FDA snubs another China-made PD-1 with rejection of Elevar, Hengrui's liver cancer combo

China-made PD-1 inhibitors just can’t get a clean pass through the FDA. 

After snubs or delays for three other China-made PD-1 drugs, Jiangsu Hengrui Pharma and Elevar Therapeutics’ respective applications for PD-1 inhibitor camrelizumab and the VEGFR inhibitor rivoceranib have been rejected by the FDA. The pair was hoping for a combination approval in first-line liver cancer.

The rejection was first revealed by Elevar’s South Korean parent, HLB, according to the Korea Biomedical Review. Hengrui also disclosed (Chinese, PDF) its complete response letter to the Shanghai Stock Exchange.

The pair’s setback is good news for Roche and its anti-PD-L1/VEGF pairing of Tecentriq and Avastin, which is the first FDA-approved immunotherapy-based treatment in first-line liver cancer.

For Hengrui and Elevar, the FDA didn’t seem to take issue with their clinical data. Instead, the problems are related to the FDA’s inspections of manufacturing and clinical trial sites.  

For one, Hengrui has yet to resolve manufacturing deficiencies the FDA spotted during an inspection for camrelizumab, which has been approved in China under the brand name AiRuiKa for various indications. 

In its CRL, the FDA said it will perform a full evaluation based on Hengrui’s responses to the manufacturing shortfalls, according to the Chinese pharma company. 

In addition, the FDA has not been able to finish all clinical trial site inspections because of travel restrictions in certain countries, Hengrui said. HLB Chairman Jin Yang-gon, in a YouTube announcement (Korean), disclosed that sites in Russia and Ukraine have yet to be inspected, according to KBR. 

Jin hopes the regulatory holdup could be resolved through alternative approaches, KBR reports. Hengrui said it plans to keep close communications with the FDA and hopes to refile as soon as possible. 

The CRL came as a surprise to Elevar because the company has been in label discussions with the FDA as recently as the past week, the company’s CEO Saeho Chong said in a statement to Fierce Pharma. Chong confirmed that the FDA did not raise questions about the clinical data. 

Manufacturing and clinical site inspection have previously caused trouble for two other China-made PD-1 meds. Before securing the FDA’s go-ahead in October, Coherus BioSciences’ Loqtorzi in 2022 received a CRL because of a quality process change required by the FDA. The company then had to wait for its partner Junshi Biosciences to solve problems the FDA found at its manufacturing facility before facing a Form 483 at a clinical trial site. 

At BeiGene, COVID-related travel restrictions forced the company to wait an extra 20 months before the FDA could complete its preapproval inspections and approve its PD-1 drug Tevimbra in March. Last week, BeiGene telegraphed a possible delay for its application to expand Tevimbra into first-line esophageal squamous cell carcinoma, because the FDA could be late in scheduling clinical site inspections.

An FDA nod could have made camrelizumab the third China-made anti-PD-1 antibody to make it to the U.S. In early 2023, Chinese regulators waved through the camrelizumab-rivoceranib combo as a first-line liver cancer therapy.

In addition, camrelizumab, sold under the brand name AiRuiKa in China, is cleared in the country as a monotherapy in second-line liver cancer. Rivoceranib, also known as apatinib and branded as Aitan, has its own single-agent nod in China as a second-line treatment.

Camrelizumab and rivoceranib proved their clinical worth in the global phase 3 CARES-310 study. In the trial, the combo showed it could reduce the risk of disease progression or death in first-line liver cancer patients by 48% compared with Bayer’s Nexavar.

At the trial’s interim analysis for overall survival, the novel combo also delivered a statistically significant improvement, reducing the risk of death by 38%. When the results were published in The Lancet last year, investigators noted that the combo’s 22.1-month median result for overall survival represented the longest observed figure for any treatment in a global phase 3 trial in the setting.

By comparison, in the IMbrave150 trial, Tecentriq and Avastin slashed the risk of death by 42% versus Nexavar at the time of the primary analysis. In a later update, the Roche regimen’s median overall survival was found to be 19.2 months.

The two studies’ results can’t be compared directly side by side because of subtle differences in patient characteristics. For example, only 17.3% of patients in CARES-301 were non-Asian, whereas about 40% of patients in IMbrave150 were Asian, excluding those in Japan.

Importantly, CARES-301 is a global study with sites in the U.S. Back in 2022, the FDA rejected Innovent Biologics’ PD-1 inhibitor Tyvyt, which was then part of a partnership Eli Lilly, because it only had pivotal data from China.

Besides Roche, the Elevar-Hengrui combo, if approved, could compete with AstraZeneca’s dual immunotherapy regimen of Imfinzi and Imjudo. In a phase 3 trial, the AZ regimen cut the risk of death by 22% over Nexavar.

In addition, Bristol Myers Squibb recently said its own immunotherapy doublet of Opdivo and Yervoy beat either Nexavar or Eisai’s Lenvima in first-line liver cancer.

Rivoceranib was originally developed by Advenchen Laboratories in Southern California and was licensed to Hengrui in China in 2005 and to Elevar—then as LSK BioPharma—for the rest of the world in 2008.

As for camrelizumab, Hengrui last year out-licensed the drug’s rights in unresectable liver cancer outside China and Korea to Elevar. HLB acquired Elevar in 2019 through a triangular merger involving the South Korea firm’s U.S. subsidiary.

Editor's Note: The story has been updated with additional comments from Elevar.