TROPION-PanTumor03 trial reports breakthrough responses with DATROWAY and Rilvegostomig combo in bladder cancer

The oncology community is taking note of new data from the TROPION-PanTumor03 Phase 2 trial, where DATROWAY (datopotamab deruxtecan) combined with rilvegostomig, a PD-1/TIGIT bispecific antibody, demonstrated robust tumor responses in metastatic urothelial carcinoma. The findings, announced by AstraZeneca and Daiichi Sankyo, highlight how targeted antibody-drug conjugates and next-generation immunotherapies may reshape outcomes in one of the most treatment-resistant solid tumors.

How strong were tumor responses and disease control rates compared with current standards of care in urothelial cancer?

In the first-line cisplatin-ineligible cohort, DATROWAY plus rilvegostomig achieved a confirmed objective response rate (ORR) of 68.2 percent and a disease control rate (DCR) of 95.5 percent. In the second-line group—patients previously treated with platinum therapy—the ORR was 38.9 percent, with a DCR of 83.3 percent. Median progression-free survival (PFS) was not reached in first-line patients, while the 12-month PFS rate stood at 73.5 percent. For second-line participants, median PFS reached 12.5 months, suggesting prolonged benefit even in heavily pretreated disease.

These results compare favorably to the landmark EV-302 (KEYNOTE-A39) trial of enfortumab vedotin plus pembrolizumab, which reported an ORR of 67.7 percent and median overall survival (OS) of 31.5 months in first-line metastatic urothelial cancer. While DATROWAY’s OS data remain immature, its ORR aligns closely with EV-302 outcomes, raising the possibility that the AstraZeneca-Daiichi Sankyo combination could rival or even exceed the efficacy of the current dual-checkpoint standard once survival endpoints mature.

What is the biological rationale behind combining DATROWAY with a PD-1/TIGIT bispecific antibody?

DATROWAY is a TROP2-directed antibody-drug conjugate (ADC) linked to a topoisomerase I inhibitor payload, designed to selectively deliver cytotoxic damage to tumor cells while sparing healthy tissue. Rilvegostomig enhances this effect by targeting both PD-1 and TIGIT pathways, unleashing a stronger immune response within the tumor microenvironment. The bispecific structure is engineered to restore exhausted T-cell activity, a known challenge in bladder cancer where immune evasion mechanisms are common.

The scientific logic rests on synergistic activation: the ADC releases tumor antigens as cells die, and the immune checkpoint blockade amplifies the immune system’s ability to recognize and destroy remaining malignant cells. This dual-action mechanism could overcome the resistance observed with traditional PD-1 monotherapy and explain the unexpectedly high disease control rate in TROPION-PanTumor03.

How does the safety profile compare to previous ADC or immunotherapy regimens?

Safety outcomes were consistent with established profiles for both agents. In the cisplatin-ineligible first-line group, grade 3 or higher treatment-related adverse events (TRAEs) occurred in 18.2 percent of patients; in the second-line setting, 38.9 percent experienced grade 3 or higher events. The most frequent toxicities included stomatitis, neutropenia, decreased appetite, and anemia. No new immune-mediated safety signals were reported.

By comparison, the EV-302 study recorded grade 3–4 TRAEs in roughly 55 percent of patients on enfortumab vedotin plus pembrolizumab, driven mainly by rash, peripheral neuropathy, and hyperglycemia. The notably lower incidence of high-grade events in the DATROWAY plus rilvegostomig regimen could become a competitive differentiator if sustained across larger datasets.

While the absence of interstitial lung disease or ocular toxicity signals is encouraging, close monitoring remains essential. ADCs carrying topoisomerase I inhibitors have historically shown rare but severe pulmonary side effects, and rilvegostomig’s dual checkpoint modulation could potentiate immune activation in vulnerable patients.

How does this fit into AstraZeneca and Daiichi Sankyo’s broader oncology pipeline and trial roadmap?

AstraZeneca and Daiichi Sankyo are pursuing a multi-trial program for datopotamab deruxtecan, positioning it as a cross-tumor ADC platform. The ongoing TROPION-Urothelial03 Phase 2/3 trial will directly compare DATROWAY plus platinum-based chemotherapy against standard treatment in patients previously exposed to enfortumab vedotin and pembrolizumab. This sequential strategy aims to test whether DATROWAY can outperform the reigning dual-checkpoint regimen in progression-resistant cases.

Both companies are betting heavily on the ADC-plus-immunotherapy model. Beyond urothelial cancer, DATROWAY is under investigation in non-small-cell lung cancer and breast cancer, while rilvegostomig is part of AstraZeneca’s expanding “2.0” bispecific antibody pipeline that includes novel PD-1/LAG-3 and PD-1/CTLA-4 constructs.

From a portfolio perspective, success in TROPION-PanTumor03 and TROPION-Urothelial03 would position AstraZeneca and Daiichi Sankyo to challenge Gilead’s Trodelvy franchise in TROP2-positive tumors and extend their joint ADC platform’s commercial footprint beyond lung and breast indications.

What factors could determine whether the DATROWAY combination overtakes enfortumab vedotin plus pembrolizumab?

Several considerations will influence competitive positioning. The first is durability of response: while the EV-302 regimen delivered a median duration of response near 22 months, DATROWAY’s duration data are still immature. The second is overall survival, the gold-standard endpoint for practice-changing oncology drugs. Without mature OS data, any claim of superiority remains speculative.

Another determinant will be real-world tolerability. EV-302’s safety burden—particularly neuropathy and hyperglycemia—has limited its use among frail, elderly, or diabetic patients. If DATROWAY maintains efficacy with fewer severe events, clinicians may prefer it for cisplatin-ineligible individuals or those who cannot tolerate enfortumab’s toxicity. Cost and accessibility will also play roles: both drugs are complex biologics likely to carry premium pricing, and payer preference could hinge on comparative survival benefit.

Finally, biomarker profiling may refine patient selection. High TROP2 expression or TIGIT co-expression could identify subgroups most likely to benefit from the DATROWAY plus rilvegostomig regimen, mirroring the precision-medicine trend that increasingly guides treatment in bladder cancer.

What are the broader implications for next-generation ADC and bispecific strategies in oncology?

TROPION-PanTumor03 underscores a paradigm shift: the convergence of targeted payload delivery and immune checkpoint synergy. For AstraZeneca, this validates its pivot toward “bispecific-anchored combinations” that move beyond PD-1 monotherapy. For Daiichi Sankyo, it reinforces confidence in the DXd payload technology that already powers Enhertu and potentially a new generation of ADC-immunotherapy hybrids.

If replicated in Phase 3, the 68 percent response rate in cisplatin-ineligible patients could redefine front-line treatment for metastatic urothelial carcinoma, signaling a move toward less toxic yet equally potent regimens. The evolving competition between DATROWAY plus rilvegostomig and enfortumab plus pembrolizumab may ultimately determine how the next decade of bladder-cancer therapy is written—one balancing depth of response, durability, and patient quality of life.

Can dual-target immunomodulation combined with ADC precision become the new backbone of urothelial cancer care?

The TROPION-PanTumor03 data suggest that combining TROP2-targeted payloads with bispecific checkpoint inhibition can yield response rates comparable to or exceeding those of today’s standards while potentially offering a cleaner safety profile. With the forthcoming randomized TROPION-Urothelial03 trial set to validate these findings, clinicians and regulators will watch closely for confirmation of survival benefit.

Should efficacy hold and toxicity remain manageable, DATROWAY plus rilvegostomig could emerge as the first true challenger to the EV-302 standard — redefining what is clinically achievable for metastatic urothelial carcinoma. The next 12 months will be pivotal as the TROPION-Urothelial03 study matures and survival data begin to read out. If overall survival aligns with the early signal of sustained progression-free survival, the combination may offer a new frontline alternative for patients historically excluded from cisplatin-based regimens. Beyond urothelial cancer, this platform also hints at a broader shift toward dual-target ADC-immunotherapy pairings across tumor types. AstraZeneca and Daiichi Sankyo’s collaboration is effectively stress-testing a next-generation oncology playbook — one where precision payloads and bispecific antibodies function as complementary engines of long-term disease control. The outcome of these trials could influence not only treatment algorithms but also how drug developers design ADC-checkpoint regimens for a future defined by tailored, immune-activated precision oncology.