Durvalumab

證據等級: L5

預測適應症: 10 個

Durvalumab: From NSCLC to Prostatic Urethra Urothelial Carcinoma

One-Sentence Summary

Durvalumab (Imfinzi®) is an anti-PD-L1 checkpoint inhibitor with established global approvals for NSCLC, small cell lung cancer, and biliary tract cancer, but currently holds no Canadian DINs per this dataset. The TxGNN model predicts it may be effective across 10 rare urothelial and gynaecological carcinoma subtypes, led by prostatic urethra urothelial carcinoma (rank 1, score 99.98%); evidence quality ranges from L2 (endocervical carcinoma) to L5 (model prediction only) depending on the specific indication. Across all 10 predictions, 3 clinical trials and 1 publication were identified; the highest-actionability indication is endocervical carcinoma (rank 6), supported by a completed Phase 1 and an ongoing Phase 2 trial.

Quick Overview

Item	Content
Original Indication	NSCLC / SCLC / biliary tract cancer (global approvals; no Canadian DIN on record in this dataset)
Predicted New Indication (Top Rank)	Prostatic Urethra Urothelial Carcinoma
TxGNN Prediction Score	99.98%
Evidence Level	L4 (rank 1 top indication); L2 best-in-class (endocervical carcinoma, rank 6)
Canada Market Status	✗ Not Marketed (0 DINs)
Number of DINs	0
Recommended Decision	Hold (urothelial subtypes, ranks 1–4); Proceed with Guardrails (endocervical carcinoma, rank 6)

Why Is This Prediction Reasonable?

Detailed MOA data from DrugBank is not available in this dataset. Based on the published literature and class pharmacology, Durvalumab is a selective, high-affinity human IgG1κ monoclonal antibody that blocks PD-L1 binding to both PD-1 and CD80 (B7.1), thereby restoring T-cell–mediated anti-tumour immune surveillance. Its proven efficacy in NSCLC, SCLC, and biliary tract cancer is underpinned by the widespread expression of PD-L1 across tumour types with high mutational burden (TMB) or carcinogen/virus-driven genomic instability.

The urothelial carcinoma predictions (ranks 1–4) share a common anatomical and histological basis: all arise from PD-L1–expressing urothelial epithelium. Durvalumab has previously been evaluated in broad urothelial carcinoma programmes (DANUBE Phase 3, NCT01693562), establishing proof-of-concept even where primary endpoints were not met. The sarcomatoid variants (ranks 2–3) are particularly compelling because sarcomatoid dedifferentiation is associated with higher TMB and elevated PD-L1 expression, increasing theoretical sensitivity to checkpoint blockade. NCT03912818 targeted the sarcomatoid bladder variant directly (Phase 2), though it was terminated early.

For the gynaecological predictions, endocervical carcinoma (rank 6) stands apart. HPV-driven E5/E7 oncoproteins directly upregulate PD-L1 expression through the JAK/STAT and PI3K pathways, creating an immune-suppressive microenvironment that is mechanistically susceptible to PD-L1 inhibition. This rationale is already being tested clinically in NCT04065269 (ATARI, Phase 2, n=174). The remaining gynaecological predictions (ranks 5, 7–10) are ultra-rare entities with distinct molecular profiles — several are HPV-negative or carry biology antagonistic to checkpoint inhibitors — and the TxGNN scores reflect topological proximity in the knowledge graph rather than direct mechanistic evidence.

Predicted Indications — All-10 Summary

Rank	Disease	TxGNN Score	Evidence Level	Decision	Key Evidence Available
1	Prostatic Urethra Urothelial Carcinoma	99.98%	L4	Hold	None
2	Kidney Pelvis Sarcomatoid Transitional Cell Carcinoma	99.98%	L3	Hold	1 trial (Early Phase 1)
3	Infiltrating Bladder Urothelial Carcinoma, Sarcomatoid Variant	99.98%	L3	Hold	2 trials (Phase 2 terminated; Early Phase 1)
4	Renal Pelvis Papillary Urothelial Carcinoma	99.98%	L4	Hold	None
5	Uterine Ligament Adenocarcinoma	99.92%	L5	Hold	None
6	Endocervical Carcinoma	99.91%	L2	Proceed with Guardrails	2 trials + 1 publication
7	Adenoid Cystic Carcinoma of the Cervix Uteri	99.91%	L5	Hold	None
8	Uterine Ligament Serous Adenocarcinoma	99.91%	L5	Hold	None
9	Signet Ring Cell Variant Cervical Mucinous Adenocarcinoma	99.90%	L5	Hold	None
10	Intestinal Variant Cervical Mucinous Adenocarcinoma	99.90%	L5	Hold	None

Clinical Trial Evidence

Trials identified across all relevant predicted indications:

Trial Number	Phase	Status	Enrollment	Key Findings
NCT03912818	Phase 2	Terminated	7	Durvalumab + neoadjuvant chemotherapy (MVAC/GC) in variant histology bladder cancer including sarcomatoid; terminated early due to low accrual — no efficacy conclusions possible, but design directly targeted this subtype
NCT02812420	Early Phase 1	Active, Not Recruiting	54	Durvalumab + tremelimumab pre-surgical in muscle-invasive high-risk urothelial carcinoma ineligible for cisplatin; safety and immune response assessment; covers upper urinary tract; no efficacy endpoint reached yet
NCT03452332	Phase 1	Completed	20	Hypofractionated SBRT + durvalumab + tremelimumab in recurrent/metastatic cervical, vaginal, or vulvar cancer; completed — safety and dosing established; results applicable to endocervical carcinoma subtype
NCT04065269	Phase 2	Active, Not Recruiting	174	ATARI trial: ATR inhibitor ceralasertib ± olaparib or durvalumab in relapsed gynaecological cancers stratified by ARID1A loss; largest ongoing Durvalumab trial in gynaecological cancers; results expected August 2026

Literature Evidence

PMID	Year	Type	Journal	Key Findings
37467967	2023	Review	Biomedical Journal	Small cell neuroendocrine carcinoma of the cervix: molecular basis and therapeutic landscape; highlights emerging role of immune checkpoint strategies in aggressive cervical cancer variants; management parallels with neuroendocrine lung cancer noted

Canada Market Information

No Canadian product authorisations for Durvalumab are registered in this dataset.

Note: Durvalumab (Imfinzi®) holds approvals from the FDA (NSCLC, ES-SCLC, biliary tract cancer, HCC) and EMA in multiple indications. If Health Canada regulatory status has changed after the data cutoff (2026-04-04), the DIN registry should be re-queried to confirm current market standing before proceeding with any repurposing strategy.

Cytotoxicity

Durvalumab is an antineoplastic agent (checkpoint inhibitor immunotherapy) indicated for cancer treatment.

Item	Content
Cytotoxicity Classification	Immunotherapy — Anti-PD-L1 checkpoint inhibitor (IgG1κ monoclonal antibody); not a conventional cytotoxic
Myelosuppression Risk	Low (haematological toxicity uncommon; primary toxicities are immune-mediated: pneumonitis, hepatitis, endocrinopathies)
Emetogenicity Classification	Low
Monitoring Items	LFTs, thyroid function (TSH / free T4), fasting glucose, CBC with differential, serum creatinine; clinical assessment for immune-related adverse events (irAEs) before each cycle
Handling Protection	Standard biohazard precautions for IV monoclonal antibody administration; cytotoxic drug handling protocols are not required

Safety Considerations

Detailed Health Canada package insert warnings and contraindications are not available in this dataset. Please refer to the Imfinzi® product monograph for complete prescribing information.

Based on class pharmacology (anti-PD-L1 checkpoint blockade), clinicians should be aware of the following key safety considerations:

Immune-related adverse events (irAEs): Pneumonitis, immune-mediated hepatitis, colitis, endocrinopathies (thyroiditis, adrenal insufficiency, type 1 diabetes), nephritis, and dermatitis — may be severe or life-threatening; require corticosteroid management and potential permanent discontinuation
Infusion-related reactions: Monitor patients during and for at least 1 hour after each infusion
Reproductive toxicity: Checkpoint inhibitors can cause immune-mediated foetal harm; effective contraception required; breastfeeding not recommended during treatment

Conclusion and Next Steps

For Urothelial Subtypes (Ranks 1–4)

Decision: Hold

Rationale: No direct clinical trial evidence exists for the specific urothelial subtypes predicted (prostatic urethral, renal pelvic sarcomatoid, renal pelvic papillary). Evidence from broader urothelial carcinoma programmes is mechanistically relevant but insufficient to justify dedicated pursuit without subtype-specific data.

To proceed, the following is needed:

Conduct a targeted literature review for subgroup analyses within DANUBE (NCT01693562) and PEARL trials that may report outcomes stratified by tumour location (upper tract vs. bladder) or histological variant
Monitor NCT02812420 (currently active, n=54) for interim results covering upper urinary tract urothelial carcinoma
For the sarcomatoid variants (ranks 2–3): assess whether future basket trials in high-TMB urothelial carcinoma could enrol these subtypes; consider partnering with a rare histology consortium

For Endocervical Carcinoma (Rank 6)

Decision: Proceed with Guardrails

Rationale: Two clinical trials provide direct support: a completed Phase 1 (NCT03452332, n=20) establishing safety in cervical cancer, and an ongoing Phase 2 (NCT04065269, ATARI, n=174) evaluating durvalumab in relapsed gynaecological cancers with ARID1A stratification. The HPV-mediated PD-L1 upregulation mechanism provides a credible biological rationale for endocervical carcinoma specifically.