Do results from CheckMate-459 challenge the position of other immune checkpoint inhibitors in the hepatocellular carcinoma treatment landscape?

The annual meeting of the European Society of Medical Oncology (ESMO) held in Barcelona, Spain from 27 Sep - 01 Oct 2019 shed light on the results from the CheckMate-459 hepatocellular carcinoma trial.

Currently, Bayer Healthcare’s Nexavar and Eisai’s Lenvima dominate the first-line treatment of advanced hepatocellular carcinoma. Other angiogenesis inhibitors, namely Stivarga (Bayer Healthcare), Cabometyx (Exelixis) and Cyramza (Eli lily) are currently approved for Nexavar-pre-treated hepatocellular carcinoma.

However, the efficacy offered by these agents is only modest and some (e.g., Nexavar, Stivarga) are associated with high toxicity. Moreover, current treatments are only available for patients with preserved liver function (Child-Pugh A), therefore a great unmet need remains for agents that improve overall survival, safety, tolerability, and eligible for patients with poorer liver function.

Immune checkpoint inhibitor is a promising drug class which is often associated with improved overall survival and tolerability. In May 2017, Opdivo became the first-immune checkpoint inhibitor to enter the hepatocellular carcinoma treatment algorithm, after receiving an accelerated approval from the FDA for Nexavar-pre-treated hepatocellular carcinoma, based on data from CheckMate-040.1

This approval opened the floodgates for the development of PD-1/PD-1 inhibitors for hepatocellular carcinoma. In July 2018, Merck & Co.’s Keytruda received an accelerated approval for Nexavar-pre-treated hepatocellular carcinoma, based on data from Phase II KEYNOTE-224 trial2. However, the confirmatory Phase III KEYNOTE-240 trial investigating Keytruda versus placebo failed to meet its coprimary endpoints of OS and PFS3.

CheckMate-459: Opdivo does not improve overall survival

In June 2019, Bristol-Myers Squibb announced that CheckMate-459 failed to meet its primary endpoint of OS in the first-line treatment of advanced hepatocellular carcinoma4.

The trial was evaluating Opdivo versus Nexavar in patients with unresectable hepatocellular carcinoma. Although the primary endpoint of OS did not achieve statistical significance (MOS: 16.4 months for Opdivo versus 14.7 months for Nexavar), data presented at ESMO 2019 revealed that Opdivo treatment led to a trend towards improvement of OS, ORR and CR rate, with no additional safety signals reported5.

While statistically insignificant, these promising trends are clinically meaningful, given that several drugs failed to challenge Nexavar in the first-line setting for over a decade.

Other ongoing Phase III trials for first-line unresectable advanced hepatocellular carcinoma: development of immune checkpoint inhibitors

At present, three angiogenesis inhibitors (i.e, Lenvima, Cabometyx, and Avastin) are being investigated in combination with an immune checkpoint inhibitor for the treatment of first-line hepatocellular carcinoma.

While Lenvima and Cabometyx have demonstrated clinical activity as monotherapies and are approved for use in the first-line and second-line settings, respectively, Avastin is yet to show such activity as a monotherapy in this indication.

Nevertheless, combinatorial approaches of immune checkpoint inhibitors and angiogenesis inhibitors are an intriguing approach to boost efficacy:

Tecentriq with Avastin. The Phase III IMbrave150 trial is evaluating Tecentriq in combination with Avastin versus Nexavar in previously untreated Hepatocellular carcinoma. Combining agents from these two drug classes is an intriguing approach to improve survival, given that inhibitors of angiogenesis and immune checkpoint inhibitors have proven clinical efficacy in hepatocellular carcinoma. The FDA granted Roche’s combination of Tecentriq plus Avastin a Breakthrough Therapy Designation (BTD) based on overall response rates achieved in a Phase 1b trial.

Tecentriq with Cabometyx. Exelixis is assessing the combination of Tecentriq with Cabometyx versus Nexavar, as a first-line therapy for hepatocellular carcinoma in the Phase III COSMIC-312, but has also initiated a multi-centre study to evaluate this combination in other solid tumors.

Keytruda with Lenvima. Merck & Co. initiated a Phase III trial (MK-7902-002/LEAP-002) to evaluate the combination of Keytruda and Lenvima versus Lenvima as a first-line treatment for advanced hepatocellular carcinoma. The FDA granted the combination of Keytruda and Lenvima a BTD based on the Phase 1b trial KEYNOTE-524 trial. This combination has recently been approved by FDA for the treatment of certain types of endometrial cancer. Considering that Lenvima is already approved for the first-line treatment of hepatocellular carcinoma, should the Phase III trial is positive, the combination of Keytruda and Lenvima could potentially become the next standard of care in this setting.

Imfinzi with or without tremelimumab. AstraZeneca is evaluating the efficacy of Imfinzi with or without tremelimumab versus Nexavar in the Phase III HIMALAYA trial in previously untreated patients. This trial is the first to examine the combination of two immune checkpoint inhibitors in hepatocellular carcinoma. If Imfinzi (with or without tremelimumab) has acceptable toxicity compared to Nexavar, the combination will have further opportunities to demonstrate superiority over Nexavar.

Tislelizumab: Tislelizumab is being investigated as a first-line treatment for advanced hepatocellular carcinoma in a Phase III study that has noninferior OS as primary outcome (compared to Nexavar). The noninferiority design of this trial could prove shrewd given that numerous agents failed to demonstrate a significant improvement in OS compared with Nexavar in the first line. It may also, however, put tislelizumab at a disadvantage, given that all other Phase III trials are designed to demonstrate significant survival improvements over Nexavar. Moreover, upon regulatory approval, as the only immune checkpoint inhibitor to be investigated as a monotherapy in this indication, tislelizumab may face competition from combination therapies, which will likely limit its uptake.

Will Checkmate-459 have a repercussion on the development of other immune checkpoint inhibitors for hepatocellular carcinoma?

Amidst the turmoil of the findings from CheckMate-459 and KEYNOTE-240, there are uncertainties surrounding the position of immune checkpoint inhibitors, especially monotherapies, in the hepatocellular carcinoma treatment algorithm.

Despite this, the drug class remains the most promising one in development in the hepatocellular carcinoma space and the success of the agents in the class is not yet completely forfeited. Combination therapies involving PD-L1 inhibitors (e.g., Roche’s Tecentriq) and angiogenesis inhibitors (e.g., Cabometyx) are still set to play a major role in shaping the future market landscape for first-line hepatocellular carcinoma.

Considering that most of the regimens being investigated for first-line advanced hepatocellular carcinoma contain a PD-1/PD-L1 inhibitor, and that Nexavar is associated with high toxicity which hinders its use, we believe that immune checkpoint inhibitors will be the front runners in the hepatocellular carcinoma treatment algorithm - a trend also observed in other indications.

As immunotherapy continues to be in the late-phase development pipeline for hepatocellular carcinoma, drug developers should explore the following strategic considerations:

Will biomarker-driven therapy change the treatment landscape for HCC?
If immunotherapy is used in the first-line, what will be physician choice for second-line treatment?
Would drugs be used in preference to chemotherapy/TACE in the intermediate settings?
Will both efficacy and safety be crucial to ensure approvals?

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  1. Kudo M et al. J Clin Oncol 37, 2019 (suppl; abstr 327).
  2. Zhu AX et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol 2018; 19: 940–52.
  3. Merck & Co., Press Release, February 19, 2019.
  4. Bristol-Myers Squibb, Press Release, June 24, 2019.
  5. Yau T et al. Annals of Oncol 30, 2019 (suppl; abstr v851-v934).

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