changing gradually. We used to think that most HCC patients were presented with advanced tumor burden and impaired liver function reserves, the latter resulting from both the underlying cirrhosis and liver tumor extent. However, several important trends in HCC epidemiology became more and more apparent in recent years. First, the incidence of virus-associated HCC may have plateaued, and in more developed regions where antiviral therapy is easily accessible, the incidence may start to decline.[1],[2] The universal hepatitis B vaccination introduced in the mid-1980s will have a more far-reaching impact in future.[3] Second, the proportion of patients who were diagnosed at earlier stages, when curative therapy was still feasible, was increasing. The second phenomenon may be related to the incorporation of antiviral therapy and regular screening for patients with chronic viral hepatitis infection. Antiviral therapy does not just reduce the incidence of HCC. As more and more patients with chronic hepatitis B receive antiviral therapy and regular follow-up, the proportion of early-stage cancers at the time of cancer diagnosis was higher than in the past, and the liver function of patients at the time of diagnosis was is relatively good. The opportunity to receive curative treatments such as surgery has thus increased.

The patterns of curative treatment for HCC are changing too. Surgery used to be the standard curative treatment. In recent years, with the advancement of equipment and technology, and the increase in the proportion of early diagnosis, the proportion of radiofrequency ablation therapy performed by hepatologists or radiologists has also increased.[4],[5],[6] The major advantage of ablation therapy is less invasiveness and fewer immediate complications. Minimally invasive surgical procedures (laparoscopic or robotic) were gaining their grounds to improve perioperative outcome.[7],[8],[9] These technical advances are transforming our perspective of locoregional therapy for HCC. In the past, people used to imagine the natural course of HCC as a linear progression from early to intermediate and then to advanced or end stages, according to the Barcelona Clinic Liver Cancer (BCLC) staging, and allocate different treatment options according to the staging. However, it is increasingly recognized that many patients with intermediate or advanced stage HCC with good performance status and liver function may still have the opportunity for curative surgery if they are taken care of by experienced hepatobiliary surgeons.[10] Moreover, combination or sequential use of liver-directed and systemic therapies is widely used in the hope of better treatment efficacy. Therefore, the dialog and cooperation between different specialties is vital for implementing real multidisciplinary management for HCC.[11]


  Challenges of New Drug Development for Advanced Hepatocellular Carcinoma: Historical Perspective Top


  1. The use of clinical diagnosis limited access to comprehensive biomarker research. Unlike other cancers for which histological or cytological examinations are prerequisite for cancer diagnosis, HCC can be diagnosed based on its epidemiology and characteristic imaging findings. The imaging features demonstrated by contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) result from the unique blood supply to the normal liver and HCC. The normal liver has two sets of blood circulation: the blood, nutrients, and oxygen to the normal liver are supplied primarily by the portal vein system (about 70%–75%) and less by the hepatic artery system. The blood supply of typical HCC in the liver, by contrast, is primarily from the hepatic artery. The differential blood supply for HCC and the normal liver results in the characteristic arterial phase hypervascularization and portal phase washout of typical HCCs found by CT or MRI and forms the basis of clinical diagnostic criteria of HCC for patients with underlying cirrhosis.[12] Acceptance of clinical diagnosis may avoid the risk of internal bleeding or cancer cell spreading associated with the invasive procedure but limits the access of tumor samples from representative HCC patient populations for comprehensive research of molecular features of HCC
  2. The underlying liver diseases reduced opportunities to early-phase oncology clinical trials. Development of new oncology drugs was usually started by Phase 1 trials testing the safety and pharmacokinetic properties of new drugs in escalating dose cohorts and defining the recommended dosage and prescription for subsequent development. Phase 2 trials then used the dosing regimen defined in Phase 1 trials to further clarify the safety and efficacy in specific patient populations, which were usually selected based on preliminary efficacy observed in Phase 1 trials. The conventional Phase 1 trials usually enrolled patients with advanced cancers without standard therapy, good organ function reserves, and no major comorbidities. Patients with chronic infection were almost always excluded. This type of design greatly limited the access of HCC patients to the early phases of new oncology drug development because the vast majority of HCC patients had cirrhosis and impaired liver function reserves caused by chronic viral hepatitis or other etiologies[13]
  3. Excessive use of liver-directed therapy compromised the patients' organ function reserves. Another limitation related to the trial design issue was the concept of “no standard therapy” for HCC patients with major tumor burden in the liver. Physicians used to exhaust all kinds of liver-directed therapy, including surgery, radiofrequency ablation, and embolization, before referring the patients to systemic therapy. These repeated liver-directed therapies may further compromise the patients' liver function reserves with questionable efficacy.[14] Therefore, in recent years, experts in this field have sought to achieve consensus about timing and criteria of transiting from liver-directed therapy to systemic therapy for HCC.[15] With increasing efficacy demonstrated by systemic therapy, more and more physicians and HCC patients are willing to try systemic therapy earlier in the disease course, when the liver function reserves are not yet compromised by the progressing tumors or previous therapies. A noticeable impact of this trend is that in clinical trials of systemic therapy, even patients who received control arm therapy (sorafenib in the first line and placebo in the second line) had better and better survival outcome (see below).



  Development of Targeted Therapy for Advanced Hepatocellular Carcinoma Top


Development of systemic therapy for advanced HCC can be broadly divided into three stages. The first stage was single-agent targeted therapy (multitarget kinase inhibitor [MKI] or monoclonal antibodies) with antiangiogenic properties. Efficacy and safety of these agents were defined through the conventional Phase 1/2/3 clinical trials, and data from head-to-head comparison with standard of care were used for regulatory approval. The second stage was single-agent immune checkpoint inhibitor (ICI), especially the anti-programmed cell death-1 (PD1)/anti-PD-L1 ICI. Accelerated approval based on surrogate efficacy endpoints (objective response rate [ORR] and duration of response) was used in this type of therapy. The third stage was ICI-based combination regimens. More complicated clinical trial design exploring multiple primary endpoints of efficacy was adopted to better define the real clinical impact of these new regimens.[11],[16]

The MKI sorafenib was developed in the historical context of clinical trial design described above. Sorafenib was initially designed as a RAF kinase inhibitor, but later, studies suggested that its antiangiogenic effects via inhibition of the vascular endothelial growth factor receptor (VEGFR) pathway played a critical role in its antitumor mechanism.[17],[18] In four Phase 1 trials of sorafenib enrolling a total of patients with advanced solid tumors, only 1 patient with HCC (out of 10 HCC patients enrolled) and 1 patient of renal cell carcinoma [RCC] (RCC, out of 11 RCC patients enrolled) documented objective tumor response by imaging.[19] A three-stage Phase 2 trial planning to enroll more than 200 HCC patients was conducted, but the trial was held after a preplanned interim analysis reporting a 2.2% response rate (3 partial responses out of 147 enrolled HCC patients).[20] Although the efficacy data were not as good as expected, the study team initiated two randomized, placebo-controlled clinical trials in patients with advanced HCC that transformed the HCC treatment landscape.[21],[22]

The two randomized trials enrolled patients with advanced HCC from Western countries (mainly in Europe) and Asia-Pacific regions, respectively. Both trials reported consistent benefit in terms of overall survival (OS, hazard ratio [HR]: 0.68–0.69) and time to tumor progression (HR: 0.57–0.58). However, sorafenib was not very popular with doctors and patients after it was approved and recommended by international practice guidelines as standard first-line therapy for patients with BCLC advanced-stage HCC. Firstly, sorafenib can prolong OS mainly by achieving tumor stabilization, and only 5%–10% of patients with advanced HCC obtained objective tumor response by imaging. Secondly, data from the randomized trials indicated that the time to symptomatic progression may be even worse, albeit not statistically significant, in patients who received sorafenib than those who received placebo. Thirdly, although sorafenib was claimed to be a “targeted” agent, the relationship between in vivo target (VEGFR, RAF kinase, etc.) inhibition and clinical efficacy was not well established. Unlike other targeted agents such as the epidermal growth factor receptor inhibitors for non-small cell lung cancer, there were no reliable molecular markers that may help identify HCC patients likely to benefit from sorafenib treatment.

The lack of specific molecular aberrations in HCC highlighted the major challenges of new drug development for HCC in the era of targeted therapy. After sorafenib became the standard first-line systemic therapy for advanced HCC, new agents had to prove their efficacy and safety in the first line through a head-to-head comparison with sorafenib, or in the second line in patients who had received sorafenib treatment, by randomized controlled trials. In the 10 years after sorafenib approval, most of the new agents under development had the common mechanism of angiogenesis inhibition. Since there were no reliable biomarkers to predict the efficacy of angiogenesis inhibition, all of these trials were designed for “all-comers” (except for the ramucirumab trial for HCC patients with elevated alpha-fetoprotein [AFP] levels, see below). Moreover, most of these trials adopted clinical diagnosis of HCC, as mentioned above. Therefore, biomarker studies were not integrated in these trials.

The only drug that can challenge the leading position of sorafenib in the targeted therapy era is another MKI lenvatinib. Lenvatinib demonstrated similar OS, better progression-free survival (PFS), and a more favorable safety profile (especially fewer hand–foot skin reaction), compared with sorafenib, in a noninferiority randomized trial.[23] The lenvatinib development team paid attention to the safety issues for patients with chronic liver disease or cirrhosis early in its development. Results of all lenvatinib Phase 1 trials were analyzed, and correlation was found between the individuals' body weight and the pharmacokinetic parameters as well as frequency of adverse events.[24],[25] This analysis led to the recommendation of lenvatinib daily dosage based on body weight in HCC patients (12 mg for patients 60 kg or over and 8 mg for patients under 60 kg) much lower than the dosage recommended for thyroid carcinoma or RCC. The favorable safety profile of lenvatinib contributed greatly to its popularity after regulatory approval around the world.

Development of second-line systemic therapy for HCC patients who had received prior sorafenib therapy was even more challenging. If patients with advanced HCC failed first-line therapy, their liver function reserves and performance status may have worsened so that the patients may no longer be candidates for trials of second-line systemic therapy. Because all of these trials were placebo controlled, the physicians tended to refer patients with low tumor burden, relatively slow clinical progression, and good liver function reserves to these trials. Therefore, in these trials, even the patients who were randomly assigned to the placebo group had an average survival time of nearly 8 months.

The MKI regorafenib improved OS (HR: 0.63 compared with placebo) in a strictly defined population (good tolerance to and documented radiographic progression after sorafenib treatment), with a median duration of 7.8 months under sorafenib treatment.[26] The MKI cabozantinib 0.76 improved OS (HR: 0.76 compared with placebo) in a different population (one or two lines of prior systemic therapy including sorafenib, with 26%–28% of enrolled patients who had received two lines of prior therapy, and median duration of about 5 months under sorafenib treatment).[27] Both MKIs had the same issue of frequent dose reduction or interruption due to treatment-related adverse events. The MKI regorafenib improved OS (HR: 0.63 compared with placebo) in a strictly defined population (good tolerance to and documented radiographic progression after sorafenib treatment), with a median duration.[28] Based on subgroup analysis suggesting AFP level as a predictive marker for efficacy, the study team conducted a second trial enrolling HCC patients with AFP level ≥400 ng/mL and having prior sorafenib therapy. This trial reported survival benefit (HR: 0.71 compared with placebo) and a favorable safety profile.[29] A common issue for these agents is the low ORR (4%–7%). It is also difficult to differentiate from one agent to another because of the overlapping target populations targeted in individual clinical trials.


  Development of Immune Checkpoint Inhibitor Therapy for Advanced Hepatocellular Carcinoma: Accelerated Approval versus Regular Approval Top


In the era of ICI therapy, new regimens and new indications have been developed much faster than in the era of cytotoxic therapy or targeted therapy, thanks to more organized clinical trial infrastructure, and more flexible clinical trial design. In early-phase trials, multicohort (basket) design was used to explore the efficacy/safety of specific regimens in many cancer types. Adaptive design to incorporate new dose escalation schemes, new combination regimens, and small-scale randomization cohorts based on preliminary efficacy/safety data was used to “pick the winner” more efficiently. Regulatory agencies such as the U. S. Food and Drug Administration (FDA) also granted conditional, accelerated approval of new ICI therapy based on surrogate efficacy data, most commonly ORR and duration of response, from these early-phase trials.[30] In pivotal randomized trials with head-to-head comparison with current standard of care, multiple primary endpoints were frequently tested in one trial to catch as many efficacy signals as possible in different patient subgroups.

The anti-PD1 ICI nivolumab and pembrolizumab were both granted accelerated approvals by the U. S. FDA based on ORR and duration of response data. The nivolumab CheckMate-040 trial exemplified the flexible trial design discussed earlier, trying to compare the efficacy of nivolumab and sorafenib, testing the combination of different doses of ipilimumab, testing nivolumab in liver dysfunction, and exploring the feasibility of combination with targeted therapy. This trial also led to the accelerated approval of nivolumab plus ipilimumab in patients with advanced HCC after sorafenib therapy. The higher response rate (single-agent anti-PD1 about 15% and anti-PD1-based combination about 30%) and generally mild adverse event profile ignited enormous enthusiasm of developing new anti-PD1/anti-PD-L1-based combination therapy for the treatment of HCC.

Despite the initial enthusiasm, in April 2021, the U. S. FDA held an Oncology Drugs Advisory Committee (ODAC) to discuss six accelerated approvals, including both nivolumab and pembrolizumab for advanced HCC.[31] The main reason that put these two indications under discussion was that the confirmatory trials, i.e., pembrolizumab versus placebo in second line (the KEYNOTE-240 trial)[32] and nivolumab versus sorafenib in first line (the CheckMate-459 trial),[33] reported negative outcomes. The accelerated approval process of the U. S. FDA was first established in the 1990s for the research and development of therapy for human immunodeficiency virus infection, hoping to provide possible treatment options earlier for life-threatening diseases. However, in the past 10 years, more than 80% of the accelerated approvals were granted to anticancer drugs. In the case of ICI therapy, about half of the indications approved by the U. S. FDA before 2019 were through accelerated approval based mainly on surrogate efficacy endpoints reported from single-arm trials.[34] The lack of correlation between ORR data reported in early-phase trials with potential survival benefit and the lack of long-term safety data have raised concerns among clinical trial experts as well as oncology community.[35],[36]

Although the U. S. FDA's regulatory approval had no binding obligation to follow the voting results of ODAC (for 49 oncology products discussed and voted by ODAC between 2009 and 2019, the final regulatory decision by the U. S. FDA went against the ODAC recommendation in 6 cases),[37] discussion and recommendation of the nivolumab and pembrolizumab indications for advanced HCC by ODAC in April 2021 (8:0 for pembrolizumab and 4:5 against nivolumab) taught us valuable lessons regarding the regulatory process as well as oncology trial design and data interpretation. One common problem of the two negative confirmatory trials was that the performance of the control group apparently exceeded estimation based on earlier data at the trial design stage.[38] In the CheckMate-459 trial, patients assigned to sorafenib arm had a median OS of 14.7 months (95% confidence interval [CI], 11.9–17.2), while earlier first-line HCC trials reported OS of about 12 months in the sorafenib (control) arms. In the KEYNOTE-240 trial, patients assigned to placebo arm had a median OS of 10.6 months (95% CI, 8.3–13.5), while earlier second-line HCC trials reported OS of about 8 months in the placebo (control) arms. The increasing willingness of the patients to receive systemic therapy earlier in their clinical course, as discussed earlier, and the availability of multiple treatment options after progression from trial-assigned treatment contributed to the improved survival in the control groups and the narrower effect size that demanded larger sample size than original planned to achieve statistical significance.

Another design issue is the use of multiple primary endpoints and multiple interim analyses, which has been frequently used in modern oncology drug trials to catch efficacy signals as soon as possible. This design requires careful selection of endpoints that most relevant to desired clinical efficacy. These endpoints may be tested in parallel or in sequence at pre-specified time points during the progress of clinical trials. Stringent definition of P values at each step of statistical testing was required to control the overall type 1 error.[39] In the KEYNOTE-240 trial, pembrolizumab demonstrated virtually the same efficacy as seen in the early trial that led to its accelerated approval,[40] and the OS and PFS were consistently better than patients who received placebo. The HRs for PFS (at the prespecified primary analysis) and OS (at the prespecified final analysis) were 0.775 (95% CI, 0.609–0.987; P = 0.0186) and 0.781 (95% CI, 0.611–0.998; P = 0.0238), respectively. Both analyses failed to reach the prespecified significance thresholds (P = 0.002 for PFS and. 0174 for OS, respectively).[32] This example illustrated the gap between statistical significance and clinical relevance.

All of the above discussion on study design pointed to a common dilemma in oncology new drug development. OS benefit is the holy grail of pivotal clinical trials for new oncology drugs. With more available treatment options and better expertise of the treating physicians to use them, it will be more and more challenging to demonstrate OS benefit, compared with current standard of care, particularly in the first-line setting. The regulatory agency, the pharmaceutical industry, and the clinical medicine community must collaborate more closely to balance the trade-off between pursuit of treatment breakthrough and trial quality, to identify endpoints most relevant to real clinical benefit, and to grasp efficacy signals out of confounding noises.


  Future Perspective: The Promise and Challenge of Combination Therapy Top


Anti-PD1/anti-PDL1 ICI has become the backbone of new combination therapy for HCC. In patients with advanced-stage disease, the two most rapidly developing combinations were the addition of antiangiogenic targeted therapy and addition of anti-CTLA4 ICI. The combination of atezolizumab and bevacizumab demonstrated superiority in terms of both OS and PFS, compared with sorafenib, as first-line therapy for advanced HCC at the trial's first interim analysis,[41] and the survival benefit persisted with longer follow-up.[42] The potential antitumor synergy between atezolizumab and bevacizumab was supported by the better PFS achieved by this combination, compared with single-agent atezolizumab therapy, in a small randomized trial (median PFS: 5.6 vs. 3·4 months, HR: 0.55, P = 0·011).[43] Finally, another randomized trial comparing the combination of sintilimab (anti-PD1) plus bevacizumab biosimilar with sorafenib demonstrated very similar survival advantage of the combination regimen as first-line therapy for advanced HCC, further supporting the increased efficacy of this type of combination therapy.[44]

Development of combination systemic therapy must face several challenges.[45] Firstly, while all the combination regimens had plausible rationale of antitumor synergy, the most relevant mechanisms of action and biologically effective dosage remained largely undetermined. Take the antiangiogenesis agents as examples. Tumor angiogenesis had profound immune-suppressive effects, and antiangiogenic therapy may activate antitumor immunity in many aspects, including increasing antigen presentation, activating effector T-cells, and counteracting immune suppressor cells in the tumor microenvironment.[46] While antiangiogenic therapy may enhance antitumor immunity, preclinical studies indicated that this effect was dose dependent. If excessively high dose of antiangiogenic therapy is used, then it will produce paradoxical hypoxia, suppression of effector T-cell function, and recruitment of immune-suppressive cells to the tumor microenvironment.[47] Clinical trials thus far have not yet addressed the optimal biological effective dosage of antiangiogenic agents as immune modulators. On the other hand, preclinical studies may help identify the optimal dosage of antiangiogenic agents on different aspects of immune modulation in the tumor microenvironment, thus improve their therapeutic window.[48],[49]

Development of anti-CTLA-4 also illustrated the challenge in identifying the optimal biologically effective dosage of immunotherapeutic agents. Both the efficacy of anti-CTLA-4 in terms of T cell activation the adverse events induced by anti-CTLA-4 treatment may increase with higher dosage of anti-CTLA-4. Therefore, the optimal biologically effective dosage should be carefully defined to balance the efficacy and safety in the clinic.[50],[51],[52] In HCC, although the U. S. FDA approved nivolumab 1 mg/kg plus ipilimumab 3 mg/kg for the treatment of advanced HCC after sorafenib treatment, it acknowledged that definite benefit-risk assessment was not possible based on data from the Cohort 4 of CheckMate-040 trial because of the small sample size of the different dosage cohorts, potential confounding by imbalances in baseline covariates, and lack of a prespecified statistical plan.[53]

The second major challenge is how to prioritize the numerous potential combination regimens for clinical development. The use of basket trial design, as discussed earlier, increased the efficiency of testing specific regimens in multiple cancer types and may facilitate the early exploration of predictive biomarkers. It is critical to enhance the access of HCC patients to these early-phase trials to increase the opportunities of detecting efficacy signals as early as possible.[16] Although everybody hopes that we may prioritize treatment options based on predefined biomarkers (from tumor tissue, peripheral blood, etc.), our knowledge and technology to dissect the complex interactions among the tumor-cell-intrinsic molecular aberrations, the host immunity, and the immune microenvironment may not live to our expectation yet.[54] In patients with advanced HCC, transcriptomic markers reflecting inflammation status or T-cell exhaustion may be associated with treatment efficacy,[55],[56] and external validation of these preliminary findings is critical for future clinical application. Finally, preclinical animal models may help explore mechanisms of antitumor immunity and drug resistance,[57] but their usefulness of identifying or prioritizing novel combination regimens, defining the optimal treatment sequence, and facilitating rational clinical trial design, remains to be determined.[58] Recent translational studies indicated that nonalcoholic steatohepatitis (NASH) may possess specific aberrations in murine liver microenvironment,[59] and anti-PD1 therapy may paradoxically enhance tumor growth in murine NASH-related HCC models.[60] These perplexing preclinical findings may support stratification based on etiologies (viral, NASH, alcoholic, etc.) in future clinical trials of ICI-based therapy for HCC.[61]


  Concluding Remarks Top


With its increasing efficacy and better safety profiles, systemic therapy for HCC is now extending its impact beyond advanced-stage diseases, and numerous clinical trials in combination with liver-directed therapy are ongoing.[16],[62] The lessons learned from previous single-agent and combination therapy trials have greatly enhanced our knowledge of trial design and data analysis. HCC patients should have more access to the early development of novel combination therapies. Comprehensive integration of clinical and translational research platforms is critical for characterization of antitumor synergy among different combinations and validation of predictive biomarkers for clinical use.

Financial support and sponsorship

Nil.

Conflicts of interest

Dr. Chiun Hsu received research grants from BMS/ONO, Roche, and Ipsen and received honorarium from the following pharmaceutical companies: AstraZeneca, Bayer, BMS/ONO, Eisai, Eli Lilly, Ipsen, Merck Serono, MSD, Novartis, Roche, and TTY Biopharm.



 
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