The 53rd American Society of Clinical Oncology (ASCO) Annual Meeting held on June 2-6, 2017 in Chicago nicely shed light on how advanced hepatocellular carcinoma (HCC) could be treated in the not-so-distant future. For a decade, Bayer HealthCare’s Nexavar was the sole pharmacological treatment option for advanced disease, for which it prevailed as the first-line standard of care. While many pharmaceutical companies have attempted to penetrate the HCC market—either by challenging Nexavar in the first-line setting or by attempting to position their drug candidate for Nexavar-pretreated patients—all had failed. That was until April 2017, when the angiogenesis inhibitor Stivarga (also a Bayer HealthCare product) was approved by the FDA for HCC patients after prior treatment with Nexavar, based on the pivotal Phase III RESORCE study that demonstrated a statistically significant improvement in MOS (10.6 months) compared with placebo (7.8 months).1 Has this opened the floodgates for future drug approvals in HCC? Perhaps data released at the 2017 ASCO meeting can provide some insight:
- Daiichi Sankyo/ArQule’s c-MET inhibitor tivantinib failed to improve OS (primary end point) or PFS over placebo in Nexavar-pretreated, MET-high HCC in the Phase III METIV-HCC study (MOS: 8.4 months vs. 9.1 months; median PFS: 2.1 months vs. 2.0 months), despite positive results from an earlier placebo-controlled Phase II study.2
- Lenvima (lenvatinib). Conversely, Eisai’s pivotal Phase III trial (Study 304) in first-line unresectable HCC demonstrated that their angiogenesis inhibitor Lenvima is non-inferior to Nexavar on OS, the primary end point (MOS: 13.6 months vs. 12.3 months, HR = 0.92). Lenvima also exhibited significant improvements over Nexavar in median PFS (7.4 months vs. 3.7 months), median TTP (8.9 months vs. 3.7 months), and ORR (24% vs. 9%).3
- Opdivo (nivolumab). In the Phase I/II CheckMate-040 trial, the efficacy and safety of the PD-1 inhibitor Opdivo (BMS/Ono Pharmaceuticals) is being assessed in Nexavar-pretreated and Nexavar-naive HCC. Investigators reported an ORR of 23% (including one complete response) and an acceptable safety profile in Nexavar-naive patients4—the setting in which Opdivo is being positioned in the Phase III CheckMate-459 In Nexavar-pretreated HCC, investigators cited an ORR of 16-19% with a 2-8% CR.4
- Imfinzi (durvalumab) with or without tremelimumab. Interim Phase I/II safety data for the AstraZeneca agents Imfinzi (a PD-L1 inhibitor) in combination with tremelimumab (a CTLA-4 inhibitor) in unresectable HCC showed no unexpected safety signals.5 In addition, Imfinzi monotherapy is being evaluated in a separate Phase I/II study in predominantly Nexavar-pretreated HCC, and demonstrated an ORR of 10%, a MOS of 13.2 months, and an acceptable safety profile.6
While the final results from the METIV-HCC study for tivantinib are disappointing, the data for Lenvima, Opdivo, and Imfinzi plus tremelimumab are extremely encouraging, and collectively, could help pave the way for an entirely new treatment algorithm in HCC. Eisai’s decision to design and complete a study with non-inferior OS as the primary end point is somewhat unorthodox in oncology because, historically, non-inferiority studies have been seldom used for regulatory approval. However, the fact that Eisai did seek regulatory guidance on the design of Study 304 before embarking on the trial provides some confidence that Lenvima could be approved as a first-line treatment of HCC, particularly given the significant and clinically meaningful benefits over Nexavar on other efficacy end points (PFS, TTP, and ORR). If approved, such an event could set a precedence not only in HCC but also in other oncology indications, particularly difficult-to-treat diseases for which many agents have failed to demonstrate superiority and/or for which treatment options have barely changed for some time. The pivotal CheckMate-459 is trialling Opdivo versus Nexavar in first-line HCC, and the interim Phase I/II data from CheckMate-040 in this patient population is promising when considering that Nexavar demonstrated an ORR of just 2% (with no complete responses) in its pivotal Phase III SHARP trial.7 If Opdivo can significantly extend OS over Nevaxar in its Phase III trial, it will likely become the standard of care in this disease setting.
What about second-line treatments for HCC? Once again, immune checkpoint inhibitors lead the way. In May 2017, BMS reported the acceptance of a sBLA to the FDA for priority review of Opdivo as a treatment in HCC after prior Nexavar therapy, based on data from CheckMate-040.8 This is welcome news given the significant unmet need which exists in advanced stage HCC, and where treatment options are limited. While cross-trial comparisons are challenging, the efficacy of Imfinzi monotherapy in previously treated HCC is intriguing (ORR: 10.3%; MOS: 13.2 months) when compared to Stivarga in the RESORCE study (ORR: 10.6%; MOS: 10.6 months). Considering that Imfinzi plus tremelimumab could be more efficacious than Imfinzi alone, this combination could be a future contender in the second-line setting; however, there is no ongoing Phase III trial assessing these treatments to date. Other agents in Phase III development for previously treated HCC include Keytruda (KEYNOTE-240) and Cyramza (REACH-2); although no data were presented at ASCO 2017 for these agents, we are likely to hear more about their respective Phase III trials in the not-so-distant future.
Despite limited progress in the challenging HCC field over the past decade, change is on the horizon, and in turn a likely much improved outlook for patients diagnosed with this devastating disease. The clinical data presented at ASCO 2017 further supports the notion that immune checkpoint inhibitors will likely dominate the HCC market in the coming years, with Nexavar (and perhaps Lenvima) being relegated as later-line therapies. At DRG, we continue to keep a finger on the pulse of the HCC market—stay tuned for more insights and analysis!
- Bruix J et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017; 389;10064:56–66.
- Rimassa L, J. Clin Oncol 35, 2017 (suppl; abstr 4000).
- Cheng A-L et al. J Clin Oncol 35, 2017 (suppl; abstr 4001).
- Crocenzi TS et al. J Clin Oncol 35, 2017 (suppl; abstr 4013).
- Kelley RK et al. J Clin Oncol 35, 2017 (suppl; abstr 4073).
- Wainberg ZA et al. J Clin Oncol 35, 2017 (suppl; abstr 4071).
- Llovet JM et al. Sorafenib in Advanced Hepatocellular Carcinoma. NEJM. 2008;359;378-390.