'Qarziba, global standard for neuroblastoma, is urgently needed to expand access to treatment’

Neuroblastoma is a solid cancer that occurs primarily in infants and young children, a deadly disease that accounts for about 15 percent of pediatric cancer deaths.

While the incidence rate is about 11-13 per million people under 5, the long-term survival rate for high-risk patients is less than 50 percent. The five-year survival rate for relapsed/refractory patients is only about 20 percent. The poor prognosis has led to an urgent need for effective treatment options.

Qarziba (dinutuximab beta), which was approved in Korea in June for treating high-risk and relapsed/refractory neuroblastoma, has emerged as a new alternative. Qarziba is an anti-GD2 antibody therapy that selectively attacks tumor cells by targeting GD2, expressed explicitly on neuroblastoma cells. Since its approval in 2017, it has been the standard of care for maintenance therapy in Europe for the past eight years.

Key international guidelines, including the U.S. National Comprehensive Cancer Network (NCCN) and the International Society of Pediatric Oncology Europe Neuroblastoma Group (SIOPEN), recommend Qarziba as a standard immunotherapy for high-risk neuroblastoma. In a phase 3 clinical trial (APN311-302) in high-risk patients, the five-year overall survival (OS) rate in the Qarziba plus immunotherapy arm was 64 percent, significantly higher than 50 percent in the non-immunotherapy arm.

Qarziba was also selected as the first drug for the Ministry of Health and Welfare's “Permit-Evaluation-Negotiation Parallel Pilot Project.” However, contrary to the intention of shortening the time from approval to health insurance enrollment to 150 days, Qarziba passed the Pharmaceutical Reimbursement Evaluation Committee only in October, one year after applying for approval and benefits, and is awaiting drug price negotiation and final deliberation by the Health Insurance Policy Review Committee.

Against this backdrop, Korea Biomedical Review spoke with Professor Koh Kyung-nam of the Department of Pediatric Oncology and Hematology at Asan Medical Center and Dr. Aleksandra Wieczorek, hematologist-oncologist at Jagiellonskim University College of Medicine in Poland, who recently visited Korea to discuss the changing treatment paradigm for high-risk neuroblastoma and the need to improve the treatment environment in Korea.

Professor Koh Kyung-nam of the Department of Pediatric Oncology and Hematology at Asan Medical Center and Dr. Aleksandra Wieczorek of the Department of Hematology and Oncology at Jagiellonskim University College of Medicine, Poland, discussed the changing paradigm in the treatment of high-risk neuroblastoma during a recent interview with Korea Biomedical Review.

KBR: Can you explain what neuroblastoma is and the current state of the disease in Korea?

Dr. Alexandra Wieczorek: Neuroblastoma is the most common solid cancer in children, excluding brain tumors, accounting for about 8 percent of all childhood cancers and about 15 percent of childhood cancer deaths. About 50 percent of neuroblastoma patients are classified as high-risk, and high-risk patients often do not have the desired outcome despite very intensive treatment. Current treatments include chemotherapy, autologous hematopoietic stem cell transplantation, and immunotherapy. Recently, new therapies, including anti-GD2 antibody therapy, have been introduced, and the outcomes have improved significantly compared to the past.

Professor Koh Kyung-nam: Pediatric cancer has a constant incidence rate, so the number of cases varies, depending on the number of newborns. In Korea, about 15 years ago, there were about 80 to 90 patients a year, but now, with the decline in the birthrate, there are about 50 to 60 patients yearly. Half of them are high-risk neuroblastoma patients who require very aggressive treatment.

KBR: What are the main symptoms of neuroblastoma, how is it diagnosed, and which hospital should a patient visit if they have suspicious symptoms?

Koh: The most common area where neuroblastoma occurs is the adrenal glands. A tumor in the adrenal gland can cause abdominal bloating, and if the tumor presses on a nerve, it can cause pain or numbness in that area. If you notice any of these symptoms, visit your pediatrician first. If a lump or tumor is palpable, seeing a pediatrician specializing in oncology is best. If the symptoms are vague, such as pain, it’s better to go to the pediatric emergency room because it’s not always easy to suspect a tumor in the first place.

The main diagnostic method is a biopsy. Genetic testing is also performed on the biopsy specimen. Patients are categorized into risk groups based on whether the MYCN gene is amplified. Various imaging tests are performed to check for metastases, including MRI, PET-CT, and CT. Bone marrow tests are also crucial because neuroblastoma can metastasize to the bone marrow.

KBR: How is neuroblastoma classified? Can you explain the definition of high-risk?

Wieczorek: When classifying neuroblastoma and determining the prognosis, the age of the diagnosed child, the extent of metastasis, and the biological characteristics of the tumor are all considered, and the treatment is directed accordingly. In general, the younger the child's age, the better the prognosis, so we categorize the risk based on the biological characteristics of the tumor along with the age of 18 or 12 months. Also, if the disease is found to have metastasized, the prognosis is poor, so if the disease has metastasized and progressed to stage 4, it is categorized as high-risk. Another critical factor is whether the MYCN gene is amplified. Amplification of the MYCN gene has a negative impact on prognosis. Even localized tumors without metastasis are classified as high-risk if they have poor tissue biology or MYCN gene amplification.

KBR: What is the global standard of care for neuroblastoma, and what treatment options are available in Korea?

Wieczorek: The global standard of care for neuroblastoma is divided into three phases -- induction, consolidation, and maintenance. First, induction therapy is used to reduce the size of the tumor that has metastasized. Chemotherapy is administered to shrink the metastatic tumor as much as possible, and any remaining lesions are surgically removed. In the consolidation phase, high-dose chemotherapy is followed by autologous hematopoietic stem cell transplantation. This is followed by radiation therapy. Studies are underway in Europe to compare the effectiveness of single stem cell transplantation with tandem stem cell transplantation. Finally, we use anti-GD2 antibodies to eliminate microscopic residual disease (MRD) and isotretinoin during the maintenance therapy phase.

Koh: The treatment of neuroblastoma in Korea follows the global standard of care. After removing more than 95 percent of the tumor with induction therapy, high-dose chemotherapy, and autologous hematopoietic stem cell transplantation are performed together as consolidation therapy. These are not separate treatments but rather a combination of therapies that actively eliminate cancer cells with high-dose chemotherapy and help patients recover through autologous stem cell transplantation. In Korea, high-dose chemotherapy can be covered up to two times, so most patients receive the maximum treatment possible.

In the maintenance phase, isotretinoin, a vitamin A, is used to differentiate neuroblastoma tumors into a less aggressive state. Although anti-GD2 antibody is the global standard of care for maintenance therapy, it is not yet covered in Korea, so only a few patients use it, and most patients in Korea use a combination of differentiation therapy with vitamin A and radiation therapy.

Dr. Aleksandra Wieczorek

KBR: Given the differences between the global standard of care and the Korean treatment environment for maintenance therapy for neuroblastoma, how does immunotherapy with anti-GD2 antibodies in maintenance therapy affect patients’ prognosis?

Wieczorek: The availability of immunotherapy has a huge impact on improving patient survival. If you look at the history of neuroblastoma treatment, conventional chemotherapy alone was only able to cure about 15 percent of patients. Later, high-dose chemotherapy increased the cure rate to around 40 percent. More recently, with the addition of anti-GD2 antibody immunotherapy, the cure rate is now around 65-70 percent. This is a huge step forward for a disease with a very poor prognosis.

Koh: The most important key to improving the long-term survival of patients is to reduce the recurrence rate. Once a patient relapses, it is very difficult for them to get another chance to be cured. Especially if they have already undergone intensive treatment, they are at high risk of developing long-term complications. This is why it is essential to reduce relapse rates during the first-line treatment phase, and studies have shown that maintenance therapy can reduce relapse rates by more than 15 percent in high-risk patients.

KBR: Can you describe the key findings of Qarziba, the anti-GD2 antibody treatment used in maintenance therapy?

Wieczorek: Qarziba was proven effective in the SIOPEN study in Europe. The initial study design called for one group to receive Qarziba plus isotretinoin and the other to receive isotretinoin alone. However, the superiority of anti-GD2 antibody immunotherapy in the U.S. led to the conclusion that this was unethical, so the study design was modified to allow both groups to receive Qarziba but one group to receive interleukin (IL)-2 and the other group not. The results showed that Qarziba was about 15 percent more effective than the historical control group that did not receive immunotherapy, regardless of the combination of IL-2.

Koh: The survival rate for relapsed neuroblastoma is known to be very low, less than 30 percent. However, a recent retrospective analysis from Germany showed positive data that the combination of Qarziba, chemotherapy, and hematopoietic stem cell transplantation in relapsed neuroblastoma patients can increase survival by nearly 50 percent.

KBR: What has been the safety profile of Qarziba in the major clinical studies, and what has been its tolerability in real-world clinical practice?

Koh: The GD2 antigen can be expressed in small amounts in normal tissues. Since it is mainly expressed in neural tissue, anti-GD2 antibodies can cause adverse events, such as neuropathic pain and other immune reactions. Typical immune reactions include fever, decreased blood pressure, and allergic reactions. If nerve tissue is affected, pain or, in rare cases, paralysis and vision impairment may occur.

However, these serious adverse reactions are rare, and most are manageable. In addition, with the widespread use of anti-GD2 antibodies abroad, there are well-established guidelines for adverse event management, and most adverse events that occur during treatment can be systematically addressed.

Wieczorek: Qarziba's safety profile is considered favorable. It's important to note that while adverse events with conventional cancer drugs tend to become more severe as patients receive more doses, Qarziba is better tolerated over time. Patients who have received multiple doses have experienced adverse events that are so mild that they don't even realize they are receiving treatment.

KBR: Qarziba is approved in Korea for indications such as high-risk neuroblastoma patients who have received myeloablative therapy and stem cell transplantation after partial response or worse following induction chemotherapy and relapsed or refractory neuroblastoma. Please share with us the progress of the treatment and prognosis of patients in clinical practice.

Koh: At our hospital, we have used Qarziba in about 20 patients. Although some patients complained of fever or pain at the beginning of the treatment, most patients tolerated it well and received stable treatment after the second or third dose. Longer follow-up periods are needed to determine the effectiveness of the treatment. Still, we have seen positive cases where tumors responded clearly to Qarziba treatment in relapsed patients.

KBR: Qarziba is undergoing the process of receiving health insurance benefits in Korea. What is the level of demand from patients and medical professionals for Qarziba’s coverage in clinical settings?

Koh: It's very high. It has been 14 years since the anti-GD2 antibody was proven effective. In Korea, however, parents must pay for the treatment out of pocket. While some caregivers have imported the drug from overseas at great expense, most patients and caregivers remain frustrated.

We are asking patients to be patient as we are in the process of reviewing the benefits. Especially for patients who have received first-line treatment, there is a criterion that maintenance therapy must be started within six months of the end of consolidation therapy, and we are desperately hoping that they will be able to start within this time frame. Patients and their caregivers anxiously await results, as they may be excluded from coverage if they wait longer than six months.

Relapsed patients are desperate to start treatment sooner, even by a day. They are hoping the review process will be finalized quickly. When the authorization and reimbursement process began last year, it was expected to be completed in about a year. However, more than a year has passed, and patients and caregivers anxiously await results. We are hopeful that the permit-assessment-negotiation pilot project will live up to its promise and that patients will be able to receive treatment as soon as possible.

Professor Koh Kyung-nam

KBR: How do you think Qarziba's inclusion in health insurance coverage will change the landscape of neuroblastoma treatment in Korea?

Koh: Previously, pediatric cancer treatments typically required the use of very powerful chemotherapy drugs, but the introduction of targeted therapies like Qarziba will provide safer and more effective treatment options for pediatric cancer patients. Overseas, Qarziba has already become the global standard of care for high-risk neuroblastoma. The introduction of Qarziba in Korea means that Korean patients will have the opportunity to receive this global standard of care.

One concern is that for relapsed or refractory patients, Qarziba may need to be used after other treatments have stabilized the tumor to receive coverage. As the clinical presentation of relapsed/refractory neuroblastoma patients is highly variable, and Qarziba may benefit patients who have not responded to other treatments or are in the early stages of relapse, we hope that the reimbursement criteria will be set to allow for more prospective use of Qarziba.

KBR: What would you like to say to neuroblastoma patients, families, and healthcare providers in Korea?

Wieczorek: Overseas, immunotherapy with Qarziba is working much better than expected. We talked earlier about some of the adverse events that concern anti-GD2 antibody therapy, but I would like to reiterate that it is a well-confirmed safety profile. I know that many neuroblastoma patients in Korea are waiting for treatment. I hope neuroblastoma patients in Korea will benefit from Qarziba as soon as possible.

Koh: We are grateful that the government is working to expedite approvals and reimbursement for patients with rare cancers like neuroblastoma. Both pediatric and adult patients are critical, but children have a long life ahead of them, 70-80 years, so it's essential to give each patient a chance to be cured. We are hopeful that the reimbursement will become a reality soon so that patients can be treated as soon as possible.