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INTRODUCTION

Hepatocellular carcinoma (HCC) is a considerable worldwide medical problem: it is the sixth most common cancer diagnosis and the third most common cause of cancer mortality.¹ In the United States (U.S.), HCC is less common than it is worldwide, but it remains 1 of the 10 most common causes of cancer-related death.² Localized or limited HCC is preferentially treated by resection, liver transplant, local therapies (i.e., radiofrequency ablation [RFA] or percutaneous ethanol injection), or chemoembolization. Advanced or metastatic disease requires systemic therapies. Prior to the introduction of tyrosine kinase inhibitors (TKIs) for HCC, no systemic therapy demonstrated survival advantage over placebo.¹ With the advent of the TKIs, however, the landscape of HCC therapy changed and now offers improved overall survival (OS).

All TKIs currently used for the treatment of HCC are oral agents that are taken by the patient chronically; therapy should continue until progressive disease is documented or unacceptable toxicities occur.^3-6 Although each agent's exact targets are different, many agents target similar pathways that are necessary for cancer cell survival and proliferation. Cell surface receptor kinases that are responsive to extracellular stimulation and represent effective targets for HCC treatment include vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), KIT (also known as CD17), and fibroblast growth factor receptor (FGFR).⁷ Intracellular signaling pathways that are inhibited include rapidly accelerated fibrosarcoma (RAF) of the MAP kinase pathway and the phosphoinositide 3-kinase pathway.

Patient case: EI is a 62-year-old man with a history of chronic hepatitis C. In 2007, he was treated with peg-interferon and ribavirin but discontinued therapy at month 3 due to toxicities. He now presents with advanced HCC with hepatic vascular invasion and 5 discrete lesions ranging from 3 to 7 cm in maximum diameter. He has preserved liver function at this point. You are the pharmacist on the HCC multidisciplinary team. The team asks you to discuss current first-line systemic therapies for advanced HCC.

FIRST-LINE SYSTEMIC THERAPIES

Currently, 2 TKIs are available for first-line treatment of HCC. They each require special considerations of dosing, adverse events and toxicities, and characteristics that influence patient adherence, compliance, and persistence.

Sorafenib

Sorafenib was one of the first TKIs to enter clinical practice for any oncology indication. This drug paved the way for a host of additional oral agents now used in cancer treatment. The "raf" portion of its name refers to its interaction with RAF of the MAP kinase pathway. Sorafenib also interacts with several other targets including VEGF, PDGF, FMS-like tyrosine kinase 3 (FLT-3), and rearranged during transfection (RET) proto-oncogene/papillary histotype carcinoma (PTC).⁴ The standard dosage of this agent is 400 mg orally twice daily. It should be taken on an empty stomach. The bioavailability is slightly less than 50%, ranging from 38% to 49%, and, if taken with a fatty meal, its absorption decreases by nearly 30%.⁴

Sorafenib was initially approved by the U.S. Food and Drug Administration (FDA) for renal cell carcinoma in 2005 and was approved for HCC in 2007. Predetermined dose decreases may be implemented if toxicities occur: initially, decrease the dose to 400 mg daily and then to 400 mg every other day if significant toxicities continue.⁴

The Sorafenib in Advanced Hepatocellular Carcinoma (SHARP) trial was pivotal within the field of oncology. Prior to the introduction of TKIs in HCC, chemotherapy was the mainstay for advanced and metastatic disease. Even after many clinical trials and decades of use, systemic chemotherapy did not demonstrate a benefit in OS for HCC. With chemotherapy, OS is driven by response rates, including partial responses (PRs) and complete responses (CRs), and the overall response rates (ORRs) for chemotherapy are a dismal 6.8%.⁸

SHARP was a large, phase 3, double-blind, randomized, international trial comparing sorafenib to placebo. The SHARP trial taught the oncology community that OS advantages could be appreciated by using TKIs, without the need for CRs and PRs. Patients enrolled in SHARP had advanced HCC and were not candidates for surgery, transplantation, or any type of local therapy. Other inclusion criteria were adequate hepatic function (Child-Pugh A classification) and good performance status (Eastern Cooperative Oncology Group [ECOG] score 0-1). The SHARP trial was conducted in North America, Europe, South America, and Australia. Nearly one-third (29%) of patients had hepatitis C and less than one-fifth (19%) had hepatitis B. For roughly one-quarter (26%) of patients, alcohol was the only cause of disease.⁹

This trial randomized 602 patients in a 1:1 ratio to receive sorafenib 400 mg twice daily or placebo. OS was 7.9 months in the placebo group and 10.7 months in the sorafenib group (hazard ratio [HR] = 0.69, p < 0.001). Time to radiographic progression was also significantly longer in the sorafenib group (5.5 months vs. 2.8 months, p < 0.001). The disease control rate (DCR), which included CRs, PRs, and stabilization of disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST), was 42% in the sorafenib group and 32% in the placebo group (p = 0.002). This represents a clinically and statistically significant improvement in DCR.⁹

Although HCC occurs in the U.S. and Western countries, it is much more prevalent and much more deadly in Eastern countries because of the increased prevalence of hepatitis B in Eastern regions. Globally, HCC poses a tremendous health burden as a leading cause of cancer-related mortality, but more than 75% of HCC cases occur in the Asia-Pacific region, with hepatitis B infection being the main causative factor. Therefore, the Asia-Pacific trial comprised an Eastern population, including patients from China, Taiwan, and South Korea. This phase 3 trial, which essentially duplicated the SHARP trial, randomized 226 patients (2:1) to receive sorafenib 400 mg twice daily or placebo.¹⁰

One notable difference from the SHARP trial was that the majority of the patients in the Asia-Pacific trial had hepatitis B, not hepatitis C. In the Asia-Pacific trial, 11% of patients had hepatitis C at baseline and 71% had hepatitis B. Similar statistically and clinically significant OS advantages were achieved with sorafenib in this patient population. The sorafenib group achieved an OS of 6.5 months and the placebo group achieved 4.2 months (HR = 0.68, p < 0.014). The Asia-Pacific trial also reported improvements in DCR of 35% and 16% in the sorafenib and placebo groups, respectively (p = 0.0019). This trial also demonstrated that CRs and PRs were not needed to realize OS advantages in advanced HCC.¹⁰

The HRs for the SHARP and Asia-Pacific trials were similar. This demonstrates that, regardless of the patient population, sorafenib was associated with an incremental and equal improvement in survival outcomes. However, the OS in the 2 trials differed by several months. The investigators noted that the patients in the Asia-Pacific trial had more extrahepatic spread and more disease at baseline than patients in the SHARP trial. Patients' baseline alpha-fetoprotein (AFP) levels, which is a marker used to measure HCC tumor burden, were increased compared to patients in the SHARP trial, and, in general, patients in the Asia-Pacific trial had more liver lesions.^9,10

Sorafenib was well-tolerated in both trials. In the SHARP trial, there was an approximate 38% discontinuation rate of the drug. Discontinuation was due to a variety of reasons, such as gastrointestinal (GI) events (6%), fatigue (5%), and liver dysfunction (5%). Approximately 26% of patients needed a dose reduction at some point during their treatments due to diarrhea, hand-foot syndrome, and skin-related toxicities. The median duration the patients were able to stay on therapy in the treatment arm was 5.3 months, with a range of 0.2 to 16 months. Three-quarters of patients were able to maintain at least 80% drug intensity throughout their therapies. The overall incidence of treatment-related adverse events in the SHARP trial was 80%. Diarrhea (39%), fatigue (22%), and hand-foot skin reactions (HFSR) (21%) topped the list of frequent toxicities associated with sorafenib.⁹ In the Asia-Pacific trial, 81.9% of patients in the sorafenib group had drug-related adverse events of any grade. These varied in frequency from the SHARP trial and included HFSR (45%), diarrhea (25.5%), alopecia (24.8%), fatigue (20.0%), rash or desquamation (20.1%), hypertension (18.8%), and anorexia (12.8%).¹⁰

One of the mechanisms of sorafenib, VEGF inhibition, is known to decrease wound healing. If patients are undergoing a major surgical procedure or are scheduled to receive a localized therapy, such as RFA or trans-arterial chemotherapy embolization (TACE) for HCC, sorafenib should be held around the time of the procedure. A common recommendation is to hold sorafenib for at least 7 days before the surgical procedure and then restart it once wound healing has begun.⁴

Most TKIs are metabolized by the cytochrome P450 (CYP) pathways, specifically CYP isozyme 3A4. Sorafenib, for example, is a substrate of CYP3A4.⁴ Therefore, consideration of concomitantly administered CYP3A4 inducers and inhibitors is key to optimizing a patient's drug therapies while on sorafenib.

Temporary or permanent discontinuation of sorafenib should be considered for certain situations. Any type of myocardial infarction (MI) or cardiac ischemia, serious hemorrhage or bleed (e.g., GI bleed, GI perforation, intracranial bleed), or persistent, uncontrolled hypertension that occurs with the initiation of sorafenib would be a reason to discontinue therapy. QT prolongation is relatively rare, but it has been demonstrated to cause significant issues if a patient's QTc interval is greater than 500 ms. In this situation, sorafenib should be held. Grade 3 or 4 drug-induced liver injury also warrants drug discontinuation. Grade 3 laboratory abnormalities include transaminase elevations greater than 5 and up to 20 times the upper limit of normal.¹¹ Elevated transaminase levels more than 20 times the upper limit of normal or transaminase elevations with significant clinical sequelae (e.g., elevated international normalized ratio [INR], ascites, transplantation) are considered grade 4 toxicities.⁴

Table 1^3-6 lists proposed monitoring criteria for patients taking sorafenib. The monitoring plan includes regular assessment of complete blood counts (CBCs), electrolytes, liver function tests (LFTs), amylase and lipase, and thyroid stimulating hormone (TSH). Other laboratory parameters are patient specific, such as monitoring the QTc interval in patients with baseline cardiac issues or other risk factors for cardiac toxicities. If a patient is receiving an antiarrhythmic or has baseline arrhythmias, an electrocardiogram should be obtained at baseline and repeated in 3 to 7 days once the drug is near steady-state concentration. Of course, such monitoring is dependent on the clinical situation. At each patient encounter, a thorough review of possible toxicities should occur, with a focus on diarrhea, fatigue, and HFSR. Note that fatigue could be due to drug-induced hypothyroidism. Increased blood pressure associated with sorafenib is primarily a function of the VEGF mechanism of action. At a minimum, blood pressure should be checked at each visit. However, daily home monitoring is encouraged in patients with hypertension prior to starting sorafenib. Pharmacists should consider a patient's medication compliance and persistence when noting toxicities and symptoms.⁴

Sorafenib and TACE

TACE is a procedure that is generally performed in patients who have regional or widespread disease in the liver and who are not candidates for surgery or other curative maneuvers. TACE is a procedure in which an embolizing agent is injected into a select portion of the hepatic artery followed by administration of chemotherapy. Alternatively, drug-eluting beads (DEB-TACE) can be delivered into the hepatic artery to a site near the tumor(s), thus cutting off blood supply to the tumor. Many phase 2 trials have investigated the benefits of sorafenib before, during, and after TACE procedures. The largest study was a retrospective review of 222 patients who received sorafenib in combination with TACE.¹² The DCRs from phase 2 trials, which included standard TACE or DEB-TACE, ranged from 70% to 95%, indicating that sorafenib provides some benefit in this patient population.^12-16 One retrospective evaluation compared TACE plus sorafenib versus TACE alone. This study included 46 patients in the TACE + sorafenib group and 45 in the TACE alone group. The results from this trial were published in 2014 and demonstrated a DCR of approximately 57% in the TACE + sorafenib group and 13% in the TACE alone group. The OS was 11 months in the TACE + sorafenib group and 6 months in the TACE alone group.¹⁷ Consequently, sorafenib is now used during and following TACE to prolong the benefits of the procedure.

Lenvatinib

Lenvatinib is an oral TKI that is FDA approved for renal cell carcinoma and thyroid cancer.⁵ The mechanism of action of lenvatinib includes interactions with multiple targets, including VEGF, PDGF, FGF, KIT, and RET. RAF is not a target, which has implications for lenvatinib's toxicity profile. First-line lenvatinib was compared to sorafenib in HCC in the phase 3 Lenvatinib versus Sorafenib in First-line Treatment of Patients with Unresectable Hepatocellular Carcinoma (REFLECT) trial. In REFLECT, lenvatinib was administered according to weight-based dosing: patients who weighed less than 60 kg received 8 mg daily, and those who weighed 60 kg or more received 12 mg daily. Dose reductions in the trial included decreases to 8 mg (from 12 mg) daily, 4 mg (from 8 mg) daily, or 4 mg every other day (from 4 mg daily). Lenvatinib could be taken with or without food. Additionally, it was dissolved in liquid for patients who had difficulty swallowing pills.¹⁸

The REFLECT trial demonstrated lenvatinib's efficacy in advanced HCC. This was a head-to-head trial with sorafenib, randomizing 954 patients in a 1:1 ratio. The inclusion criteria were similar to those of the SHARP and Asia-Pacific trials: advanced disease, Child-Pugh A liver disease, and no prior therapies. This trial was intended to be a non-inferiority trial. OS was 13.6 months in the lenvatinib group and 12.3 months in the sorafenib group (HR = 0.92). The ORR was 24.1% in the lenvatinib group and 9.2% in the sorafenib group (p < 0.0001). The REFLECT trial concluded that lenvatinib was not inferior to sorafenib in terms of OS.¹⁸ Therefore, lenvatinib was recognized as another first-line systemic therapy option for advanced HCC.

The toxicity profile of lenvatinib has notable similarities and differences to that of sorafenib. Specifically, in clinical trials, lenvatinib had a lower incidence of diarrhea than sorafenib (39% vs. 46%), but sorafenib caused less fatigue than lenvatinib (25% vs. 30%). RAF inhibition, which is believed to be a primary driver of HFSR, is not a mechanism of lenvatinib. Consequently, HFSR occurred less with lenvatinib than with sorafenib (27% vs. 52%). Hypertension (both all-grade and grade 3/4) occurred at a higher rate with lenvatinib (all-grade, 47% vs. 30%; grade 3/4, 23% vs. 14%). These toxicities should be considered when making therapeutic selections for patients.^9,18

Monitoring of lenvatinib therapy is similar to that for sorafenib. A CBC with differential should be obtained initially, at 2 weeks, monthly for 4 months, and then every 3 to 4 months as patients continue therapy. Blood chemistry, particularly creatinine and calcium, should be assessed monthly. Lenvatinib mechanisms include a VEGF component, so monitoring for proteinuria is warranted. As with sorafenib, routine monitoring of TSH or thyroid function tests and LFTs is critical for patients receiving lenvatinib.^4,5

Patient case: You shared data with the HCC multidisciplinary team about sorafenib and lenvatinib, including proper dosing, survival data, and an overview of the toxicities. The team decides to start EI on sorafenib 400 mg orally twice daily. He is scheduled to meet with you to receive education on sorafenib, such as proper administration, a review of toxicities, and management strategies. What important points should be discussed with EI?

Lessons learned from negative trials in the first-line setting

The Adjuvant Sorafenib for Hepatocellular Carcinoma After Resection or Ablation (STORM) trial was a phase 3, randomized, placebo-controlled study that focused on the use of adjuvant sorafenib following surgical resection or local ablation (RFA or percutaneous ethanol injections). Patients included in STORM had already received therapy that was believed to be definitive and curative with a documented radiological CR. In all, 1114 patients were randomized (1:1) to receive sorafenib 400 mg twice daily or placebo for 4 years. The addition of sorafenib did not increase recurrence-free survival (RFS), but it did increase the overall adverse event rate (94% with sorafenib vs. 46% with placebo). Because of these conclusions, sorafenib should not be used as adjuvant therapy following definitive surgery or local ablation.¹⁹

Sorafenib with erlotinib has been compared to sorafenib alone in advanced HCC. A phase 3 trial published in 2015 enrolled 720 patients with either metastatic or locally advanced HCC who had not received any prior systemic therapy.²⁰ Patients were randomized to receive standard sorafenib 400 mg twice daily or sorafenib 400 mg twice daily with a standard dose of erlotinib 150 mg orally once daily. There was a slight trend toward an OS advantage with the combination therapy (9.5 vs. 8.5 months, p = 0.408), but this difference was not statistically significant. DCR was similar for the 2 groups (52.5% for sorafenib and 43.9% for combination therapy; p = 0.021). Although this difference was statistically significant, it was not clinically significant. Serious drug-related adverse events were similar between the groups. The final conclusion was that the combination of sorafenib and erlotinib did not improve survival and it is, therefore, not used in standard practice.

Linifanib is a TKI that inhibits all VEGF and PDGF receptors. This drug has shown successes in phase 2 trials. One phase 3 trial enrolled 1035 patients and randomized them in a 1:1 ratio to receive sorafenib or linifanib.²¹ The design of the trial included predefined superiority and non-inferiority outcomes. The objectives were not met for this trial. Median OS was 9.1 months in the linifanib group (95% confidence interval [CI], 8.1 to 10.2 months) and 9.8 months in the sorafenib group (95% CI, 8.3 to 11.0 months; HR = 1.046, 95% CI, 0.896 to 1.221 months). Median time to progression was 5.4 months in the linifanib group (95% CI, 4.2 to 5.6 months) and 4.0 months in the sorafenib group (95% CI, 2.8 to 4.2 months; HR = 0.759, 95% CI, 0.643 to 0.895 months; P = 0.001). Ultimately, this trial failed to meet its primary objective and this drug has not been approved by the FDA for an HCC indication.

Patient case: EI continues on sorafenib for 11 months. He had ongoing toxicities of HFSR and gradually increasing blood pressures. At 11 months, a computed tomography scan reveals progressive disease of his hepatic lesions. Again, the HCC multidisciplinary team looks to you for drug therapy recommendations for second-line systemic therapy.

SECOND-LINE AND LATER SYSTEMIC THERAPIES

When first-line therapy fails to achieve a curative response, TKIs can be considered for second-line and later therapy. Several clinical trials have focused on TKIs in this setting, and, as with first-line therapy, TKIs should be selected by considering potential benefits, possible toxicities, and patient-specific factors.

Regorafenib

Regorafenib was the first TKI to receive an indication for second-line therapy for advanced HCC. Like sorafenib, its name gives a clue regarding its mechanism of action: RAF inhibition. However, regorafenib also interacts with several other cellular surface kinases, including VEGF, PDGF, KIT, and FGFR. The target dose for regorafenib in HCC is 160 mg orally daily for 21 days followed by 7 days of no regorafenib for a 28-day cycle. This drug must be taken after a low-fat meal. If dose decreases are needed for toxicities, regorafenib is available in a 40-mg tablet and decreasing the dose in 40-mg increments is recommended. The lowest recommended dose is 80 mg daily.³

The clinical trial that introduced regorafenib into the armamentarium for HCC was a double-blind, international, phase 3 trial called the Regorafenib for Patients with Hepatocellular Carcinoma Who Progressed on Sorafenib Treatment (RESORCE) trial.²² All enrolled patients experienced disease progression during first-line therapy with sorafenib. All patients were classified as Child-Pugh class A, indicating good liver function. This study included 573 patients with advanced HCC who were randomized (2:1) to the treatment arm (regorafenib 160 mg orally daily for 21 days out of a 28-day cycle) or the comparator arm. When the trial began, there was no standard of care for second-line therapy, so placebo as second-line treatment for HCC was the comparator. With regorafenib, OS improved by approximately 2.5 months: the OS was 10.6 months in the regorafenib group and 7.8 months in the placebo group (p < 0.001). Progression-free survival (PFS) doubled with treatment: 3.1 months in the regorafenib group compared to 1.5 months in the placebo group (p < 0.0001). The DCR nearly doubled in the regorafenib group, as well (65% vs. 35%, p < 0.001). These are both statistically and clinically significant improvements.

During the RESORCE trial, approximately 15% of patients discontinued the drug because of toxicity. Additionally, 54% of patients had their doses interrupted, held, or reduced.²² The median time the patients remained on therapy was just over 3.5 months, with a range of 1.6 to 7.6 months in the regorafenib group. The median dose of regorafenib in the trial was 144 mg; the goal was 160 mg, so reasonable dose intensity was demonstrated.²²

All patients (100%) in the regorafenib group of RESORCE reported at least 1 type of adverse event. Some of the most common issues with this agent were HFSR (52%), diarrhea (33%), fatigue (29%), and hypertension (23%).²² Regorafenib is associated with serious side effects that include cardiac infarction and ischemia and severe uncontrolled hypertension. Hepatotoxicity is a considerable concern with regorafenib, and its labeling contains a black-box warning of this risk.³ Fatal hepatotoxicity occurred in up to 1.6% of patients in clinical trials of regorafenib, which warrants aggressive monitoring of LFTs. Specifically, LFTs need to be checked at baseline and then every 2 weeks for 4 times and then monthly. Chemistries and electrolytes should also be checked, particularly to assess the risk of cardiac toxicities, at least monthly for the first 4 months and then every 3 to 4 months.³

Table 1^3-6 offers additional recommendations for monitoring patients receiving regorafenib. Anemia (16%), thrombocytopenia (10%), and, rarely, neutropenia (< 10 %) can occur, so a CBC with differential along with chemistries is an important part of patient monitoring.²² Although there is not a specific drug-drug interaction with warfarin, regorafenib impacts wound healing and increased incidents of serious bleeds have been documented. Ensuring that INRs are closely monitored, maintaining INRs in the therapeutic range, and targeted interviewing of patients about bleeding issues are critical for patients at risk of bleeding, because serious events can occur quickly. Blood pressure monitoring should occur weekly for the first 6 weeks, and then with each visit. In patients with baseline hypertension, a more aggressive monitoring program is warranted and at-home blood pressure monitoring may be considered.

Many drug-food interactions must be considered when optimizing regorafenib therapy. Taking regorafenib with fatty foods greatly increases its plasma concentration and can, therefore, increase the occurrence of toxicities. For example, in one study, a high-fat meal (945 calories and 54.6 grams of fat) increased the exposure of regorafenib by 48%. As a patient starts regorafenib therapy, it is important to have a detailed discussion about eating low-fat meals, which are defined as meals containing fewer than 600 calories and less than 30% fat.³ Regorafenib is taken once daily; therefore, the low-fat meal should be eaten around the time of day when the patient plans to take the dose. When helping a patient decide when to take the dose, consider what he or she likes to eat at each meal. A sample low-fat breakfast would include 4 ounces of 1% low fat cottage cheese; 1 English muffin; fat-free butter, jam, or preserves; and apple juice. A sample lunch may be 2 slices of turkey breast lunch meat with 2 slices of white bread, real mayonnaise, lettuce and tomato, a large apple, and 8 ounces of cranberry juice. Consider the implications that these food recommendations may have for patients as they take their medications, and work with them to find how drug administration best fits into their normal days.

Other considerations with regorafenib, as with many TKIs, involve drug interactions through the CYP3A4 pathway. Therefore, concomitant administration of strong CYP3A4 inducers and inhibitors should be avoided. Regorafenib does have an anti-VEGF component to its mechanism, so decreased wound healing is a concern. If patients are undergoing surgery, regorafenib should be stopped at least 2 weeks before the surgery and then restarted on the basis of wound healing.³ If patients have a wound that seems not to be healing, regorafenib should not be restarted until healing and recovery are achieved.

Cabozantinib

Cabozantinib is FDA approved for indications outside of HCC, but it has been identified as an option following first-line therapy with sorafenib in HCC. Additionally, recent literature reports its use in second-and third-line settings for advanced HCC.²³ Cabozantinib is a multikinase inhibitor and interacts with VEGF, MET, RET, ROS1, AXL, KIT, and several other targets.⁶ Currently available data for cabozantinib in HCC focus on its use as second-line therapy. The Cabozantinib versus Placebo in Patients With Advanced Hepatocellular Carcinoma Who Have Received Prior Sorafenib (CELESTIAL) trial was a randomized, phase 3, placebo-controlled trial that randomized patients (2:1) to receive cabozantinib 60 mg orally daily or placebo. Patients must have received prior sorafenib, experienced progressive disease following at least 1 prior therapy, and be classified as having Child-Pugh A liver function. No crossover was allowed.²³

A total of 707 patients were enrolled in the CELESTIAL trial. The etiology of HCC was defined as hepatitis B in 38% of patients and hepatitis C in 22% of patients. OS was 2.2 months longer (10.2 vs. 8 months, p = 0.0049) with cabozantinib in the second-line setting, and PFS in the cabozantinib group was more than double that in the placebo group (5.2 months vs. 1.9 months; p < 0.0001). This additional PFS has a cumulative impact when sequenced after another TKI in the first-line setting.²³

The discontinuation rate of cabozantinib in CELESTIAL was fairly low (16%) compared to other agents. However, 62% of patients required dose reduction of cabozantinib, and the final median average daily dose in the trial was 35.8 mg. The primary conclusion from CELESTIAL was that cabozantinib significantly improves OS after prior therapy. Further, this agent demonstrated an acceptable safety profile. Low incidences of grade 3/4 toxicities were reported during the trial: palmar-plantar erythrodysesthesia (17%), hypertension (16%), aspartate aminotransferase increase (12%), fatigue (10%), and diarrhea (10%).²³

Axitinib

Axitinib is another TKI that has been studied as second-line therapy following anti-angiogenic therapy for HCC. Like cabozantinib, axitinib is FDA approved for indications other than HCC but was studied as second-line therapy in HCC. A phase 2, randomized trial concluded that axitinib did not improve OS compared to placebo in the patients enrolled. The estimated HR for OS was 0.907 (95% CI, 0.646 -1.274; 1-sided stratified P = 0.287) for axitinib plus best supportive care (n = 134) compared to placebo plus best supportive care (n = 68), and the median OS was 12.7 months (range, 10.2-14.9 months) for axitinib and 9.7 months (range, 5.9-11.8 months) for placebo. Despite these results, axitinib did not impact the treatment landscape for axitinib and this agent has not been approved for use in HCC.²⁴

In summary, sorafenib and lenvatinib are the TKIs available for first-line systemic therapy in HCC. The STORM trial demonstrated that the use of adjuvant sorafenib following surgical resection or local ablation did not improve RFS, and sorafenib is not currently recommended in this setting. Currently available data indicate a survival benefit associated with the use of sorafenib, or other TKIs, during and after arterial-directed therapies (i.e., TACE or DEB-TACE), but larger, phase 3 trial data are needed. Therapeutic options following first-line sorafenib therapy include regorafenib and cabozantinib. Trials comparing other viable second-and third-line options are needed.

Patient case: EI is started on regorafenib 160 mg orally daily on days 1 to 21 of a 28-day cycle. You discuss with him the dosing schedule and make a calendar of the first cycle for him. You discuss what administration time would work best for his schedule. EI decides that taking the regorafenib in the morning would work best for him. What advice will you give him about his diet, considering a morning administration time?

TOXICITY MANAGEMENT

Owing to their mechanisms of action, TKIs are associated with several notable adverse events and toxicities that require special attention. Pharmacists are well-positioned to ensure proper monitoring and treatment for such events and to educate patients about self-care that can optimize drug therapy and reduce the risks of adverse effects.

Dermatological toxicities

HFSR is a common adverse reaction associated with TKIs. (HFSR is also referred to as palmar-plantar erythrodysesthesia syndrome and hand-foot syndrome.) The incidence of HFSR is 21% to 57% with sorafenib,^9,18 27% with lenvatinib,¹⁸ 52% with regorafenib,²² and 42% with cabozantinib.⁶ According to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), a grade 1 reaction is defined as minimal skin changes or dermatitis (e.g., erythema, edema, or hyperkeratosis) without pain; a grade 2 event involves skin changes (e.g., peeling, blisters, bleeding, fissures, edema, or hyperkeratosis) with pain that limits instrumental activities of daily living; and a grade 3 event involves severe skin changes (as with grade 2) with pain that limits self-care activities of daily living; a grade 4 event is not defined.¹¹ Grade 3 and 4 HFSR is uncommon, with incidences ranging from 3% to 13% for TKIs.

Although hand-foot syndrome can be caused by some chemotherapy agents, such as capecitabine and prolonged infusions of fluorouracil and cytarabine, the syndrome experienced with TKIs is a somewhat different reaction. The similarities between TKI-induced HFSR and chemotherapy-induced hand-foot syndrome include redness, swelling, and pain.^25,26 The presence of hyperkeratosis, blisters, and skin fissures differentiates TKI-induced HFSR from other presentations of hand-foot syndrome. Individuals experience calluses particularly at sites of pressure, such as the fingers, the tips of fingers, and the heels where shoes may rub up against the feet.

Patients must be aware of the risk for HFSR and be educated about self-care to minimize or prevent this toxicity. Patients can take simple measures to avoid or mitigate hand-foot symptomatology. For example, patients should avoid hot showers and baths, which can worsen skin symptoms. Also, they should avoid clothes and shoes that cause friction. Specifically, patients should consider if their shoes or socks fit too tight and if repetitive motions with their hands in their day-to-day work activities may cause friction or irritation. Patients should also consider the perfumes that they use and chemicals to which they are exposed. Alcohol-based products such as lotions or gels may need to be omitted from their daily schedules because these may worsen skin dryness and irritation. Sunlight will also exacerbate skin irritation, and minimizing exposure to direct sunlight and using sunblock with a sun protection factor of at least 15 are advisable. Moisturizing is very important for keeping skin healthy and regular use of gentle moisturizers should be advised. Moisturizers should be applied gently and patients should avoid rubbing or massaging the moisturizer directly into affected parts of the hands and feet. It may be advisable to recommend a manicure and/or pedicure before TKI treatment starts in order to remove excess calluses that may worsen symptoms of HFSR. Additionally, a podiatrist referral may be warranted for preventative maintenance or treatment during the course of TKI therapy.²⁷

Treatment of HFSR primarily involves application of moisturizers. Topical keratolytics will help remove calluses and urea cream (10% to 40%) applied 3 times daily or ammonia lactate (5% to 10%) applied 2 times daily can be recommended.²⁶ If a patient is having significant pain and difficulty that is not relieved with these initial therapies, topical lidocaine and topical steroids (e.g., clobetasol) can be beneficial. The next tier of therapy for severe toxicities includes nonsteroidal anti-inflammatory drugs, opioids, and gabapentin.²⁶ Ultimately, dose reduction of the TKI may be warranted if HFSR is affecting quality of life.

Diarrhea

Diarrhea is another common toxicity associated with oral TKIs used across all indications. According to the CTCAE, grade 1 diarrhea is defined as an increase in stool frequency of less than 4 stools per day or an increase in ostomy output; grade 2 diarrhea is defined as an increase of 4 to 6 stools per day or moderate increase in ostomy output that limits instrumental activities of daily living; grade 3 diarrhea is defined as an increase of greater than or equal to 7 stools per day over baseline or severe increase in ostomy output that requires hospitalization and limits self-care activities of daily living, and grade 4 diarrhea is associated with life-threatening clinical consequences and urgent intervention is indicated.¹¹ Generally, diarrhea associated with TKIs is mild (grade 1 or 2).^3-6

Still, TKIs are usually administered daily and chronically, so diarrhea, even mild cases, can be an ongoing issue, which can greatly impact quality of life. Sometimes, patients will avoid situations because they are concerned about having an episode of diarrhea: patients may not participate in important life events or, even, everyday activities such as going to the park with grandchildren, attending church, or eating out with friends because they worry about having diarrhea. With these patients, education and supportive therapy with loperamide can help reduce the diarrhea. A 4-mg oral dose of loperamide after the first loose stool followed by a 2-mg dose after each loose stool is generally recommended.²⁸ However, doses of loperamide can be titrated to achieve a patient's baseline stool frequency. For example, a patient may need a daily dose of 4 mg to maintain regularity.

Encouraging adequate hydration is also paramount to managing diarrhea and avoiding dehydration. Use caution when recommending hydration for patients with renal dysfunction, congestive heart failure, and pulmonary issues so that fluid overload is avoided. Additionally, pharmacists can help patients determine if there are any aggravating factors for the diarrhea or frequent stools, such as alcohol, caffeine-containing foods and beverages, and greasy or spicy food, so that these may be avoided. Pharmacists should also ensure that patients are working to optimize their own medication use by maintaining medication persistence: the goal of TKI therapy is to control the disease for as long as possible.²⁸ Additional consideration should be given to patients who have more than 5 episodes of explosive, watery diarrhea. Infection must be ruled out, and other causes of diarrhea should be addressed and treated as much as possible.

Hypertension

Hypertension due to HCC drug therapy is primarily driven by the VEGF mechanism of many of the TKIs. In fact, some studies document that an increase in blood pressure during VEGF therapy correlates with improved clinical outcomes. Baseline blood pressures should be documented, and frequent follow-up during early therapy is recommended. Patients who have baseline hypertension require increased monitoring and attention. Treatment should be recommended for patients who experience hypertension (i.e., blood pressure of 130/80 mmHg or higher or a diastolic blood pressure that increases more 20 mmHg above baseline) during TKI therapy.^3-6

Several antihypertensive agents may be considered for the treatment of TKI-associated hypertension.^29,30 Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and beta-blockers have been studied in this setting.²⁹ Verapamil, diltiazem, and other calcium channel blockers are associated with CYP-mediated drug-drug interactions, so these agents may not be the best choice in patients who require new antihypertensive therapy during TKI therapy.

TKIs are associated with additional cardiac issues and toxicities. Cardiac ischemia and MI have been reported with both sorafenib (2.7%) and regorafenib (0.9%).^3,4 Though these toxicities occur with single-digit frequencies, they are reasons to stop TKI therapy if they occur. Hypertensive crisis has been reported in 0.2% of patients taking regorafenib, and monitoring for this toxicity is warranted.⁴ Rarely, TKIs cause decreased ejection fraction.^3-6

In summary, some of the most common chronic toxicities that necessitate continuous monitoring and management include diarrhea, HFSR, and hypertension. Although not every patient will experience these adverse events, every patient should be questioned about these symptoms at each visit. Even uncommon side effects associated with TKIs can greatly affect a patient's quality of life. Anorexia, nausea, and abdominal discomfort should be managed as clinically appropriate. Several rare, but serious, toxicities with TKIs also exist. Grade 3 or 4 drug-induced hepatic toxicity, hypertensive emergency, cardiac ischemia or MI, life-threatening hemorrhage, GI perforation, and QTc prolongation have been documented with TKIs used in HCC. A thorough monitoring plan includes screening for these concerning toxicities.

Patient case: One month into therapy with regorafenib, EI meets with you for medication therapy management. His blood pressure is 150/85 mmHg. (His baseline blood pressure was 125/62 mmHg.) He also complains of painful areas on the palms of his hands and heels. How are you going to help him?

ASSISTING PATIENTS WITH MEDICATION THERAPY

Medication adherence and compliance refer to how a patient is taking his or her medication on a day-to-day basis, such as using the appropriate dosing interval, taking it with or without food as necessary, and taking the correct number of tablets. Medication persistence refers to the duration of time a patient is able to stay on the therapy correctly. Pharmacists can play key roles in symptom management, therapy adherence, and therapy persistence for patients receiving TKI therapy.

To optimize medication therapy and help patients manage medication-associated challenges and barriers, always consider social, medical, non-medical, and financial factors affecting the patient. Together, these influence medication compliance and persistence.³¹ Other questions to answer with patients may include:

• What are the goals of therapy?
• Are the patient's goals of therapy consistent with the prescriber's goals of therapy?
• What is the emotional status of the patient?
• Are there other comorbid illnesses that need to be managed at this time?
• Are there drug-specific side effects that will pose particular issues for this specific patient?
• Are the drug costs or co-pays going to be an issue or is the patient concerned about payment?
• What is the patient's relationship with his or her oncology providers?
• Does the patient have appropriate access to medications and healthcare?
• Does the patient need assistance with transportation?

Additionally, pharmacists should consider what they can do to help patients.

• Can you encourage the patient to set alarms on his or her phone or other device as a reminder to take medication? Can you set the alarms for him or her?
• Can you help the patient get and organize a pillbox?
• Can you help the patient start a pill diary and a toxicity diary?
• Can you make an administration calendar for drugs that are not given every day, such as regorafenib?

CONCLUSION

With the use of oral TKIs in HCC, incremental increases in OS have been achieved. It is important to note that these survival benefits are only achieved when patients remain on medication therapy as long as is possible or tolerated. Understanding potential toxicities, monitoring requirements, and compassionate management will enable pharmacists to help patients optimize medication adherence and persistence. Focusing on the assessment and management of key chronic toxicities of HFSR, hypertension, and diarrhea will ensure that patients achieve optimized drug therapy. And, remembering rare but serious toxicities of TKIs that affect cardiac health, bleeding, decreased wound healing, and hepatic function are crucial. Sorafenib and lenvatinib offer effective systemic first-line therapy for patients with advanced HCC; regorafenib and cabozantinib offer options in the second-line setting. Although serious toxicities and concerns exist with TKI therapy, management of the most frequent toxicities that affect a patient's quality of life is possible.

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