Are there no solutions for stage 4 gastric cancer patients in insurance’s blind spot?

The first-line treatment of stage 4 gastric cancer has recently been revolutionized with the introduction of a series of immuno- and targeted-anticancer drugs.

Unlike the global trend, however, Korean patients are facing a bleak outlook with limited access to new drugs due to blind spots in reimbursement.

The emergence of anti-PD-1 immuno-oncology and Claudin 18.2 targeted therapy has recently reshaped the landscape of first-line treatment for stage 4 gastric cancer patients in Korea.

Depending on the expression of PD-L1, HER2-positive patients can use trastuzumab combined with conventional fluoropyrimidine and platinum chemotherapy if they are PD-L1-negative or a three-drug regimen by adding Keytruda (pembrolizumab) if they are PD-L1-positive.

HER2-negative patients can use Keytruda or Opdivo (nivolumab) in combination with conventional fluoropyrimidine and platinum chemotherapy regardless of PD-L1 expression. However, if a patient is Claudin 18.2-positive, they can use the combination with Vyloy(zolbetuximab) instead of an immuno-oncology agent.

Still, this is purely a classification based on the approval by the Ministry of Food and Drug Safety (MFDS). According to the reimbursement standards set by the Health Insurance Review and Assessment Service (HIRA), the first-line treatment strategy is more complicated for patients with stage 4 gastric cancer in Korea.

First, Keytruda is not yet available for HER2-positive patients. Since the Keytruda combination is pre-reimbursement, patients must still use the old two-drug regimen of chemotherapy and trastuzumab. While patients may be able to receive the treatment at 100 percent co-payment under the approval, this will increase their out-of-pocket costs as the previously covered chemotherapy and trastuzumab combination will not be covered.

The situation is the same for HER2-negative patients. The Opdivo combination is reimbursed, but only for patients with PD-L1 “CPS 5 or higher,” according to the reimbursement criteria. This means that patients with less than CPS 5 will have to pay out of pocket for the Opdivo combination and their existing covered chemotherapy.

That is also true for the recently approved Vyloy combination in Korea. If a patient diagnosed with Claudin 18.2 positivity wants to use the Vyloy combination, even the chemotherapy will not be reimbursed.

Recently, the Korean Cancer Association requested that patients with a CPS of less than 5 be allowed to pay 100 percent of the cost of Opdivo while keeping the existing chemotherapy benefits. However, the Cancer Disease Review Committee (CDRC) rejected the request in August.

Dr. Rha Sun-young, a medical oncologist at Severance Hospital who is also the president of the Korean Cancer Association and the chair of the gastric cancer subcommittee of the Korean Cancer Study Group, expressed concerns about this coverage gap at the European Society for Medical Oncology Annual Congress (ESMO 2024) last month.

Professor Rha also raised equity issues with other cancers. For example, she pointed to the recent approval of Imfinzi (durvalumab) in biliary tract cancer in combination with gemcitabine/cisplatin (GemCis) with 100 percent patient co-payment.

Such cases are not limited to biliary tract cancer. When a new drug is added to an existing treatment, the existing treatment remains covered, and the new drug is made available at 100 percent patient co-pay.

Its examples include the combination of Kadcyla (trastuzumab emtansine) in HER2-positive early breast cancer and Darzalex (daratumumab) in the first-line treatment of multiple myeloma.

“Aside from the issue of equity among cancer types, our association will continue to engage in discussions with the government to address the issue of reimbursement for new drug combinations,” Professor Rha said.

“The Keytruda combination is particularly important for HER2-positive patients,” she emphasized. Professor Rha pointed out that for HER2-negative patients, there are two immuno-oncology options, Keytruda and Opdivo, but for HER2-positive patients, Keytruda is the only immunotherapy option.

At ESMO 2024, overall survival (OS) data from the phase 3 KEYNOTE-811 study evaluating the Keytruda combination in HER2-positive patients were presented. Professor Rha evaluated the data and said, “Trastuzumab and pembrolizumab are now mandatory in patients who are both HER2-positive and PD-L1-positive. If you don't use them, it's not a good medical choice and a disservice to the patient.”

The KEYNOTE-811 study is the first and only study to evaluate an immuno-oncology agent in HER2-positive patients and obtain OS data. In patients with PD-L1 CPS 1 or higher, the median OS in the Keytruda arm was 20.1 months vs. 15.7 months in the control arm, demonstrating that adding Keytruda to conventional chemotherapy was associated with a 21 percent lower risk of death (HR 0.79)

However, access to Keytruda in HER-positive patients is expected to take some time due to the shortcomings of the current reimbursement system.

The reimbursement review for Keytruda has been stalled for over a year, and no resolution is in sight.

In June last year, MSD Korea immediately submitted the expanded indications for reimbursement to Keytruda. Still, the reimbursement system in Korea is not yet in place to accommodate multi-indication drugs, such as the indication-specific drug pricing system, so the application was unsuccessful.

The CDRC selected some indications with the highest clinical needs among the 15 indications applied by MSD Korea. Still, it concluded that “no salary standard was set” in April. At the time, the committee stipulated that it would “re-discuss whether or not to set a reimbursement standard when submitting an additional financial allocation plan,” As of October, however, there has been no progress in this discussion.

In the meantime, MSD Korea has submitted two additional indications (HER2-positive and HER2-negative) for the first-line treatment of Keytruda in stage 4 gastric cancer. The new indications were requested after the previous applications failed to meet the CDRC threshold.

“We have no idea whether the government will add the two new indications for gastric cancer to the current application,” MSD Korea said, expressing frustration with the secretive review process.