Envafolimab (KN035), a novel subcutaneously administered PD-L1 inhibitor developed by Alphamab Oncology, has been granted Orphan Drug Designation (ODD) by the U.S. Food and Drug Administration for the treatment of gastric cancer and gastroesophageal junction (GC/GEJ) cancer. This marks the third FDA Orphan Drug Designation for envafolimab, following prior designations in advanced biliary tract cancer and soft tissue sarcoma.
Gastric and GEJ cancers remain a major global health burden, with limited therapeutic options and poor outcomes in advanced disease. In the United States alone, an estimated 26,890 new cases and 10,880 deaths were projected in 2024, and five-year overall survival remains below 40%. While fluoropyrimidine- and platinum-based regimens constitute standard first-line therapy, outcomes in the second-line and later-line settings are modest, with median overall survival typically ranging from 8–9 months and objective response rates of only 15–25%.
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What Is FDA Orphan Drug Designation?
FDA Orphan Drug Designation (ODD) is a regulatory program established under the U.S. Orphan Drug Act to encourage the development of therapies for rare diseases—defined as conditions affecting fewer than 200,000 people in the United States.
For oncology, ODD plays a critical role in advancing treatments for rare cancers or molecularly defined subtypes with high unmet medical need. When granted, the designation provides sponsors with several incentives designed to accelerate clinical development and regulatory review, including:
- Seven years of U.S. market exclusivity upon FDA approval
- Tax credits for qualified clinical trial expenditures
- Waiver of FDA prescription drug user fees
- Eligibility for accelerated regulatory pathways and enhanced FDA guidance
Importantly, Orphan Drug Designation is not an approval but a development milestone that reflects the FDA’s recognition of a therapy’s potential clinical value in a rare disease setting. For envafolimab, receiving a third ODD highlights both the unmet need in GC/GEJ cancer and the growing regulatory confidence in its immunotherapeutic potential.
A First-in-Class Subcutaneous PD-L1 Inhibitor
Envafolimab is the world’s first subcutaneously injectable PD-L1 inhibitor, representing a significant innovation in immune checkpoint blockade delivery. Unlike conventional intravenous antibodies, envafolimab can be administered in approximately 30 seconds, offering a major advantage in convenience and patient compliance. This feature is particularly relevant for frail patients, elderly individuals, and those unable to tolerate intravenous infusions.
From a molecular standpoint, envafolimab is a single-domain antibody Fc fusion protein that effectively blocks PD-1/PD-L1 interactions, thereby restoring antitumor T-cell activity. Its smaller molecular size—approximately half that of a conventional monoclonal antibody—may enhance tissue penetration and tumor accessibility via lymphatic circulation.
Clinical Evidence Supporting the Designation
The FDA’s decision to grant Orphan Drug Designation in GC/GEJ cancer was supported by encouraging results from a Phase II clinical study in advanced disease. In this trial, the combination of envafolimab plus FOLFOX chemotherapy demonstrated:
• An objective response rate (ORR) of 60%
• A disease control rate (DCR) of 100%
• A favorable safety and tolerability profile
• No treatment-related deaths or discontinuations due to adverse events
These findings compare favorably with historical outcomes in this population and suggest that envafolimab-based regimens may offer clinically meaningful benefit in advanced gastric and GEJ cancers.
Outlook
The FDA’s third Orphan Drug Designation for envafolimab underscores growing regulatory confidence in this next-generation, patient-friendly PD-L1 inhibitor. If ongoing studies confirm its early efficacy signals, envafolimab may emerge as a differentiated immunotherapy option—particularly in settings where treatment convenience, tolerability, and access are critical considerations.