Global Withdrawal of Breakthrough Drug Leaves Patients Like Wei Zexi Without Treatment Options

(Health Times reporter Xu Tingting) The life of young Wei Zexi was forever frozen on April 12, 2016, due to soft tissue sarcoma. Meanwhile, Xiu Yi (pseudonym) from Lianyungang City, Jiangsu Province, remains trapped in the same predicament due to the same disease: treatment options for soft tissue sarcoma have remained stagnant for decades.

Olaraumab, a new drug under Eli Lilly, was once considered the first new therapy in 40 years capable of addressing the challenges posed by soft tissue sarcoma. Due to the inability to confirm that the drug extends survival, Eli Lilly’s official website recently announced the initiation of global market withdrawal proceedings for olaraumab.

In China, more than 30,000 new cases of soft tissue sarcoma are diagnosed each year. After an initial period of hope, patients often fall into despair due to the lack of effective treatments.

Fudan University Shanghai Cancer Center annually treats nearly 1,000 patients undergoing surgery for soft tissue tumors. The center performs procedures such as barrier resection for sarcomas, vascular replacement, flap reconstruction for wound coverage, and functional reconstruction, thereby accumulating extensive clinical experience. (Photo from Health Times; photographed by Wang Yihui, Fudan University Shanghai Cancer Center)

A Notice

The hope of saving a life was shattered.

“It means there is even less hope.” Xiu Yi felt deeply helpless when discussing the market withdrawal of olaratumab. Since olaratumab was launched in the United States and the European Union in 2016, expediting its entry into the Chinese market has been, in Xiu Yi’s words, “a narrow path to survival.”

Xiu Yi is a patient with soft tissue sarcoma. He was only 27 years old when he was diagnosed with the disease. In April 2015, he was shortlisted for a position at a public institution. Just as Xiu Yi and his family were immersed in joy, the demon had quietly arrived. During a pre-employment medical examination, he was diagnosed with advanced malignant soft tissue sarcoma (two years later, the final pathological type was confirmed as synovial sarcoma through a biopsy at Shanghai Cancer Hospital).

Soft Tissue Sarcoma: A Dual Identity. It is both a cancer and a rare disease. According to data from the Center for Drug Evaluation of the National Medical Products Administration, its incidence rate is 2.63 per 100,000 people. In other words, fewer than three individuals out of every 100,000 are likely to develop this condition.

“The doctor said this is a highly malignant soft tissue sarcoma of unknown etiology, a rare disease,” said Xiu Yi. He only became aware of the condition when it had already metastasized to the lungs; it has now spread to the ribs. Analgesics are no longer effective in controlling the severe pain, leaving him bedridden.

After shuttling back and forth among Beijing, Shanghai, and Lianyungang, Xiu Yi came to realize that no drugs capable of significantly improving the survival of patients with soft tissue sarcoma had been approved for marketing in recent decades. “I have never given up seeking new treatment options, such as enrolling in clinical trials for novel agents, applying for PD-1 inhibitor trial groups, or joining other recruitment programs, but none met the eligibility criteria.”

At nearly the same time that Xiuyi was diagnosed with this disease, Eli Lilly recruited 148 untreated patients with advanced soft tissue sarcoma in the United States for a Phase II clinical trial of olaratumab. The results showed that the addition of olaratumab extended the overall survival of patients with advanced soft tissue sarcoma by 11.8 months, and the research findings were published in the internationally authoritative academic journal The Lancet.

It was precisely on the basis of this clinical trial that, in 2016, the United States and the European Union granted accelerated approval for olaratumab as a first-line treatment for patients with advanced soft tissue sarcoma. So-called accelerated approval refers to rapid market authorization based on the results of Phase II clinical trials.

In September 2016, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued an opinion supporting the conditional approval of olaratumab in combination with doxorubicin for the treatment of patients with advanced soft tissue sarcoma who are not candidates for curative radiotherapy or surgery. One month later, the drug received approval for the same indication in the United States. On October 19, 2016, the U.S. Food and Drug Administration (FDA) approved olaratumab through its accelerated review pathway.

“The Biggest Breakthrough in Soft Tissue Sarcoma in 40 Years,” “First-Line Targeted Therapy for Sarcoma,” and “Nearly Doubling Overall Survival Rates”: Olaratumab Was Once Surrounded by Such Glowing Accolades. In China, olaratumab was also included in the first batch of emergency clinical drugs announced by the Center for Drug Evaluation of the National Medical Products Administration.

For a moment, excitement and exhilaration surged; in Xiu Yi’s words, it felt as if help had finally arrived. Since olaratumab was launched in the United States and the European Union, Xiu Yi and other soft-tissue sarcoma patients in China had been eagerly awaiting the early introduction of this new drug for soft-tissue sarcoma into China for three years—more than 1,000 days.

Until April 25, 2019, all hopes came to an abrupt halt. Eli Lilly announced on its official website that olaratumab, a new drug for advanced soft tissue sarcoma, was being fully withdrawn from the market.

After a long wait, what finally arrived was not a life-saving drug, but dashed hopes, with the imminent threat of amputation or even death.

Efficacy cannot be confirmed

The U.S. and EU drug regulatory agencies do not recommend its use.

What Xiuyi found incomprehensible was why a drug already on the market would be withdrawn due to failed clinical trials. A reporter from Health Times learned that this stems from the “accelerated approval” policy.

What propelled Olaratumab to fame was the tremendous success achieved in its Phase II clinical trial for the treatment of soft tissue sarcoma.

Under the “Accelerated Approval” criteria of the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), when an investigational prescription drug demonstrates the potential to treat serious conditions or address unmet medical needs, the preclinical evidence supporting its efficacy may be less robust than that required for conventional approval. However, upon granting accelerated approval, the FDA mandates that pharmaceutical companies conduct post-approval confirmatory studies.

In other words, if a drug is approved for market entry based on Phase II clinical trials, larger-scale post-marketing studies must be conducted to ensure its broad applicability. If the clinical data from post-marketing studies fail to support the initial approval decision, the new drug may be withdrawn from the market.

However, olaratumab has only this single indication, which is for the treatment of advanced soft tissue sarcoma; removing this indication would mean its complete withdrawal from the market.

Unfortunately, according to the results announced on Eli Lilly’s official website, olaratumab yielded surprising and deeply disappointing outcomes in the large-scale Phase III ANNOUNCE study conducted after its market launch.

The preliminary results of the ANNOUNCE study, announced on January 18, 2019, did not demonstrate a significant survival benefit comparable to that observed in the Phase II clinical trial across the entire treated population.

On the day the study results were announced, Anne White, head of Eli Lilly’s oncology business, stated that the company would “carefully analyze the detailed clinical data to identify discrepancies between the two sequential clinical studies and engage with global regulatory authorities to determine the next steps for olaratumab.”

Subsequently, the U.S. FDA and the European EMA determined that, based on the results of the Phase III clinical trials of olaratumab, it failed to effectively prolong overall survival in patients with soft tissue sarcoma, and thus the clinical benefit of olaratumab was not definitively confirmed.

“Olaraumab is not recommended for the treatment of newly diagnosed patients with soft tissue sarcoma.” From January 23 to 24, 2019, the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) successively published this information on their official websites.

The European Medicines Agency issued a press release on its official website, advising physicians not to prescribe olaratumab to new patients. For patients currently undergoing treatment who demonstrate clinical benefit, physicians may consider continuing therapy. Approximately 1,000 patients in Europe are currently receiving olaratumab treatment.

According to statistics from the American Cancer Society, there were 12,750 newly diagnosed cases in the United States in 2019, with over 5,000 deaths. According to Eli Lilly’s 2018 annual report, global sales revenue for olaratumab reached $305 million, representing a 50% increase.

The U.S. FDA recommends that patients consult their healthcare providers regarding whether to continue treatment with olaratumab. The EMA will send letters to healthcare professionals who may prescribe olaratumab, informing them of the current study results and treatment recommendations. The U.S. FDA is evaluating the data and working with the manufacturer to determine appropriate follow-up actions.

Meanwhile, Eli Lilly announced its market withdrawal response plan. Patients receiving treatment with olaratumab may consult with their attending physicians. Provided that patients are fully informed of the risks and Phase III study results, and in compliance with applicable laws and pharmaceutical regulatory requirements of respective governments, they may decide, at their own discretion and according to their personal wishes, whether to continue treatment.

In addition, patients currently participating in olaratumab clinical trials, as well as new patients, are no longer permitted to receive olaratumab treatment. This also means that many Chinese patients with soft tissue sarcoma, including Xiu Yi, will be completely deprived of the opportunity to use olaratumab.

No targeted drugs have been approved in China.

Chinese Patients Have No Medications Available

“On January 22, I sought medical help and medication, but had no choice but to give up as no medicine was available. I was left in tears.”

“On March 31, I hope that effective medications will soon be available to address the disease, ensuring that all patients have access to treatment.”

“On April 17, the pain started again this afternoon. Once I feel better, I must go out for a walk.”…

Since falling ill, Xiu Yi has meticulously documented his daily journey of seeking medical care and treatment. For patients with soft tissue sarcoma like Xiu Yi, the scarcity of medical resources and medications has made their path exceedingly difficult.

“The incidence of sarcoma is so low that certain subtypes are so rare that even the top three hospitals in the United States basically only encounter them during autopsies, let alone have treatments and regimens available,” said a patient with soft tissue sarcoma.

According to the cancer drug list published by the U.S. National Cancer Institute (NCI), there are fewer than 10 drugs approved worldwide for sarcoma, a disease with more than 50 subtypes. Among these, only three are targeted therapies, all indicated for soft tissue sarcoma. One of these, olaratumab, is currently being withdrawn from the global market.

Currently, none of the aforementioned drugs have been approved in China for the treatment of soft tissue sarcoma, and there are no targeted therapies approved domestically for this indication. Several Chinese pharmaceutical companies are conducting research and development on drugs for soft tissue sarcoma, but all are still in clinical trial stages and none have been marketed.

According to public data from the Center for Drug Evaluation of the National Medical Products Administration, soft tissue sarcoma has a low incidence rate and a poor prognosis, with a median survival of approximately one year for patients with advanced-stage disease, and there is a lack of effective therapeutic agents. However, in June 2018, the highly anticipated First Batch of Rare Diseases Catalogue was finally released in China, including 121 rare diseases; yet sarcomas were not listed among them.

“There is no established treatment for our condition; we are essentially feeling our way forward,” said Xiu Yi. Apart from a limited number of chemotherapy agents, the only hope lies in targeted therapies that have not yet been approved for soft tissue sarcoma.

Wang Donglin, Director of the Department of Medical Oncology at Chongqing University Cancer Hospital, revealed, “Currently, surgical treatment is the mainstay for early-stage patients. However, for patients with unresectable or metastatic advanced soft tissue sarcoma, chemotherapy remains the first-line treatment regimen. For patients who have failed chemotherapy, there is currently no standard recommended second-line treatment regimen in China’s consensus guidelines.”

Other drugs already marketed in China: Pazopanib is currently the only targeted therapy approved by the FDA for second-line treatment of advanced soft tissue sarcoma, but it has not yet been approved in China for this indication. Although it has long been explicitly included in international guidelines for the treatment of soft tissue sarcoma, it is not covered by China’s national medical insurance for sarcoma patients.

“Every month, I have to spend tens of thousands of yuan purchasing targeted drugs from abroad. I’ve seen many fellow patients who can only sustain their treatment by buying leftover medications from other patients who have developed drug resistance or passed away,” said Xiu Yi. He noted that since these foreign medications have not been introduced into China, patients must purchase them overseas to continue their treatment; however, only a small minority of patients are able to travel abroad for this purpose.

Over the past three years, Xiu Yi has spent more than 500,000 yuan of his family’s savings. To fund his treatment, his elderly mother has begun discussing the possibility of selling their home, with estimated costs for subsequent care reaching as high as 1 million yuan. “The repeated onslaughts of this disease have left me feeling helpless amid the pain. Seeing my mother repeatedly collapse from exhaustion while caring for me keeps me tossing and turning at night. Witnessing fellow patients around me pass away one after another has further underscored the fragility of life,” said Xiu Yi.

Xiu Yi’s wish is to try various treatment plans to extend his survival time, holding on until new drugs and therapies become available. In short, he hopes to witness the day when soft tissue sarcoma is conquered within his lifetime.

Xiu Yi said, "If I could walk, I would still like to go outside and take a look."