Understanding Rilvegostomig (AZD2936)
Rilvegostomig, also known by its development code AZD2936, is an innovative investigational drug in the field of cancer immunotherapy [1.6.8]. Developed by AstraZeneca, it is classified as a bispecific antibody, meaning it is engineered to simultaneously bind to two different targets [1.2.1, 1.2.6]. This dual-targeting capability represents a sophisticated approach aimed at overcoming tumor resistance mechanisms more effectively than single-target therapies. Rilvegostomig is currently being evaluated in multiple Phase II and Phase III clinical trials for its safety and efficacy in treating various advanced solid tumors, including non-small cell lung cancer (NSCLC), biliary tract cancer, gastric cancer, and hepatocellular carcinoma [1.2.6, 1.4.3]. As of late 2025, it is not yet approved for marketing by the U.S. Food and Drug Administration (FDA) [1.6.1, 1.6.2].
The Dual Mechanism of Action: Targeting PD-1 and TIGIT
The therapeutic potential of rilvegostomig lies in its unique mechanism of action, which involves the simultaneous inhibition of two critical immune checkpoint proteins: Programmed Cell Death Protein 1 (PD-1) and T-cell Immunoreceptor with Ig and ITIM domains (TIGIT) [1.3.1, 1.3.3].
- PD-1 Inhibition: PD-1 is a well-known checkpoint receptor expressed on activated T-cells. When it binds to its ligands (PD-L1 or PD-L2), which are often overexpressed on cancer cells, it sends an inhibitory signal that 'turns off' the T-cell, preventing it from attacking the tumor [1.3.1]. By blocking this interaction, rilvegostomig restores the T-cell's ability to recognize and eliminate cancer cells.
- TIGIT Inhibition: TIGIT is another inhibitory receptor found on key immune cells like T-cells and Natural Killer (NK) cells [1.3.1]. It competes with a co-stimulatory receptor called CD226 to bind to the same ligand, CD155 (PVR), on tumor cells. When TIGIT binds to CD155, it suppresses the immune response. By blocking TIGIT, rilvegostomig prevents this suppression and allows the activating CD226 receptor to dominate, further amplifying the anti-tumor immune attack [1.3.1].
This bispecific approach is designed to produce a more robust and durable immune response compared to blocking either pathway alone [1.3.6]. The molecule is also engineered with a modified Fc domain to reduce the risk of unintentionally depleting the very immune cells it is meant to activate [1.3.6].
Clinical Applications and Efficacy
Rilvegostomig is being extensively studied across a wide range of cancers, both as a monotherapy and in combination with other anticancer agents like chemotherapy and antibody-drug conjugates [1.4.3, 1.4.4, 1.4.7].
Promising Results in Non-Small Cell Lung Cancer (NSCLC)
Much of the promising data for rilvegostomig has come from trials in NSCLC. In the ARTEMIDE-01 study, which focused on checkpoint inhibitor-naïve patients, rilvegostomig demonstrated significant efficacy [1.3.9, 1.5.6].
- High PD-L1 Expression (≥50%): Patients receiving the 750 mg dose showed a confirmed objective response rate (ORR) of 61.8% [1.5.6].
- Low PD-L1 Expression (1-49%): The ORR in this group was 29.0% [1.5.6].
- Durability: Across all responders, the median duration of response (DoR) was 10.5 months, with 80% of responses ongoing at the time of data analysis [1.5.6].
These results have supported the selection of the 750 mg dose for ongoing and planned Phase III registrational studies, such as ARTEMIDE-Lung04, which compares rilvegostomig monotherapy to pembrolizumab [1.4.6, 1.5.3].
Other Investigated Cancers
Beyond lung cancer, rilvegostomig is in active Phase III trials for:
- Biliary Tract Cancer (BTC): The ARTEMIDE-Biliary01 study is evaluating rilvegostomig plus chemotherapy as an adjuvant therapy after surgery [1.4.2, 1.4.5].
- Hepatocellular Carcinoma (HCC): A Phase III trial is assessing rilvegostomig in combination with bevacizumab [1.4.1].
- Gastric Cancer: The ARTEMIDE-Gastric01 trial is testing rilvegostomig with trastuzumab deruxtecan (T-DXd) and chemotherapy in HER2-positive patients [1.6.7].
Rilvegostomig vs. Standard Immunotherapy (Pembrolizumab)
Pembrolizumab is a standard-of-care immunotherapy that targets only the PD-1 pathway [1.5.1]. Rilvegostomig's potential advantage lies in its dual blockade of both PD-1 and TIGIT.
| Feature | Rilvegostomig | Pembrolizumab |
|---|---|---|
| Target(s) | PD-1 and TIGIT [1.2.1] | PD-1 only [1.5.1] |
| Molecule Type | Bispecific Monoclonal Antibody [1.2.1] | Monoclonal Antibody [1.5.1] |
| Mechanism | Dual checkpoint blockade to restore and enhance T-cell and NK cell activity [1.3.1]. | Single checkpoint blockade to restore T-cell activity [1.5.1]. |
| Primary Indication | Investigational for NSCLC, BTC, Gastric Cancer, HCC, etc. [1.4.3] | Approved for NSCLC, Melanoma, and many other cancers [1.5.1, 1.6.6]. |
| Status | In Phase II/III Clinical Trials as of Sept 2025 [1.6.5, 1.6.8] | FDA Approved and widely used in clinical practice [1.6.1]. |
Safety and Tolerability Profile
Across multiple clinical trials, rilvegostomig has been generally well-tolerated [1.3.5, 1.5.6]. The safety profile appears manageable, which is a critical factor for combination therapies. In studies, treatment-related adverse events (TRAEs) leading to discontinuation have been low (around 4.2%) [1.5.3, 1.5.6].
Commonly reported side effects (mostly low-grade) include [1.5.2, 1.5.3, 1.5.5]:
- Rash
- Increased lipase levels
- Fatigue
- Pyrexia (fever)
- Hypothyroidism
- Infusion-related reactions
More serious immune-mediated adverse events can occur, as with any immunotherapy, but have been reported at a low rate [1.5.3]. No new, unexpected safety signals have emerged, and there were no treatment-related deaths reported in key studies [1.5.5].
Conclusion
Rilvegostomig represents a promising next-generation immunotherapy. By simultaneously targeting both the PD-1 and TIGIT pathways, it has the potential to overcome immune resistance and offer a new, effective treatment option for patients with various solid tumors, particularly non-small cell lung cancer. Its encouraging efficacy and manageable safety profile in numerous ongoing Phase III trials underscore its significance in the evolving landscape of oncology. As data from these registrational studies mature, the full clinical impact of this dual checkpoint inhibitor will become clearer.
Disclaimer: Rilvegostomig is an investigational drug and is not approved for clinical use outside of trials.
For more information on clinical trials involving this drug, visit the National Cancer Institute's clinical trials database. [1.4.3]
