By Emily Benesh, Ph.D., Analyst, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Vice President, Clinical & Scientific Assessment, Kantar Health
It is an exciting time for patients and their doctors fighting advanced hepatocellular carcinoma (HCC). In mid-2016 the HCC community witnessed the first randomized trial to successfully improve survival outcomes in Nexavar® (sorafenib, Onyx/Amgen/Bayer)-pretreated HCC when the multikinase inhibitor Stivarga® (regorafenib, Bayer) demonstrated a 38% reduction in the risk of death compared with placebo in the Phase III RESOURCE trial.1 This led to submission of a supplemental new drug application with the U.S. Food and Drug Administration (FDA) in November 2016. Additionally, Opdivo® (nivolumab, BMS/Ono Pharmaceuticals) is showing very promising activity as treatment of advanced HCC, and the excitement around these results was palpable at the 2017 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in San Francisco.
Historically, the unmet needs in HCC have been insurmountable. Even with the best therapeutic options available, the prognosis for advanced HCC has been quite poor; first-line patients receiving the standard of care, Nexavar, have a median overall survival of 10.7 months. In 2007, Nexavar, a multityrosine kinase inhibitor, was established as the first targeted agent FDA-approved in this indication. It achieved this by besting a placebo control with a 2.8-month improvement in overall survival,2 although patients did not experience improvements in time to symptomatic progression or complete responses with use of this agent. Additionally, use of Nexavar came at a high price. In the SHARP trial, 80% of Nexavar-recipient patients experienced serious adverse events including diarrhea, hand-foot skin reaction and others.2
The last nine years have seen novel therapeutic contenders struggle to improve outcomes and unseat Nexavar as front-line therapy. This is due, in part, to liver dysfunction (cirrhosis) present in many HCC patients as well as other comorbidities resulting from infection with hepatitis B or hepatitis C, and/or occurrence of non-alcoholic fatty liver disease. In practice, systemic therapies such as Nexavar are limited to patients with the least degree of cirrhosis (Child-Pugh A). Those with greatly impaired liver function (Child-Pugh C) are often unable to tolerate current therapeutic options and generally receive only best supportive care. Even those with reasonable liver function may struggle to tolerate combination therapies that include Nexavar as a backbone.
Thus, a novel agent is greatly needed that makes strides in both efficacy and tolerability in order to encompass more patients in the treatable population. Such an agent would find an open market with a reasonable patient base; in 2016 HCC ranked as the 14th most commonly diagnosed cancer in the United States with an incidence of roughly 30,000 newly diagnosed patients.3 In Eastern countries the population suffering from HCC is slightly larger; it ranked ninth in Japan with nearly 36,000 new cases reported in 2016.3
Against this backdrop of high unmet need and reasonable opportunity, BMS/Ono entered the competitive landscape in 2012. Opdivo is a human immunoglobulin IgG4 monoclonal antibody that binds to the programmed cell death protein-1 (PD-1) receptor on immune cells, releasing tumor-driven inhibition of immune reactions. Results of Opdivo trials have shown incredible promise with overall survival gains and remarkably durable responses in multiple tumors, leading to its FDA approval in metastatic melanoma (alone or in combination with Yervoy® (ipilimumab, BMS/Ono)), metastatic non-small cell lung cancer, advanced renal cell carcinoma, classical Hodgkin’s lymphoma and squamous cell carcinoma of the head and neck.
The CheckMate-040 Phase I/II trial (NCT01658878) was initiated to evaluate the safety, tolerability, dose-limiting toxicities and maximum tolerated dose of Opdivo in 1) uninfected HCC subjects, 2) HCC patients with hepatitis B, and 3) HCC patients with hepatitis C. Patients had unresectable advanced HCC, with a Child Pugh score of ≤7 (dose escalation) or ≤6 (dose expansion). Patients could not have active HBV or HCV and were required to be on antiviral therapy with a viral load of <100 IU/mL. Subpopulations of patients were Nexavar-naïve and Nexavar-refractory.
The patient characteristics between the dose escalation and expansion cohorts were well balanced; both cohorts favored male subjects (75% and 80%, respectively) and were enriched for Asians (38% and 47%, respectively). Seventy-six percent of patients were systemic therapy-experienced, two-thirds of whom had received prior Nexavar. In October 2016, interim data were presented for 48 patients treated in the dose escalation cohort and 214 patients in the dose-expansion cohort,4 and Friday at the ASCO Gastrointestinal Cancers Symposium in San Francisco updated results were presented.5 As of the data cut-off (August 8, 2016), investigators had treated 262 patients across the dose escalation and expansion phases of the trial. Twenty-five percent of patients experienced Grade 3/4 or greater adverse events, including AST increase (10%), ALT increase (6%) and lipase increase (13%). While hematologic liver parameters are of particular concern to the HCC patient population, these were considered manageable and did not result in hepatitis. Health-related quality of life outcomes, as measured by EQ-5D index scores, did not show differences in first- or second-line patients and were stable from baseline to week 25. Thus, the relatively mild toxicity profile of Opdivo monotherapy in these pretreated HCC patients was encouraging.
In second-line Nexavar-experienced patients, 37 patients were evaluable in the escalation cohort and 145 were evaluable in the expansion cohort. Investigator assessed objective response rate (ORR) were 16.2% and 18.6% in the escalation and expansion phases, respectively, including complete response (CR) rates of 8.1% and 2.1%. Blinded independent central review noted lower rates of CR (2.7% and 0.7%, respectively), but the ORR was only slightly lower than that reported by investigators (18.9% and 14.5, respectively). The duration of response was 17.1 months in the dose escalation cohort and had not been reached in the dose expansion cohort. The median overall survival of the dose escalation cohort was 15.0 months; it was 13.2 months in the dose expansion cohort. At nine months’ follow-up, 67% and 71% of patients were alive in the escalation and expansion cohorts, respectively. In the escalation cohort, 46% of patients were alive at 18 months. In the dose expansion Nexavar-naïve cohort (69 patients), 21.7% had an objective response (all partial). Six- and nine-month overall survival rates were 87% and 77%, respectively. Expression of PD-L1 did not correlate with response to Opdivo in either patient population. Despite PD-L1 level appearing inconsequential to outcomes in this population, the discussant stated that detailed biomarker analyses (e.g., mutational burden, tumor-infiltrating lymphocytes or immune gene signatures) would further enrich the population for responders and improve survival rates even more.6
Results from the CheckMate-040 trial were very promising. Cross-trial comparisons of Opdivo and Nexavar suggest that Opdivo far outstrips efficacy numbers put up by Nexavar in previous trials (in the SHARP trial, ORR was 2% and median overall survival was 10.7 months2). Based on these encouraging results, BMS is pursuing several avenues to establish and expand the reach of Opdivo in this space. In November 2015, BMS initiated a randomized global Phase III head-to-head trial (CheckMate-459) of Opdivo versus Nexavar. The trial is recruiting treatment-naïve, Child-Pugh A advanced HCC patients in the United States, EU, Asia and Australia. According to the presenter, patient recruitment for CheckMate-459 is almost finished. In addition, BMS is exploring Opdivo use as a monotherapy and in combination with Yervoy or other novel agents in Phase I and II trials in various HCC treatment settings.
While the BMS/Ono developmental program has a head start, they are not alone in pursuing opportunities in the HCC space. Merck also has a strong program for Keytruda® (pembrolizumab, Merck & Co.). An ongoing Phase III trial (Keynote-240, NCT02702401) is investigating Keytruda versus best supportive care in relapsed/refractory HCC. An ongoing randomized Phase II trial is pitting the PD-1 inhibitor durvalumab (AstraZeneca) monotherapy versus the CTLA4 inhibitor tremelimumab (AstraZeneca) monotherapy versus the durvalumab/tremelimumab combination in Nexavar-refractory patients (NCT02519348). Another agent in development is Pexa-Vec® (pexastimogene devacirepvec, SillaJen), an oncolytic virus that also delivers GM-CSF to tumor cells. Pexa-Vec is being paired with Nexavar versus Nexavar monotherapy as first-line therapy in Child-Pugh A advanced HCC in a Phase III trial (NCT02562755). Beyond immunotherapy approaches, other targeted therapy agents are in late-stage development in HCC: Stivarga has been filed for FDA approval in second-line HCC based on the positive RESOURCE trial results, and Phase III trials are ongoing for Cabometyx® (cabozantinib, Exelixis/Ipsen), Cyramza® (ramucirumab, Eli Lilly), and tivantinib (ArQule) in second-line, and Lenvima® (lenvatinib, Eisai) in first-line.
Thus, a host of agents are seeking entry into a space that promises to become increasingly crowded in the near future. It remains to be seen whether final results from the dose expansion cohort of CheckMate-040 might prompt an accelerated approval approach, or whether BMS will wait to file until CheckMate-459 data report. Nonetheless, the data that are unfolding continue to support a potential future scenario in which Opdivo emerges triumphant as a new leader in HCC management, potentially unseating Nexavar in the front-line and bringing a more effective and tolerable treatment to a very ill patient population greatly in need of some hope.