On December 27, local time, the US FDA announced that it had approved Bristol-Myers Squibb's "Nivolumab" subcutaneous injection (Opdivo Qvantig) for marketing, for the treatment of adult solid tumor indications previously approved for its intravenous injection Opdivo. This is the world's first approved subcutaneous PD-1 inhibitor.

▍Approved indications
The approved indications for subcutaneous injection of Nivolumab include renal cell carcinoma, melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, urothelial carcinoma, colorectal cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

Screenshot source: FDA official website
Nivolumab is the world's first approved PD-1 inhibitor. It has been approved for marketing in more than 65 countries and regions including the United States, the European Union, Japan and China, covering 12 tumor types, including lung cancer, head and neck cancer, gastric cancer, esophageal cancer, liver cancer, kidney cancer, colorectal cancer, urothelial carcinoma, melanoma, Hodgkin's lymphoma, pleural tumors, and tumors of unknown primary site.

▍Previously, only PD-L1 injection formulations were approved
The Insight database shows that previously only two subcutaneous PD-L1 antibodies were approved in the world, namely Envolizumab from Sildi/Alphamab and Atezolizumab from Roche. BMS's Nivolumab is the world's first approved subcutaneous PD-1 inhibitor.

In China, currently only one subcutaneous PD-L1 has been approved, namely Envolizumab. Roche's subcutaneous PD-L1 atezolizumab was launched in July this year and is expected to be approved in Q3 next year. Envolizumab injection was approved for marketing in China in November 2021 and is suitable for the treatment of adult patients with advanced solid tumors with unresectable or metastatic microsatellite high instability (MSI-H) or mismatch repair gene deficiency (dMMR).

At present, Envolizumab injection is conducting clinical trials for multiple tumor indications in China, the United States and Japan, and multiple indications have entered the registration phase 3 clinical trial. Earlier, the product was also granted orphan drug qualifications for advanced biliary tract cancer and soft tissue sarcoma by the US FDA.

Roche's atezolizumab injection was also accepted by the Drug Evaluation Center of the China National Medical Products Administration on July 27 this year. Atezolizumab is a PD-L1 inhibitor that has been approved for multiple indications worldwide. The drug has been approved worldwide for the treatment of various cancers, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma, urothelial carcinoma, PD-L1-positive metastatic triple-negative breast cancer, and BRAF V600-mutated advanced melanoma. In China, it was approved as a first-line treatment for extensive-stage small cell lung cancer in 2020.

▍Clinical data of subcutaneous nivolumab formulation
The subcutaneous version of nivolumab is formulated with nivolumab and Halozyme's proprietary recombinant human hyaluronidase (rHuPH20), which increases the dispersion and absorption of nivolumab in the subcutaneous space.

Compared with intravenous injection, subcutaneous injection of nivolumab has many advantages, including: significantly shortened administration time, intravenous injection usually takes 30 to 60 minutes, while subcutaneous injection only takes 3 to 5 minutes; at the same time, subcutaneous administration can reduce the need for intravenous catheter ports, thereby reducing the risk of related complications such as infection and phlebitis.

The approval was based on the results of the Phase III trial CheckMate -67T (NCT04810078), which is also the first Phase III clinical trial of subcutaneous injection of "nivolumab", which aims to evaluate the pharmacokinetics, efficacy and safety of the drug, which are not inferior to its intravenous formulation. The study population is patients with advanced or metastatic renal clear cell carcinoma (ccRCC) who have received systemic treatment. A total of 495 patients were randomly assigned to receive subcutaneous injection (1200 mg, once every 4 weeks) or intravenous injection (3 mg/kg, once every 2 weeks) treatment.

According to the latest data disclosed in the FDA's press release, the trial achieved the primary endpoint, with an ORR of 24% in the subcutaneous injection group and 18% in the intravenous injection group. The subcutaneous injection group and the intravenous injection group have similar safety, and the most common adverse reactions are fatigue, musculoskeletal pain, itching, rash and cough. The analysis showed that compared with intravenous Opdivo, subcutaneous Opdivo Qvantig showed non-inferiority in average serum concentration (Cavgd28) and steady-state serum trough concentration (Cminss) over a 28-day period.

▍Current status of subcutaneous PD-1 inhibitors

In addition, there are 1 subcutaneous PD-L1 and 7 subcutaneous PD-1 in clinical trials worldwide. Three subcutaneous PD-1 antibodies have entered Phase III, from Junshi (Toripalimab), Merck (Pembrolizumab), and Pfizer (Sasanlimab).

The Drug Clinical Trial Registration and Information Disclosure Platform shows that Junshi Bio's Teplizumab (JS001) subcutaneous injection JS001sc has launched a multicenter, open, randomized controlled Phase III study to evaluate the pharmacokinetic characteristics, efficacy, and safety of JS001sc combined with standard chemotherapy vs. JS001 combined with standard chemotherapy for first-line treatment of recurrent or metastatic non-squamous non-small cell lung cancer (NSCLC). This is also the first domestic PD-1 antibody subcutaneous preparation to enter the Phase III clinical stage.

Merck announced the pivotal Phase III MK-3475A-D77 study of pembrolizumab subcutaneous injection on November 19 this year, and the results were positive. The study evaluated the pharmacokinetics (PK), efficacy, and safety of pembrolizumab subcutaneous injection MK-3475A combined with chemotherapy for first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) compared with pembrolizumab intravenous injection Keytruda. Pfizer's Sasanlimab is currently in Phase III trials for non-muscle invasive bladder cancer.

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