Editor’s Note:

Platinum-based, taxane, anthracycline, and other chemotherapy drugs are commonly used in the treatment of various cancers such as breast and lung cancer. However, these chemotherapy agents, known marrow suppressors, can lead to chemotherapy-induced anemia (CIA), resulting in a decline in functional capacity and diminished quality of life for patients. This year’s ESMO conference revealed the results of a Phase III clinical study on roxadustat in treating CIA in patients with non-myeloid malignancies, offering a more convenient treatment option for CIA patients. “Oncology Frontier” is honored to invite Professor Yongmei Yin from Jiangsu Provincial People’s Hospital and Professor Jian Zhang  from Fudan University Cancer Hospital to share insights into the current challenges in CIA treatment and the significance of this study for CIA patients.

Research Background:

Chemotherapy-induced anemia (CIA) is a common complication during cancer treatment and is a significant risk factor for poor prognosis. Recombinant human erythropoietin-alpha (rHuEPO-α) is the standard treatment for CIA but still presents safety concerns. Roxadustat is the first hypoxia-inducible factor prolyl hydroxylase inhibitor (HIFPHI) approved for the treatment of chronic kidney disease-related anemia. This study evaluated the efficacy and safety of roxadustat in treating CIA in non-myeloid malignancies.

Research Methods:

This was an open-label, non-inferiority, multicenter, Phase III study conducted in China. Patients were randomized (1:1) to receive either oral roxadustat or subcutaneous injection of rHuEPO-α, both administered three times a week for 12 weeks. The starting dose of roxadustat varied based on patient weight (100 mg, 120 mg, and 150 mg) for patients weighing 40-50 kg, 50-60 kg, and >60 kg, respectively. The starting dose of rHuEPO-α was 150 IU/kg three times a week. Both roxadustat and rHuEPO-α doses were adjustable to maintain hemoglobin (Hb) levels between 100 g/L and 120 g/L. The primary efficacy endpoint was the least squares mean (LSM) change in Hb concentration from baseline to weeks 9-13, and adverse events (AE) were also analyzed.

Research Results:

From baseline to weeks 9-13, the LSM change in Hb concentration was 17.1 g/L (95% CI, 13.58, 20.71) for the roxadustat group and 15.4 g/L (95% CI, 11.34, 19.50) for the rHuEPO-α group. The lower limit of the one-sided 97.5% CI for the treatment difference (-3.4 g/L) exceeded the predefined margin of -6.6 g/L, confirming the non-inferiority of roxadustat. Additionally, the proportion of patients in the roxadustat group with Hb increases of ≥10 g/L, ≥15 g/L, and ≥20 g/L was higher than that in the rHuEPO-α group. The incidence of AEs was similar between the two treatments, consistent with previous findings.

Expert Interview:

“Oncology Frontier”: Could you briefly introduce the clinical characteristics and common pathogenic mechanisms of chemotherapy-induced anemia (CIA)?

• Professor Yongmei Yin: Anemia is one of the most common symptoms in cancer patients during disease or treatment. In China, approximately half of patients experience cancer-related anemia, with chemotherapy-induced anemia (CIA), caused by anti-tumor chemotherapy, being the most common. CIA is characterized by a reduction in the number of red blood cells per unit volume of peripheral blood, a decrease in hemoglobin (Hb) concentration, and a reduction in hematocrit below normal levels. CIA is mainly associated with bone marrow suppression from chemotherapy drugs and the impact on erythropoietin (EPO) production.
• Specifically, chemotherapy drugs can block the synthesis of red blood cell precursors, directly affecting the hematopoietic function of the bone marrow. The bone marrow suppressive effects may accumulate during the treatment cycle, leading to an increased incidence and severity of anemia with prolonged chemotherapy cycles. Furthermore, renal toxicity induced by platinum-based drugs is another significant cause of CIA. Platinum drugs can promote red blood cell apoptosis and cause damage to renal tubular cells, leading to a decrease in endogenous EPO and resulting in anemia. In addition, gastrointestinal adverse reactions caused by chemotherapy may affect the patient’s appetite, leading to iron and vitamin deficiencies, which are also closely related to CIA.

“Oncology Frontier”: Currently, what is the incidence of CIA in China, and what disease burdens does it impose on cancer patients?

• Professor Yongmei Yin: The incidence of CIA is relatively high in China, but the treatment rate is low. This indicates that there is still insufficient attention to CIA among domestic peers. In the treatment process of cancer patients, chemotherapy not only induces anemia but may also exacerbate pre-existing anemia in patients. A prospective study in China found that the incidence of pre-chemotherapy anemia was about 30%, mainly mild anemia. However, the post-chemotherapy anemia rate (nearly 80%) was much higher than pre-chemotherapy, predominantly moderate anemia. As the chemotherapy cycle increases, the incidence of anemia gradually rises. More and more studies suggest that CIA may make it difficult for cancer patients to tolerate full-dose chemotherapy regimens, thereby affecting treatment efficacy. Moreover, anemia can cause fatigue, weakness, memory decline, and cognitive impairment, severely impacting the quality of life. It may also lead to psychological problems such as depression and anxiety. In summary, CIA deserves clinical attention, and effective, timely, and targeted treatment is needed for CIA patients.

“Oncology Frontier”: Could you briefly introduce the current treatment options for CIA?

• Professor Yongmei Yin: The treatment plan for CIA depends on various factors. For patients with severe anemia, immediate elevation of Hb levels is necessary, and transfusion of red blood cell suspensions is the preferred treatment. However, for the long-term management of CIA, the use of EPO or iron supplements should be based on an individual’s risk assessment for anemia. Since the generation of red blood cells is regulated by endogenous EPO, clinically, EPO has been proven to effectively alleviate anemia symptoms and reduce the occurrence of CIA, making it the mainstay of current CIA treatment.
• Professor Jian Zhang : Whether in lung cancer or breast cancer, platinum-based drugs are essential treatment modalities. Platinum drugs and other chemotherapy agents (such as taxanes and anthracyclines) can potentially induce chemotherapy-related anemia, with an incidence exceeding 80%. Although there are various ways to treat anemia, the overall treatment rate is less than 10%. Currently, blood transfusion is a challenging method for managing CIA, as the blood supply is sometimes limited. EPO treatment, typically administered weekly or three times a week, poses inconvenience for patients. In contrast, the oral form of roxadustat is very convenient.

We hope that through this non-inferiority clinical study, roxadustat can be approved and provide a new treatment option for chemotherapy-induced anemia in the future, improving the clinical practice of CIA.

“Oncology Frontier”: The results of the global Phase III study of the first HIFPH inhibitor roxadustat for the treatment of CIA in non-myeloid malignancies were officially announced at this year’s ESMO conference. Based on the data from this study, what insights do you think this research will bring to the diagnosis and treatment of CIA?

• Professor Yongmei Yin: In recent years, exploring novel agents for erythropoiesis has become a research hotspot. Roxadustat, presented at this year’s ESMO conference, is a novel anemia treatment with a completely new mechanism. As a HIFPH inhibitor, it can stimulate red blood cell production, regulate iron metabolism, and correct anemia. This study compared the efficacy and safety of roxadustat with rHuEPO-α in treating CIA in non-myeloid malignancies. Including 140 patients, the study results showed that the Hb for the roxadustat group was 17.1 g/L, while for rHuEPO-α, it was 15.4 g/L. The lower limit of the one-sided 97.5% CI for the treatment difference (-3.4 g/L) was higher than the predefined margin, confirming the safety and efficacy of oral roxadustat. Roxadustat is the first internationally developed original drug based on the HIF mechanism and has been approved for the treatment of chronic kidney disease-related anemia in multiple countries and regions. In this study, roxadustat achieved breakthrough progress in the field of CIA, and there is hope for further expanding its clinical applications to benefit more cancer patients. We look forward to the early approval of roxadustat for the new indication of treating CIA in China, further improving the quality of life for cancer patients undergoing chemotherapy and alleviating their disease burden.
• Professor Jian Zhang: It is precisely because of the challenges in managing CIA mentioned above that we urgently need to explore new treatment approaches. This study analyzed 140 patients, comparing the efficacy of roxadustat with the standard control rHuEPO-α through randomization. The main outcome was the rise in Hb from baseline to weeks 9-13, and the final result of non-inferiority received recognition from many experts at the ESMO conference. As an HIFPH inhibitor, roxadustat has been widely used in the treatment of renal anemia in the past, but there has been limited research on cancer treatment-related anemia. This innovative clinical study explored its application in solid tumors, both at the Shanghai Chest Hospital of Shanghai Jiao Tong University School of Medicine and Fudan University Affiliated Cancer Hospital. Both institutions are pleased with the achieved non-inferiority results.
• In practice, blood transfusion is a challenging method for managing CIA, and the effectiveness of rHuEPO-α treatment is often relatively low. Although overall relief can be achieved in about 60% of cases, many unmet needs remain. Additionally, transfusion or EPO treatment may lead to thrombotic events, posing certain risks. The oral form of roxadustat is very convenient. Through this non-inferiority clinical study, we hope that roxadustat can be approved, providing a new treatment option for chemotherapy-induced anemia in the future, improving the current clinical practice of CIA.

Professor, Chief Physician, Ph.D. Supervisor

Vice President of Jiangsu Provincial People’s Hospital

Vice Chairman of the Chinese Society of Clinical Oncology (CSCO)

Vice Chairman of the Beijing Hyskon Clinical Oncology Foundation

Secretary-General of the CSCO Breast Cancer Expert Committee

Standing Committee Member of the Chinese Anti-Cancer Association Breast Cancer Professional Committee

Designate Chairman of the CSCO Patient Education Expert Committee

Chief Physician, Doctor of Medicine

Director of Phase I Clinical Research Ward, Fudan University Affiliated Cancer Hospital

Chief Physician of Oncology

Shanghai “Medical Talent” Outstanding Young Talent Awardee

Designate Chairman of the Shanghai Anti-Cancer Association Tumor Drug Clinical Research Professional Committee

Standing Committee Member of the Chinese Anti-Cancer Association Breast Cancer Professional Committee

Deputy Convener of the Chinese Anti-Cancer Association Breast Cancer Professional Committee Youth Committee

Chairman of the Yangtze River Academic Leading Breast Alliance YBCSG

Vice Chairman of the Chinese Research Hospital Association Breast Professional Committee Youth Committee

Deputy Chairman of the National Anti-Tumor Drug Clinical Application Monitoring Youth Committee

Vice Chairman of the Shanghai Anti-Cancer Association Tumor Cardiology Professional Committee

Standing Committee Member of the CSCO Oncology Support and Rehabilitation Expert Committee

Standing Committee Member of the Chinese Society of Rehabilitation Medicine Cancer Rehabilitation Professional Committee

Member of the CSCO Breast Cancer Expert Committee

Member of the Chinese Anti-Cancer Association Tumor Clinical Research Management Professional Committee

First Batch of Clinical Part-Time Reviewers for Oncology in the National Medical Products Administration CDE

Recipient of the 2023 Top Ten Medical Pioneers Award and the 2023 “People’s Good Doctor” Outstanding Contribution Award

Deputy Editor-in-Chief of “Diseases & Research”

Author of 70 first/sole/corresponding author SCI papers (published in journals such as Lancet Oncol, Ann Oncol, Nat Commun, Clin Cancer Res, J Hematol Oncol, etc.)