With new anticancer drugs entering the liver cancer treatment market, where combination therapy has been gaining prominence, attention is focused on whether a paradigm shift will occur.

This is because a new competitive landscape is forming with the arrival of newly approved drugs and newly reimbursed drugs.

# According to industry sources on the 7th, the US Food and Drug Administration (FDA) recently approved the combination therapy of Bristol Myers Squibb (BMS) and Ono Pharmaceutical's Opdivo (nivolumab)+Yervoy (ipilimumab) combination as a first-line treatment for adult patients with unresectable or metastatic hepatocellular carcinoma (HCC).

The approval was based on the results of a randomized, open-label, global Phase III clinical trial (CheckMate-9DW) comparing the combination therapy of Opdivo and Yervoy (335 patients) with either lenvatinib or sorafenib monotherapy (333 patients).

The trial was conducted on patients with unresectable or metastatic HCC who had not previously received systemic therapy.

The CheckMate-9DW results showed that the median overall survival (mOS) in the Opdivo+Yervoy combination therapy group was 23.7 months (95% CI: 18.8-29.4), compared to 20. 6 months (95% CI: 17.5-22.5) in the control group (n=333), reducing the risk of death by 21% (HR=0.79; P=0.0180).

In addition, the 3-year survival rate was 38% in the Opdivo+Yervoy combination therapy group, higher than the 24% in the control group.

The objective response rate (ORR) was also significantly higher in the combination therapy group at 36.1% (95% CI: 31–41.5) compared to 13.2% (95% CI: 9.8–17.3; P<0.0001) in the control group. The median duration of response (mDOR) was also longer in the combination therapy group at 30.4 months (95% CI: 21.2-NR) compared to 12.9 months (95% CI: 10.2-31.2) in the control group.

With such promising data, attention is now on the timing of its domestic approval. This is because, similar to the global situation, there are limited treatment options for liver cancer in domestic clinical settings.

Currently, the representative treatment option on-site is Roche's Tecentriq (atezolizumab) and Avastin (bevacizumab) combination therapy. In Korea, this combination therapy is covered by health insurance and is the first-line combination treatment used for HCC on-site.

In addition, AstraZeneca's ‘Imfinzi (durvalumab)-Imjudo (tremelimumab)’ combination therapy, which improves the risk of bleeding, a representative side effect of existing treatments, has been approved by the Ministry of Food and Drug Safety, but is not reimbursed by health insurance and can only be used without reimbursement.  AstraZeneca, which owns the treatment, pushed for reimbursement and cleared the Health Insurance Review and Assessment Service's Cancer Disease Review Committee review in November last year, but the drug’s approval is still in the pharmacoeconomic evaluation stage by the Drug Reimbursement Evaluation Subcommittee.

However, the industry believes that there is a possibility that it will pass pharmacoeconomic evaluation in the second half of this year and be reimbursed by health insurance.

Ultimately, the Opdivo+Yervoy combo will likely be approved in Korea at a time when competing options are already covered by reimbursement.

Still, what is promising is that the MOHW improved its reimbursement policy for combination therapy in May. Given that no specific guidelines have been issued, at least one of the drugs used in combination therapy may be covered by reimbursement.

For reference, Opdivo is currently approved in Korea as part of various combination therapies for melanoma, non-small cell lung cancer, malignant pleural mesothelioma, renal cell carcinoma, urothelial carcinoma, gastric cancer, and esophageal cancer, and has various treatment options that can be covered by the government's new reimbursement plan for combination therapies.

A pharmaceutical industry insider who requested anonymity stated, “We expect the Opdivo+Yervoy combination therapy to receive domestic approval in the second half of the year. In the meantime, the Imfinzi-Imjudo combination therapy may pass the cost-effectiveness evaluation. The importance of using these therapies is being emphasized through the National Assembly and other channels. We anticipate intense competition in the HCC treatment market in the future.”

Meanwhile, major medical societies led by the Korean Liver Cancer Association have submitted proposals to HIRA to improve reimbursement standards due to frequent cuts made in reimbursements for HCC treatments. The reason is that there is a discrepancy between the indications and clinical studies for each treatment and the reimbursement standards.

Professor Hyun Yang from Eunpyeong St. Mary's Hospital (Gastroenterology) said, “There is a gap between reality and the application of reimbursement benefits for systemic treatment of HCC. There is ambiguity in the reimbursement criteria for the combination therapy of Tecentriq and Avastin, which states its use for ‘patients not eligible for local therapy’. There is also a discrepancy between the reimbursement standards and the indications set during the Phase III clinical trial for the Imfinzi+Imujudo combination therapy.”

Professor Soon Sun Kim, Insurance Director of the Korean Liver Cancer Association (Gastroenterology, Ajou University Hospital), said, “We submitted the consensus opinion statement collected by experts from the Liver Cancer Association, the Korean Association for the Study of the Liver, and the Koeran Society of Medical Oncology to HIRA regarding the application of medical reimbursement for systemic treatment of HCC,” adding, “We submitted the opinion to improve the ambiguity in the reimbursement criteria for the use of HCC treatments.”