First Successful Phase III IO+ADC Neoadjuvant/Adjuvant Trial Paves the Way for PD-1/VEGF (IL-2) Bispecifics Combined with ADCs

Aug 12, 2025 18:26 CST Updated 18:26

MSD

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On August 12, 2025, Merck (NYSE: MRK, known as MSD outside the United States and Canada) announced positive topline results from its Phase 3 clinical trial KEYNOTE-905 (also referred to as EV-303), which focused on patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy. In this study, compared to surgery alone (radical cystectomy), treatment with Keytruda® (pembrolizumab) in combination with Padcev (enfortumab vedotin-ejfv) administered before and after surgery (prior to radical cystectomy and postoperatively) demonstrated statistically significant and clinically meaningful improvements in the primary endpoint of event-free survival (EFS), as well as in key secondary endpoints overall survival (OS) and pathological complete response (pCR) rate.

"Patients with muscle-invasive bladder cancer who are not suitable for cisplatin-based chemotherapy have seen no treatment advancements beyond surgery, and even after bladder removal, they face high disease recurrence rates and poor prognosis," said Dr. Christof Vulsteke, Head of the Integrated Cancer Center Gent (IKG) and Director of the Oncology Clinical Trials Unit, and principal investigator of KEYNOTE-905. "The results of the KEYNOTE-905 study mark the first time a systemic treatment used before and after surgery has demonstrated significantly superior survival benefits compared to standard-of-care surgery in this patient population, proving the potential of this combination regimen to address this critical unmet need."

This trial evaluates MSD's anti-PD-1 therapy Keytruda® (pembrolizumab) in combination with the antibody-drug conjugate (ADC) Padcev (enfortumab vedotin), conducted in collaboration with Pfizer (formerly Seagen) and Astellas. The success of this trial builds on the clinical achievements of this combination therapy in locally advanced or metastatic urothelial carcinoma. The trial will continue to assess the secondary endpoints of EFS, OS, and pCR rate for neoadjuvant and adjuvant Keytruda® compared to surgery alone, as these data are still maturing.

"For patients with bladder cancer who are not eligible for cisplatin-containing therapy, there is indeed an urgent need for more effective options," said Dr. Marjorie Green, Senior Vice President of Merck Sharp & Dohme AG Research Laboratories and Head of Global Clinical Development Oncology. "The compelling survival outcomes observed in this study reinforce the potential of Keytruda® in combination with antibody-drug conjugates to help address the significant unmet needs of this vulnerable patient population."

The safety profile of Keytruda® in combination with Padcev in this study was consistent with the known safety profiles of each drug. No new safety signals were identified for this combination therapy.

The combination of PD1 antibody and ADC has always been a major research direction. The combination of PD1 antibody and MMAE ADC has been proven:

According to data presented by Seagen and Astellas at ESMO, the combination therapy of their jointly developed antibody-drug conjugate (ADC) Padcev (enfortumab vedotin) and MSD's PD-1 inhibitor Keytruda (pembrolizumab) showed impressive results in the Phase 3 EV-302 clinical trial comparing chemotherapy for treatment-naive patients with locally advanced or metastatic urothelial carcinoma (la/mUC).

At the data cutoff, the median follow-up time was 17.2 months.Compared with chemotherapy, the PFS of patients in the combination therapy group was significantly prolonged.(Median PFS was 12.5 months vs 6.3 months, respectively, reducing the risk of disease progression or death by 55%.；HR=0.45，95% CI：0.38-0.54，P<0.00001）。Compared with the chemotherapy group, the OS in the combination therapy group was significantly prolonged, with a 53% reduction in the risk of death (median OS was 31.5 months vs 16.1 months; HR=0.47, 95% CI: 0.38-0.58, P<0.00001).The confirmed ORR in the combination therapy group and chemotherapy group were 67.7% and 44.4%, respectively (P<0.00001).Combination Therapy Group (EV+P）Significantly improved previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC) The efficacy of patients,Compared with chemotherapy,Nearly doubled the median PFS and OS.The safety profile is manageable overall, with no new safety signals. These results support EV+P as a first-line standard treatment for la/mUC.

As for whether the combination of PD-1 antibody and topoisomerase inhibitor ADC is superior, it remains uncertain until Gilead releases the data.Trodelvy in Combination with Keytruda ShowsCompared with standard treatment (Keytruda in combination with chemotherapy, for untreated PD-L1+ (CPS ≥10)mTNBCAn early trend toward improved overall survival in patients.It has been confirmed,The advantage of PD1 antibody plus topoisomerase inhibitor ADC. Of course, the next step is to look at the OS advantage.

On April 21, 2025, Gilead announced positive key results from its Phase III clinical trial ASCENT-04/KEYNOTE-D19. The results showed that Trodelvy®⁽Sacituzumab Govitecan-hziy) in combination with Keytruda®⁽Pembrolizumab) therapy significantly improved progression-free survival (PFS) in patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) whose tumors express PD-L1 (CPS ≥ 10), compared to Keytruda combined with chemotherapy. The study met its primary endpoint, achieving a statistically significant and clinically meaningful improvement in PFS.

In the ASCENT-04 study, the safety of Trodelvy and Keytruda was consistent with the known safety profile of each drug. No new safety signals were identified with the combination.

Overall Survival (OS) is a key secondary endpoint, which was not yet mature at the time of the primary PFS analysis. However, in the ASCENT-04 study, the combination therapy of Trodelvy and Keytruda showed an early trend toward OS improvement. Gilead will continue to monitor the OS results and plans to follow up with patients for further analysis.

The detailed results of the study will be presented at a future medical conference and discussed with regulatory agencies. The treatment of Trodelvy in combination with Keytruda for untreated PD-L1+ metastatic triple-negative breast cancer (TNBC) patients is still under investigation, and its safety and efficacy have not been established.

The significant and meaningful improvement in PFS demonstrated in ASCENT-04 further enhances the potential of Trodelvy plus Keytruda as a much-needed new treatment option for previously untreated, inoperable (unresectable) PD-L1+ locally advanced or mTNBC patients.

Multiple research results show promising prospects for the next generation of PD-1 inhibitors, such as PD-1/VEGF, PD-L1/VEGF, PD-1/cytokine, and more. The fundamental rationale for supporting the development of PD-1/VEGF over the years has been the belief that the future will rely on it.PD1/VEGF, PDL1/VEGF combined with ADC against PD1 antibody plus chemotherapy, as long as the threshold is raised, a high barrier will be established. However, if the combination of PD1 antibody and ADC has already been successful, it will be very difficult for subsequent PD1/VEGF and PDL1/VEGF combined with ADC to enter the market.

Currently, AK112 from Akeso and PDL1/VEGF from BioNtech have demonstrated promising efficacy. Of course, it is also highly beneficial for other next-generation PD1 inhibitors, such as PD1/cytokines.

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