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CELESTIAL: Divining the role of cabozantinib in HCC

by Stephanie Hawthorne | Jan 25, 2018

Co-authored by Len Kusdra, Ph.D.

Patients with hepatocellular carcinoma (HCC) face one of the deadliest malignancies, which is associated with a very poor prognosis and limited treatment options. The first (and arguably only) major advance for advanced disease came in 2007 when Nexavar® (sorafenib, Onyx/Bayer) was approved for the first-line treatment of advanced/metastatic HCC based on the results from Llovet and colleagues who showed an approximate 2-month improvement in overall survival (OS) for Nexavar compared to placebo1.  Since its approval, Nexavar has become standard of care in first-line advanced / metastatic HCC. Indeed, about 60% of patients in the United States receive Nexavar alone or in combination with doxorubicin as their first-line treatment2. For patients who relapse on Nexavar, treatment options were few, with standard chemotherapy or best supportive care being the only recourse for this population. Adding to the grim scenario of HCC, there has been a dearth of significant clinical development and successes in the treatment of HCC since the approval of Nexavar. This trend began to change with the recent U.S. FDA approval of Stivarga® (regorafenib, Bayer) in April 2017 for patients who had been previously treated with Nexavar. Approval of Stivarga was based data from the Phase III RESORCE trial showing a median OS of 10.6 months for Stivarga versus 7.8 months for placebo3. The rapid uptake of Stivarga in the second-line setting (utilized in about 40% of patients within just a few months of approval)2 underscores the high unmet need for effective therapies in this disease. Checkpoint inhibitors have also begun to make landfall in the HCC landscape with the U.S. FDA approval of Opdivo® (nivolumab, BMS/Ono) in September 2017 as second-line therapy following Nexavar treatment based on the promising response rate (20%), disease control rate (64%), and 9-month overall survival rate (28%) observed in the Phase 1/2 CheckMate-040 trial (NCT01658878)4.

CELESTIAL (NCT01908426) will add cabozantinib (Exelixis; marketed as Cometriq® for medullary thyroid cancer and CabometyxTM for renal cell carcinoma) to the armamentarium in the treatment of HCC, and results were presented at the 2018 Gastrointestinal Cancers Symposium of the American Society of Clinical Oncology5. CELESTIAL is a double-blind, placebo controlled Phase III trial evaluating cabozantinib versus placebo in patients with HCC who had prior Nexavar treatment and had received up to two prior lines of systemic therapy. Patients (n=760) were randomized 2:1 to receive either cabozantinib at 60mg orally once daily (n=470) or placebo (n=237) until lack of clinical benefit or toxicity, with no cross over allowed in the trial. In the cabozantinib arm, 68% had Grade 3-4 adverse events while 36% of patients in the placebo arm had a Grade 3-4 adverse event. The most common adverse events in the cabozantinib arm were hand-foot syndrome (17%), hypertension (16%), increase in aspartate aminotransferase (12%), fatigue (10%), and diarrhea (10%). Six patients who received cabozantinib had Grade 5 treatment-related events; the causes of these deaths were hepatic failure, esophagobronchial fistula, portal vein thrombosis, upper gastrointestinal hemorrhage, pulmonary embolism, and hepatorenal syndrome; one death occurred in the placebo arm from hepatic failure. The trial met the primary endpoint of improvement in OS with cabozantinib compared to placebo (10.2 months for cabozantinib vs. 8.0 months for placebo; HR=0.76, p=0.0049). Progression-free survival (PFS) was also improved in patients treated with cabozantinib versus placebo (5.2 months vs. 1.9 months; HR=0.44, p<0.0001). Objective responses were rare, but did occur more frequently in cabozantinib-treated patients (4% vs. 0.4%, p=0.0086); disease control rate was also improved with cabozantinib (64% versus 33%).

Data from the CELESTIAL trial will support regulatory approval of cabozantinib in the treatment of Nexavar-pretreated HCC. However, the role this agent will play in the treatment algorithm is unclear. Being a tyrosine kinase inhibitor, cabozantinib will compete directly with Stivarga in this space. An examination of the efficacy benefits between RESORCE and CELESTIAL (with an understanding of the caveats underscoring cross-trial comparisons) shows very similar efficacy benefits between these agents - OS being around 10 months and an approximate 30% reduction in the risk of death, both compared to placebo. The adverse event profiles also appear similar between Stivarga and cabozantinib, apart from diarrhea and hand-foot syndrome which occurred at very slightly higher rates with cabozantinib (which arguably may not truly be differentiating). Having similar mechanisms of action, efficacy benefits, and toxicity profile puts cabozantinib at a disadvantage given the existing entrenchment of Stivarga in the second-line setting. Both of these agents will face significant competition from checkpoint inhibitors — Opdivo is already posing a competitive threat, and Keytruda® (pembrolizumab, Merck/MSD) may soon enter the fray if it gains accelerated FDA approval based on results from its Phase II KEYNOTE-224 trial (NCT02702414), which showed a promising response rate of 17% and a disease control rate of 64%6.

The fate of both Stivarga and cabozantinib will also hinge on changes in the first-line setting. There are several near-term competitors that are seeking to displace Nexavar as the first-line standard of care. Lenvima® (lenvatinib, Eisai) was recently shown to have non-inferior OS (primary endpoint) as well as improved response rate compared to Nexavar in the Phase III REFLECT study (NCT01761266)7; In addition, Lenvima may arguably have a better toxicity profile, particularly in the rates of hand-foot syndrome. Based on the results from REFLECT, the company has filed for regulatory approval of Lenvima with global authorities in the U.S., Europe, and Japan for use in first-line HCC8. Opdivo, Pexa-vec (pexastimogene devacirepvec, SillaJen/Transgene), and Imfinzi® (durvalumab, AstraZeneca) with or without tremelimumab (AstraZeneca) are also being evaluated in the first-line setting. If Nexavar is replaced as the first-line choice for patients with HCC, this may delay the use of newer agents whose regulatory labels restrict their use to Nexavar-pretreated patients (Stivarga and potentially cabozantinib).  This will further pose a risk for cabozantinib as subgroup analysis of CELESTIAL showed that patients derived greater benefit with cabozantinib if they were being treated after one prior line of therapy as opposed to after two prior lines (HR for OS: 0.74 versus 0.90, respectively). Additionally, if the label follows the inclusion criteria of CELESTIAL (patients with a maximum of two prior lines of therapy) cabozantinib’s utilization would be further curtailed if pushed past second-line.

Despite these concerns, it is heartening to see another agent entering a disease that has suffered from a lack of extensive clinical development, providing new options and hope for patients with HCC.

 

1 Llovet JM, Ricci MD, Mazzaferro V, et al. Sorafenib in Advanced Hepatocellular Carcinoma. N Eng J Med. 359: 378-390, 2008.

2 Kantar Health, CancerMPact® Treatment Architecture U.S., accessed January 2018.

3 Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 389: 55-66, 2017.

4 El-Khoueiry AB, Sangro B, Yau, T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 389: 2492-2502, 2017.

5 Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib versus placebo in patients with advanced hepatocellular carcinoma who have received prior sorafenib: results from the randomized phase 3 CELESTIAL trial. Abstract 207, Gastrointestinal Cancers Symposium Meeting, January 2018.

6 Zhu AX, Finn RS, Cattan S, et al. KEYNOTE-224: Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. Abstract 209, Gastrointestinal Cancers Symposium Meeting, January 2018.  

7 Cheng A-L, Finn RS, Qin S, et al. Phase III trial of lenvatinib (LEN) vs sorafenib (SOR) in first-line treatment of patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 2017;35 (suppl; abstr 4001).

8 Eisai, press release, July 25, 2017

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