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Advances in systemic therapy for hepatocellular carcinoma
Overview
Hepatocellular carcinoma (HCC) represents a challenging malignancy of global importance (see Chapter 89 ). It is the fifth most common solid tumor in terms of incidence and the third leading cause of cancer-related death worldwide. Its incidence mirrors that of chronic liver injury, which is predominantly attributable to viral hepatitis infection, both hepatitis B and C (see Chapter 68 ). Other etiologic factors that cause chronic liver injury and cirrhosis include alcohol; nonalcoholic steatohepatitis (NASH) (see Chapter 69 ), commonly associated with morbid obesity and diabetes; and other metabolic diseases, for instance, hemochromatosis. The highest incidence of HCC remains in Southeast Asia and sub-Saharan Africa, driven chiefly by hepatitis B viral infection. However, there is continued concern about the rising incidence of HCC in North America. A 3-fold increase in the age-adjusted rates for HCC associated with hepatitis C, from 2.3 per 100,000 between 1993 and 1995 to 7.0 per 100,000 between 1996 and 1998, has been observed. This is most likely explained by the increased incidence of hepatitis C that has been seen in North America during that time period. In an effort to understand the projected incidence of HCC among United States population, a forecast model based on data from the Surveillance, Epidemiology, and End Results (SEER) database and the US census bureau was used. Asians/Pacific Islanders population had the highest incidence of HCC. In the projected period through 2030, a decline is expected with a rise among Hispanic and Black populations. This is mostly attributed to the historically high incidence of hepatitis B virus (HBV) infection among the Asian population, which started to decrease after the introduction of universal vaccination. The majority of HCC cases are attributed to metabolic syndrome and diabetes and this incidence is expected to continue to rise as the obesity epidemic continues. Hispanics and Blacks are among the populations with the highest obesity prevalence. In fact, an analysis of 18 SEER registries showed that in the United States, HCC incidence and mortality has decreased among Asians/Pacific Islanders between the year 2000 and 2010, whereas a higher incidence of HCC was observed among Blacks, Hispanics, and Whites. Hepatitis C virus (HCV) infection constitutes a large proportion of HCC incidence in the United States, and the advent of second-generation direct antiviral therapy is expected to improve the incidence of HCC. Nonetheless the cost of these medications might preclude its widespread use and is a barrier to HCV eradication. A plateauing of HCC cases by 2025 is expected; however, this and other predictions do not necessarily reflect the global incidence and prevalence of HCC. For example, in sub-Saharan Africa, the rate of HBV vaccination remains low, thus a significant decline in HBV-related HCC cases is not expected. In Europe, HCV was driving the majority of HCC cases, and it is being replaced by alcoholic cirrhosis and nonalcoholic fatty liver disease. HCC incidence and etiology vary by geography, ethnicity, and socioeconomic factors. Global studies are crucial to delineate the intrinsic disease differences (see Chapter 89 ).
Chemotherapeutic agents, either as monotherapy or in combination, demonstrated a low response rate (RR) and limited survival advantage. The advent of targeted therapies and checkpoint inhibitors, and their demonstrated positive survival impact for patients with HCC, led to an explosion of novel therapeutic approaches and a paradigm shift in the management of advanced HCC cases, with evolving opportunities to explore systemic therapeutic indications in other stages of the disease (e.g., adjuvant and neoadjuvant).
Hepatocellular carcinoma and cirrhosis: Two diseases in one
A fundamental challenge in HCC is the coexistence of underlying liver injury and hepatic dysfunction as the premalignant environment in the majority of patients. Both the underlying cirrhosis and the tumor itself affect the HCC patient’s overall survival (OS; see Chapter 74 ). Thus there is a need to evaluate the cirrhosis status of patients with liver cancer to guide treatment decisions. The original scoring system, developed by Child in 1964, consisted of three key parameters: jaundice (bilirubin), ascites, and encephalopathy. This scoring system was later updated by Pugh and colleagues, with the addition of hepatic synthetic function assessment by evaluation of serum albumin levels and prothrombin time ( Table 99.1 ). Today this combined score is known as the Child-Pugh score. It remains the most commonly used scoring system for liver cirrhosis (see Chapter 4 ). The major pitfall of the Child-Pugh score is the lack of inclusion of any parameters relating to the cancer itself, as it was developed in patients who had cirrhosis but not cancer. As such, it is unlikely to be the best predictor of outcome in patients with HCC.
TABLE 99.1
Child-Pugh Scoring System
| POINTS | |||
|---|---|---|---|
| PARAMETER | 1 | 2 | 3 |
| Albumin (g/dL) | >3.5 | 2.8–3.5 | <2.8 |
| Bilirubin (mg/dL) | <2 | 2–3 | >3 |
| Ascites | Absent | Slight | Moderate |
| Encephalopathy | None | I–II | III–IV |
| PT (INR) | <1.7 | 1.8–2.3 | >2.3 |
| Score | A | B | C |
| Points | 5–6 | 7–9 | 10–15 |
INR, International normalized ratio; PT, prothrombin time.
Okuda and colleagues 11 recognized the need for an HCC staging system that incorporated factors related to both the background cirrhosis and the tumor itself and, therefore, designed the Okuda staging system, which encompasses four variables: albumin, bilirubin, ascites, and tumor size defined as a percentage function to the size of the liver (greater or less than 50%). The Okuda staging system served as a platform for more advanced and sophisticated prospective scoring systems that used the Cox proportional hazard regression model. The Cancer of the Liver Italian Program (CLIP) devised a scoring system in patients with HCC, and primarily hepatitis C as the etiologic driver, , that determined the independent prognostic variables for HCC patients to be the Child-Pugh score plus three additional variables relating to the tumor itself: tumor morphology (assessed by the number of lesions and extent in the liver), presence or absence of portal vein thrombosis, and α-fetoprotein (AFP) level ( Table 99.2 ). Patients with high scores of 4 to 6 were shown to have a median survival of only 3.2 months.
TABLE 99.2
Cancer of the Liver Italian Program Scoring System
| SCORE | |||||
|---|---|---|---|---|---|
| PARAMETER | 0 | 1 | 2 | ||
| Child-Pugh score | A | B | C | ||
| Tumor morphology | Uninodular and extension ≤50% | Multinodular and extension ≤50% | Massive or extension >50% | ||
| Portal vein thrombosis | No | Yes | |||
| α-Fetoprotein (ng/dL) | <400 | ≥400 | |||
| Score | 0 | 1 | 2 | 3 | 4–6 |
The Chinese University Prognostic Index (CUPI), another scoring system that is based on multivariate analysis, in contrast to CLIP, was developed mainly in patients with hepatitis B–associated HCC. This prognostic index identified bilirubin, alkaline phosphatase, and presence or absence of ascites, in addition to tumor stage based on the tumor-node-metastasis (TNM) staging, and AFP levels, as the most important predictors of outcome. Furthermore, a clinical assessment parameter of presence or absence of symptoms at presentation was incorporated ( Table 99.3 ). An important aspect of the CUPI index is the different weight attributed to the various parameters. The median survival of the highest-risk group was close to 1 month. Other scoring systems include the Groupe d’Étude et de Traitement du Carcinoma Hépatocellulaire (GETCH) staging system, the Japan Integrated Staging (JIS) score, and the Barcelona Clinic Liver Cancer (BCLC) classification system.
TABLE 99.3
Chinese University Prognostic Index Scoring System
| PARAMETER | WEIGHT (CUPI SCORE) | |||||
|---|---|---|---|---|---|---|
| Bilirubin (mg/dL) | <1.9 | 0 | 1.9–2.8 | 3 | ≥2.9 | 4 |
| Ascites | Present | 3 | ||||
| Alkaline. phosphatase | ≥200 IU/L | 3 | ||||
| Tumor-node-metastasis stage | I and II | −3 | IIIa and IIIb | −1 | IVa and IVb | 0 |
| α-Fetoprotein (ng/mL) | ≥500 | 2 | ||||
| Disease symptoms on presentation | None | −4 | ||||
| Risk group | Low | Intermediate | High | |||
| Score | −7 to 1 | 2–7 | 8–12 | |||
CUPI, Chinese University Prognostic Index Scoring System.
The BCLC was created with the aim of fine-tuning the differences between patients with early-stage disease, which is a feature that the Okuda staging system fails to characterize. However, by the same token, the BCLC staging system had limited permutations for patients with advanced disease and grouped patients with unresectable disease, with Okuda stage I or II, or with Child-Pugh A or B in the exact same category of advanced disease. In a retrospective analysis of patients with advanced HCC reviewed by medical oncologists at Memorial Sloan-Kettering Cancer Center (MSKCC) during a 5-year period, we attempted to identify which of these well-known eight scoring systems would be most valuable in this specific clinical setting. Using a concordance index (c-index), the GETCH, CLIP, and CUPI were the most informative staging systems in predicting survival in patients with advanced HCC. BCLC did not score well in this exercise studying a specific niche of patients with advanced HCC, all of whom fall within the single basket of category C of BCLC that lacks any discriminatory abilities. Other groups have come to the same conclusion regarding BCLC independently. Another liver function assessment model was developed in Japan and several geographic regions, the Albumin-Bilirubin (ALBI) score. As opposed to the Child-Pugh score developed in patients with liver cirrhosis and no HCC, the ALBI score was studied in patients with HCC with a validation cohort of patients with liver cirrhosis only. ALBI score relies solely on objective measures of liver function being albumin and bilirubin, as evaluation of ascites and hepatic encephalopathy can be clinically challenging. The score stratifies patients into three categories and compared well with the Child-Pugh score. Interestingly ALBI score provided further dissection within the Child-Pugh A score, where patients could be dichotomized into two groups with significant survival difference. ,
Role of chemotherapy in hepatocellular carcinoma
Almost every class of chemotherapy has been investigated in advanced HCC. Doxorubicin is one of the most studied drugs in this disease setting. This is partly due to a solitary trial originally reported by Olweny and colleagues in 1975. Many subsequent attempts to try to replicate this high RR have been made, both as monotherapy and in combination with other chemotherapeutic agents, but to no avail.
Other older and newer chemotherapeutic agents have also been studied in HCC, including cisplatin, etoposide, mitoxantrone, vinblastine, capecitabine, gemcitabine, irinotecan, and paclitaxel, all with reported dismal RRs and no impact on survival.
Although several combination chemotherapy regimens have led to improved RRs, the impact on survival was not marked in the majority of cases. A combination of cisplatin, interferon (IFN), doxorubicin, and 5-fluorouracil (5-FU), which became commonly known as PIAF. PIAF was subsequently modified and studied in the outpatient setting. An RR of 26% was observed in this Phase II trial of 50 patients. More importantly, 18% (9 patients) proceeded to surgical resection of their tumor after completion of therapy, and of these resected patients, 4 had pathologic complete responses (CRs) noted in the resected tumor specimen. A randomized trial of PIAF versus doxorubicin followed. This trial revealed the same 21% RR for PIAF, versus 10% for single-agent doxorubicin. The study failed, however, to show any survival advantage in favor of the PIAF combination (8.7 vs. 6.8 months, P = .83). Although the study failed to bolster support for the use of PIAF as a conventional palliative treatment option for advanced disease, the regimen remains rarely used for carefully selected patients with potentially resectable tumors as a conversion therapy. A phase III trial of FOLFOX4 (infusional fluorouracil, leucovorin, and oxaliplatin) versus doxorubicin as palliative chemotherapy for advanced HCC was performed in Asia and included 371 patients. The primary end point was OS; secondary end points included progression-free survival (PFS), RR by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (version 1.0), and safety. At the prespecified final analysis, median OS was 6.40 months with FOLFOX4 (95% confidence interval [CI], 5.30–7.03) and 4.97 months with doxorubicin (95% CI, 4.23–6.03; P = .07; hazard ratio [HR], 0.80; 95% CI, 0.63–1.02). It is not until continued follow-up that a true survival benefit of FOLFOX4 was noted (HR, 0.79; 95% CI, 0.63–0.99; P = .04). Toxicity was consistent with previous experiences with FOLFOX4; proportions of grade 3 to 4 adverse events were similar between treatments. It is important to note that the doxorubicin dose was only 50 mg/m in this study. Although the study did not meet its primary end point, the trend toward improved OS with FOLFOX4, along with an increased PFS and RR, led to the approval of FOLFOX4 as an accepted standard regimen for advanced HCC in China.
Some of the generally disappointing results seen to date may be explained by the genetic make-up of HCC. HCC is comprised of highly resistant clones of cancer cells. HCC cells carry a high “genetic mutational load,” making them less amenable to the destructive cytotoxic actions of chemotherapy.
Floxuridine (FUDR) and dexamethasone administered via hepatic arterial infusion (HAI) was also explored in HCC. Among 8 patients studied, the RR was 25%, and the hepatic PFS was 9.4 months. HAI will be discussed in more detail in Chapter 97 .
In summary, no chemotherapy agent, whether used alone or in combination, has so far shown any real impact on survival in patients with HCC. The emergence of several novel targeted agents and checkpoint inhibitors has changed the treatment paradigm in HCC as a viable option where cytotoxic chemotherapy failed. However, chemotherapy is not necessarily forgotten, as the potential of combining it with targeted therapies may carry a certain promise in HCC, given the success of such a strategy in other solid tumors models.
Biologic therapies in hepatocellular carcinoma
The advent of novel targeted therapeutics in oncology, together with an imminent need in terms of therapeutics for advanced HCC, led to the exploration of several relevant targets in HCC along the signal transduction pathways ( Fig. 99.1 ).
The epidermal growth factor receptor (EGFR) was one of the first and well-studied therapeutic targets in HCC, despite controversial views on the expression of EGFR between HCC and noncancerous diseased liver tissue. Efforts evaluating erlotinib, cetuximab, , lapatinib, , and a combination regimen of cetuximab in conjunction with gemcitabine-oxaliplatin chemotherapy, did not demonstrate satisfactory outcomes to enhance further investigation. Insulin growth factors (IGFs) are reported to be strong mitogens of HCC, exerting their effect through the IGF-1 receptor (IGF-1R) led ultimately to a phase II study of cixutumumab monotherapy with poor outcome. Rapamycin and everolimus mTOR pathway inhibitors were evaluated preclinically and in clinical trial to no avail. Thus there is no concrete foundation to recommend the routine use of any of the single agents, such as EGFR, mTOR, or IGF-R inhibitors, in the management of HCC.
Tyrosine kinase inhibitors
Sorafenib is a small molecule multikinase inhibitor that inhibits the serine/threonine kinase RAF-1 in vitro in addition to both proangiogenic (vascular endothelial growth factor receptor [VEGFR]-1, -2, -3; platelet-derived growth factor receptor-β [PDGFR-β]) and tumorigenic (RET, FLT3, c-KIT receptor tyrosine kinases [RTKs]).
The initial phase II trial evaluating response to sorafenib in patients with advanced HCC showed an RR of 2% when assessed by conventional RECIST criteria, yet 34% of patients had stable disease for a minimum of 4 months. This was associated with a median time-to-progression (TTP) of 4.2 months and median OS of 9.2 months, both of which compare favorably with historic controls at that time. The main grade 3 to 4 toxicities were fatigue (9.5%), diarrhea (8%), and palmar-plantar erythrodysesthesia (5.1%), known as hand-foot syndrome (HFS). The high rate of stable disease was associated with an observed phenomenon of central tumor necrosis in many patients on the study whose tumors were evaluated by using triphasic computed tomography (CT) scans, including an arterial phase ( Fig. 99.2 ; see Chapter 14 ). This central tumor necrosis was quantified, and the volume of the tumor it encompassed within was measured by using a computer algorithm for semiautomated delineation of tumors. It was later found that the ratio of the percentage of the described tumor necrosis to the tumor volume correlates with the objective response. This phenomenon is still pending validation and is currently the subject of many prospective correlative studies of ongoing HCC clinical trials.
The signal of improved outcome in this phase II study led to a large, double-blind, randomized phase III trial evaluating sorafenib versus placebo in patients with advanced HCC and Child-Pugh A cirrhosis. with two primary end points: OS and time-to-symptomatic progression (TTSP) using the FHSI8 (Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8)-TSP instrument. This pivotal phase III SHARP trial demonstrated an improvement in survival of 10.7 months in the sorafenib group versus 7.9 months for the placebo arm (HR, 0.69; P < .001). The second primary end point evaluating for TTSP showed no difference between the two arms ( P = .77). This observation is limited, however, by the poor understanding of the validity of FHS18-TSP instrument in this setting. In addition, a significant proportion of patients on this study, including 17% with locally advanced tumor BCLC B patients, had an excellent performance status and lacked any symptoms that the FHS18-TSP instrument would otherwise depend on for its measurements. The toxicity profile was similar to that noted in the phase II study, with grade 3 to 4 diarrhea developing in 8% of patients and 8% experiencing HFS. There were rare bleeding events (<1%), which required caution considering the antiangiogenic nature of sorafenib, similar to other agents in its class (for instance, bevacizumab and sunitinib) that may cause fatal bleeds. ,
A second randomized phase III study evaluating sorafenib in patients with advanced HCC and Child-Pugh A cirrhosis was conducted in the Asia-Pacific geographic area. The study had similar eligibility criteria compared with the SHARP trial yet had two fundamental differences in the design. The study had a 2:1 randomization design, typically done to help encourage accrual, and did not have a predefined primary end point; rather, it looked at several end points. Similar to the SHARP trial, the Asia-Pacific study showed an improvement in survival in favor of sorafenib (6.5 months) versus placebo (4.2 months). This statistically significant improvement ( P = .014), however, was not of the same magnitude as the SHARP trial, despite a similar HR of 0.68 and 0.69 in the Asia-Pacific and SHARP study, respectively. In an attempt to explain the difference in magnitude of the OS, it was argued that in the Asia-Pacific study, patients were more ill at the time of accrual, compared with the SHARP trial, and had more extensive-stage disease. This observation may partly explain the difference in magnitude of benefit from sorafenib between those two populations, and suggests, in view of the similar HRs, that the benefit for sorafenib was expressed on the survival curve at two different time points in the natural history of HCC: an earlier one in the SHARP trial and a later one for the Asia-Pacific study. Another possible explanation for this numerical difference could be attributed to higher incidence of HBV-related HCC in the Asia-Pacific study population, as opposed to HCV, which was associated with better outcomes with sorafenib.
Patients with unresectable HCC and Child-Pugh A liver function who are eligible for sorafenib based on the SHARP trial encompass no more than 50% of the patients seen in daily clinical practice by medical oncologists. The safety and efficacy of sorafenib in patients with Child-Pugh B or C cirrhosis, who comprise the other 50% of HCC patients, remains a subject of debate. In the phase II study evaluating sorafenib in HCC, 28% of patients had Child-Pugh B cirrhosis, with pharmacokinetic profiles including area under the curve (AUC) and maximum concentration (C max ) that were comparable to patients with Child-Pugh A score. The Child-Pugh B patients were, however, noted to have more frequent worsening of their liver function, including elevated total serum bilirubin, worsening ascites, and encephalopathy. In a phase I study evaluating two different dosage regimens of sorafenib in Japanese patients with advanced HCC, geometric means of AUC 0 to 12 and C max were slightly lower in patients with Child-Pugh B cirrhosis compared with Child-Pugh A cirrhosis, despite the lack of any substantial differences in the incidence of adverse events between the two groups. One further study, evaluating sorafenib in 150 patients with a variety of solid tumor malignancies in predefined cohorts with different levels of liver dysfunction helps give some guidance on the optimal use of sorafenib in such patients. Among all the cohorts with higher than normal total bilirubin, the most commonly reported drug-limiting toxicity (DLT) was further elevation of bilirubin. The study suggested the following dosing of sorafenib: 400 mg orally twice per day if bilirubin is below upper limit of normal (ULN), 200 mg orally twice per day for bilirubin up to 1.5 ULN, 200 mg orally once per day for bilirubin 1.5 to 3 times ULN, and to avoid prescribing sorafenib for bilirubin higher than 3 times ULN. These recommendations continue to serve as a clinical guideline until more data are available regarding the safety and efficacy of sorafenib in patients with HCC and Child-Pugh B or C. This would require a randomized study that will allow analysis of the natural history of the disease and means of evaluating worsening cirrhosis in noninvasive ways, but with more predictive measures than simply bilirubin levels.
Lenvatinib, a multiple receptor kinase inhibitor became of interest with HCC-related targeting of angiogenesis (VEGFR 1–3), fibroblast growth factor (FGF) receptor (FGFR 1–4), and PDGFR. , The REFLECT trial was a multicenter, phase III, open-label, randomized, noninferiority study of lenvatinib versus sorafenib as a first-line therapy in unresectable and metastatic HCC. Nine hundred fifty-four patients were randomized to receive lenvatinib or sorafenib in a 1:1 fashion. Eligible patients had to have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, Child-Pugh A liver function, and adequate organ function. Patients with more than 50% liver involvement, or Vp4 main portal vein invasion (defined as presence of a tumor thrombus in the main trunk of the portal vein or a portal vein branch contralateral to the primarily involved lobe or both lobes) were excluded. The study showed a median survival of 13.6 months (95% CI, 12.1–14.9) for lenvatinib compared with 12.3 months (10.4–13.9) in the sorafenib group (HR, 0.92 [95% CI, 0.79–1.06]), confirming noninferiority as per predetermined statistical design. Secondary end points included TTP, PFS, and objective response rate (ORR). Median TTP was 8.9 months (95% CI, 7.4–9.2) for lenvatinib compared with a TTP of 3.7 months (3.6–5.4) for sorafenib (HR, 0.63 [0.53–0.73], P < .0001). Lenvatinib-associated PFS was 7.4 months (6.9–8.8) compared with 3.7 months (3.7–4.6) on the sorafenib arm (HR, 0.66 [0.57–0.77], P < .0001). ORR as defined by modified RECIST (mRECIST) was 24.1% (20.2–27.9) for lenvatinib compared with 9.2% (6.6–11.8) in the sorafenib group with P < .0001. The improvements in all secondary end points were clinically and statistically meaningful. The difference was consistently noted when using blinded independent imaging review according to RECIST1.1 (18.8% vs. 6.5%, P < .0001). This was among the first phase III trials to depend prospectively on mRECIST. The most common observed adverse events were hypertension, diarrhea, decreased appetite for lenvatinib, palmar-plantar erythrodysesthesia, diarrhea, and hypertension in the sorafenib arm. This study confirmed noninferiority to sorafenib and established lenvatinib as another first-line treatment in advanced HCC.
Sunitinib, a multitargeted RTK inhibitor that targets angiogenic pathways, was evaluated as a single agent in patients with advanced HCC in two phase II studies. , Despite nonreassuring findings, enthusiasm remained regarding the potential therapeutic value of sunitinib in HCC, prompting a phase III clinical trial evaluating sunitinib versus sorafenib in patients with advanced HCC. This study of 1074 patients was terminated early. For sunitinib and sorafenib, respectively, median OS was 7.9 versus 10.2 months (HR, 1.30; one-sided P = .9990; two-sided P = .0014), and median PFS (3.6 vs. 3.0 months; HR, 1.13; one-sided P = .8785; two-sided P = .2286) were comparable.
Surprisingly, regorafenib, an oral tyrosine kinase inhibitor, that similarly to sorafenib targets angiogenesis among other cancer pathways with more potent antiangiogenic activity and distinct oncogenic targets, was evaluated as a second-line treatment for patients who have radiologically progressed on sorafenib in the first line. RESORCE was an international phase III, randomized, placebo-controlled, double-blind study. Patients had to have tolerated sorafenib to be included in the RESORCE study. Tolerance to sorafenib was defined as the ability of patients to tolerate the drug for 20 of the last 28 days at a minimum dose of 400 mg per day. Five hundred and seventy-three patients were randomized in a 2:1 fashion. Median duration on prior sorafenib was 7.8 months, and the median interval from progression on sorafenib until start of regorafenib was 1.4 months. Response was assessed by mRECIST criteria. Patients receiving regorafenib had a median OS of 10.6 months (95% CI, 9.1–12.1) versus 7.8 months (6.3–8.8) for patients who received placebo (HR, 0.63 [95% CI, 0.50–0.79]; P < .0001). Median PFS was 3.1 months (95% CI, 2.8–4.2) with regorafenib and 1.5 months (1.4–1.6) with placebo. Median TTP was 3.2 months (95% CI, 2.9–4.2) with regorafenib and 1.5 months (1.4–1.6) with placebo. The most clinically relevant grade 3 or 4 adverse events with regorafenib were hypertension, HFS, and fatigue. Authors looked at the collective survival outcomes in patients who received sorafenib followed by regorafenib as an exploratory retrospective analysis of the RESORCE trial. Median OS reached 26 months (22.6–28.1) for patients who received subsequent regorafenib compared with 19.2 months (16.3–22.8) for placebo.
Hepatocyte growth factor (HGF), and its receptor c-MET, which were found to be overexpressed in 33% and 20% of human HCC tissues, respectively, were zoomed in as potential oncologic targets in HCC. c-MET was overexpressed preferentially in early-stage resected HCC, but without effect on outcome as measured by OS. Tivantinib, a tyrosine kinase inhibitor with anti c-MET activity, was studied in both the phase I and phase II setting with encouraging results. In a phase II trial of advanced HCC patients with progression post–first-line therapy, tivantinib therapy led to a median TTP of 2.7 months versus 1.4 months for placebo (HR, 0.43; 95% CI, 0.19–0.97) and a median OS of 7.2 months versus 3.8 months for placebo (HR, 0.38; 95% CI, 0.18–0.81) in those patients with high MET-expressing tumors. Interestingly, high MET expression in the placebo group was associated with shorter OS (median OS, 3.8 vs. 9.0 months), suggesting that MET may also be a prognostic biomarker. Given these data, tivantinib was tested in a randomized phase III multicenter, randomized, placebo-controlled, double-blind clinical study of 340 patients with advanced HCC and excellent hepatic function, who experienced disease progression while receiving sorafenib. Of interest, tivantinib was administered only to patients with high MET expression (defined as >50%; 3 to 4+ expression by immunohistochemistry [IHC]), offering the first example of a trial using an a priori molecular characteristic to enrich for activity in HCC. Median OS was 8.4 months (95% CI, 6.8–10.0) in the tivantinib group and 9.1 months (7.3–10.4) in the placebo group (HR, 0.97; 95% CI, 0.75–1.25; P = .81). Cabozantinib fared better. In addition to MET and VEGFR-2, cabozantinib inhibits other tyrosine kinases, including RET, KIT, AXL, and FLT3. It has shown promising efficacy in a cohort of 41 patients with advanced HCC. In 78% of patients, tumor regression was observed by RECIST criteria with a 5% confirmed partial response (PR). The median PFS for the cohort was estimated at 4.2 months. These results led to the phase III CELESTIAL study, a multicenter randomized double-blind placebo-controlled phase III trial in patients whose disease has progressed after at least one and up to two lines of systemic therapy, including sorafenib. Given the molecular intertumoral heterogeneity of HCC (see Chapter 9C ), cabozantinib was evaluated in all-comers as opposed to the strategy used in tivantinib. Seven hundred and seven patients were enrolled and randomized in a 2:1 fashion. Patients had a histologically confirmed diagnosis of HCC, Child-Pugh A liver function, ECOG performance status of 0 to 1, and adequate organ function. Patients received cabozantinib at 60 mg orally daily. Cabozantinib was associated with a median OS of 10.2 months compared with a median OS of 8 months with placebo (HR, 0.76; 95% CI, 0.63–0.92; P = .005). Median PFS, which was the secondary end point, was superior for cabozantinib over placebo, 5.2 vs 1.9 months (HR, 0.44; 95% CI, 0.36–0.52; P < .001). Subgroup analysis showed favorable outcomes with cabozantinib across various etiologic and demographic factors. In the subgroup of patients who received sorafenib as the only prior systemic therapy, median OS was 11.3 months with cabozantinib and 7.2 months with placebo (HR, 0.70; 95% CI, 0.55–0.88). Most common clinically relevant grade 3 or 4 adverse events observed on the cabozantinib arm included palmar-plantar erythrodysesthesia (17%), hypertension (16%), fatigue (10%), and diarrhea (10%).
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